TREM COMPOSITIONS AND METHODS RELATING THERETO

BACKGROUND

Transfer RNAs (tRNAs) are complex, naturally occurring RNA molecules that possess a number of functions including initiation and elongation of proteins.

SUMMARY

The present disclosure features modified tRNA-based effector molecules (TREMs, e.g., a TREM, TREM core fragment, or TREM fragment), as well as related compositions and uses thereof. A TREM or a related composition thereof can be used, inter alia, to modulate a production parameter (e.g., an expression parameter and/or a signaling parameter) of an RNA corresponding to, or a polypeptide encoded by, a nucleic acid sequence comprising an endogenous open reading frame (ORF) having a premature termination codon (PTC). Accordingly, in an aspect, the present disclosure provides a method of modulating a production parameter of an mRNA corresponding to, or polypeptide encoded by, an endogenous open reading frame (ORF) in a cell, which ORF comprises a codon having a first sequence, comprising contacting the cell with a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and/or for a time sufficient to modulate the production parameter of the mRNA or polypeptide, thereby modulating the production parameter in the cell. In an embodiment, the TREM, TREM core fragment, or TREM fragment has an anticodon that pairs with the codon having the first sequence.

In another aspect, provided herein is method of modulating a production parameter of an mRNA corresponding to, or polypeptide encoded by, an endogenous open reading frame (ORF) in a subject, which ORF comprises a codon having a first sequence, comprising contacting the subject with a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and/or for a time sufficient to modulate the production parameter of the mRNA or polypeptide, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence, thereby modulating the production parameter in the subject. In an embodiment, the production parameter comprises a signaling parameter and/or an expression parameter, e.g., as described herein.

In another aspect, provided herein is a method of modulating expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a codon having a first sequence, comprising contacting the cell with a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and/or for a time sufficient to modulate expression of the encoded protein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence, thereby modulating expression of the protein in the cell.

In yet another aspect, provided herein is a method of modulating expression of a protein in a subject, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a codon having a first sequence, comprising contacting the subject with a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and/or for a time sufficient to modulate expression of the encoded protein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence, thereby modulating expression of the protein in the subject.

In an aspect, the disclosure provides, a method of treating a subject having an endogenous open reading frame (ORF) which comprises a codon having a first sequence, comprising providing a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein wherein the TREM comprises a tRNA moiety having an anticodon that pairs with the codon of the ORF having the first sequence; contacting the subject with the composition comprising a TREM, TREM core fragment or TREM fragment in an amount and/or for a time sufficient to treat the subject, thereby treating the subject.

In one aspect, provided herein is a method of modulating a production parameter of an mRNA corresponding to, or polypeptide encoded by, an endogenous open reading frame (ORF) in a subject, which ORF comprises a premature termination codon (PTC), contacting the subject with a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and/or for a time sufficient to modulate the production parameter of the mRNA or polypeptide, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence, thereby modulating the production parameter in the subject. In an embodiment, the production parameter comprises a signaling parameter and/or an expression parameter, e.g., as described herein.

In an aspect, the disclosure provides a method of treating a subject having an endogenous open reading frame (ORF) which comprises a premature termination codon (PTC), comprising providing a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein, wherein the TREM comprises a tRNA moiety having an anticodon that pairs with the PTC in the ORF; contacting the subject with the composition comprising a TREM, TREM core fragment or TREM fragment in an amount and/or for a time sufficient to treat the subject, thereby treating the subject. In an embodiment, the PTC comprises UAA, UGA or UAG.

In yet another aspect, disclosed herein is a method of modulating expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a premature termination codon (PTC), comprising contacting the cell with a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and/or for a time sufficient to modulate expression of the encoded protein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the PTC, thereby modulating expression of the protein in the cell. In an embodiment, the PTC comprises UAA, UGA or UAG.

In one aspect, provided herein is a method of modulating expression of a protein in a subject, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a premature termination codon (PTC), comprising contacting the subject with a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and/or for a time sufficient to modulate expression of the encoded protein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the PTC, thereby modulating expression of the protein in the subject. In an embodiment, the PTC comprises UAA, UGA or UAG.

In an aspect, provided herein is a method of increasing expression of a protein in a subject wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a premature termination codon (PTC), comprising contacting the subject, in an amount and/or for a time sufficient to increase expression of the protein, with a TREM composition that (i) has an anticodon that pairs with the PTC, (ii) recognizes an aminoacyl-tRNA synthetase specific for Trp, Tyr, Cys, Glu, Lys, Gln, Ser, Leu, Arg, or Gly, (iii) comprises a sequence of Formula A, or (iv) comprises one or more of a 2′-O-MOE, pseudouridine or 5,6 dihydrouridine modification. In an embodiment, the PTC comprises UAA, UGA or UAG. In an embodiment, the TREM composition comprises (i). In an embodiment, the TREM composition comprises (ii). In an embodiment, the TREM composition comprises (iii). In an embodiment, the TREM composition comprises (iv). In an embodiment, the TREM composition comprises two of (i)-(iv). In an embodiment, the TREM composition comprises three of (i)-(iv). In an embodiment, the TREM composition comprises each of (i)-(iv).

In an aspect, provided herein is a method of increasing expression of a protein in a subject wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a premature termination codon (PTC), comprising: contacting the subject, in an amount and/or for a time sufficient to increase expression of the protein, with a TREM composition that (i) has an anticodon that pairs with the PTC, (ii) recognizes an aminoacyl-tRNA synthetase specific for Trp, Tyr, Cys, Glu, Lys, Gln, Ser, Leu, Arg, or Gly, (iii) comprises a sequence of Formula B, or (iv) comprises one or more of a 2′-O-MOE, pseudouridine or 5,6 dihydrouridine modification. In an embodiment, the PTC comprises UAA, UGA or UAG. In an embodiment, the TREM composition comprises (i). In an embodiment, the TREM composition comprises (ii). In an embodiment, the TREM composition comprises (iii). In an embodiment, the TREM composition comprises (iv). In an embodiment, the TREM composition comprises two of (i)-(iv). In an embodiment, the TREM composition comprises three of (i)-(iv). In an embodiment, the TREM composition comprises each of (i)-(iv).

In an embodiment of any of the methods disclosed herein, the codon having the first sequence comprises a mutation (e.g., a point mutation, e.g., a nonsense mutation), resulting in a premature termination codon (PTC) chosen from UAA, UGA or UAG. In an embodiment, the codon having the first sequence or the PTC comprises a UAA mutation. In an embodiment, the codon having the first sequence or the PTC comprises a UGA mutation. In an embodiment, the codon having the first sequence or the PTC comprises a UAG mutation.

In an embodiment of any of the methods disclosed herein, the codon having the first sequence or the PTC comprises a UAA, UGA or UAA mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid which maintains a property, e.g., function, of a polypeptide encoded by the ORF into which the amino acid is incorporated.

In an embodiment of any of the methods disclosed herein, the codon having the first sequence or the PTC comprises a UAA, UGA or UAA mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid which does not alter, e.g., maintains, a production parameter, e.g., an expression parameter and/or a signaling parameter, of an mRNA corresponding to the ORF or a polypeptide encoded by the ORF. In an embodiment, the production parameter is compared to an mRNA corresponding to, or a polypeptide encoded by, an otherwise similar ORF having a pre-mutation, e.g., wildtype, amino acid incorporated at the position corresponding to the first sequence codon or PTC.

In an embodiment of any of the methods disclosed herein, the TREM or TREM fragment comprises a sequence of Formula A. In an embodiment of any of the methods disclosed herein, the TREM core fragment comprises a sequence of Formula B.

In an embodiment of any of the methods disclosed herein, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for any one of the 20 amino acids. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for Trp, Tyr, Cys, Glu, Lys, Gln, Ser, Leu, Arg, or Gly. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for Trp. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for Tyr. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for Cys. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for Glu. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for Lys. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for Gln. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for Ser. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for Leu. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for Arg. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes an aminoacyl-tRNA synthetase specific for Gly.

In an embodiment of any of the methods disclosed herein, the TREM, TREM core fragment or TREM fragment comprises one or more of a 2′-O-MOE, pseudouridine, or a 5,6 dihydrouridine modification. In an embodiment of any of the methods disclosed herein, the TREM, TREM core fragment or TREM fragment comprises a 2′-O-MOE modification. In an embodiment of any of the methods disclosed herein, the TREM, TREM core fragment or TREM fragment comprises a pseudouridine modification. In an embodiment of any of the methods disclosed herein, the TREM, TREM core fragment or TREM fragment comprises a 5,6 dihydrouridine modification.

In an aspect, provided herein is a TREM comprising a sequence of Formula A:

[L1]-[ASt Domain1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain2],

wherein independently, [L1] and [VL Domain], are optional; and one of [L1], [ASt Domain1], [L2]-[DH Domain], [L3], [ACH Domain], [VL Domain], [TH Domain], [L4], and [ASt Domain2] comprises a nucleotide having a non-naturally occurring modification.

In an embodiment, the TREM: (a) retains the ability to: support protein synthesis, be charged by a synthetase, be bound by an elongation factor, introduce an amino acid into a peptide chain, support elongation, or support initiation; (b) comprises at least X contiguous nucleotides without a non-naturally occurring modification, wherein X is greater than 10; (c) comprises at least 3, but less than all of the nucleotides of a type (e.g., A, T, C, G or U) comprise the same non-naturally occurring modification; (d) comprises at least X nucleotides of a type (e.g., A, T, C, G or U) that do not comprise a non-naturally occurring modification, wherein X=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50; (e) comprises no more than 5, 10, or 15 nucleotides of a type (e.g., A, T, C, G or U) that comprise a non-naturally occurring modification; or (f) comprises no more than 5, 10, or 15 nucleotides of a type (e.g., A, T, C, G or U) that do not comprise a non-naturally occurring modification.

In an embodiment, the TREM comprises feature (a). In an embodiment, the TREM comprises feature (b). In an embodiment, the TREM comprises feature (c). In an embodiment, the TREM comprises feature (d). In an embodiment, the TREM comprises feature (e). In an embodiment, the TREM comprises feature (f). In an embodiment, the TREM comprises two of features (a)-(f). In an embodiment, the TREM comprises three of features (a)-(f). In an embodiment, the TREM comprises four of features (a)-(f). In an embodiment, the TREM comprises five of features (a)-(f). In an embodiment, the TREM comprises all of features (a)-(f).

In an embodiment, the TREM Domain comprising the non-naturally occurring modification retains a function, e.g., a domain function described herein.

In an aspect, provided herein is a TREM core fragment comprising a sequence of Formula B:

[L1]_y-[ASt Domain1]_x-[L2]_y-[DH Domain]_y-[L3]_y-[ACH Domain]_x-[VL Domain]_y-[TH Domain]_y-[L4]_y-[ASt Domain2]_x,

wherein x=1 and y=0 or 1; and one of [ASt Domain1], [ACH Domain], and [ASt Domain2] comprises a nucleotide having a non-naturally occurring modification.

In an embodiment, the TREM retains the ability to support protein synthesis. In an embodiment, the TREM retains the ability to be able to be charged by a synthetase. In an embodiment, the TREM retains the ability to be bound by an elongation factor. In an embodiment, the TREM retains the ability to introduce an amino acid into a peptide chain. In an embodiment, the TREM retains the ability to support elongation. In an embodiment, the TREM retains the ability to support initiation.

In an embodiment, the [ASt Domain 1] and/or [ASt Domain 2] comprising the non-naturally occurring modification retains the ability to initiate or elongate a polypeptide chain.

In an embodiment, the [ACH Domain] comprising the non-naturally occurring modification retains the ability to mediate pairing with a codon.

In an embodiment, y=1 for any one, two, three, four, five, six, all or a combination of [L1], [L2], [DH Domain], [L3], [VL Domain], [TH Domain], [L4].

In an embodiment, y=0 for any one, two, three, four, five, six, all or a combination of [L1], [L2], [DH Domain], [L3], [VL Domain], [TH Domain], [L4].

In an embodiment, y=1 for linker [L1], and L1 comprises a nucleotide having a non-naturally occurring modification.

In an embodiment, y=1 for linker [L2], and L2 comprises a nucleotide having a non-naturally occurring modification.

In an embodiment, y=1 for [DH Domain (DHD)], and DHD comprises a nucleotide having a non-naturally occurring modification. In an embodiment, the DHD comprising the non-naturally occurring modification retains the ability to mediate recognition of aminoacyl-tRNA synthetase.

In an embodiment, y=1 for linker [L3], and L3 comprises a nucleotide having a non-naturally occurring modification.

In an embodiment, y=1 for [VL Domain (VLD)], and VLD comprises a nucleotide having a non-naturally occurring modification.

In an embodiment, y=1 for [TH Domain (THD)], and THD comprises a nucleotide having a non-naturally occurring modification. In an embodiment, the THD comprising the non-naturally occurring modification retains the ability to mediate recognition of the ribosome.

In an embodiment, y=1 for linker [L4], and L4 comprises a nucleotide having a non-naturally occurring modification.

In another aspect, the disclosure provides a TREM fragment comprising a portion of a TREM, wherein the TREM comprises a sequence of Formula A:

[L1]-[ASt Domain1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain2], and wherein the TREM fragment comprises a non-naturally occurring modification.

In an embodiment, the TREM fragment comprises one, two, three or all or any combination of the following: (a) a TREM half (e.g., from a cleavage in the ACH Domain, e.g., in the anticodon sequence, e.g., a 5′half or a 3′ half); (b) a 5′ fragment (e.g., a fragment comprising the 5′ end, e.g., from a cleavage in a DH Domain or the ACH Domain); (c) a 3′ fragment (e.g., a fragment comprising the 3′ end, e.g., from a cleavage in the TH Domain); or (d) an internal fragment (e.g., from a cleavage in any one of the ACH Domain, DH Domain or TH Domain).

In an embodiment, the TREM fragment comprise (a) a TREM half which comprises a nucleotide having a non-naturally occurring modification.

In an embodiment, the TREM fragment comprise (b) a 5′ fragment which comprises a nucleotide having a non-naturally occurring modification.

In an embodiment, the TREM fragment comprise (c) a 3′ fragment which comprises a nucleotide having a non-naturally occurring modification.

In an embodiment, the TREM fragment comprise (d) an internal fragment which comprises a nucleotide having a non-naturally occurring modification.

In another aspect, the disclosure provides a pharmaceutical composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein for use in a method disclosed herein.

In another aspect, the disclosure provides a method of making a TREM, a TREM core fragment, or a TREM fragment disclosed herein, comprising linking a first nucleotide to a second nucleotide to form the TREM.

In an embodiment, the TREM, TREM core fragment or TREM fragment is synthetic.

In an embodiment, the TREM, TREM core fragment or TREM fragment is made by cell-free solid phase synthesis.

In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM Domain comprises a plurality of nucleotides each having a non-naturally occurring modification. In an embodiment, the non-naturally occurring modification comprises a nucleobase modification, a sugar (e.g., ribose) modification, or a backbone modification. In an embodiment, the non-naturally occurring modification is a sugar (e.g., ribose) modification. In an embodiment, the non-naturally occurring modification is 2′-ribose modification, e.g., a 2′-OMe, 2′-halo (e.g., 2′-F), 2′-MOE, or 2′-deoxy modification. In an embodiment, the non-naturally occurring modification is a backbone modification, e.g., a phosphorothioate modification.

In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM sequence comprises a CCA sequence on a terminus, e.g., the 3′ terminus. In an embodiment, the TREM sequence does not comprise a CCA sequence on a terminus, e.g., the 3′ terminus.

In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the non-naturally occurring modification is a modification in a base or a backbone of a nucleotide, e.g., a modification chosen from any one of Tables 5, 6, 7, 8 or 9.

In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the non-naturally occurring modification is a base modification chosen from a modification listed in Table 10.

In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the non-naturally occurring modification is a backbone modification chosen from a modification listed in Table 13.

Additional features of any of the aforesaid TREMs, TREM core fragments, TREM fragments, TREM compositions, preparations, methods of making TREM compositions and preparations, and methods of using TREM compositions and preparations include one or more of the following enumerated embodiments.

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following enumerated embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-IC are graphs depicting the cell readthrough data of premature termination codons (PTC) in exemplary disease reporters (FIG. 1A—Factor IX at position 298 (FIX^R298X); FIG. 1B—Tripeptidyl-peptidase 1 at position 208 (TPP1^R298X); and FIG. 1C—Protocadherin Related 15 at position 245 (PCDH15^R245X)) after treatment with the unmodified arginine non-cognate TREM and modified arginine non-cognate TREM (TREM-Arg-TGA-Biotin-47), as outlined in Example 15.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The present disclosure features methods of modulating a production parameter (e.g., an expression parameter and/or a signaling parameter) of an RNA corresponding to, or polypeptide encoded by, a nucleic acid sequence comprising an endogenous ORF having a premature termination codon (PTC) in a cell or a subject, comprising administering a tRNA-based effector molecule composition (TREM) to the cell or subject. In an embodiment, the TREM composition comprises a TREM, a TREM core fragment, or a TREM fragment comprising a non-naturally occurring modification, e.g., as described herein. Also disclosed herein are methods of modulating expression of a protein in a subject or cell, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF) having a first sequence, e.g., a mutation, e.g., a premature termination codon (PTC), and methods of treating a subject having an endogenous open reading frame (ORF) which comprises a premature termination codon (PTC). Further disclosed herein are TREMs comprising a non-naturally occurring modification, methods of making the same and compositions thereof.

As disclosed herein, TREMs are complex molecules which can mediate a variety of cellular processes. TREM compositions, e.g., pharmaceutical TREM compositions, e.g., TREMs comprising a non-naturally occurring modification, can be administered to a cell, a tissue, or to a subject to modulate these functions. TREMs of the disclosure include TREMs, TREM core fragments and TREM fragments. TREMs, TREM core fragments or TREM fragments can be modified with non-naturally occurring modifications to, e.g., increase the level and/or activity (e.g., stability) of the TREM.

Without wishing to be bound by theory in every case, it is believed that in some embodiments, administration of a TREM composition to a subject or cell having an endogenous ORF having a PTC results in read-through of the PTC, e.g., expression, e.g., increased expression (e.g., increased level and/or activity) of a polypeptide encoded by the ORF having the PTC. In an embodiment, administration of a TREM composition results in modulation of, e.g., increase of, a production parameter of an RNA corresponding to the full length ORF or a polypeptide encoded by a nucleic acid sequence comprising the full length ORF. In some embodiments, the PTC comprises a UAG, UGA or UAA stop codon. In some embodiments, the TREM comprises an anticodon that pairs with, e.g., recognizes, a stop codon, e.g., a stop codon chosen from UAA, UGA or UAG, and mediates incorporation of an amino acid at the position corresponding to the stop codon. In some embodiments, the production parameter comprises a signaling parameter and/or an expression parameter, e.g., as described herein.

Definitions

“Acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a value, e.g., a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value. “Directly acquiring” refers to performing a process (e.g., performing an analytical method) to obtain the value. “Indirectly acquiring” refers to receiving the value from another party or source (e.g., a third party laboratory that directly acquired the or value).

An “isoacceptor,” as that term is used herein, refers to a plurality of tRNA molecule or TREMs wherein each molecule of the plurality comprises a different naturally occurring anticodon sequence and each molecule of the plurality mediates the incorporation of the same amino acid and that amino acid is the amino acid that naturally corresponds to the anticodons of the plurality.

A“stop codon” as that term is used herein, refers to a three nucleotide contiguous sequence within messenger RNA that specifies a termination of translation. For example, UAG, UAA, UGA (in RNA) and TAG, TAA or TGA (in DNA) are stop codons. The stop codons are also known as amber (UAG), ochre (UAA), and opal (UGA).

A “premature termination codon” or “PTC” as those terms are used herein, refer to a stop codon that occurs in an open reading frame (ORF) of a DNA or mRNA. In an embodiment, a PTC occurs at a position upstream of a naturally occurring stop codon in an ORF. In an embodiment, a PTC that occurs upstream of a naturally occurring stop codon, e.g., in an ORF, results in modulation of a production parameter of the corresponding mRNA or polypeptide encoded by the ORF. In an embodiment, a PTC can differ (or arise) from a pre-mutation sequence by a point mutation, e.g., a nonsense mutation. In an embodiment, a PTC can differ (or arise) from a pre-mutation sequence by a genetic change, e.g., abnormality, other than a point mutation, e.g., a frameshift, a deletion, an insertion, a rearrangement, an inversion, a translocation, a duplication, or a transversion. In an embodiment, a PTC results in the production of a truncated protein which lacks a native activity or which is associated with a mutant, disease, or other unwanted phenotype.

A “disease or disorder associated with a PTC” as that term is used herein includes, but is not limited to, a disease or disorder in which cells express, or at one time expressed, a polypeptide encoded by an ORF comprising a PTC. In some embodiments, a disease associated with a PTC is chosen from: a proliferative disorder (e.g., a cancer), a genetic disorder, a metabolic disorder, an immune disorder, an inflammatory disorder or a neurological disorder. Exemplary diseases or disorders associated with a PTC are provided in any one of Tables 15, 16 and 17.

An “ORF having a PTC” as that phrase is used herein, refers to an open reading frame (ORF) which comprises a premature termination codon (PTC). In an embodiment, the ORF having the PTC is associated with a disease or disorder associated with a PTC, e.g., as described herein, e.g., a disease or disorder listed in any one of Tables 15, 16 and 17. In an embodiment, the ORF having the PTC is not associated with a disease or disorder associated with a PTC.

A “nucleotide,” as that term is used herein, refers to an entity comprising a sugar, typically a pentameric sugar; a nucleobase; and a phosphate linking group. In an embodiment, a nucleotide comprises a naturally occurring, e.g., naturally occurring in a human cell, nucleotide, e.g., an adenine, thymine, guanine, cytosine, or uracil nucleotide.

A “modification,” as that term is used herein with reference to a nucleotide, refers to a modification of the chemical structure, e.g., a covalent modification, of the subject nucleotide. The modification can be naturally occurring or non-naturally occurring. In an embodiment, the modification is non-naturally occurring. In an embodiment, the modification is naturally occurring. In an embodiment, the modification is a synthetic modification. In an embodiment, the modification is a modification provided in Tables 5, 6, 7, 8 or 9.

A “non-naturally occurring modification,” as that term is used herein with reference to a nucleotide, refers to a modification that: (a) a cell, e.g., a human cell, does not make on an endogenous tRNA; or (b) a cell, e.g., a human cell, can make on an endogenous tRNA but wherein such modification is in a location in which it does not occur on a native tRNA, e.g., the modification is in a domain, linker or arm, or on a nucleotide and/or at a position within a domain, linker or arm, which does not have such modification in nature. In either case, the modification is added synthetically, e.g., in a cell free reaction, e.g., in a solid state or liquid phase synthetic reaction. In an embodiment, the non-naturally occurring modification is a modification that is not present (in identity, location or position) if a sequence of the TREM is expressed in a mammalian cell, e.g., a HEK293 cell line. Exemplary non-naturally occurring modifications are found in Tables 5, 6, 7, 8 or 9.

A “non-naturally modified nucleotide,” as that term is used herein, refers a nucleotide comprising a non-naturally occurring modification on or of a sugar, nucleobase, or phosphate moiety.

A “non-naturally occurring sequence,” as that term is used herein, refers to a sequence wherein an Adenine is replaced by a residue other than an analog of Adenine, a Cytosine is replaced by a residue other than an analog of Cytosine, a Guanine is replaced by a residue other than an analog of Guanine, and a Uracil is replaced by a residue other than an analog of Uracil. An analog refers to any possible derivative of the ribonucleotides, A, G, C or U. In an embodiment, a sequence having a derivative of any one of ribonucleotides A, G, C or U is a non-naturally occurring sequence.

A “naturally occurring nucleotide,” as that term is used herein, refers to a nucleotide that does not comprise a non-naturally occurring modification. In an embodiment, it includes a naturally occurring modification.

A “production parameter,” refers to an expression parameter and/or a signaling parameter. In an embodiment a production parameter is an expression parameter. An expression parameter includes an expression parameter of a polypeptide or protein encoded by the endogenous ORF having a first sequence or PTC; or an expression parameter of an RNA, e.g., messenger RNA, encoded by the endogenous ORF having a first sequence or PTC. In an embodiment, an expression parameter can include:

(a) protein translation;

(b) expression level (e.g., of polypeptide or protein, or mRNA);

(d) folding (e.g., of polypeptide or protein, or mRNA),

(e) structure (e.g., of polypeptide or protein, or mRNA),

(f) transduction (e.g., of polypeptide or protein),

(g) compartmentalization (e.g., of polypeptide or protein, or mRNA),

(h) incorporation (e.g., of polypeptide or protein, or mRNA) into a supermolecular structure, e.g., incorporation into a membrane, proteasome, or ribosome,

(i) incorporation into a multimeric polypeptide, e.g., a homo or heterodimer, and/or

(j) stability.

In an embodiment, a production parameter is a signaling parameter. A signaling parameter can include:

(1) modulation of a signaling pathway, e.g., a cellular signaling pathway which is downstream or upstream of the protein encoded by the endogenous ORF having a first sequence or PTC;

(2) cell fate modulation;

(3) ribosome occupancy modulation;

(4) protein translation modulation;

(5) mRNA stability modulation;

(6) protein folding and structure modulation;

(7) protein transduction or compartmentalization modulation; and/or (8) protein stability modulation.

A “tRNA-based effector molecule” or “TREM,” as that term is used herein, refers to an RNA molecule comprising a structure or property from (a)-(v) below, and which is a recombinant TREM, a synthetic TREM, or a TREM expressed from a heterologous cell. The TREMs described in the present invention are synthetic molecules and are made, e.g., in a cell free reaction, e.g., in a solid state or liquid phase synthetic reaction. TREMs are chemically distinct, e.g., in terms of primary sequence, type or location of modifications from the endogenous tRNA molecules made in cells, e.g., in mammalian cells, e.g., in human cells. A TREM can have a plurality (e.g., 2, 3, 4, 5, 6, 7, 8, 9) of the structures and functions of (a)-(v).

In an embodiment, a TREM is non-native, as evaluated by structure or the way in which it was made.

In an embodiment, a TREM comprises one or more of the following structures or properties:

(a′) an optional linker region of a consensus sequence provided in the “Consensus Sequence” section, e.g., a Linker 1 region;

(a) an amino acid attachment domain that binds an amino acid, e.g., an acceptor stem domain (AStD), wherein an AStD comprises sufficient RNA sequence to mediate, e.g., when present in an otherwise wildtype tRNA, acceptance of an amino acid, e.g., its cognate amino acid or a non-cognate amino acid, and transfer of the amino acid (AA) in the initiation or elongation of a polypeptide chain. Typically, the AStD comprises a 3′-end adenosine (CCA) for acceptor stem charging which is part of synthetase recognition. In an embodiment the AStD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring AStD, e.g., an AStD encoded by a nucleic acid in Table 9. In an embodiment, the TREM can comprise a fragment or analog of an AStD, e.g., an AStD encoded by a nucleic acid in Table 9, which fragment in embodiments has AStD activity and in other embodiments does not have AStD activity. (One of ordinary skill can determine the relevant corresponding sequence for any of the domains, stems, loops, or other sequence features mentioned herein from a sequence encoded by a nucleic acid in Table 9. E.g., one of ordinary skill can determine the sequence which corresponds to an AStD from a tRNA sequence encoded by a nucleic acid in Table 9.)

In an embodiment the AStD falls under the corresponding sequence of a consensus sequence provided in the “Consensus Sequence” section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions;

In an embodiment, the AStD comprises residues R₁-R₂-R₃-R₄-R₅-R₆-R₇and residues R₆₅-R₆₆-R₆₇-R₆₈-R₆₉-R₇₀-R₇₁of Formula I_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

In an embodiment, the AStD comprises residues R₁-R₂-R₃-R₄-R₅-R₆-R₇and residues R₆₅-R₆₆-R₆₇-R₆₈-R₆₉-R₇₀-R₇₁of Formula II_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

In an embodiment, the AStD comprises residues R₁-R₂-R₃-R₄-R₅-R₆-R₇and residues R₆₅-R₆₆-R₆₇-R₆₈-R₆₉-R₇₀-R₇₁of Formula III_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

(a′-1) a linker comprising residues R₈-R₉of a consensus sequence provided in the “Consensus Sequence” section, e.g., a Linker 2 region;

(b) a dihydrouridine hairpin domain (DHD), wherein a DHD comprises sufficient RNA sequence to mediate, e.g., when present in an otherwise wildtype tRNA, recognition of aminoacyl-tRNA synthetase, e.g., acts as a recognition site for aminoacyl-tRNA synthetase for amino acid charging of the TREM. In embodiments, a DHD mediates the stabilization of the TREM's tertiary structure. In an embodiment the DHD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring DHD, e.g., a DHD encoded by a nucleic acid in Table 9. In an embodiment, the TREM can comprise a fragment or analog of a DHD, e.g., a DHD encoded by a nucleic acid in Table 9, which fragment in embodiments has DHD activity and in other embodiments does not have DHD activity.

In an embodiment the DHD falls under the corresponding sequence of a consensus sequence provided in the “Consensus Sequence” section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions;

In an embodiment, the DHD comprises residues R₁₀-R₁₁-R₁₂-R₁₃-R₁₄R₁₅-R₁₆-R₁₇-R₁₈-R₁₉-R₂₀-R₂₁-R₂₂-R₂₃-R₂₄-R₂₅-R₂₆-R₂₇-R₂₈of Formula I_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

In an embodiment, the DHD comprises residues R₁₀-R₁₁-R₁₂-R₁₃-R₁₄R₁₅-R₁₆-R₁₇-R₁₈-R₁₉-R₂₀-R₂₁-R₂₂-R₂₃-R₂₄-R₂₅-R₂₆-R₂₇-R₂₈of Formula II_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

In an embodiment, the DHD comprises residues R₁₀-R₁₁-R₁₂-R₁₃-R₁₄R₁₅-R₁₆-R₁₇-R₁₈-R₁₉-R₂₀-R₂₁-R₂₂-R₂₃-R₂₄-R₂₅-R₂₆-R₂₇-R₂₈of Formula III_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

(b′-1) a linker comprising residue R₂₉of a consensus sequence provided in the “Consensus Sequence” section, e.g., a Linker 3 region;

(c) an anticodon that binds a respective codon in an mRNA, e.g., an anticodon hairpin domain (ACHD), wherein an ACHD comprises sufficient sequence, e.g., an anticodon triplet, to mediate, e.g., when present in an otherwise wildtype tRNA, pairing (with or without wobble) with a codon; In an embodiment the ACHD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring ACHD, e.g., an ACHD encoded by a nucleic acid in Table 9. In an embodiment, the TREM can comprise a fragment or analog of an ACHD, e.g., an ACHD encoded by a nucleic acid in Table 9, which fragment in embodiments has ACHD activity and in other embodiments does not have ACHD activity.

In an embodiment the ACHD falls under the corresponding sequence of a consensus sequence provided in the “Consensus Sequence” section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions;

In an embodiment, the ACHD comprises residues -R₃₀-R₃₁-R₃₂-R₃₃-R₃₄-R₃₅-R₃₆-R₃₇-R₃₈-R₃₉-R₄₀-R₄₁-R₄₂-R₄₃-R₄₄-R₄₅-R₄₆of Formula I_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

In an embodiment, the ACHD comprises residues -R₃₀-R₃₁-R₃₂-R₃₃-R₃₄-R₃₅-R₃₆-R₃₇-R₃₈-R₃₉-R₄₀-R₄₁-R₄₂-R₄₃-R₄₄-R₄₅-R₄₆of Formula II_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

In an embodiment, the ACHD comprises residues -R₃₀-R₃₁-R₃₂-R₃₃-R₃₄-R₃₅-R₃₆-R₃₇-R₃₈-R₃₉-R₄₀-R₄₁-R₄₂-R₄₃-R₄₄-R₄₅-R₄₆of Formula III_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

(d) a variable loop domain (VLD), wherein a VLD comprises sufficient RNA sequence to mediate, e.g., when present in an otherwise wildtype tRNA, recognition of aminoacyl-tRNA synthetase, e.g., acts as a recognition site for aminoacyl-tRNA synthetase for amino acid charging of the TREM. In embodiments, a VLD mediates the stabilization of the TREM's tertiary structure. In an embodiment, a VLD modulates, e.g., increases, the specificity of the TREM, e.g., for its cognate amino acid, e.g., the VLD modulates the TREM's cognate adaptor function. In an embodiment the VLD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring VLD, e.g., a VLD encoded by a nucleic acid in Table 9. In an embodiment, the TREM can comprise a fragment or analog of a VLD, e.g., a VLD encoded by a nucleic acid in Table 9, which fragment in embodiments has VLD activity and in other embodiments does not have VLD activity.

In an embodiment the VLD falls under the corresponding sequence of a consensus sequence provided in the “Consensus Sequence” section.

In an embodiment, the VLD comprises residue -[R₄₇]_xof a consensus sequence provided in the “Consensus Sequence” section, wherein x=1-271 (e.g., x=1-250, x=1-225, x=1-200, x=1-175, x=1-150, x=1-125, x=1-100, x=1-75, x=1-50, x=1-40, x=1-30, x=1-29, x=1-28, x=1-27, x=1-26, x=1-25, x=1-24, x=1-23, x=1-22, x=1-21, x=1-20, x=1-19, x=1-18, x=1-17, x=1-16, x=1-15, x=1-14, x=1-13, x=1-12, x=1-11, x=1-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70-271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271);

(e) a thymine hairpin domain (THD), wherein a THD comprises sufficient RNA sequence, to mediate, e.g., when present in an otherwise wildtype tRNA, recognition of the ribosome, e.g., acts as a recognition site for the ribosome to form a TREM-ribosome complex during translation. In an embodiment the THD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring THD, e.g., a THD encoded by a nucleic acid in Table 9. In an embodiment, the TREM can comprise a fragment or analog of a THD, e.g., a THD encoded by a nucleic acid in Table 9, which fragment in embodiments has THD activity and in other embodiments does not have THD activity.

In an embodiment the THD falls under the corresponding sequence of a consensus sequence provided in the “Consensus Sequence” section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions;

In an embodiment, the THD comprises residues -R₄₈-R₄₉-R₅₀-R₅₁-R₅₂-R₅₃-R₅₄-R₅₅-R₅₆-R₅₇-R₅₈-R₅₉-R₆₀-R₆₁-R₆₂-R₆₃-R₆₄of Formula I_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

In an embodiment, the THD comprises residues -R₄₈-R₄₉-R₅₀-R₅₁-R₅₂-R₅₃-R₅₄-R₅₅-R₅₆-R₅₇-R₅₈-R₅₉-R₆₀-R₆₁-R₆₂-R₆₃-R₆₄of Formula II_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

In an embodiment, the THD comprises residues -R₄₈-R₄₉-R₅₀-R₅₁-R₅₂-R₅₃-R₅₄-R₅₅-R₅₆-R₅₇-R₅₈-R₅₉-R₆₀-R₆₁-R₆₂-R₆₃-R₆₄of Formula III_ZZZ, wherein ZZZ indicates any of the twenty amino acids;

(e′1) a linker comprising residue R₇₂of a consensus sequence provided in the “Consensus Sequence” section, e.g., a Linker 4 region;

(f) under physiological conditions, it comprises a stem structure and one or a plurality of loop structures, e.g., 1, 2, or 3 loops. A loop can comprise a domain described herein, e.g., a domain selected from (a)-(e). A loop can comprise one or a plurality of domains. In an embodiment, a stem or loop structure has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring stem or loop structure, e.g., a stem or loop structure encoded by a nucleic acid in Table 9. In an embodiment, the TREM can comprise a fragment or analog of a stem or loop structure, e.g., a stem or loop structure encoded by a nucleic acid in Table 9, which fragment in embodiments has activity of a stem or loop structure, and in other embodiments does not have activity of a stem or loop structure;

(g) a tertiary structure, e.g., an L-shaped tertiary structure;

(h) adaptor function, i.e., the TREM mediates acceptance of an amino acid, e.g., its cognate amino acid and transfer of the AA in the initiation or elongation of a polypeptide chain;

(i) cognate adaptor function wherein the TREM mediates acceptance and incorporation of an amino acid (e.g., cognate amino acid) associated in nature with the anti-codon of the TREM to initiate or elongate a polypeptide chain;

(j) non-cognate adaptor function, wherein the TREM mediates acceptance and incorporation of an amino acid (e.g., non-cognate amino acid) other than the amino acid associated in nature with the anti-codon of the TREM in the initiation or elongation of a polypeptide chain;

(k) a regulatory function, e.g., an epigenetic function (e.g., gene silencing function or signaling pathway modulation function), cell fate modulation function, mRNA stability modulation function, protein stability modulation function, protein transduction modulation function, or protein compartmentalization function;

(l) a structure which allows for ribosome binding;

(m) a post-transcriptional modification, e.g., a naturally occurring post-trasncriptional modification;

(n) the ability to inhibit a functional property of a tRNA, e.g., any of properties (h)-(k) possessed by a tRNA;

(o) the ability to modulate cell fate;

(p) the ability to modulate ribosome occupancy;

(q) the ability to modulate protein translation;

(r) the ability to modulate mRNA stability;

(s) the ability to modulate protein folding and structure;

(t) the ability to modulate protein transduction or compartmentalization;

(u) the ability to modulate protein stability; or

(v) the ability to modulate a signaling pathway, e.g., a cellular signaling pathway.

In an embodiment, a TREM comprises a full-length tRNA molecule or a fragment thereof.

In an embodiment, a TREM comprises the following properties: (a)-(e).

In an embodiment, a TREM comprises the following properties: (a) and (c).

In an embodiment, a TREM comprises the following properties: (a), (c) and (h).

In an embodiment, a TREM comprises the following properties: (a), (c), (h) and (b).

In an embodiment, a TREM comprises the following properties: (a), (c), (h) and (e).

In an embodiment, a TREM comprises the following properties: (a), (c), (h), (b) and (e).

In an embodiment, a TREM comprises the following properties: (a), (c), (h), (b), (e) and (g).

In an embodiment, a TREM comprises the following properties: (a), (c), (h) and (m).

In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m), and (g).

In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m) and (b).

In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m) and (e).

In an embodiment, a TREM comprises the following properties: (a), (c), (h), (in), (g), (b) and (e).

In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m), (g), (b), (e) and (q).

In an embodiment, a TREM comprises:

(i) an amino acid attachment domain that binds an amino acid (e.g., an AStD, as described in (a) herein; and

(ii) an anticodon that binds a respective codon in an mRNA (e.g., an ACHD, as described in (c) herein).

In an embodiment the TREM comprises a flexible RNA linker which provides for covalent linkage of (i) to (ii).

In an embodiment, the TREM mediates protein translation.

In an embodiment a TREM comprises a linker, e.g., an RNA linker, e.g., a flexible RNA linker, which provides for covalent linkage between a first and a second structure or domain. In an embodiment, an RNA linker comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ribonucleotides. A TREM can comprise one or a plurality of linkers, e.g., in embodiments a TREM comprising (a), (b), (c), (d) and (e) can have a first linker between a first and second domain, and a second linker between a third domain and another domain.

In an embodiment, the TREM comprises a sequence of Formula A: [L1]-[ASt Domain1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain2].

In an embodiment, a TREM comprises an RNA sequence at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical with, or which differs by no more than 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 ribonucleotides from, an RNA sequence encoded by a DNA sequence listed in Table 9, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises an RNA sequence encoded by a DNA sequence listed in Table 9, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises an RNA sequence encoded by a DNA sequence at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical with a DNA sequence listed in Table 9, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises a TREM domain, e.g., a domain described herein, comprising at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical with, or which differs by no more than 1, 2, 3, 4, 5, 10, or 15, ribonucleotides from, an RNA encoded by a DNA sequence listed in Table 9, or a fragment or a functional fragment thereof. In an embodiment, a TREM comprises a TREM domain, e.g., a domain described herein, comprising an RNA sequence encoded by DNA sequence listed in Table 9, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises a TREM domain, e.g., a domain described herein, comprising an RNA sequence encoded by DNA sequence at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical with a DNA sequence listed in Table 9, or a fragment or functional fragment thereof.

In an embodiment, a TREM is 76-90 nucleotides in length. In embodiments, a TREM or a fragment or functional fragment thereof is between 10-90 nucleotides, between 10-80 nucleotides, between 10-70 nucleotides, between 10-60 nucleotides, between 10-50 nucleotides, between 10-40 nucleotides, between 10-30 nucleotides, between 10-20 nucleotides, between 20-90 nucleotides, between 20-80 nucleotides, 20-70 nucleotides, between 20-60 nucleotides, between 20-50 nucleotides, between 20-40 nucleotides, between 30-90 nucleotides, between 30-80 nucleotides, between 30-70 nucleotides, between 30-60 nucleotides, or between 30-50 nucleotides.

In an embodiment, a TREM is aminoacylated, e.g., charged, with an amino acid by an aminoacyl tRNA synthetase.

In an embodiment, a TREM is not charged with an amino acid, e.g., an uncharged TREM (uTREM).

In an embodiment, a TREM comprises less than a full length tRNA. In embodiments, a TREM can correspond to a naturally occurring fragment of a tRNA, or to a non-naturally occurring fragment. Exemplary fragments include: TREM halves (e.g., from a cleavage in the ACHD, e.g., in the anticodon sequence, e.g., 5′halves or 3′ halves); a 5′ fragment (e.g., a fragment comprising the 5′ end, e.g., from a cleavage in a DHD or the ACHD); a 3′ fragment (e.g., a fragment comprising the 3′ end, e.g., from a cleavage in the THD); or an internal fragment (e.g., from a cleavage in one or more of the ACHD, DHD or THD).

A “TREM core fragment,” as that term is used herein, refers to a portion of the sequence of Formula B: [L1]_y-[ASt Domain1]_x-[L2]_y-[DH Domain]_y-[L3]_y-[ACH Domain]_x-[VL Domain]_y-[TH Domain]_y-[L4]_y-[ASt Domain2]_x, wherein: x=1 and y=0 or 1.

A “TREM fragment,” as used herein, refers to a portion of a TREM, wherein the TREM comprises a sequence of Formula A: [L1]-[ASt Domain1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain2].

A “cognate adaptor function TREM,” as that term is used herein, refers to a TREM which mediates initiation or elongation with the AA (the cognate AA) associated in nature with the anti-codon of the TREM.

“Decreased expression,” as that term is used herein, refers to a decrease in comparison to a reference, e.g., in the case where altered control region, or addition of an agent, results in a decreased expression of the subject product, it is decreased relative to an otherwise similar cell without the alteration or addition.

“Increased expression,” as that term is used herein, refers to an increase in comparison to a reference, e.g., in the case where altered control region, or addition of an agent, results in an increased expression of the subject product, it is increased relative to an otherwise similar cell without the alteration or addition.

As used herein, the terms “increasing” and “decreasing” refer to modulating that results in, respectively, greater or lesser amounts of function, expression, or activity of a particular metric relative to a reference. For example, subsequent to administration to a cell, tissue or subject of a TREM described herein, the amount of a marker of a metric (e.g., protein translation, mRNA stability, protein folding) as described herein may be increased or decreased by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98%, 2×, 3×, 5×, 10× or more relative to the amount of the marker prior to administration or relative to the effect of a negative control agent. The metric may be measured subsequent to administration at a time that the administration has had the recited effect, e.g., at least 12 hours, 24 hours, one week, one month, 3 months, or 6 months, after a treatment has begun.

An “exogenous nucleic acid,” as that term is used herein, refers to a nucleic acid sequence that is not present in or differs by at least one nucleotide from the closest sequence in a reference cell, e.g., a cell into which the exogenous nucleic acid is introduced. In an embodiment, an exogenous nucleic acid comprises a nucleic acid that encodes a TREM.

An “exogenous TREM,” as that term is used herein, refers to a TREM that:

(a) differs by at least one nucleotide or one post transcriptional modification from the closest sequence tRNA in a reference cell, e.g., a cell into which the exogenous nucleic acid is introduced;

(b) has been introduced into a cell other than the cell in which it was transcribed;

(d) has an expression profile, e.g., level or distribution, that is non-wildtype, e.g., it is expressed at a higher level than wildtype. In an embodiment, the expression profile can be mediated by a change introduced into a nucleic acid that modulates expression or by addition of an agent that modulates expression of the RNA molecule. In an embodiment an exogenous TREM comprises 1, 2, 3 or 4 of properties (a)-(d).

A “GMP-grade composition,” as that term is used herein, refers to a composition in compliance with current good manufacturing practice (cGMP) guidelines, or other similar requirements. In an embodiment, a GMP-grade composition can be used as a pharmaceutical product.

A “non-cognate adaptor function TREM,” as that term is used herein, refers to a TREM which mediates initiation or elongation with an AA (a non-cognate AA) other than the AA associated in nature with the anti-codon of the TREM. In an embodiment, a non-cognate adaptor function TREM is also referred to as a mischarged TREM (mTREM).

A “pharmaceutical TREM composition,” as that term is used herein, refers to a TREM composition that is suitable for pharmaceutical use. Typically, a pharmaceutical TREM composition comprises a pharmaceutical excipient. In an embodiment the TREM will be the only active ingredient in the pharmaceutical TREM composition. In embodiments the pharmaceutical TREM composition is free, substantially free, or has less than a pharmaceutically acceptable amount, of host cell proteins, DNA, e.g., host cell DNA, endotoxins, and bacteria.

“Post-transcriptional processing,” as that term is used herein, with respect to a subject molecule, e.g., a TREM, RNA or tRNAs, refers to a covalent modification of the subject molecule. In an embodiment, the covalent modification occurs post-transcriptionally. In an embodiment, the covalent modification occurs co-transcriptionally. In an embodiment the modification is made in vivo, e.g., in a cell used to produce a TREM. In an embodiment the modification is made ex vivo, e.g., it is made on a TREM isolated or obtained from the cell which produced the TREM.

A “synthetic TREM,” as that term is used herein, refers to a TREM which was synthesized other than in or by a cell having an endogenous nucleic acid encoding the TREM, e.g., a synthetic TREM is synthetized by cell-free solid phase synthesis. A synthetic TREM can have the same, or a different, sequence, or tertiary structure, as a native tRNA.

A “recombinant TREM,” as that term is used herein, refers to a TREM that was expressed in a cell modified by human intervention, having a modification that mediates the production of the TREM, e.g., the cell comprises an exogenous sequence encoding the TREM, or a modification that mediates expression, e.g., transcriptional expression or post-transcriptional modification, of the TREM. A recombinant TREM can have the same, or a different, sequence, set of post-transcriptional modifications, or tertiary structure, as a reference tRNA, e.g., a native tRNA.

A “tRNA”, as that term is used herein, refers to a naturally occurring transfer ribonucleic acid in its native state.

A “TREM composition,” as that term is used herein, refers to a composition comprising a plurality of TREMs, a plurality of TREM core fragments and/or a plurality of TREM fragments.

A TREM composition can comprise one or more species of TREMs, TREM core fragments or TREM fragments. In an embodiment, the composition comprises only a single species of TREM, TREM core fragment or TREM fragment. In an embodiment, the TREM composition comprises a first TREM, TREM core fragment or TREM fragment species; and a second TREM, TREM core fragment or TREM fragment species. In an embodiment, the TREM composition comprises X TREM, TREM core fragment or TREM fragment species, wherein X=2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the TREM, TREM core fragment or TREM fragment has at least 70, 75, 80, 85, 90, or 95, or has 100%, identity with a sequence encoded by a nucleic acid in Table 9. A TREM composition can comprise one or more species of TREMs, TREM core fragments or TREM fragments. In an embodiment, the TREM composition is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 or 99% dry weight TREMs (for a liquid composition dry weight refers to the weight after removal of substantially all liquid, e.g., after lyophilization). In an embodiment, the composition is a liquid. In an embodiment, the composition is dry, e.g., a lyophilized material. In an embodiment, the composition is a frozen composition. In an embodiment, the composition is sterile. In an embodiment, the composition comprises at least 0.5 g, 1.0 g, 5.0 g, 10 g, 15 g, 25 g, 50 g, 100 g, 200 g, 400 g, or 500 g (e.g., as determined by dry weight) of TREM.

In an embodiment, at least X % of the TREMs in a TREM composition has a non-naturally occurring modification at a selected position, and X is 80, 90, 95, 96, 97, 98, 99, or 99.5.

In an embodiment, at least X % of the TREMs in a TREM composition has a non-naturally occurring modification at a first position and a non-naturally occurring modification at a second position, and X, independently, is 80, 90, 95, 96, 97, 98, 99, or 99.5. In embodiments, the modification at the first and second position is the same. In embodiments, the modification at the first and second position are different. In embodiments, the nucleotide at the first and second position is the same, e.g., both are adenine. In embodiments, the nucleotide at the first and second position are different, e.g., one is adenine and one is thymine.

In an embodiment, at least X % of the TREMs in a TREM composition has a non-naturally occurring modification at a first position and less than Y % have a non-naturally occurring modification at a second position, wherein X is 80, 90, 95, 96, 97, 98, 99, or 99.5 and Y is 20, 20, 5, 2, 1, 0.1, or 0.01. In embodiments, the nucleotide at the first and second position is the same, e.g., both are adenine. In embodiments the nucleotide at the first and second position are different, e.g., one is adenine and one is thymine.

“Pairs with” or “pairing,” as those terms are used herein, refer to the correspondence of a codon with an anticodon and includes fully complementary codon:anticodon pairs as well as “wobble” pairing, in which the third position need not be complementary. Fully complementary pairing refers to pairing of all three positions of the codon with the corresponding anticodon according to Watson-Crick base pairing. Wobble pairing refers to complementary pairing of the first and second positions of the codon with the corresponding anticodon according to Watson-Crick base pairing, and flexible pairing at the third position of the codon with the corresponding anticodon.

A “subject,” as this term is used herein, includes any organism, such as a human or other animal. In embodiments, the subject is a vertebrate animal (e.g., mammal, bird, fish, reptile, or amphibian). In embodiments, the subject is a mammal, e.g., a human. In embodiments, the method subject is a non-human mammal. In embodiments, the subject is a non-human mammal such as a non-human primate (e.g., monkeys, apes), ungulate (e.g., cattle, buffalo, sheep, goat, pig, camel, llama, alpaca, deer, horses, donkeys), carnivore (e.g., dog, cat), rodent (e.g., rat, mouse), or lagomorph (e.g., rabbit). In embodiments, the subject is a bird, such as a member of the avian taxa Galliformes (e.g., chickens, turkeys, pheasants, quail), Anseriformes (e.g., ducks, geese), Paleaognathae (e.g., ostriches, emus), Columbiformes (e.g., pigeons, doves), or Psittaciformes (e.g., parrots). The subject may be a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)). A non-human subject may be a transgenic animal.

The terms modified, replace, derived and similar terms, when used or applied in reference to a product, refer only to the end product or structure of the end product, and are not restricted by any method of making or manufacturing the product, unless expressly provided as such in this disclosure.

Headings, titles, subtitles, numbering or other alpha/numeric hierarchies are included merely for ease of reading and absent explicit language to the contrary do not indicate order of performance, order of importance, magnitude or other value.

Premature Termination Codons (PTC) and ORFs Comprising PTCs

Mutations underlie many diseases. For example, a point mutation in the open reading frame (ORF) of a gene which creates a premature stop codon (PTC) can result in altered expression and/or activity of a polypeptide encoded by the gene. Table 1 provides single mutations in codons encoding amino acids which can result in a stop codon. In an embodiment, a PTC disclosed herein comprises a mutation disclosed in Table 1.

In an embodiment, the codon having the first sequence or the PTC comprises a mutation disclosed in Table 1. In an embodiment, the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is an original codon sequence provided in Table 1 and the amino acid corresponding to the non-mutated codon is an original AA provided in Table 1.

In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes a stop codon and mediates incorporation of the original AA provided in Table 1 at the position of the stop codon. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes a stop codon and mediates incorporation of an amino acid belonging to the same group as the original AA, e.g., as provided in Table 2. Other genetic abnormalities, such as insertions and/or deletions can also result in a PTC in an ORF.

TABLE 1

Select amino acids and stop codons

One mutation

Original
Original
to stop

AA
codon
codon

TRP
UGG
UGA

TYR
UAU
UAA

UAC
UAG

CYS
UGU
UGA

UGC
UGA

GLU
GAA
UAA

GAG
UAG

LYS
AAA
UAA

AAG
UAG

GLN
CAA
UAA

CAG
UAG

SER
UCA
UGA

UCG
UAG

LEU
UUA
UAA OR UGA

UUG
UAG

ARG
CGA
UGA

GLY
GGA
UGA

TABLE 2

Amino acids and amino acid groupings

Group
Amino acid

Nonpolar, aliphatic R group
leucine

methionine

isoleucine

glycine

alanine

valine

Polar, uncharged R group
serine

threonine

cysteine

proline

asparagine

glutamine

positively charged r group
lysine

arginine

histidine

Negatively charged R group
aspartate

glutamate

Nonpolar, aromatic R group
phenylalanine

tyrosine

tryptophan

Disclosed herein, inter alia, are endogenous ORFs comprising a codon having a first sequence, e.g., a mutation, e.g., a PTC. An ORF having a PTC, e.g., as described herein, can be present, or part of in any gene. As an example, the ORF can be present or be part of any gene in the human genome.

In an embodiment, a PTC disclosed herein is present in a gene disclosed in any one of Tables 4, 6 or 3. Exemplary genes having ORFs comprising a PTC are provided in Table 3.

TABLE 3

Exemplary genes with ORFs having a PTC

A2ML1
ARFGEF1
CACNA1G
CNOT1
DLG4

AARS1
ARFGEF2
CACNA1S
COG1
DLL1

AARS2
ARHGAP21
CACNA2D1
COL11A2
DNA2

ABCA13
ARHGEF9
CACNA2D2
COL13A1
DNM1L

ABCB11
ARMC4
CACNB2,
COL4A1
DNMT1

NSUN6

ABCG5
ARV1
CAD
COL4A2
DNMT3A

ABHD5
ARX
CAMTA1
COL4A4
DNMT3B

ACAD8
ASCC3
CARS2
COL9A1
DPH1

ACADL
ASH1L
CCDC140
COQ4
DPYD-AS1

ACSF3
ASPH
CCDC8
COQ6
DSEL

ACTA2
ASXL2
CCM2
COX14
DSPP

ACTC1,
ATAD3A
CD40LG
CPE
DUOXA1

ACTN2
ATP2A2
CDAN1
CPEB1-AS1
DUOXA2

ACVR1
ATP6V1B1
CDH15
CREBBP
DVL1

ADAR
ATP8A2
CDK11A
CRELD1
EARS2

ADAT3
AUH
CEBPA
CSNK2A1
EBF3

ADCY5
AUTS2
CELF5
CSNK2B
EBP

ADIPOQ
AVPR2
CELSR2
CSTA
EDAR

ADIPOQ-AS1
B3GLCT
CEP135
CTNND2
EFHC1

ADIPOR1
B4GAT1
CEP164
CTSA
EFNB1

AFF2
BCAP31
CEP83
CTSC
EFTUD2

ALG11
BCL11A
CETP
CUL3
EIF2B5

ALG14
BCL11B
CFI
CYLD
ELANE

ALG6
BCORL1
CHAMP1
CYP11A1
EMC1

ALOXE3
BEND2
CHAT
DAG1
EMC1-AS1

AMER1
BGN
CHD1
DARS2
ENO3

AMH
BMP4
CHD4
DCX
ENTPD5

AMMECR1
BRD4
CHD8
DDHD2
EP300

AMN
BRPF1
CHRM2
DDR2
EPM2A

ANK2
BRSK2
CHRNB1
DEAF1
ERLIN2

ANK3
BUB1B
CIC
DENND5A
EVC

ANKS6
BUB1B-PAK6
CLCN7
DGAT1
EZH2

ANOS1
C8G
CLTC
DHFR
FAM111A

AP1S1
CACNA1E
CNGA3
DIAPH3
FAM126A

AP3B2
CACNA1F
CNKSR2
DISP1
FAN1

FANCD2
GJB6
ISLR2
LOC110673972
MTR

FANCE
GJC2
ITGA3
LOC112997540
MYCBP2

FASTKD2
GK
ITGA8
LOC113788297
MYCNOS

FAT1
GLI2
ITGB6
LOC349160
MYH7B

FBN2
GNAI1
JMJD1C
LONP1
MYL3

FBP1
GNB1L
KANK1
LORICRIN
MYOM1

FDXR
GNE
KANSL1
LPIN1
MYPN

FGA
GNRH1
KBTBD13
LPIN2
MYT1L

FGD1
GNS
KCNA2
LRP2
NAA15

FGF10
GPAA1
KCNB1
LRRTM4
NAGA

FGFR1
GPD1L
KCND2
MAB21L2
NARS2

FGFR2
GRIN2A
KCNE3
MAF
NAXE

FIBP
GTPBP3
KCNMA1
MARS1
NCAPH2

FLAD1
HACE1
KCNQ5
MARS2
NCF2

FLG-AS1
HADH
KCTD7
MASP1
NDP

FLVCR1
HADHB
KIDINS220
MBOAT7
NDP-AS1

FLVCR2
HDAC4
KIF21B
MCM3AP
NDRG1

FMN2
HERC1
KIF6
MCM3AP-AS1
NDUFA2,

TMCO6

FOXA2
HESX1
KIT
MED13
NDUFAF1

FOXC1
HIBCH
KLHL40
MED17
NDUFAF5

FOXC2
HNF4A
KLHL41
MEGF10
NDUFAF6

FOXC2-AS1
HNRNPH2
KNL1
MET
NDUFAF7

FOXP2
HPRT1
KRAS
MGAT2
NDUFS1

FREM1
HRG
LAMB1
MIB1
NDUFS3

FRYL
HUWE1
LAMB2
MICU1
NEFH

FTL
IARS1
LAMC3
MIR302CHG
NEK8

FUS
IBA57
LARP7
MIR5004
NEXMIF

GABRG2
IDH2
LARS1
MIR6501
NFIA

GAN
IFNAR1
LCT
MITD1
NFKB1

GATA2
IFT122
LEMD3
MMP13
NHEJ1

GATA4
IFT80
LGI4
MMP21
NICN1

GATAD1
IGF2
LIAS
MNX1
NID1

GDF5
ILDR1
LINS1
MNX1-AS2
NKX2-1

GDF5-AS1
ILK, TAF10
LIPC
MPDU1
NLRP1

GFM1
INF2
LIPT1
MRPS22
NLRP3

GH-LCR
INS-IGF2
LOC101448202
MSL3
NOD2

GHRHR
INSR
LOC106804612,
MSRB3
NONO

HBA2

GHSR
IRAK1BP1
LOC107303338
MT-ND2
NOTCH3

GJA1
IRAK3
RARS2
SETD1B
SPTLC1

NPHP4
PLEKHG5
RAX
SETD2
SRD5A3

NPR2
PLEKHM2
RBM10
SETX
SRPX2

NR2F2
PLK4
RELN
SFTA3
SSBP2

NR5A1
PLPBP
RERE
SHANK2
ST3GAL3

NRL, PCK2
PNKD
RFT1
SHH
ST3GAL5

NRXN1
PNPLA1
RMND1
SIN3A
STAMBP

NT5DC1
POC1A
RNASEH1
SIX3
STAT3

NTRK2
POLG2, MILR1
RNF17
SKI
STIL

NUBPL
POMGNT2
ROR2
SLC13A5
STX11

NUS1
PPM1D
RP2
SLC16A1
STX1B

OCRL
PPP3CA
RPL11
SLC16A2
SUCLA2

OPTN
PRDM1
RPS19
SLC17A8
SYN1

P4HA1
PRDM12
RRM2B
SLC18A3
SYN2

PAK6
PREPL
RS1
SLC20A2
SYNJ1

PBX1
PRICKLE1
RUNX2
SLC25A4
TAB2

PCARE
PRKAG2
RXYLT1
SLC25A46
TACR3

PCDH12
PROS1
S100PBP
SLC2A1
TBCD

PDCD10
PRPF31
SALL4
SLC39A8
TBL1XR1

PDE11A-AS1
PRPF8
SAMD9
SLC52A2
TBX1

PDE4D
PRPS1
SAR1B
SLC6A3
TBX18

PDE6A
PRSS1, TRB
SASH3
SLC6A8
TCIRG1

PDHX
PSAT1
SBF2
SLC6A9
TELO2

PDLIM3
PSMD12
SBF2-AS1
SLC7A9
TFAP2A

PDP1
PSTPIP1
SCAMP4
SMAD2
TFG

PDSS1
PTCHD1
SCLT1
SMAD9
TGIF1

PEX5
PTF1A
SCN10A
SMARCA2
THAP1

PHF21A
PTPN23
SCN11A
SMC3
TINF2

PHF8
PTPRQ
SCN1B
SMOC2
TLK2

PHKA2
PTRH2
SCN3A
SNTA1
TMEM43

PHKB
PUS1
SCN4A
SNX14
TMIE

PIEZO1
PYCR2
SCN4B
SNX22
TMPO

PIGG
QARS1
SCN8A
SOCS1
TMPRSS15

PIGL
RAB3GAP1,
SCO2
SOX11
TMTC3

ZRANB3

PIGM
RAB3GAP2
SCYL1
SOX17
TNFAIP3

PIGP
RAC1
SEMA4A
SPATA5
TNFRSF11A

PIK3CA
RAF1
SEPTIN9
SPATA7
TOE1

PIN4, ERCC6L
RAG1
SET
SPRED1
TOR1AIP1

PLAT
RARB
SETD1A
SPTBN2
TPK1

TPM1
UTP14C
ZEB1

TRAPPC9
VPS53
ZFHX4

TRIM37
WDR19
ZFPM2

TRIM59-IFT80
WDR26
ZFPM2-AS1

TRIO
WDR62
ZIC1

TRIP12
WDR81
ZIC2

TRIP4
WNT1
ZMYND11

TRPM1
WNT10A
ZNF335

TSEN54
WRAP53
ZNF423

TUBA4A
WWOX
ZNF469

TUBGCP4
YARS1

TUBGCP6
YARS2

TWNK
YY1

TXNRD2
ZAP70

UBA2
ZBTB20

UBA5
ZBTB24

UMOD
ZC4H2

UNC5B
ZDHHC9

Diseases or Disorders Associated with a PTC

A TREM composition disclosed herein can be used treat a disorder or disease associated with a PTC, e.g., as described herein. Exemplary diseases or disorders associated with a PTC are listed in Tables 4, 5, and 6.

In an embodiment, the subject has a disease or disorder provided in any one of Tables 4-6. In an embodiment, the cell is associated with, e.g., is obtained from a subject who has, a disorder or disease listed in any one of Tables 4-6.

For example, the disorder or disease can be chosen from the left column of Table 4. As another example, the disorder or disease is chosen from the left column of Table 4 and, in embodiments the PTC is in a gene chosen from the right column of Table 4, e.g., any one of the genes provided in the right column of Table 4. In some embodiments, the PTC is in a gene corresponding to the disorder or disease provided in the left column of Table 4. As a further non-limiting example, the PTC can be at a position provided in Table 4.

As another example, the disorder or symptom is chosen from a disorder or disease provided in Table 5.

As yet another example, the disorder or symptom is chosen from a disorder or disease provided in Table 6. In an embodiment, the disorder or symptom is chosen from a disorder or disease provided in Table 6 and, in embodiments, the PTC is in any gene provided in Table 6. In an embodiment, the disorder or symptom is chosen from a disorder or disease provided in Table 6 and the PTC is in a corresponding gene provided in Table 6, e.g., a gene corresponding to the disease or disorder. In an embodiment, the disorder or symptom is chosen from a disorder or disease provided in Table 6 and the PTC is not in a gene provided in Table 6.

In an embodiment of any of the methods disclosed herein, the PTC is at any position within the ORF of the gene, e.g., upstream of the naturally occurring stop codon.

TABLE 4

Exemplary diseases or disorders

Disease/disorder or protein
Exemplary Point Mutation

G to A point mutations

Dihydropyrimidine dehydrogenase
NM 000110.3(DPYD): c.1905 + 1G > A

deficiency

Noonan syndrome
NM 005633.3(SOS1): c.2536G > A

(p.Glu846Lys)

Lynch syndrome
NM 000251.2(MSH2): c.212 − 1G > A

Breast-ovarian cancer, familial 1
NM 007294.3(BRCA1): c.963G > A

(p.Trp321Ter)

Cystic fibrosis
NM 000492.3(CFTR): c.57G > A (p.Trpl9Ter)

Anemia, due to G6PD deficiency
NM 000402.4(G6PD): c.292G > A

(p.Val98Met)

AVPR2
NM 000054.4(AVPR2): c.878G > A

Nephrogenic diabetes insipidus, X-linked
(p.Trp293Ter)

FANCC
NM 000054.4(AVPR2): c.878G > A

Fanconi anemia, complementation group C
(p.Trp293Ter)

FANCC
NM 000136.2(FANCC): c.1517G > A

Fanconi anemia, complementation group C
(p.Trp506Ter)

IL2RG
NM 000206.2(IL2RG): c.710G > A

X-linked severe combined
(p.Trp237Ter)

immunodeficiency

F8 Hereditary factor VIII deficiency
NM 000132.3(F8): c.3144G > A

disease
(p.Trpl048Ter)

LDLR
NM 000527.4(LDLR): c.1449G > A

Familial hypercholesterolemia
(p.Trp483Ter)

CBS
NM 000071.2(CBS): c.162G > A

Homocystinuria due to CBS deficiency
(p.Trp54Ter)

HBB
NM 000518.4(HBB): c. 114G > A

betaThalassemia
(p.Trp38Ter)

ALDOB
NM 000035.3(ALDOB): c.888G > A

Hereditary fmctosuria
(p.Trp296Ter)

DMD
NM 004006.2(DMD): c.3747G > A

Duchenne muscular dystrophy
(p.Trpl249Ter)

SMAD4
NM 005359.5(SMAD4): c.906G > A

Juvenile polyposis syndrome
(p.Trp302Ter)

BRCA2
NM 000059.3(BRCA2): c.582G > A

Familial cancer ofbreastlBreast-ovarian
(p.Trpl94Ter)

cancer, familial 2

GRIN2A
NM 000833.4(GRIN2A): c.3813G > A

Epilepsy, focal, with speech disorder and
(p.Trpl271Ter)

with or without mental retardation

SCN9A
NM 002977.3(SCN9A): c.2691G > A

Indifference to pain, congenital,
(p.Trp897Ter)

autosomal recessive

TARDBP
NM 007375.3(TARDBP): c.943G > A

Amyotrophic lateral sclerosis type 10
(p.Ala315Thr)

CFTR
NM 000492.3(CFTR): c.3846G > A

Cystic fibrosislHereditary
(p.Trpl282Ter)

pancreatitislnot providedlataluren

response - Efficacy

UBE3A
NM 130838. l(UBE3A): c.2304G > A

Angelman syndrome
(p.Trp768Ter)

SMPD1
NM 000543.4(SMPD1): c.168G > A

Niemann-Pick disease, type A
(p.Trp56Ter)

USH2A
NM 206933.2(USH2A): c.9390G > A

Usher syndrome, type 2A
(p.Trp3130Ter)

MENl
NM 130799.2(MEN1): c.1269G > A

Hereditary cancer-predisposing syndrome
(p.Trp423Ter)

C8orf37
NM 177965.3(C8orf37): c.555G > A

Retinitis pigmentosa 64
(p.Trpl85Ter)

MLHl
NM 000249.3(MLH1): c.1998G > A

Lynch syndrome
(p.Trp666Ter)

TSC2
NM 000548.4(TSC2): c.2108G > A

Tuberous sclerosis 21Tuberous
(p.Trp703Ter)

sclerosis syndrome 46

NFl
NM 000267.3(NF1): c.7044G > A

Neurofibromatosis, type 1
(p.Trp2348Ter)

MSH6
NM 000179.2(MSH6): c.3020G > A

Lynch syndrome
(p.Trpl007Ter)

SMNl
NM 000344.3(SMN1): c.305G > A

Spinal muscular atrophy, type III
(p.Trpl02Ter)

Kugelberg- Welander disease

SH3TC2
NM 024577.3(SH3TC2): c.920G > A

Charcot-Marie-Tooth disease, type 4C
(p.Trp307Ter)

DNAH5
NM 001369.2(DNAH5): c.8465G > A

Primary ciliary dyskinesia
(p.Trp2822Ter)

MECP2
NM 004992.3(MECP2): c.311G > A

Rett syndrome
(p.Trpl04Ter)

ADGRVl
NM 032119.3(ADGRV1): c.7406G > A

Usher syndrome, type 2C
(p.Trp2469Ter)

AHil
NM 017651.4(AHI1): c.2174G > A

Joubert syndrome 3
(p.Trp725Ter)

PRKN
NM 004562.2(PRKN): c.1358G > A

Parkinson disease 2
(p.Trp453Ter)

COL3Al
NM 000090.3(COL3Al): c.3833G > A

Ehlers-Danlos syndrome, type 4
(p.Trpl278Ter)

BRCAl
NM 007294.3(BRCA1): c.5511G > A

Familial cancer ofbreastlBreast-ovarian
(p.Trpl837Ter)

cancer, familial 1

MYBPC3
NM 000256.3(MYBPC3): c.3293G > A

Primary familial hypertrophic
(p.Trpl098Ter)

cardiomyopathy

APC
NM 000038.5(APC): c.1262G > A

Familial adenomatous polyposis 1
(p.Trp421Ter)

BMPR2
NM 001204.6(BMPR2): c.893G > A

Primary pulmonary hypertension
(p.W298*)

T to C point mutations

Wilson disease
NM_000053.3(ATP7B): c.3443T > C

(p.Ile l l 48Thr)

Leukodystrophy, hypomyelinating, 2
NM_020435.3(GJC2): c.857T > C

(p.Met286Thr)

Alport syndrome, X-linked recessive
NM_000495.4(COL4A5): c.438 + 2T > C

Leigh disease
NC 012920.l: m.9478T > C

Gaucher disease, type 1
NM_001005741.2(GBA): c.751T > C

(p.Tyr251His)

Renal dysplasia, retinal pigmentary
NM_0l4714.3(IFT140): c.4078T > C

dystrophy, cerebellar ataxia and skeletal
(p.Cysl360Arg)

dysplasia

Marfan syndrome
NM_000138.4(FBN1): c.3793T > C

(p.Cysl265Arg)

Deficiency of UDPglucose-hexose-1-
NM_000155.3(GALT): c.482T > C

phosphate uridylyltransferase
(p.Leul61Pro)

Familial hypercholesterolemia
NM_000527.4(LDLR): c.694 + 2T > C

Episodic pain syndrome, familial, 3
NM_001287223.1(SCN11A): c.1142T > C

(p.Ile381Thr)

Navajo neurohepatopathy
NM_002437.4(MPV17): c.186 + 2T > C

Congenital muscular dystrophy, LMNA-
NM_l 70707.3(LMNA): c.l139T > C

related
(p.Leu380Ser)

Hereditary factor VIII deficiency disease
NM_000132.3(F8): c.5372T > C (p.Metl

791Thr)

Insulin-dependent diabetes mellitus
NM_0l4009.3(FOXP3): c.970T > C

secretory diarrhea syndrome
(p.Phe324Leu)

Hereditary factor IX deficiency disease
NM_000133.3(F9): c.1328T > C (p.Ile443Thr)

Familial cancer of breast, Breast-ovarian
NM_000059.3(BRCA2): c.316 + 2T > C

cancer, familial 2, Hereditary cancer

predisposing syndrome

Cardiac arrhythmia
NM_000238.3(KCNH2): c.1945 + 6T > C

Tangier disease
NM_005502.3(ABCA1): c.4429T > C

(p.Cysl477Arg)

Dilated cardiomyopathy 1AA
NM_001103.3(ACTN2): c.683T > C

(p.Met228Thr)

Mental retardation 3, X-linked
NM_005334.2(HCFC1): c.−970T > C

Limb-girdle muscular dystrophy, type 2B
NM_003494.3(DYSF): c.1284 + 2T > C

Macular dystrophy, vitelliform, 5
NM_0l6247.3(IMPG2): c.370T > C

(p.Phel24Leu)

Retinitis pigmentosa
NM_000322.4(PRPH2): c.736T > C

(p.Trp246Arg)

TABLE 5

Additional exemplary disorders

5q-syndrome
Adams-Oliver syndrome 1

Adams-Oliver syndrome 3
Adams-Oliver syndrome 5

Adams-Oliver syndrome 6
Alagille syndrome 1

Autoimmune lymphoproliferative syndrome
Autoimmune lymphoproliferative syndrome

type IA
type V

Autosomal dominant deafness-2A
Brain malformations with or without urinary

tract defects (BRMUTD)

Carney complex type 1
CHARGE syndrome

Cleidocranial dysplasia
Currarino syndrome

Denys-Drash syndrome/Frasier syndrome
Developmental delay

intellectual disability
obesity

and dysmorphic features (DIDOD)
DiGeorge syndrome (TBXl-associated)

Dravet syndrome
Duane-radial ray syndrome

Ehlers-Danlos syndrome (classic-like)
Ehlers-Danlos syndrome (vascular type)

Feingold syndrome 1
Frontotemporal lobar degeneration with

TDP43 inclusions (FTFD-TDP)

GRN-related
GFUT1 deficiency syndrome

Greig cephalopolysyndactyly syndrome
Hereditary hemorrhagic telangiectasia type 1

Holoprosencephaly 3
Holoprosencephaly 4

Holoprosencephaly 5
Holt-Oram syndrome

Hypoparathyroidism
sensorineural deafness

and renal disease (HDR)
Kleefstra syndrome 1

Klippel-Trenaunay syndrome (AAGF-related)
Feri-Weill dyschondrosteosis

Marfan syndrome
Mental retardation and distinctive facial

features with or without cardiac defects

(MRFACD)

Mental retardation
autosomal dominant 1

Mental retardation
autosomal dominant 19

Mental retardation
autosomal dominant 29

Nail-patella syndrome (NPS)
Phelan-McDermid syndrome

Pitt-Hopkins syndrome
Primary pulmonary hypertension 1

Rett syndrome (congenital variant)
Smith-Magenis syndrome (RAI1-associated)

Sotos syndrome 1
Sotos syndrome 2

Stickler syndrome type I
Supravalvular aortic stenosis

SYNGAP1 -related intellectual disability
Treacher Collins syndrome

Trichorhinophalangeal syndrome type I
Ulnar-mammary syndrome

van der Woude syndrome 1
Waardenburg syndrome type 1

Waardenburg syndrome type 2A
Waardenburg syndrome type 4C.

TABLE 6

Exemplary genes with ORFs comprising a PTC and exemplary disorders

Gene
Disease/Disorder

AAAS
Glucocorticoid deficiency with achalasia

AAGAB
Keratosis palmoplantaris papulosa

AASS
Hyperlysinemia

ABCA1
Tangier disease

ABCA12,
Autosomal recessive congenital ichthyosis 4B

SNHG31

ABCA3
3, Surfactant metabolism dysfunction, pulmonary

ABCA4
Bietti crystalline corneoretinal dystrophy, Cone-rod degeneration, Cone-rod

dystrophy 3, Macular dystrophy, Retinal dystrophy, Retinitis pigmentosa, Retinitis

pigmentosa 19, Stargardt disease, Stargardt disease 1

ABCB4
Cholestasis, Progressive familial intrahepatic cholestasis 3, intrahepatic, of

pregnancy 3

ABCC2
Dubin-Johnson syndrome

ABCC6
Cutis laxa, Generalized arterial calcification of infancy 2, Papule, Pseudoxanthoma

elasticum, forme firuste

ABCC8
1, Familial hyperinsulinism, Hyperinsulinemic hypoglycemia, familial

ABCC9
Arrhythmogenic right ventricular cardiomyopathy, Cardiomyopathy,

Cardiovascular phenotype, Dilated cardiomyopathy 1O, Primary dilated

cardiomyopathy

ABCD1
Adrenoleukodystrophy, Spastic gait, Spastic paraplegia

ABHD12
Polyneuropathy, and cataract, ataxia, hearing loss, retinitis pigmentosa

ABRAXAS1
Hereditary breast and ovarian cancer syndrome

ACAD9
Acyl-CoA dehydrogenase family, deficiency of, member 9

ACADM
Medium-chain acyl-coenzyme A dehydrogenase deficiency

ACADS
Deficiency of butyryl-CoA dehydrogenase

ACADVL
Very long chain acyl-CoA dehydrogenase deficiency

ACAN
Osteochondritis dissecans, Spondyloepiphyseal dysplasia, kimberley type

ACAT1
Deficiency of acetyl-CoA acetyltransferase

ACBD5
RETINAL DYSTROPHY WITH LEUKODYSTROPHY

ACBD6, LHX4,
Short stature-pituitary and cerebellar defects-small sella turcica syndrome

LHX4-AS1

ACE
Renal dysplasia

ACOX1
Peroxisomal acyl-CoA oxidase deficiency

ACP5
Spondyloenchondrodysplasia with immune dysregulation

ACP5, ZNF627
Spondyloenchondrodysplasia with immune dysregulation

ACTA1
Congenital myopathy with excess of thin filaments

ACTB
Baraitser-Winter syndrome

ACVRL1
Hereditary hemorrhagic telangiectasia type 1, Primary pulmonary hypertension,

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia,

Telangiectasia, hereditary hemorrhagic, type 2

ACY1
Neurological conditions associated with aminoacylase 1 deficiency

ADA
Severe combined immunodeficiency disease, Severe combined immunodeficiency

due to ADA deficiency

ADAM10
Reticulate acropigmentation of Kitamura

ADAMTS17
Weill-Marchesani syndrome 4

ADAMTS2
Ehlers-Danlos syndrome dermatosparaxis type

ADAMTSL4
Ectopia lentis et pupillae

ADAMTSL4
Ectopia lentis, Ectopia lentis 2, Ectopia lentis et pupillae, autosomal recessive,

isolated

ADCY3
BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 19

ADCY3, CENPO
BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 19

ADGRG1
Polymicrogyria, bilateral frontoparietal

ADGRG2
Congenital bilateral aplasia of vas deferens from CFTR mutation, Vas deferens, X-

linked, congenital bilateral aplasia of

ADGRG6
Arthrogryposis multiplex congenita, Lethal congenital contracture syndrome 9

ADGRV1
4, Febrile seizures, Rare genetic deafness, Retinal dystrophy, Usher syndrome,

familial, type 2C

ADNP
Helsmoortel-Van der Aa Syndrome, History of neurodevelopmental disorder,

Inborn genetic diseases

AEBP1
2, CLASSIC-LIKE, EHLERS-DANLOS SYNDROME

AGA
Aspartylglucosaminuria

AGK
Sengers syndrome

AGK, DENND11
Cataract, Sengers syndrome, autosomal recessive congenital 5

AGL
Glycogen storage disease, Glycogen storage disease IIIa, Glycogen storage disease

IIIb, Glycogen storage disease type III

AGPAT2
Congenital generalized lipodystrophy type 1

AGRN
Congenital myasthenic syndrome

AGT
Renal dysplasia

AGTR1
Renal dysplasia

AGXT
Primary hyperoxaluria, type I

AHDC1
Delayed speech and language development, Global developmental delay,

Intellectual disability, Muscular hypotonia, Neonatal hypotonia, Sleep apnea, Xia-

Gibbs syndrome

AHI1
Joubert syndrome, Joubert syndrome 3, Retinal dystrophy, Retinitis pigmentosa

AHR
Retinitis pigmentosa 85

AIRE
Autoimmune polyglandular syndrome type 1, Polyglandular autoimmune

syndrome, type 1, with reversible metaphyseal dysplasia

ALB
Analbuminemia

ALDH18A1
Cutis laxa-corneal clouding-oligophrenia syndrome

ALDH3A2
SjÃ¶gren-Larsson syndrome

ALDH5A1
Succinate-semialdehyde dehydrogenase deficiency

ALDH7A1
Pyridoxine-dependent epilepsy, Seizures

ALDOB
Hereditary fructosuria

ALG1
ALG1-CDG, Congenital disorder of glycosylation

ALG3
ALG3-CDG

ALMS1
Alstrom syndrome

ALOX12B
Autosomal recessive congenital ichthyosis 2

ALPK3
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC 27, Hypertrophic

cardiomyopathy

ALPL
Hypophosphatasia, Infantile hypophosphatasia

ALS2
Amyotrophic lateral sclerosis type 2, Infantile-onset ascending hereditary spastic

paralysis, Juvenile primary lateral sclerosis

ALX4
Parietal foramina 2

AMPD2
Pontocerebellar hypoplasia, type 9

AMT
Non-ketotic hyperglycinemia

ANAPC1
Rothmund-Thomson syndrome type 1

ANGPTL3,
2, Hypobetalipoproteinemia, familial

DOCK7

ANKRD1
ANKRD1-related dilated cardiomyopathy, Cardiovascular phenotype, Primary

dilated cardiomyopathy

ANKRD11
Abnormal facial shape, Clinodactyly of the 5th finger, Conductive hearing

impairment, Delayed speech and language development, Global developmental

delay, Inborn genetic diseases, Intellectual disability, KBG syndrome, Ptosis,

Seizures, Short foot, Short palm, Unilateral cryptorchidism

ANO10
Autosomal recessive cerebellar ataxia, Spinocerebellar ataxia, autosomal recessive

10

ANO5
ANO5-Related Disorders, Achilles tendon contracture, Elevated serum creatine

phosphokinase, Gnathodiaphyseal dysplasia, Limb-girdle muscular dystrophy,

Lower limb amyotrophy, Lower limb muscle weakness, Miyoshi muscular

dystrophy 3, Muscular Diseases, Polycystic kidney dysplasia, type 2L

ANTXR1
Odontotrichomelic syndrome

AP1B1
Autosomal recessive keratitis-ichthyosis-deafhess syndrome

AP3B1
Hermansky-Pudlak syndrome 2

AP4B1, AP4B1-
Inborn genetic diseases, Spastic paraplegia 47, autosomal recessive

AS1

AP4M1
Spastic paraplegia 50, autosomal recessive

AP5Z1
Spastic paraplegia 48, autosomal recessive

APC
Adenomatous colonic polyposis, Adenomatous polyposis coli with congenital

cholesteatoma, Brain tumor-polyposis syndrome 2, Carcinoma of colon, Colon

adenocarcinoma, Colorectal cancer, Craniopharyngioma, Desmoid disease,

Desmoid tumors, Duodenal polyposis, Familial adenomatous polyposis, Familial

adenomatous polyposis 1, Familial multiple polyposis syndrome, Gardner

syndrome, Gastric polyposis, Hepatocellular carcinoma, Hereditary cancer-

predisposing syndrome, Hyperplastic colonic polyposis, Intestinal polyp,

Malignant Colorectal Neoplasm, Neoplasm of stomach, Neoplasm of the large

intestine, Periampullary adenoma, hereditary, susceptibility to

APOA1, APOA1-
Familial hypoalphalipoproteinemia

AS

APOB
1, Familial hypobetalipoproteinemia, Hypobetalipoproteinemia, familial,

normotriglyceridemic

APOC2
APOLIPOPROTEIN C-II (NIJMEGEN), Apolipoprotein C2 deficiency

APOC2, APOC4-
APOLIPOPROTEIN C-II (PADOVA), Apolipoprotein C2 deficiency

APOC2

APTX
Ataxia-oculomotor apraxia type 1

AR
Androgen resistance syndrome, Bulbo-spinal atrophy X-linked, Partial androgen

insensitivity syndrome

ARCN1
Short stature, and developmental delay, micrognathia, rhizomelic, with

microcephaly

ARG1, MED23
Arginase deficiency

ARHGEF18
Retinitis pigmentosa 78

ARID1A
Mental retardation, autosomal dominant 14

ARID1B
Absent speech, Blepharophimosis, Coffin-Siris syndrome 1, Constipation,

Decreased body weight, Failure to thrive, Inborn genetic diseases, Intellectual

disability, Long eyelashes, Microcephaly, Recurrent respiratory infections,

Seizures, Short stature, Thick lower lip vermilion, Thin upper lip vermilion,

moderate

ARID2
COFFIN-SIRIS SYNDROME 6

ARL2BP
Retinitis pigmentosa 82 with or without situs inversus

ARMC2
Male infertility with teratozoospermia due to single gene mutation,

SPERMATOGENIC FAILURE 38, Sperm tail anomaly

ARMC2,
Male infertility with teratozoospermia due to single gene mutation,

ARMC2-AS1
SPERMATOGENIC FAILURE 38

ARMC5
Acth-independent macronodular adrenal hyperplasia 2

ARSA
Metachromatic leukodystrophy, Pseudoarylsulfatase A deficiency, late infantile

ARSB
Metachromatic leukodystrophy, Mucopolysaccharidosis type 6

ART4
Blood group, Dombrock system

ASAH1
Farber disease, Spinal muscular atrophy-progressive myoclonic epilepsy syndrome

ASL
Argininosuccinate lyase deficiency

ASPA, SPATA22
Canavan Disease, Familial Form, Spongy degeneration of central nervous system

ASPM
Microcephaly, Primary autosomal recessive microcephaly, Primary autosomal

recessive microcephaly 1, Primary autosomal recessive microcephaly 5

ASS1
Citrullinemia type I

ASXL1
Bohring-Opitz syndrome, Inborn genetic diseases

ASXL3
Bainbridge-Ropers syndrome

ATF6
Achromatopsia, Achromatopsia 7

ATL1
Hereditary spastic paraplegia 3A

ATM
Ataxia-telangiectasia syndrome, Familial cancer of breast, Hereditary breast and

ovarian cancer syndrome, Hereditary cancer-predisposing syndrome, Ovarian

Neoplasms

ATM, C11orf65,
Ataxia-telangiectasia syndrome, Ataxia-telangiectasia without immunodeficiency,

ATP13A2
Breast cancer, Familial cancer of breast, Hereditary breast and ovarian cancer

syndrome, Hereditary cancer-predisposing syndrome, Neoplasm of the breast,

susceptibility to Kufor-Rakeb syndrome

ATP1A2
Abnormality of neuronal migration, Arthrogryposis multiplex congenita, Epilepsy,

Hydrops fetalis

ATP2A1
Brody myopathy

ATP2C1
Familial benign pemphigus

ATP6V0A2
ALG9 congenital disorder of glycosylation, Cutis laxa with osteodystrophy

ATP6V0A4
Renal tubular acidosis, autosomal recessive, distal

ATP7A
Cutis laxa, Menkes kinky-hair syndrome, X-linked

ATP7B
Inborn genetic diseases, Wilson disease

ATRX
1, Alpha thalassemia-X-linked intellectual disability syndrome, Intellectual

disability, Mental retardation-hypotonic facies syndrome, Mental retardation-

hypotonic facies syndrome X-linked, X-linked

AXIN2
Oligodontia-colorectal cancer syndrome

B3GALNT1
p phenotype

B3GALNT2
11, Muscular dystrophy-dystroglycanopathy (congenital with brain and eye

anomalies), type a

B3GALT6
Spondylo-epi-(meta)-physeal dysplasia

B4GALNT1
Hereditary spastic paraplegia 26, Inborn genetic diseases

B4GALT7
Ehlers-Danlos syndrome progeroid type

B9D1
Joubert syndrome, Meckel syndrome, Meckel-Gruber syndrome, type 9

B9D2
Joubert syndrome

BAG3
BAG3-related, Cardiovascular phenotype, Dilated cardiomyopathy 1HH, Inborn

genetic diseases, Myofibrillar myopathy, Primary dilated cardiomyopathy

BAP1
Hereditary cancer-predisposing syndrome, Tumor susceptibility linked to germline

BAP1 mutations

BARD1
Breast cancer, Familial cancer of breast, Hereditary breast and ovarian cancer

syndrome, Hereditary cancer-predisposing syndrome, Triple-Negative Breast

Cancer Finding, susceptibility to

BBS1
Bardet-Biedl syndrome

BBS1, ZDHHC24
Bardet-Biedl syndrome, Bardet-Biedl syndrome 1

BBS10
Bardet-Biedl syndrome, Bardet-Biedl syndrome 1, Bardet-Biedl syndrome 10,

Bardet-biedl syndrome 6/10, Inborn genetic diseases, Retinal dystrophy, Retinitis

pigmentosa, digenic

BBS2
Bardet-Biedl syndrome, Bardet-Biedl syndrome 2, Bardet-biedl syndrome ½,

Bardet-biedl syndrome 2/6, Retinal dystrophy, Retinitis pigmentosa, Retinitis

pigmentosa 74, digenic

BBS5
Bardet-Biedl syndrome 5

BBS9
Bardet-Biedl syndrome

BCKDHA
Maple syrup urine disease, Maple syrup urine disease type 1A

BCKDHB
CLASSIC, MAPLE SYRUP URINE DISEASE, Maple syrup urine disease, Maple

syrup urine disease type 1B, TYPE IB

BCOR
Oculofaciocardiodental syndrome

BCS1L
BCS1L-Related Disorders, GRACILE syndrome, Leigh syndrome, Mitochondrial

complex III deficiency, Pili torti-deafness syndrome, nuclear type 1

BEST1
Bestrophinopathy, Retinal dystrophy, Vitelliform macular dystrophy type 2,

autosomal recessive

BET1
Progressive muscle weakness, Seizures

BFSP1
Cataract 33, multiple types

BLM
Bloom syndrome, Hereditary breast and ovarian cancer syndrome, Hereditary

cancer-predisposing syndrome

BMP1
Osteogenesis imperfecta, type xiii

BMP2
AND SKELETAL ANOMALIES WITH OR WITHOUT CARDIAC

ANOMALIES, FACIAL DYSMORPHISM, SHORT STATURE

BMPR1A
Hereditary cancer-predisposing syndrome, Juvenile polyposis syndrome

BMPR2
Primary pulmonary hypertension

BNC1
PREMATURE OVARIAN FAILURE 16

BOLA3
Multiple mitochondrial dysfunctions syndrome 2

BPNT2
Chondrodysplasia with joint dislocations, GPAPP type

BPTF
NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND

DISTAL LIMB ANOMALIES

BRAT1
Inborn genetic diseases, NEURODEVELOPMENTAL DISORDER WITH

CEREBELLAR ATROPHY AND WITH OR WITHOUT SEIZURES, Rigidity

and multifocal seizure syndrome, lethal neonatal

BRCA1
Breast and/or ovarian cancer, Breast carcinoma, Breast-ovarian cancer,

COMPLEMENTATION GROUP S, Dysgerminoma, FANCONI ANEMIA,

Familial cancer of breast, Hereditary breast and ovarian cancer syndrome,

Hereditary cancer-predisposing syndrome, Infiltrating duct carcinoma of breast,

Neoplasm of ovary, Neoplasm of the breast, Ovarian Neoplasms, Ovarian Serous

Surface Papillary Adenocarcinoma, Ovarian cancer, Pancreatic cancer, Pancreatic

cancer 4, Porokeratosis punctata palmaris et plantaris, Rhabdomyosarcoma

(disease), bilateral breast cancer, breast cancer, familial 1, susceptibility to

BRCA2
Asthma, BRCA2-Related Disorders, Breast and/or ovarian cancer, Breast

carcinoma, Breast-ovarian cancer, Cancer of the pancreas, Colorectal cancer,

Diffuse intrinsic pontine glioma, Ectopic ossification, Familial cancer of breast,

Fanconi anemia, Focal seizures, Genetic non-acquired premature ovarian failure,

Glioma susceptibility 3, Headache, Hereditary Cancer Syndrome, Hereditary

breast and ovarian cancer syndrome, Hereditary cancer-predisposing syndrome,

Inborn genetic diseases, Malignant tumor of prostate, Medulloblastoma, Migraine,

Muscle weakness, Neoplasm of the breast, Nephrolithiasis, Obesity, Ovarian

Neoplasms, Ovarian cancer, Pancreatic cancer 2, Polydactyly, Short attention span,

Striae distensae, Tracheoesophageal fistula, Tumor susceptibility linked to

germline BAP1 mutations, Wilms tumor 1, complementation group D1, familial 1,

familial 2

BRIP1
BRIP1-Related Disorders, Breast cancer, Carcinoma of colon, Familial cancer of

breast, Fanconi anemia, Hereditary breast and ovarian cancer syndrome,

Hereditary cancer-predisposing syndrome, Neoplasm of ovary, Neoplasm of the

breast, Ovarian Cancers, Ovarian Neoplasms, Tracheoesophageal fistula,

complementation group J, early-onset

BRWD3
Mental retardation, X-linked 93

BSND
Bartter disease type 4a

BTD
Biotinidase deficiency

BTK
Agammaglobulinemia, X-linked agammaglobulinemia, X-linked

agammaglobulinemia with growth hormone deficiency, non-Bruton type

C11orf65, ATM
Ataxia-telangiectasia syndrome, Hereditary breast and ovarian cancer syndrome,

Hereditary cancer-predisposing syndrome

C12orf4
AUTOSOMAL RECESSIVE 66, Attention deficit hyperactivity disorder,

Intellectual disability, MENTAL RETARDATION, Muscular hypotonia

C12orf65
Combined oxidative phosphorylation deficiency 7, Spastic paraplegia

C19orf12
Neurodegeneration with brain iron accumulation 4, Spastic paraplegia 43,

autosomal recessive

C1QB
C1q deficiency

C1S
Complement component c1s deficiency

C2
Complement component 2 deficiency

C2CD3
Orofaciodigital syndrome xiv

C5
Leiner disease

C6
Complement component 6 deficiency, Immunodeficiency due to a late component

of complement deficiency

C7
Complement component 7 deficiency

C8B
Complement component 6 deficiency, Type II complement component 8

deficiency

C8orf37
Cone-rod dystrophy 16

C8orf37
Retinitis pigmentosa 64

CA2
Osteopetrosis with renal tubular acidosis

CABP4
Congenital stationary night blindness, type 2B

CACNA1A
42, Bulbar palsy, Epileptic encephalopathy, Episodic ataxia, Episodic ataxia type

2, Recurrent respiratory infections, and epilepsy, early infantile, type 2

CACNA1C
Long QT syndrome

CACNA2D4
Abnormality of the eye, Retinal cone dystrophy 4

CAPN1
Spastic paraplegia 76, autosomal recessive

CAPN3
Absent Achilles reflex, Absent muscle fiber calpain-3, Arrhythmia, Calf muscle

hypertrophy, Congenital muscular dystrophy, Contractures of the joints of the

lower limbs, Difficulty walking, EMG: myopathic abnormalities, EMG:

neuropathic changes, Elbow flexion contracture, Elevated serum creatine

phosphokinase, Limb-Girdle Muscular Dystrophy, Limb-girdle muscle weakness,

Limb-girdle muscular dystrophy, Migraine, Muscle weakness, Muscular Diseases,

Muscular dystrophy, Myositis, Paresthesia, Positive Romberg sign, Progressive

spinal muscular atrophy, Recessive, Shoulder girdle muscle weakness,

eosinophilic, type 2A

CASK
Mental retardation and microcephaly with pontine and cerebellar hypoplasia

CASP14
Ichthyosis, autosomal recessive 12, congenital

CASQ2
2, Ventricular tachycardia, catecholaminergic polymorphic

CASR
Hypocalciuric hypercalcemia, Inborn genetic diseases, familial, type 1

CAST
Peeling skin with leukonychia, acral punctate keratoses, and knuckle pads, cheilitis

CAST, ERAP1
Peeling skin with leukonychia, acral punctate keratoses, and knuckle pads, cheilitis

CAT
Acatalasemia, Acatalasia, Japanese type

CATSPER1
Spermatogenic failure 7

CAV1
Lipoqdystrophy, congenital generalized, type 3

CAV3, SSUH2
Long QT syndrome

CBL
Noonan syndrome-like disorder with or without juvenile myelomonocytic

leukemia

CBS
CYSTATHIONINE BETA-SYNTHETASE POLYMORPHISM, Classic

homocystinuria, Homocystinuria

CC2D1A
Mental Retardation, Mental retardation, Psychosocial, autosomal recessive 3

CC2D2A
Joubert syndrome, Joubert syndrome 9, Meckel syndrome type 6, Meckel-Gruber

syndrome

CCBE1
Hennekam lymphangiectasia-lymphedema syndrome 1

CCDC103
Primary ciliary dyskinesia

CCDC28B
Bardet-Biedl syndrome, Bardet-Biedl syndrome 1, modifier of

CCDC39
14, Ciliary dyskinesia, Primary ciliary dyskinesia, primary

CCDC40
15, Ciliary dyskinesia, Primary ciliary dyskinesia, primary

CCDC47
Global developmental delay with dysmorphic features,

Trichohepatoneurodevelopmental syndrome, and woolly hair, liver dysfunction,

pruritus

CCDC65
27, Ciliary dyskinesia, Kartagener syndrome, Primary ciliary dyskinesia, primary

CCDC78
4, Myopathy, centronuclear

CCDC88C
Congenital hydrocephalus 1

CCN6
Progressive pseudorheumatoid dysplasia

CCNH, RASA1
Capillary malformation-arteriovenous malformation

CCNO
29, Ciliary dyskinesia, Kartagener syndrome, Primary ciliary dyskinesia, primary

CCNQ
Syndactyly-telecanthus-anogenital and renal malformations syndrome

CD19
Common variable immunodeficiency 3

CD247
Immunodeficiency due to defect in cd3-zeta

CD36
Malaria, Platelet glycoprotein IV deficiency, cerebral, susceptibility to

CD46
Atypical hemolytic-uremic syndrome 2

CD55
CROMER BLOOD GROUP SYSTEM, Dr(a-) PHENOTYPE, Protein-losing

enteropathy (disease)

CDC14A
Deafness, Rare genetic deafness, autosomal recessive 32

CDC73
Parathyroid adenoma, Parathyroid carcinoma

CDH1
Blepharocheilodontic syndrome 1, Breast cancer, Endometrial carcinoma, Familial

cancer of breast, Hereditary cancer-predisposing syndrome, Hereditary diffuse

gastric cancer, Malignant tumor of prostate, Neoplasm of ovary, lobular

CDH11
Brachioskeletogenital syndrome

CDH23
Deafness, Inborn genetic diseases, MULTIPLE TYPES, PITUITARY

ADENOMA 5, Rare genetic deafness, Usher syndrome type 1D, autosomal

recessive 12

CDH23,
Rare genetic deafness

C10orf105

CDH23, CDH23-
DIGENIC, TYPE ID/F, USHER SYNDROME, Usher syndrome type 1, Usher

AS1
syndrome type 1D

CDH3
Congenital hypotrichosis with juvenile macular dystrophy, EEM syndrome,

Hypotrichosis with juvenile macular dystrophy, Macular dystrophy

CDHR1
Cone-rod dystrophy 15, Leber congenital amaurosis, Retinal dystrophy, Retinitis

pigmentosa 65

CDK10
AL KAISSI SYNDROME

CDK13
Congenital heart defects, and intellectual developmental disorder, dysmorphic

facial features

CDK5RAP2
Primary autosomal recessive microcephaly 3

CDKL5
Angelman syndrome-like, Atypical Rett syndrome, Early infantile epileptic

encephalopathy 2, Epileptic encephalopathy, Inborn genetic diseases

CDKN2A
Hereditary cancer-predisposing syndrome, Hereditary cutaneous melanoma,

Melanoma-pancreatic cancer syndrome, Neoplasm

CDSN,
Peeling skin syndrome 1

PSORS1C1

CEL
Maturity-onset diabetes of the young type 8

CELA2A
Coronary artery disease, Diabetes, Familial partial lipodystrophy 6, Hypertensive

disorder, Hypertriglyceridemia

CENPF
Stromme syndrome

CENPJ
Congenital microcephaly, Intellectual disability, Perisylvian polymicrogyria,

Primary autosomal recessive microcephaly, Primary autosomal recessive

microcephaly 1, Primary autosomal recessive microcephaly 6, Seckel syndrome 4,

Type III lissencephaly, moderate

CEP120
JOUBERT SYNDROME 31

CEP152
Seckel syndrome

CEP290
Abnormality of the kidney, Bardet-Biedl syndrome 14, Blindness, CEP290-

Related Disorders, Cerebellar cyst, Cerebellar vermis hypoplasia, Global

developmental delay, Hyperechogenic kidneys, Joubert syndrome, Joubert

syndrome 5, Leber congenital amaurosis 10, Meckel syndrome, Meckel-Gruber

syndrome, Nephronophthisis, Polycystic kidney dysplasia, Retinal dystrophy,

Senior-Loken syndrome 6, type 4

CEP290,
Bardet-Biedl syndrome 14, Joubert syndrome, Joubert syndrome 5, Meckel-Gruber

C12orf29
syndrome, Nephronophthisis

CEP41
Joubert syndrome 15

CEP78
Cone-rod degeneration, Cone-rod dystrophy and hearing loss 1, Sensorineural

hearing loss

CFAP251
Male infertility with teratozoospermia due to single gene mutation, Non-syndromic

male infertility due to sperm motility disorder, SPERMATOGENIC FAILURE 18,

SPERMATOGENIC FAILURE 33, asthenozoospermia, dysplasia of the

mitochondrial sheath, multiple morphologic abnormalities of the sperm flagellum

CFAP410
Axial spondylometaphyseal dysplasia, RETINAL DYSTROPHY WITH OR

WITHOUT MACULAR STAPHYLOMA

CFAP43
SPERMATOGENIC FAILURE 19

CFAP44
SPERMATOGENIC FAILURE 20

CFHR5
CFHR5 deficiency

CFTR
Bronchiectasis with or without elevated sweat chloride 1, CFTR-related disorders,

Congenital bilateral aplasia of vas deferens from CFTR mutation, Cystic fibrosis,

Hereditary pancreatitis, Inborn genetic diseases, ataluren response - Efficacy

CFTR, CFTR-
CFTR-related disorders, Congenital bilateral aplasia of vas deferens from CFTR

AS1
mutation, Cystic fibrosis

CFTR,
Bronchiectasis with or without elevated sweat chloride 1, CFTR-related disorders,

LOC111674472
Congenital bilateral aplasia of vas deferens from CFTR mutation, Cystic fibrosis,

Hereditary pancreatitis

CFTR,
Bronchiectasis with or without elevated sweat chloride 1, CFTR-related disorders,

LOC111674475
Congenital bilateral aplasia of vas deferens from CFTR mutation, Cystic fibrosis,

Hereditary pancreatitis, Inborn genetic diseases, ataluren response - Efficacy

CFTR,
Cystic fibrosis

LOC111674477

CFTR,
Bronchiectasis with or without elevated sweat chloride 1, CFTR-related disorders,

LOC113633877
Congenital bilateral aplasia of vas deferens from CFTR mutation, Cystic fibrosis,

Hereditary pancreatitis

CFTR,
Bronchiectasis with or without elevated sweat chloride 1, Congenital bilateral

LOC113664106
aplasia of vas deferens from CFTR mutation, Cystic fibrosis, Hereditary

pancreatitis

CHD2
CHD2-Related Disorder, Epileptic encephalopathy, History of neurodevelopmental

disorder, childhood-onset

CHD7
CHARGE association, Hypogonadism with anosmia, Hypogonadotropic

hypogonadism 5 with or without anosmia

CHEK2
3, Astrocytoma, B Lymphoblastic Leukemia/Lymphoma, Breast and colorectal

cancer, Breast cancer, CHEK2-Related Cancer Susceptibility, Colitis, Congenital

heart defects, Diffuse intrinsic pontine glioma, Familial cancer of breast,

Hematochezia, Hereditary breast and ovarian cancer syndrome, Hereditary cancer,

Hereditary cancer-predisposing syndrome, Inflammation of the large intestine,

Leiomyosarcoma, Li-Fraumeni syndrome, Li-Fraumeni syndrome 2, Malignant

tumor of prostate, Neoplasm of the breast, Not Otherwise Specified,

Osteosarcoma, Ovarian Neoplasms, Prostate cancer, Thrombocytopenia, multiple

types, somatic, susceptibility to

CHM
Retinal dystrophy

CHRDL1
Megalocornea

CHRNA1
Congenital myasthenic syndrome

CHRNA2
Autosomal dominant nocturnal frontal lobe epilepsy

CHRNA3
CHRNA3-related condition

CHRND
Lethal multiple pterygium syndrome

CHRNE
4a, Congenital myasthenic syndrome, Congenital myasthenic syndrome 4C,

Myasthenic syndrome, congenital, slow-channel

CHRNE,
4a, 4b, Congenital myasthenic syndrome, Congenital myasthenic syndrome 4C,

C17orf107
Myasthenic syndrome, congenital, fast-channel, slow-channel

CHRNG
Autosomal recessive multiple pterygium syndrome, CHRNG-Related Disorders,

Inborn genetic diseases, Lethal multiple pterygium syndrome

CHST14
Ehlers-Danlos syndrome, musculocontractural type

CHST3
Spondyloepiphyseal dysplasia with congenital joint dislocations

CHSY1
Temtamy preaxial brachydactyly syndrome

CIB1
3, EPIDERMODYSPLASIA VERRUCIFORMIS, SUSCEPTIBILITY TO

CIITA
Bare lymphocyte syndrome 2

CKAP2L
Filippi syndrome

CLCN1
Autosomal dominant intermediate Charcot-Marie-Tooth disease, Congenital

myotonia, EMG: myopathic abnormalities, Muscular Diseases, Myotonia

congenita, autosomal dominant form, autosomal recessive form

CLCN2
Epilepsy, Leukoencephalopathy with ataxia, juvenile myoclonic 8

CLCN5
Nephrolithiasis, X-linked recessive, X-linked recessive nephrolithiasis with renal

failure

CLDN1, CLDN16
Neonatal ichthyosis-sclerosing cholangitis syndrome

CLIC5
Deafness, autosomal recessive

CLN3
Juvenile neuronal ceroid lipofuscinosis, Neuronal ceroid lipofuscinosis

CLN5, FBXL3
Neuronal ceroid lipofuscinosis, Neuronal ceroid lipofuscinosis 5

CLRN1
Rare genetic deafness, Retinal dystrophy, Retinitis pigmentosa, Usher syndrome,

type 3A

CNGA1,
Retinal dystrophy, Retinitis pigmentosa 49

LOC101927157

CNGB1
Retinal dystrophy, Retinitis pigmentosa, Retinitis pigmentosa 45

CNGB3
Abnormality of the eye, Achromatopsia, Achromatopsia 3, CNGB3-Related

Disorders, Cone-rod dystrophy, Leber congenital amaurosis, Recessive, Retinal

dystrophy, Retinitis pigmentosa, Stargardt Disease

CNNM2
Hypomagnesemia 6, renal

CNNM4
Jalili syndrome

CNTNAP1
Lethal congenital contracture syndrome 7

CNTNAP2
Pitt-Hopkins-like syndrome 1

COASY
Neurodegeneration with brain iron accumulation 6

COG4
Congenital disorder of glycosylation type 2J

COG5
Congenital disorder of glycosylation type 2i

COG5, DUS4L,
Congenital disorder of glycosylation type 2i

DUS4L-BCAP29

COL10A1
Metaphyseal chondrodysplasia, Schmid type

COL11A1
Fibrochondrogenesis 1

COL12A1
Ullrich congenital muscular dystrophy 2

COL17A1
Epidermolysis bullosa, Junctional epidermolysis bullosa, junctional, localisata

variant, non-Herlitz type

COL18A1
GLAUCOMA, Knobloch syndrome 1, PRIMARY CLOSED-ANGLE

COL18A1,
Knobloch syndrome 1, Macular dystrophy, Retinal dystrophy, Retinitis pigmentosa

SLC19A1

COL1A1
Ehlers-Danlos syndrome, Infantile cortical hyperostosis, Osteogenesis imperfecta,

Osteogenesis imperfecta type I, Osteogenesis imperfecta type III, Osteogenesis

imperfecta with normal sclerae, Postmenopausal osteoporosis, dominant form,

procollagen proteinase deficient, recessive perinatal lethal

COL1A2
COL1A2-Related Disorder, Ehlers-Danlos syndrome, Inborn genetic diseases,

Osteogenesis imperfecta type I, autosomal recessive, cardiac valvular form, classic

type

COL2A1
Spondyloperipheral dysplasia-short ulna syndrome, Stickler syndrome type 1

COL3A1
Ehlers-Danlos syndrome, type 4

COL4A3, MFF-
Alport syndrome, autosomal recessive

DT

COL4A5
Alport syndrome 1, X-linked recessive

COL5A1
Ehlers-Danlos syndrome, classic type

COL5A2
Ehlers-Danlos syndrome, Ehlers-Danlos syndrome classic type 2, classic type

COL6A1
Bethlem myopathy 1

COL6A2
Bethlem myopathy 1, Ullrich congenital muscular dystrophy 1

COL6A3
Bethlem myopathy 1

COL7A1
Dystrophic epidermolysis bullosa, Epidermolysis bullosa pruriginosa, Recessive

dystrophic epidermolysis bullosa, Transient bullous dermolysis of the newborn,

autosomal dominant

COL9A2
Stickler syndrome, type 5

COLEC10
3MC syndrome 3

COLEC10,
3MC syndrome 3

LOC101927513

COLQ
Congenital myasthenic syndrome, Endplate acetylcholinesterase deficiency

COQ2
Coenzyme Q10 deficiency, primary, primary 1

COQ8A
4, ADCK3-Related Disorders, Coenzyme Q10 deficiency, primary

COQ9
5, Coenzyme Q10 deficiency, primary

COX15
Cardioencephalomyopathy, Leigh syndrome, Leigh syndrome due to

mitochondrial complex IV deficiency, due to cytochrome c oxidase deficiency 2,

fatal infantile

CP
Ceruloplasmin belfast, Deficiency of ferroxidase, Hemosiderosis, due to

aceruloplasminemia, systemic

CPAMD8
Anterior segment dysgenesis 8

CPLANE1
Global developmental delay, Jaundice, Joubert syndrome, Joubert syndrome 1,

Joubert syndrome 17, Orofaciodigital syndrome type 6, Typical Joubert syndrome

MRI findings

CPOX
Coproporphyria

CPS1
Congenital hyperammonemia, type I

CPSF1
MYOPIA 27

CPT2
Carnitine palmitoyltransferase II deficiency, infantile, lethal neonatal, myopathic,

stress-induced

CRB1
Leber congenital amaurosis 8

CRB2
Focal segmental glomerulosclerosis 9, Steroid-resistant nephrotic syndrome

CRIPT
Ateleiotic dwarfism, Short stature with microcephaly and distinctive facies

CRPPA
7, Congenital muscular dystrophy-dystroglycanopathy with brain and eye

anomalies, Muscular dystrophy-dystroglycanopathy (limb-girdle), type A7, type c

CRTAP
Osteogenesis imperfecta type 7

CRX
Leber congenital amaurosis 7

CRYAB
Alpha-B crystallinopathy, Dilated cardiomyopathy 1II

CRYBA4,
Cataract, autosomal recessive 3, congenital nuclear

CRYBB1

CRYBB2
Cataract 3, Congenital cataract, multiple types

CSGALNACT1
MILD, SKELETAL DYSPLASIA, WITH JOINT LAXITY AND ADVANCED

BONE AGE

CSPP1
Joubert syndrome 21, Meckel-Gruber syndrome

CSRP3
Cardiovascular phenotype

CSTB
Inborn genetic diseases, Progressive myoclonic epilepsy, Unverricht-Lundborg

syndrome

CTC1
Cerebroretinal microangiopathy with calcifications and cysts, Cerebroretinal

microangiopathy with calcifications and cysts 1, Dyskeratosis congenita

CTCF
Mental retardation, autosomal dominant 21

CTNNB1
EXUDATIVE VITREORETINOPATHY 7, Exudative vitreoretinopathy 1,

Hepatocellular carcinoma, Inborn genetic diseases, Mental retardation, autosomal

dominant 19

CTNND1, TMX2-
Blepharocheilodontic syndrome 2

CTNND1

CTNS
Cystinosis, Juvenile nephropathic cystinosis, Nephropathic cystinosis, Ocular

cystinosis

CTSD
Neuronal ceroid lipofuscinosis 10

CTSH
Variant of unknown significance

CTU2
AND AMBIGUOUS GENITALIA SYNDROME, FACIAL DYSMORPHISM,

MICROCEPHALY, RENAL AGENESIS

CUBN
Megaloblastic anemia due to inborn errors of metabolism

CUL4B
Cabezas type, Syndromic X-linked mental retardation

CUL7
Three M syndrome 1

CWC27
Retinitis pigmentosa with or without skeletal anomalies

CWF19L1
Spinocerebellar ataxia, autosomal recessive 17

CYB5R3
Methemoglobinemia type 2

CYBB
Chronic granulomatous disease, X-linked

CYP11B1,
Deficiency of steroid 11-beta-monooxygenase

LOC106799833

CYP17A1
20-lyase deficiency, Combined partial 17-alpha-hydroxylase/17, Complete

combined 17-alpha-hydroxylase/17, Deficiency of steroid 17-alpha-

monooxygenase

CYP1B1
A, Anterior segment dysgenesis 6, CYP1B1-Related Disorders, Congenital

glaucoma, Congenital ocular coloboma, Glaucoma, Glaucoma 3, Irido-corneo-

trabecular dysgenesis, b, congenital, primary congenital, primary infantile

CYP21A2,
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

LOC106780800

CYP21A2,
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

TNXB,

LOC106780800

CYP24A1
1, Hypercalcemia, infantile

CYP26C1
Optic nerve hypoplasia

CYP27A1
Cholestanol storage disease

CYP27B1
Vitamin D-dependent rickets, type 1

CYP2C19
CYP2C19: no function, Clopidogrel response, Mephenytoin, Proguanil,

Toxicity/ADR, amitriptyline response - Efficacy, citalopram response - Efficacy,

clomipramine response - Efficacy, clopidogrel response - Efficacy, poor

metabolism of

CYP2D6
Debrisoquine, Deutetrabenazine response, Tamoxifen response, Toxicity/ADR,

Tramadol response, amitriptyline response - Dosage, antidepressants response -

Dosage, clomipramine response - Dosage, desipramine response - Dosage, doxepin

response - Dosage, imipramine response - Dosage, nortriptyline response - Dosage,

poor metabolism of, tamoxifen response - Efficacy, trimipramine response -

Dosage

CYP2U1
Spastic paraplegia 56, autosomal recessive

CYP4F22
Autosomal recessive congenital ichthyosis 5

CZ1P-ASNS,
Asparagine synthetase deficiency

ASNS

DBH
Orthostatic hypotension 1

DBT
Maple syrup urine disease, Maple syrup urine disease type 2

DCAF17
Hypogonadism, alopecia, diabetes mellitus, mental retardation and

electrocardiographic abnormalities

DCLRE1C
Severe combined immunodeficiency, Severe combined immunodeficiency due to

DCLRE1C deficiency, partial

DCN
Congenital Stromal Corneal Dystrophy

DDHD1
Spastic paraplegia 28, autosomal recessive

DDRGK1
Shohat type, Spondyloepimetaphyseal dysplasia

DDX3X
Delayed speech and language development, Global developmental delay, History

of neurodevelopmental disorder, Mental retardation, Microcephaly, X-linked 102

DDX41
Acute myeloid leukemia, Myeloproliferative/lymphoproliferative neoplasms,

familial (multiple types), susceptibility to

DEPDC5
DEPDC5-Related Disorder, Familial focal epilepsy with variable foci

DES
Muscular dystrophy, Myofibrillar myopathy 1, Neuromuscular disease, Primary

dilated cardiomyopathy, limb-girdle, type 2R

DGKE
Nephrotic syndrome, type 7

DGUOK
Mitochondrial DNA depletion syndrome, Mitochondrial DNA-depletion syndrome

3, Progressive external ophthalmoplegia with mitochondrial DNA deletions,

autosomal recessive 4, hepatocerebral, hepatocerebral form due to DGUOK

deficiency

DHCR7
2-3 toe syndactyly, Congenital microcephaly, Elevated 7-dehydrocholesterol,

History of neurodevelopmental disorder, Inborn genetic diseases, Small for

gestational age, Smith-Lemli-Opitz syndrome

DHH
46, XY sex reversal, type 7

DHTKD1
2-aminoadipic 2-oxoadipic aciduria

DIAPH1
Seizures, and microcephaly syndrome, cortical blindness

DICER1
DICER1-related pleuropulmonary blastoma cancer predisposition syndrome,

Hereditary cancer-predisposing syndrome

DIPK1A, RPL5
Diamond-Blackfan anemia 6

DLD
Maple syrup urine disease, type 3

DLG3
X-Linked mental retardation 90

DLL3, PLEKHG2
Leukodystrophy and acquired microcephaly with or without dystonia,

Spondylocostal dysostosis 1, autosomal recessive

DLX3
Amelogenesis imperfecta, Tricho-dento-osseous syndrome, type IV

DLX4
Orofacial cleft 15

DMD
Becker muscular dystrophy, Duchenne muscular dystrophy

DMP1
Autosomal recessive hypophosphatemic vitamin D refractory rickets

DNAAF2
Primary ciliary dyskinesia

DNAAF4,
Primary ciliary dyskinesia

DNAAF4-CCPG1

DNAH1
Non-syndromic male infertility due to sperm motility disorder,

SPERMATOGENIC FAILURE 18

DNAH11
7, Ciliary dyskinesia, Primary ciliary dyskinesia, primary

DNAH17
SPERMATOGENIC FAILURE 39

DNAH5
3, Ciliary dyskinesia, Primary ciliary dyskinesia, primary

DNAI1
Kartagener syndrome, Primary ciliary dyskinesia

DNAI2
9, Ciliary dyskinesia, Primary ciliary dyskinesia, primary

DNAJB2
5, Charcot-Marie-Tooth disease, Spinal muscular atrophy, autosomal recessive,

distal

DNAJC12
Hyperphenylalaninemia, mild, non-bh4-deficient

DNAL1
16, Ciliary dyskinesia, Primary ciliary dyskinesia, primary

DNM2
Charcot-Marie-Tooth disease, dominant intermediate B

DNMBP
CATARACT 48

DOCK6
Adams-Oliver syndrome 2

DOCK6,
Adams-Oliver syndrome, Adams-Oliver syndrome 2

LOC105372273

DOCK8
Hyperimmunoglobulin E recurrent infection syndrome, Inborn genetic diseases,

autosomal recessive

DOK7
Congenital myasthenic syndrome, Inborn genetic diseases, Myasthenia, Pena-

Shokeir syndrome type I, familial, limb-girdle

DOLK
Congenital disorder of glycosylation type 1M

DONSON
AND LIMB ABNORMALITIES, MICROCEPHALY, Microcephaly-micromelia

syndrome, SHORT STATURE

DPY19L2
Spermatogenic failure 9

DPYD
Dihydropyrimidine dehydrogenase deficiency, fluorouracil response - Other

DRAM2
Cone-rod dystrophy 21, Retinal dystrophy

DRC1
21, Ciliary dyskinesia, Kartagener syndrome, Primary ciliary dyskinesia, primary

DSC2
11, Arrhythmogenic right ventricular cardiomyopathy, Arrhythmogenic right

ventricular dysplasia, familial, type 11, with mild palmoplantar keratoderma and

woolly hair

DSC2, DSCAS
Arrhythmogenic right ventricular cardiomyopathy, type 11

DSG1
Palmoplantar keratoderma i, focal, or diffuse, striate

DSG1, DSG1-
Erythroderma, and hyper-ige, congenital, hypotrichosis, with palmoplantar

AS1
keratoderma

DSG2
Arrhythmogenic right ventricular cardiomyopathy, Cardiac arrest,

Cardiomyopathy, Cardiovascular phenotype, Dilated Cardiomyopathy, Dominant,

Hypertrophic cardiomyopathy, type 10

DSG2, DSG2-
Dilated cardiomyopathy 1BB

AS1

DSG4, DSG1-
Hypotrichosis 6

AS1

DSP
Arrhythmogenic right ventricular cardiomyopathy, Arrhythmogenic right

ventricular dysplasia/cardiomyopathy, Cardiac arrest, Cardiomyopathy,

Cardiovascular phenotype, DSP-Related Disorders, Dilated cardiomyopathy with

woolly hair and keratoderma, Keratosis palmoplantaris striata II, Left ventricular

noncompaction cardiomyopathy, Lethal acantholytic epidermolysis bullosa, Long

QT syndrome 1, Primary dilated cardiomyopathy, Skin fragility-woolly hair-

palmoplantar keratoderma syndrome, Ventricular tachycardia, and tooth agenesis,

dilated, keratoderma, type 8, with woolly hair

DST
Epidermolysis bullosa simplex, Neuropathy, autosomal recessive 2, hereditary

sensory and autonomic, type VI

DUOX2
Congenital hypothyroidism, Familial thyroid dyshormonogenesis, Inborn genetic

diseases, Nongoitrous Euthyroid Hyperthyrotropinemia, Thyroid

dyshormonogenesis 6

DVL3
Robinow syndrome, autosomal dominant 1, autosomal dominant 3

DYNC2H1
Jeune thoracic dystrophy, Short Rib Polydactyly Syndrome, Short-rib polydactyly

syndrome type III, Short-rib thoracic dysplasia 3 with or without polydactyly

DYNC2I1
Short-rib thoracic dysplasia 8 with or without polydactyly

DYNC2I2
Jeune thoracic dystrophy, Short-rib thoracic dysplasia 11 with or without

polydactyly

DYNC2LI1
Short-rib thoracic dysplasia 15 with polydactyly

DYRK1A
Mental retardation, autosomal dominant 7

DYSF
Autosomal recessive limb-girdle muscular dystrophy type 2B, Miyoshi muscular

dystrophy 1, Myopathy, Qualitative or quantitative defects of dysferlin, distal, with

anterior tibial onset

ECEL1
Distal arthrogryposis type 5D, Inborn genetic diseases

ECHS1
Inborn genetic diseases, Mitochondrial short-chain enoyl-coa hydratase 1

deficiency

ECM1
Lipid proteinosis

EDA
Hypohidrotic X-linked ectodermal dysplasia

EDARADD
Ectodermal dysplasia 11b, autosomal recessive, hypohidrotic/hair/tooth type

EDN3
Congenital central hypoventilation, Dominant, Hirschsprung Disease,

Hirschsprung disease, Waardenburg syndrome, Waardenburg syndrome type 4B

EDNRB,
Rare genetic deafness

EDNRB-AS1

EFEMP2
Autosomal recessive cutis laxa type 1B, Autosomal recessive cutis laxa type IA

EHMT1
Kleefstra syndrome 1

EIF2AK3
Wolcott-Rallison dysplasia

EIF2AK4
Pulmonary venoocclusive disease 2, autosomal recessive

EIF2B2
Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy

EIF2S3
MEHMO syndrome

ELN
Inborn genetic diseases, Supravalvar aortic stenosis

ELOVL4
Retinal dystrophy, Stargardt Disease 3

ELP1
Familial dysautonomia

ELP2
ELP2-Related Disorders, Mental retardation, autosomal recessive 58

EMD
Cardiovascular phenotype, Emery-Dreifuss muscular dystrophy 1, Neuromuscular

disease, X-linked

ENAM
Amelogenesis imperfecta, Amelogenesis imperfecta - hypoplastic autosomal

dominant - local, type IC

ENG
Hereditary hemorrhagic telangiectasia, Hereditary hemorrhagic telangiectasia type

1

ENG,
Hereditary hemorrhagic telangiectasia type 1

LOC102723566

EOGT
Adams-Oliver syndrome, Adams-Oliver syndrome 4

EPB42
Spherocytosis type 5

EPCAM
Diarrhea 5, congenital, with tufting enteropathy

EPG5
Vici syndrome

EPHB4
Capillary malformation-arteriovenous malformation 2

EPHB4,
Capillary malformation-arteriovenous malformation 2

SLC12A9

EPOR
Primary familial polycythemia due to EPO receptor mutation

ERCC2
Metachromatic leukodystrophy variant, Trichothiodystrophy 1, Xeroderma

pigmentosum, group D, photosensitive

ERCC3
Xeroderma pigmentosum, complementation group b

ERCC4
Cockayne syndrome, Fanconi anemia, Hutchinson-Gilford syndrome, Pre-B-cell

acute lymphoblastic leukemia, XFE progeroid syndrome, Xeroderma

pigmentosum, complementation group Q, group F

ERCC5, BIVM-
Xeroderma pigmentosum, group G

ERCC5

ERCC6
Cerebrooculofacioskeletal syndrome 1, Cockayne syndrome B, DE SANCTIS-

CACCHIONE SYNDROME

ERCC8
Cockayne syndrome type A

ERCC8, ERCC8-
Cockayne syndrome type A

AS1

ERCC8,
Cockayne syndrome type A, MITOCHONDRIAL COMPLEX I DEFICIENCY,

NDUFAF2
NUCLEAR TYPE 10

ERF
Craniosynostosis 1, Craniosynostosis 4

ERI1
Abnormality of finger, Coarse facial features, Global developmental delay,

Unilateral renal agenesis

ESCO2
Roberts-SC phocomelia syndrome

ESRP1
AUTOSOMAL RECESSIVE 109, DEAFNESS

ESRRB
Rare genetic deafness

ETFDH
Multiple acyl-CoA dehydrogenase deficiency

ETHE1
Ethylmalonic encephalopathy

EVC2
Curry-Hall syndrome, Ellis-van Creveld syndrome

EXOSC3
Pontocerebellar hypoplasia, type 1b

EXPH5
Epidermolysis bullosa, autosomal recessive, nonspecific

EXT1
Chondrosarcoma, Multiple congenital exostosis, Multiple exostoses type 1,

sporadic

EXT2
Multiple exostoses type 2

EYA1
Branchiootic syndrome, Melnick-Fraser syndrome, Rare genetic deafness

EYA4
Deafness, Dilated cardiomyopathy 1J, Rare genetic deafness, autosomal dominant

10

EYA4, TARID
EYA4-Related Disorders

EYS
Retinal dystrophy, Retinitis pigmentosa, Retinitis pigmentosa 25

F13A1
Factor XIII subunit A deficiency

F13B
Factor XIII, b subunit, deficiency of

F2
Prothrombin deficiency, congenital

F5
Factor V deficiency

F8
Hereditary factor VIII deficiency disease

F9
Hereditary factor IX deficiency disease, Thrombophilia, X-linked, due to factor IX

defect

FA2H
Spastic paraplegia 35

FAH
Tyrosinemia type I

FAM161A
Retinal dystrophy, Retinitis pigmentosa, Retinitis pigmentosa 28

FAM20A
Amelogenesis imperfecta type 1G

FANCA
Fanconi anemia, complementation group A

FANCB
Fanconi anemia, complementation group B

FANCC
Fanconi anemia, Hereditary cancer-predisposing syndrome, complementation

group C

FANCC, AOPEP
Fanconi anemia, Hereditary cancer-predisposing syndrome, Tracheoesophageal

fistula, complementation group C

FANCF
Fanconi anemia, complementation group F

FANCM
Fanconi anemia, Malignant germ cell tumor of ovary, SPERMATOGENIC

FAILURE 28

FARS2
Combined oxidative phosphorylation deficiency 14

FARSB
Interstitial lung and liver disease, Rajab interstitial lung disease with brain

calcifications

FAS
Autoimmune lymphoproliferative syndrome

FAT4
Van Maldergem syndrome

FBN1
Acromicric dysplasia, Acute aortic dissection, Cardiovascular phenotype, Ectopia

lentis, Familial thoracic aortic aneurysm, Familial thoracic aortic aneurysm and

aortic dissection, Geleophysic dysplasia 2, Inborn genetic diseases, MASS

syndrome, Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic

Aneurysms and Dissections, Marfan lipodystrophy syndrome, Marfan syndrome,

Stiff skin syndrome, Weill-Marchesani syndrome 2, autosomal dominant, isolated

FBN1,
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms

LOC113939944
and Dissections, Marfan syndrome

FBXL4
Inborn genetic diseases, Mitochondrial DNA depletion syndrome, Mitochondrial

DNA depletion syndrome 13 (encephalomyopathic type)

FERMT1
Kindlers syndrome

FEZF1-AS1,
Hypogonadotropic hypogonadism 22 with anosmia

FEZF1

FGD4
Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 4

FGF16
Metacarpal 4-5 fusion

FGF3
Deafness with labyrinthine aplasia microtia and microdontia (LAMM)

FGG
Afibrinogenemia, Hypofibrinogenemia, congenital

FH
Fumarase deficiency, Hereditary cancer-predisposing syndrome, Hereditary

leiomyomatosis and renal cell cancer

FIG4
Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 4, Yunis-Varon

syndrome, type 4J

FKBP10
Bruck syndrome 1, Osteogenesis imperfecta type 12

FKBP14,
Congenital muscular dystrophy, Ehlers-Danlos syndrome with progressive

FKBP14-AS1
kyphoscoliosis, Inborn genetic diseases, Joint hypermobility, Muscular hypotonia,

Pes valgus, Thoracolumbar scoliosis, and hearing loss, myopathy

FKRP
Limb-girdle muscular dystrophy-dystroglycanopathy, type C5

FKTN
Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies,

Congenital muscular dystrophy-dystroglycanopathy without mental retardation,

FKTN-Related Disorders, Fukuyama congenital muscular dystrophy, Limb-girdle

muscular dystrophy-dystroglycanopathy, Walker-Warburg congenital muscular

dystrophy, type A4, type B4, type C4

FLCN
Hereditary cancer-predisposing syndrome, Multiple fibrofolliculomas,

Pneumothorax, primary spontaneous

FLG
2, Dermatitis, FLG-Related Disorder, Ichthyosis vulgaris, atopic, susceptibility to

FLNA
Periventricular nodular heterotopia 1

FLNB
Spondylocarpotarsal synostosis syndrome

FLNC
26, 4, Cardiomyopathy, Dilated Cardiomyopathy, Dominant, Myofibrillar

myopathy, Myopathy, distal, familial hypertrophic, filamin C-related

FLNC, FLNC-
26, 4, Cardiomyopathy, Dilated Cardiomyopathy, Dominant, Myofibrillar

AS1
myopathy, Myopathy, distal, familial hypertrophic, filamin C-related

FLT4
7, CONGENITAL HEART DEFECTS, MULTIPLE TYPES

FMR1
Intellectual disability

FOXF1
Persistent fetal circulation syndrome

FOXG1
History of neurodevelopmental disorder, Rett syndrome, congenital variant

FOXL2
Blepharophimosis, and epicanthus inversus, and epicanthus inversus syndrome

type 1, ptosis

FOXN1
AUTOSOMAL DOMINANT, INFANTILE, T-CELL LYMPHOPENIA, T-cell

immunodeficiency, WITH OR WITHOUT NAIL DYSTROPHY, and nail

dystrophy, congenital alopecia

FOXP1
Mental retardation with language impairment and with or without autistic features

FOXRED1
Leigh syndrome, Mitochondrial complex I deficiency, nuclear type 1

FRAS1
Fraser syndrome 1

FREM2
Cryptophthalmos, FRASER SYNDROME 2, Fraser syndrome 1, isolated,

unilateral or bilateral

FSHB
Hypogonadotropic hypogonadism 24 without anosmia

FSIP2
SPERMATOGENIC FAILURE 34

FSIP2, FSIP2-
SPERMATOGENIC FAILURE 34

AS1

FTCD
GLUTAMATE FORMIMINOTRANSFERASE DEFICIENCY

FTSJ1
Mental retardation 9, X-linked

FUCA1
Fucosidosis

FYCO1
Cataract 18

FZD4, PRSS23
Exudative retinopathy, Familial exudative vitreoretinopathy

G6PC
Glycogen storage disease, Glycogen storage disease due to glucose-6-phosphatase

deficiency type IA

GAA
Glycogen storage disease, type II

GABRA1
19, Epilepsy, Epileptic encephalopathy, early infantile, juvenile myoclonic 5

GABRA6
GABRA6-Related Disorder

GALC
Galactosylceramide beta-galactosidase deficiency

GALM
GALACTOSEMIA IV

GALNS
MPS-IV-A, Morquio syndrome, Mucopolysaccharidosis

GALT
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

GAMT
Cerebral creatine deficiency syndrome, Deficiency of guanidinoacetate

methyltransferase

GAREM2,
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, Mitochondrial

HADHA
trifunctional protein deficiency

GATA1
Acute megakaryoblastic leukemia

GATA3
Hypoparathyroidism-deafness-renal disease syndrome

GATA6
Abnormality of cardiovascular system morphology, Congenital diaphragmatic

hernia, Pancreatic agenesis and congenital heart disease, Persistent truncus

arteriosus

GATAD1, PEX1
Deafness enamel hypoplasia nail defects, Peroxisome biogenesis disorder 1A

(Zellweger)

GATAD2B
GATAD2B-Related Disorder, Mental retardation, autosomal dominant 18

GBA
Acute neuronopathic Gauchers disease, Gaucher disease, Gaucher disease type

3C, Gauchers disease, Subacute neuronopathic Gauchers disease, type 1

GBA,
Gaucher disease, Gauchers disease, perinatal lethal, type 1

LOC106627981

GBE1
Glycogen storage disease, Glycogen storage disease IV, classic hepatic, fatal

perinatal neuromuscular, type IV

GCDH
Glutaric aciduria, type 1

GCH1
Dystonia 5

GCK
Maturity onset diabetes mellitus in young, Maturity-onset diabetes of the young,

type 2

GDAP1
Charcot-Marie-Tooth disease, recessive intermediate A, type 4A

GDF1, CERS1
Heterotaxia

GDF9
PREMATURE OVARIAN FAILURE 14

GFER
Mitochondrial diseases

GHR
Laron syndrome with elevated serum GH-binding protein, Laron-type isolated

somatotropin defect

GJB1
Charcot-Marie-Tooth Neuropathy X, Charcot-Marie-Tooth disease

GJB2
Bilateral conductive hearing impairment, Bilateral sensorineural hearing

impairment, Deafness, Dominant, GJB2-Related Disorders, GJB2/GJB3,

GJB2/GJB6, Hearing impairment, Hearing loss, Hystrix-like ichthyosis with

deafness, Inborn genetic diseases, Keratitis ichthyosis and deafness syndrome,

Keratitis-ichthyosis-deafness syndrome, Knuckle pads, Mutilating keratoderma,

Nonsyndromic Hearing Loss, Nonsyndromic hearing loss and deafness,

Palmoplantar keratoderma-deafness syndrome, Rare genetic deafness, Recessive,

Severe sensorineural hearing impairment, X-linked 2, autosomal dominant,

autosomal dominant 3a, autosomal recessive 1A, autosomal recessive 1b, deafness

AND leukonychia syndrome, digenic

GJB3
Deafness, autosomal dominant 2b

GLA, RPL36A-
Fabry disease

HNRNPH2

GLB1
GLB1-Related Disorders, GM1 gangliosidosis, GM1 gangliosidosis type 2, GM1

gangliosidosis type 3, GM1-gangliosidosis, Infantile GM1 gangliosidosis, MPS-

IV-B, Mucopolysaccharidosis, type I, with cardiac involvement

GLDC
Non-ketotic hyperglycinemia

GLDN
Lethal congenital contracture syndrome 11

GLI3
Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, Postaxial

polydactyly, Preaxial polydactyly 4, type A1/B

GLIS3
Diabetes mellitus, neonatal, with congenital hypothyroidism

GLMN
Glomuvenous malformations

GLRA1
Hyperekplexia 1

GNAS
Progressive osseous heteroplasia, Pseudohypoparathyroidism,

Pseudopseudohypoparathyroidism

GNAT2
Achromatopsia 4

GNB5
Intellectual developmental disorder with cardiac arrhythmia, Language delay and

attention deficit-hyperactivity disorder/cognitive impairment with or without

cardiac arrhythmia

GNPAT
Rhizomelic chondrodysplasia punctata type 2

GNPTAB
GNPTAB-Related Disorders, Inborn genetic diseases, MUCOLIPIDOSIS III

ALPHA/BETA, Mucolipidosis, Mucolipidosis type II, Pseudo-Hurler

polydystrophy

GNPTG
Mucolipidosis, Mucolipidosis type III gamma

GORAB
Geroderma osteodysplastica

GOSR2,
Progressive myoclonic epilepsy

LRRC37A2

GPC3
Simpson-Golabi-Behmel syndrome, Wilms tumor 1

GPC4
Keipert syndrome

GPC6
Autosomal recessive omodysplasia

GPC6, GPC6-AS2
Autosomal recessive omodysplasia

GPI
Hemolytic anemia, due to glucose phosphate isomerase deficiency, nonspherocytic

GPNMB
3, AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS

GPR143
Ocular albinism, type I

GPR179
Congenital stationary night blindness, Retinal dystrophy, type 1E

GPSM2
Chudley-McCullough syndrome, GPSM2-Related Disorders, Rare genetic

deafness

GRHL2
Deafness, autosomal dominant 28

GRHL3
Van der Woude syndrome 2

GRHPR
Nephrocalcinosis, Nephrolithiasis, Primary hyperoxaluria, type II

GRIN2B
Mental retardation, autosomal dominant 6

GRIP1
FRASER SYNDROME 3

GRN
Frontotemporal dementia

GRXCR1
Deafness, Rare genetic deafness, autosomal recessive 25

GSDME
Deafness, autosomal dominant 5

GUCY2C,
Meconium ileus

C12orf60

GUSB
Mucopolysaccharidosis type 6, Mucopolysaccharidosis type 7

GYG1
Glycogen storage disease XV, Polyglucosan body myopathy 2

GYS1
Glycogen storage disease 0, muscle

GYS2
Glycogen storage disease, Glycogen storage disease due to hepatic glycogen

synthase deficiency

GZF1
AND MYOPIA, JOINT LAXITY, SHORT STATURE

H1-4
Inborn genetic diseases, RAHMAN SYNDROME

H6PD
Cortisone reductase deficiency 1

HADHA
HADHA-Related Disorders, Long-chain 3-hydroxyacyl-CoA dehydrogenase

deficiency, Mitochondrial trifunctional protein deficiency

HADHA,
HADHA-Related Disorders, Inborn genetic diseases, LCHAD Deficiency, Lchad

GAREM2
deficiency with maternal acute fatty liver of pregnancy, Long-chain 3-

hydroxyacyl-CoA dehydrogenase deficiency, Mitochondrial trifunctional protein

deficiency

HAX1
Severe congenital neutropenia 3, autosomal recessive

HBA2,
Alpha plus thalassemia

LOC106804612

HBB,
Anemia, Beta thalassemia major, Beta-plus-thalassemia, Beta-thalassemia,

LOC106099062,
Erythrocytosis 6, Fetal hemoglobin quantitative trait locus 1, HBB-Related

LOC107133510
Disorders, Hb SS disease, Heinz body anemia, Hemoglobin E, Hemoglobin E

disease, Hemoglobin E/beta thalassemia disease, Hemoglobin M disease,

Hemoglobinopathy, Malaria, Susceptibility to malaria, alpha Thalassemia, beta

Thalassemia, beta{circumflex over ( )}0{circumflex over ( )} Thalassemia, dominant inclusion body type, familial,

resistance to

HBB,
beta Thalassemia

LOC107133510,

LOC110006319

HCN4
Brugada syndrome 8, Sick sinus syndrome 2, autosomal dominant

HEXA
Inborn genetic diseases, Tay-Sachs disease

HEXB
Sandhoff disease, infantile

HFM1
Premature ovarian failure 9

HGD
Alkaptonuria

HGSNAT
MPS-III-C, Mucopolysaccharidosis, Retinitis pigmentosa 73, Sanfilippo syndrome

HIVEP2
Angelman syndrome-like, Mental retardation, autosomal dominant 43

HJV
Hemochromatosis type 2A

HLCS
Holocarboxylase synthetase deficiency

HMCN1
Age-related macular degeneration 1

HMGB3
Microphthalmia, syndromic 13

HMGCL
Deficiency of hydroxymethylglutaryl-CoA lyase

HNF1A
20, Clear cell carcinoma of kidney, Diabetes mellitus, Diabetes mellitus type 1,

Hepatic adenomas, Maturity onset diabetes mellitus in young, Maturity-onset

diabetes of the young, familial, insulin-dependent, type 3

HNF1B
Familial hypoplastic, Renal cysts and diabetes syndrome, glomerulocystic kidney

HNRNPK
AU-KLINE SYNDROME

HNRNPU
Epileptic encephalopathy

HOXA1
Athabaskan brainstem dysgenesis syndrome, Bosley-Salih-Alorainy syndrome

HOXA11
Radioulnar synostosis with amegakaryocytic thrombocytopenia 1

HOXD13
Synpolydactyly 1

HPGD
1, HPGD-Related Disorders, Hypertrophic osteoarthropathy, autosomal recessive,

primary

HPS1
Hermansky-Pudlak syndrome, Hermansky-Pudlak syndrome 1

HPS5
Hermansky-Pudlak syndrome, Hermansky-Pudlak syndrome 5

HPS6
Hermansky-Pudlak syndrome, Hermansky-Pudlak syndrome 6

HPSE2
Urofacial syndrome 1

HR
Atrichia with papular lesions

HSD17B10
HSD10 disease

HSD17B4
Bifunctional peroxisomal enzyme deficiency, Perrault syndrome

HSPA9
4, Anemia, Even-plus syndrome, sideroblastic

HSPB1
Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease axonal type 2F, Distal

hereditary motor neuronopathy type 2B

HSPG2
Lethal Kniest-like syndrome, Schwartz-Jampel syndrome

HYAL1
Deficiency of hyaluronoglucosaminidase

HYDIN
5, Ciliary dyskinesia, primary

ICAM4
Landsteiner-Wiener phenotype

IDS
MPS-II, Mucopolysaccharidosis

IDS,
MPS-II, Mucopolysaccharidosis

LOC106050102

IDUA
Hurler syndrome, MPS-I-H/S, MPS-I-S, Mucopolysaccharidosis,

Mucopolysaccharidosis type 1

IDUA, SLC26A1
Hurler syndrome, MPS-I-H/S, MPS-I-S, Mucopolysaccharidosis,

Mucopolysaccharidosis type 1

IFIH1
Aicardi-Goutieres syndrome 7, Singleton-Merten syndrome 1

IFNGR1
Disseminated atypical mycobacterial infection, IFN-gamma receptor 1 deficiency,

Immunodeficiency 27b, Inherited Immunodeficiency Diseases

IFNGR2
Immunodeficiency 28

IFT140
Retinitis pigmentosa 80

IFT140,
Jeune thoracic dystrophy, Joubert syndrome with Jeune asphyxiating thoracic

LOC105371046
dystrophy, Renal dysplasia, cerebellar ataxia and skeletal dysplasia, retinal

pigmentary dystrophy

IFT172
Short-rib thoracic dysplasia 10 with or without polydactyly

IFT52
Short Rib Polydactyly Syndrome, Short-rib thoracic dysplasia 16 with or without

polydactyly

IGF1
Growth delay due to insulin-like growth factor type 1 deficiency

IGF1R
Inborn genetic diseases

IGFALS
Acid-labile subunit deficiency

IGHM
Agammaglobulinemia, non-Bruton type

IGHMBP2
1, Autosomal dominant distal hereditary motor neuropathy, Charcot-Marie-Tooth

disease, Distal spinal muscular atrophy, Inborn genetic diseases, Spinal muscular

atrophy, autosomal recessive, axonal, distal, type 2S

IGLL1
Agammaglobulinemia 2, autosomal recessive

IGSF1
Hypothyroidism, and testicular enlargement, central

IGSF3
Lacrimal duct defect

IKBKG
Ectodermal dysplasia and immunodeficiency 1, Immunodeficiency without

anhidrotic ectodermal dysplasia, Incontinentia pigmenti, atypical

IL12B
Immunodeficiency 29

IL12RB1
Immunodeficiency 30

IL2RB
Ichthyosis (disease)

IL2RG
Combined immunodeficiency, X-linked, X-linked severe combined

immunodeficiency

IL36RN
Pustular psoriasis, generalized

IL7R
B cell-positive, NK cell-positive, Severe combined immunodeficiency, T cell-

negative, autosomal recessive

INPP5E
Retinal dystrophy

INPPL1
Opsismodysplasia

INTU
Mohr syndrome, Orofaciodigital syndrome 17

IQCB1
Renal dysplasia and retinal aplasia

IQCE
POLYDACTYLY, POSTAXIAL, TYPE A7

IQSEC2
Mental retardation, Severe intellectual deficiency, X-linked 1

IRAK4
Immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency

IRF2BPL
ABNORMAL MOVEMENTS, AND SEIZURES, LOSS OF SPEECH,

NEURODEVELOPMENTAL DISORDER WITH REGRESSION,

Neurodevelopmental disorder

IRF6
Van der Woude syndrome

IRS4
9, CONGENITAL, HYPOTHYROIDISM, NONGOITROUS

ISCA2
Multiple mitochondrial dysfunctions syndrome 4

ISG15
Immunodeficiency 38 with basal ganglia calcification

ITGA7
Muscular dystrophy, congenital, due to integrin alpha-7 deficiency

ITGB2
Leukocyte adhesion deficiency

ITGB4
Epidermolysis bullosa junctionalis with pyloric atresia

ITPA
35, Epileptic encephalopathy, Inosine triphosphatase deficiency, early infantile

ITPR1
Gillespie syndrome

IVD
Isovaleric acidemia, Isovaleryl-CoA dehydrogenase deficiency, type III

JAG1
Alagille syndrome 1, Arteriohepatic dysplasia, Heart, malformation of

JAK3
B cell-positive, NK cell-negative, Severe combined immunodeficiency, Severe

combined immunodeficiency disease, T cell-negative, autosomal recessive

KAT6A
History of neurodevelopmental disorder, Mental retardation, autosomal dominant

32

KAT6B
Blepharophimosis - intellectual disability syndrome, SBBYS type

KAT6B, DUPD1
Blepharophimosis - intellectual disability syndrome, Genitopatellar syndrome,

Inborn genetic diseases, SBBYS type

KATNIP
Joubert syndrome 26

KCNA1
Episodic ataxia type 1

KCNA5
7, Atrial fibrillation, familial

KCNC1
Epilepsy, progressive myoclonic 7

KCNE1
Long QT syndrome

KCNH2
Cardiac arrhythmia, Cardiovascular phenotype, Congenital long QT syndrome,

Long QT syndrome, Long QT syndrome ½, Long QT syndrome 2, digenic

KCNK18
Migraine, with or without aura 13

KCNQ1
Cardiac arrhythmia, Cardiovascular phenotype, Congenital long QT syndrome,

Jervell and Lange-Nielsen syndrome, Jervell and Lange-Nielsen syndrome 1,

KCNQ1-Related Disorders, LQT1 subtype, Long QT syndrome, Long QT

syndrome 1, Rare genetic deafness, Romano-Ward syndrome, recessive

KCNQ1-AS1,
Jervell and Lange-Nielsen syndrome 1

KCNQ1

KCNQ1, KCNQ1-
Cardiovascular phenotype, Long QT syndrome, Long QT syndrome 1

AS1

KCNQ1,
Congenital long QT syndrome, LQT1 subtype, Long QT syndrome

KCNQ1OT1

KCNQ2
Benign familial neonatal seizures 1, Early infantile epileptic encephalopathy, Early

infantile epileptic encephalopathy 7, Epileptic encephalopathy, Inborn genetic

diseases, Seizures

KCNQ3
Intellectual disability, Seizures

KCNQ4
Autosomal dominant nonsyndromic deafness 2A

KCNT1
5, Early infantile epileptic encephalopathy 14, Epilepsy, nocturnal frontal lobe

KCNV2
Cone dystrophy with supernormal rod response, Progressive cone dystrophy

(without rod involvement), Retinal dystrophy, Stargardt disease

KDM5B
Intellectual disability, autosomal recessive 65

KDM5C
Claes-Jensen type, Mental retardation, X-linked, syndromic

KDM6A
Kabuki syndrome 2

KERA
Cornea plana 2

KHDC3L
2, Hydatidiform mole, recurrent

KIAA0586
Congenital cerebellar hypoplasia, Intellectual disability, Joubert syndrome, Joubert

syndrome 23, Retinal dystrophy, Rod-cone dystrophy, Short-rib thoracic dysplasia

14 with polydactyly

KIAA0753
Orofaciodigital syndrome XV

KIAA0825
POLYDACTYLY, POSTAXIAL, Postaxial polydactyly type A1, TYPE A10

KIΛA1549
RETINITIS PIGMENTOSA 86

KIF11
Microcephaly with or without chorioretinopathy, lymphedema, or mental

retardation

KIF7
Acrocallosal syndrome, Joubert syndrome 12

KIFBP
Goldberg-Shprintzen megacolon syndrome

KISS1R
Hypogonadotropic hypogonadism 8 without anosmia

KIZ
Retinitis pigmentosa 69

KMT2A
Wiedemann-Steiner syndrome

KMT2B
Dystonia 28, childhood-onset

KMT2C
Kleefstra syndrome due to a point mutation

KMT2D
CHARGE association, Kabuki syndrome, Kabuki syndrome 1

KMT2E
Epilepsy, Leukoencephalopathy, Macrocephalus, O DONNELL-LURIA-RODAN

SYNDROME, See cases, intellectual deficiency

KPTN
Mental retardation, autosomal recessive 41

KRIT1
Cavernous malformations of CNS and retina, Cerebral cavernous malformation,

Cerebral cavernous malformations 1

KRT1
Ichthyosis histrix, curth-macklin type

KRT10
Bullous ichthyosiform erythroderma

KRT10, TMEM99
Bullous ichthyosiform erythroderma

KRT14
Epidermolysis bullosa simplex, autosomal recessive

KRT5
Dowling-Degos disease 1

KRT6A
Pachyonychia congenita 3

KRT85
pure hair-nail type, Ectodermal dysplasia

KYNU
AND LIMB DEFECTS SYNDROME 2, CARDIAC, Congenital NAD deficiency

disorder, RENAL, VERTEBRAL

L1CAM
MASA syndrome, Spastic paraplegia

L2HGDH
L-2-hydroxyglutaric aciduria

LACC1
JUVENILE ARTHRITIS

LAMA2
Inborn genetic diseases, Laminin alpha 2-related dystrophy, Merosin deficient

congenital muscular dystrophy

LAMA3
Junctional epidermolysis bullosa gravis of Herlitz

LAMA4
Dilated cardiomyopathy 1JJ

LAMB3
Amelogenesis imperfecta, Junctional epidermolysis bullosa, Junctional

epidermolysis bullosa gravis of Herlitz, non-Herlitz type, type IA

LAMC2
Junctional epidermolysis bullosa, Junctional epidermolysis bullosa gravis of

Herlitz, non-Herlitz type

LAMP2
Cardiomyopathy, Danon disease, Hypertrophic cardiomyopathy, Primary dilated

cardiomyopathy

LARGE1
Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type

B6

LBR
Disproportionate short stature, Femoral bowing, Pelger-HuÃ«t anomaly,

Regressive spondylometaphyseal dysplasia, Retrognathia, Rhizomelic arm

shortening, Rhizomelic leg shortening, Short long bone

LDB3
Cardiomyopathy, Myofibrillar myopathy, ZASP-related

LDLR
Familial hypercholesterolemia, Familial hypercholesterolemia 1, Homozygous

familial hypercholesterolemia

LDLRAP1
Familial hypercholesterolemia 4

LEP
Leptin deficiency or dysfunction

LFNG
Spondylocostal dysostosis 3, autosomal recessive

LGI1
Familial temporal lobe epilepsy 1

LHFPL5
Rare genetic deafness

LHX3
Non-acquired combined pituitary hormone deficiency with spine abnormalities

LIFR
StÃ¼ve-Wiedemann syndrome

LIG4
LIG4-Related Disorders, Lig4 syndrome

LIPA
Lysosomal acid lipase deficiency

LIPE
Familial partial lipodystrophy 6

LIPE, LIPE-AS1,
Familial partial lipodystrophy 6

LOC101930071

LIPH
Hypotrichosis 7, Woolly hair, autosomal recessive 2, with or without hypotrichosis

LIPN
Autosomal recessive congenital ichthyosis 8

LMBR1
Acheiropodia

LMBRD1
Inborn genetic diseases, Methylmalonic aciduria and homocystinuria type cblF

LMNA
Cardiovascular phenotype, Charcot-Marie-Tooth disease, Primary dilated

cardiomyopathy, type 2

LMOD3
Nemaline myopathy 10

LMX1B
Nail-patella syndrome

LOC100507346,
Gorlin syndrome, Medulloblastoma

PTCH1

LOC101927055,
Dilated cardiomyopathy 1G, Limb-girdle muscular dystrophy, Primary dilated

TTN
cardiomyopathy, type 2J

LOC101927157,
Retinitis pigmentosa, Retinitis pigmentosa 49

CNGA1

LOC101927188,
Poretti-Boltshauser syndrome

LAMA1

LOC102723566,
Hereditary hemorrhagic telangiectasia type 1

ENG

LOC106694316,
Myeloperoxidase deficiency

MPO

LOC110006319,
beta Thalassemia

HBB,

LOC107133510

LOXHD1
Deafness, Rare genetic deafness, autosomal recessive 77

LPL
Hyperlipoproteinemia, Lpl-arita, type I

LRAT
EARLY-ONSET SEVERE, JUVENILE, LRAT-RELATED, Leber congenital

amaurosis, Leber congenital amaurosis 14, RETINAL DYSTROPHY, RETINITIS

PIGMENTOSA

LRBA
Common variable immunodeficiency 8, with autoimmunity

LRIT3
Congenital stationary night blindness, type 1F

LRP4
Cenani-Lenz syndactyly syndrome

LRP5
Exudative vitreoretinopathy 4, Familial exudative vitreoretinopathy, autosomal

dominant

LRP6
7, Tooth agenesis, selective

LRPAP1
Myopia 23, Rare isolated myopia, autosomal recessive

LRPPRC
Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type

LRSAM1
Charcot-Marie-Tooth disease type 2P

LRTOMT
Deafness, Rare genetic deafness, autosomal recessive 63

LTBP2
Congenital glaucoma, Microspherophakia

LTBP3
Dental anomalies and short stature

LTBP4
Cutis laxa with severe pulmonary, and urinary abnormalities, gastrointestinal

LYRM7
Mitochondrial complex III deficiency, nuclear type 8

LZTFL1
Bardet-Biedl syndrome 17

LZTR1
Noonan syndrome 2, Schwannomatosis 2

MAB21L1,
AND GENITAL SYNDROME, CEREBELLAR, CRANIOFACIAL, OCULAR

NBEA

MAFB
Duane retraction syndrome 2, Duane retraction syndrome 3 with or without

deafness, Duane syndrome type 1, Duane syndrome type 3

MAGED2
Barrier syndrome, antenatal, transient, type 5

MAGEL2
Inborn genetic diseases, Schaaf-Yang syndrome

MAGT1
Epstein-Barr virus infection, Immunodeficiency, X-Linked, and neoplasia, with

magnesium defect

MAK
Retinal dystrophy

MAN2B1
Deficiency of alpha-mannosidase

MANBA
Beta-D-mannosidosis

MAP2K2
Rasopathy

MAPRE2
2, Skin creases, congenital symmetric circumferential

MARVELD2
Deafness, Rare genetic deafness, autosomal recessive 49, neurosensory

MAX
Hereditary cancer-predisposing syndrome

MBD5
Mental retardation, autosomal dominant 1

MC2R
ACTH resistance

MC4R
Monogenic diabetes, Obesity, Schizophrenia

MCCC1
3 Methylcrotonyl-CoA carboxylase 1 deficiency

MCCC2
3-methylcrotonyl CoA carboxylase 2 deficiency

MCM5
MEIER-GORLIN SYNDROME 8

MCM8
Premature ovarian failure 10

MCOLN1
Mucolipidosis type IV

MCPH1
Abnormality of brain morphology, Primary autosomal recessive microcephaly 1

MECP2
Angelman syndrome, Atypical Rett syndrome, Autism, Delayed gross motor

development, Delayed speech and language development, Developmental

regression, Encephalopathy, Global developmental delay, History of

neurodevelopmental disorder, Inborn genetic diseases, Intellectual disability, Loss

of ability to walk, Mental retardation, Rett syndrome, Severe neonatal-onset

encephalopathy with microcephaly, Smith-Magenis Syndrome-like, Syndromic X-

linked intellectual disability Lubs type, X-linked, X-linked 3, neonatal

severeMental retardation, susceptibility to, syndromic 13, syndromic 13Rett

syndrome

MED12
Cardiovascular phenotype, FG syndrome 1, History of neurodevelopmental

disorder

MED13L
Mental retardation and distinctive facial features with or without cardiac defects

MED25
Broad-based gait, Charcot-Marie-Tooth disease, Decreased body weight, Failure to

thrive, Generalized hypotonia, Impaired distal proprioception, Sensory ataxia,

Sensory ataxic neuropathy, Sensory neuropathy, type 2

MEF2C
MEF2C-Related Disorder, Mental retardation, and/or cerebral malformations,

epilepsy, stereotypic movements

MEFV
Familial Mediterranean fever

MEN1
Hereditary cancer-predisposing syndrome, Lipoma, Multiple endocrine neoplasia,

somatic, type 1

MERTK
Retinitis pigmentosa 38

MESD
OSTEOGENESIS IMPERFECTA, TYPE XX

METTL23
Inborn genetic diseases, Mental retardation, autosomal recessive 44

MFN2
Charcot-Marie-Tooth disease, type 2

MFRP, C1QTNF5
Microphthalmia, Nanophthalmos 2, isolated 5

MFSD8
Neuronal ceroid lipofuscinosis 7

MIP
Cataract 15, multiple types

MIR6886, LDLR
Familial hypercholesterolemia, Familial hypercholesterolemia 1, Homozygous

familial hypercholesterolemia

MITF
Coloboma, Rare genetic deafness, Waardenburg syndrome type 2A, albinism, and

deafness, macrocephaly, microphthalmia, osteopetrosis

MKRN3
2, Precocious puberty, central

MKS1
Joubert syndrome, Joubert syndrome 28, Meckel syndrome type 1, Meckel-Gruber

syndrome

MLC1
Megalencephalic leukoencephalopathy with subcortical cysts 1

MLH1
Carcinoma of colon, Colon cancer, Hereditary cancer-predisposing syndrome,

Hereditary nonpolyposis colon cancer, Lynch syndrome, Lynch syndrome I, Lynch

syndrome II, Muir-TorrÃ © syndrome, Turcot syndrome

MLH3
Hereditary nonpolyposis colorectal cancer type 7

MLYCD
Deficiency of malonyl-CoA decarboxylase

MMAA
Methylmalonic acidemia, Vitamin B12-responsive methylmalonic acidemia type

cblA

MMAB
Methylmalonic acidemia, Vitamin B12-responsive methylmalonic acidemia type

cblB

MMACHC
DIGENIC, Disorders of Intracellular Cobalamin Metabolism,

METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, Methylmalonic

acidemia with homocystinuria, Methylmalonic aciduria due to methylmalonyl-

CoA mutase deficiency, cblC TYPE

MME
Charcot-Marie-Tooth disease, Congenital membranous nephropathy due to

fetomatemal anti-neutral endopeptidase alloimmunization, axonal, type 2T

MMUT
Methylmalonic acidemia, Methylmalonic aciduria due to methylmalonyl-CoA

mutase deficiency

MOCS2
Molybdenum cofactor deficiency, complementation group B

MPDZ
2, Congenital hydrocephalus, Hydrocephalus, congenital, with or without brain or

eye anomalies

MPL
Congenital amegakaryocytic thrombocytopenia, essential thrombocytemia

MPLKIP
Trichothiodystrophy, nonphotosensitive 1

MPO
Myeloperoxidase deficiency

MPV17
Navajo neurohepatopathy

MPZ
Charcot-Marie-Tooth disease

MPZL2
AUTOSOMAL RECESSIVE 111, DEAFNESS

MRE11
Hereditary cancer-predisposing syndrome

MSH2
Carcinoma of colon, Colon cancer, Glioblastoma, Hereditary cancer-predisposing

syndrome, Hereditary nonpolyposis colon cancer, Lynch syndrome, Lynch

syndrome I, Malignant tumor of ascending colon, Malignant tumor of sigmoid

colon, Muir-TorrÃ © syndrome, Ovarian Neoplasms, Turcot syndrome

MSH6
Endometrial carcinoma, Hereditary cancer-predisposing syndrome, Hereditary

nonpolyposis colon cancer, Hereditary nonpolyposis colorectal cancer type 5,

Hereditary nonpolyposis colorectal carcinoma, Lynch syndrome, Lynch syndrome

I, Turcot syndrome

MSTO1
Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome

MSX2
Parietal foramina 1

MTFMT
Abnormal facial shape, Combined oxidative phosphorylation deficiency 15,

Cytochrome C oxidase-negative muscle fibers, Decreased activity of mitochondrial

complex I, Inability to walk by childhood/adolescence, Leigh syndrome,

MITOCHONDRIAL COMPLEX I DEFICIENCY, Mitochondrial oxidative

phosphorylation disorder, NUCLEAR TYPE 27, Poor speech, Short stature

MTHFD1
COMBINED IMMUNODEFICIENCY AND MEGALOBLASTIC ANEMIA

WITH OR WITHOUT HYPERHOMOCYSTEINEMIA

MTM1
Severe X-linked myotubular myopathy

MTRR
Disorders of Intracellular Cobalamin Metabolism, Homocystinuria without

methylmalonic aciduria, Homocystinuria-Megaloblastic anemia due to defect in

cobalamin metabolism, cblE complementation type

MTTP
Abetalipoproteinaemia

MUTYH
Carcinoma of colon, Colon cancer, Familial colorectal cancer, Hereditary cancer-

predisposing syndrome, MUTYH-associated polyposis, MYH-associated

polyposis, Neoplasm of stomach, Pilomatrixoma

MVK
Hyperimmunoglobulin D with periodic fever, Mevalonic aciduria, Porokeratosis 3,

disseminated superficial actinic type

MYBPC3
Asymmetric septal hypertrophy, Cardiomyopathy, Cardiovascular phenotype,

Dyspnea, Familial dilated cardiomyopathy, Familial hypertrophic cardiomyopathy

1, Familial hypertrophic cardiomyopathy 4, Heart block, Hypertrophic

cardiomyopathy, Inborn genetic diseases, Left ventricular hypertrophy, Left

ventricular noncompaction, Left ventricular noncompaction 10, Long QT

syndrome, MYBPC3-Related Disorders, Noncompaction cardiomyopathy, Primary

dilated cardiomyopathy, Primary familial hypertrophic cardiomyopathy,

Tachycardia, Ventricular extrasystoles

MYCN
Inborn genetic diseases

MYEF2,
Albinism, oculocutaneous, type VI

SLC24A5

MYF5
Abnormality of the ribs, EXTERNAL, External ophthalmoplegia,

OPHTHALMOPLEGIA, Scoliosis, WITH RIB AND VERTEBRAL

ANOMALIES

MYH11, NDE1
Familial aortopathy

MYH2, MYHAS
Myopathy, and ophthalmoplegia, proximal

MYH3
Contractures, Spondylocarpotarsal synostosis syndrome, and variable skeletal

fusions syndrome 1A, pterygia

MYH6
Familial hypertrophic cardiomyopathy 1

MYH7
Hypertrophic cardiomyopathy, Primary dilated cardiomyopathy

MYH7, MHRT
Cardiomyopathy, Cardiovascular phenotype, Hypertrophic cardiomyopathy,

MYH7-Related Disorders

MYL2,
Familial hypertrophic cardiomyopathy 10

LOC114827850

MYLK
Visceral myopathy

MYO15A
Congenital sensorineural hearing impairment, Deafness, Nonsyndromic hearing

loss and deafness, Rare genetic deafness, autosomal recessive 3

MYO3A
Deafness, autosomal recessive 30

MYO5B
Congenital microvillous atrophy

MYO6
Deafness, Nonsyndromic hearing loss and deafness, Rare genetic deafness,

autosomal dominant 22

MYO7A
Deafness, MYO7A-Related Disorders, Rare genetic deafness, Retinal dystrophy,

Retinitis pigmentosa, Usher syndrome, Usher syndrome type 1, autosomal

dominant 11, autosomal recessive 2, type 1B

MYOCD
CONGENITAL, MEGABLADDER, Prune belly syndrome

MYRF
CARDIAC-UROGENITAL SYNDROME

NADSYN1
AND LIMB DEFECTS SYNDROME 3, CARDIAC, Congenital NAD deficiency

disorder, RENAL, VERTEBRAL

NAGLU
Charcot-Marie-Tooth disease, MPS-III-B, Mucopolysaccharidosis, Sanfilippo

syndrome, axonal type 2V

NALCN
Hypotonia, infantile, with psychomotor retardation and characteristic facies 1

NBAS
Fever-associated acute infantile liver failure syndrome, Infantile liver failure

syndrome 2

NBN
Acute lymphoid leukemia, Aplastic anemia, Breast-ovarian cancer, Familial cancer

of breast, Hereditary breast and ovarian cancer syndrome, Hereditary cancer-

predisposing syndrome, Lissencephaly, Microcephaly, Ovarian Neoplasms,

familial 1, normal intelligence and immunodeficiency

NCF1,
Chronic granulomatous disease, Chronic granulomatous disease due to deficiency

LOC106029312
of NCF-1, Granulomatous disease, autosomal recessive, autosomal recessive

cytochrome b-positive, chronic, cytochrome b-positive, type 1, type III

NCR1, NLRP7
1, Hydatidiform mole, recurrent

NCSTN
Familial acne inversa 1

NDE1
Lissencephaly 4

NDNF
HYPOGONADOTROPIC HYPOGONADISM 25 WITH ANOSMIA

NDUFA12
Leigh syndrome

NDUFAF2
Inborn genetic diseases, Leigh syndrome, MITOCHONDRIAL COMPLEX I

DEFICIENCY, Mitochondrial complex I deficiency, NDUFAF2-Related

Disorders, NUCLEAR TYPE 10, nuclear type 1

NDUFAF3
Mitochondrial complex I deficiency

NDUFB11
Linear skin defects with multiple congenital anomalies 3

NDUFS4
Leigh syndrome, Mitochondrial complex I deficiency, nuclear type 1

NDUFS6
MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 9

NDUFV1
MITOCHONDRIAL COMPLEX I DEFICIENCY, Mitochondrial complex I

deficiency, NUCLEAR TYPE 4, nuclear type 1

NEB
Inborn genetic diseases, Nemaline myopathy, Nemaline myopathy 2, Non-immune

hydrops fetalis

NEB, RIF1
Nemaline myopathy, Nemaline myopathy 2

NEBL
Hypertrophic cardiomyopathy, Long QT syndrome, Primary dilated

cardiomyopathy, Primary familial hypertrophic cardiomyopathy, Sudden

unexplained death

NEFL
Charcot-Marie-Tooth disease type 2E

NEK1
24, AMYOTROPHIC LATERAL SCLEROSIS, Majewski type,

SUSCEPTIBILITY TO, Short rib-polydactyly syndrome, Short-rib thoracic

dysplasia 3 with or without polydactyly

NEUROD1
Maturity-onset diabetes of the young type 6

NEXN
Dilated cardiomyopathy 1CC, Familial hypertrophic cardiomyopathy 20

NF1
Axillary freckling, CafÃ ©-au-lait macules with pulmonary stenosis, Focal T2

hyperintense basal ganglia lesion, Ganglioglioma, Hereditary cancer-predisposing

syndrome, Inborn genetic diseases, Juvenile myelomonocytic leukemia, Multiple

cafe-au-lait spots, Neurofibroma, Neurofibromas, Neurofibromatosis,

Neurofibromatosis-Noonan syndrome, Optic nerve glioma, Pilocytic astrocytoma,

Tibial pseudoarthrosis, familial spinal, type 1

NF1,
Hereditary cancer-predisposing syndrome, Neurofibromatosis, type 1

LOC111811965

NF2
Meningioma, Neurofibromatosis, type 2

NFIB
ACQUIRED, Intellectual disability, MACROCEPHALY, Macrocephalus, WITH

IMPAIRED INTELLECTUAL DEVELOPMENT

NFIX
Marshall-Smith syndrome

NGLY1
Congenital disorder of deglycosylation, Intellectual disability, Neuromotor delay,

Peripheral neuropathy

NHLRC1
Epilepsy, Lafora disease, progressive myoclonic 2b

NHLRC2
AND CEREBRAL ANGIOMATOSIS, FIBROSIS, NEURODEGENERATION

NHS
Nance-Horan syndrome

NIPAL4
Autosomal recessive congenital ichthyosis 6

NIPBL
Cornelia de Lange syndrome 1

NKX2-5
Abnormality of cardiovascular system morphology, Atrial septal defect 7 with or

without atrioventricular conduction defects

NKX3-2
Spondylo-megaepiphyseal-metaphyseal dysplasia

NKX6-2
AUTOSOMAL RECESSIVE, SPASTIC ATAXIA 8, WITH

HYPOMYELINATING LEUKODYSTROPHY

NLGN4X
Autism, Non-syndromic X-linked intellectual disability, X-linked 2, susceptibility

to

NLRP7
1, Hydatidiform mole, recurrent

NOTCH1
Adams-Oliver syndrome 5, Aortic valve disorder, congenital heart defect

NPC1
Niemann-Pick disease, Niemann-Pick disease type C1, type C

NPHP1
Nephronophthisis, Nephronophthisis 1

NPHP3, NPHP3-
Meckel syndrome type 7

ACAD11

NPHS1
Finnish congenital nephrotic syndrome

NPHS2
Idiopathic nephrotic syndrome, Nephrotic syndrome, idiopathic, steroid-resistant

NPHS2,
Idiopathic nephrotic syndrome, Nephrotic range proteinuria, Nephrotic syndrome,

AXDND1
idiopathic, steroid-resistant

NPRL3, HBA-
Epilepsy, familial focal, with variable foci 3

LCR

NR0B1
Congenital adrenal hypoplasia, X-linked

NR2E3
Abnormality of color vision, Cone-rod dystrophy, Enhanced s-cone syndrome,

Horizontal nystagmus, NR2E3-Related Disorders, Retinal dystrophy, Retinitis

pigmentosa, Retinitis pigmentosa 37, Visual impairment

NR3C2
Autosomal dominant pseudohypoaldosteronism type 1

NSD1
Beckwith-Wiedemann syndrome, Inborn genetic diseases, Sotos syndrome 1

NSD2
4p partial monosomy syndrome, Wolf-Hirschhom like syndrome

NSMCE2
Seckel syndrome 10

NSMF
Hypogonadotropic hypogonadism 9 with or without anosmia

NSUN2
Mental retardation, autosomal recessive 5

NT5E
Calcification of joints and arteries

NTHL1
Familial adenomatous polyposis 3, Hereditary cancer-predisposing syndrome

NTRK1
Hereditary insensitivity to pain with anhidrosis

OAT
Ornithine aminotransferase deficiency

OBSL1
Three M syndrome 2

OCA2
1, Skin/hair/eye pigmentation, Tyrosinase-positive oculocutaneous albinism,

variation in

OCLN
Pseudo-TORCH syndrome 1

OFD1
Joubert syndrome, Orofaciodigital syndrome I, Simpson-Golabi-Behmel

syndrome, type 2

OPA1
Abortive cerebellar ataxia, Dominant hereditary optic atrophy, Inborn genetic

diseases, Mitochondrial diseases, Retinal dystrophy

OPHN1
Mental retardation X-linked with cerebellar hypoplasia and distinctive facial

appearance

OPN1LW
Cone monochromatism

ORC6
Meier-Gorlin syndrome 3

OSGIN2, NBN
Hereditary cancer-predisposing syndrome, Microcephaly, normal intelligence and

immunodeficiency

OTC
Abnormality of ornithine metabolism, Hyperammonemia, Ornithine

carbamoyltransferase deficiency, Protein avoidance

OTOA
Deafness, Rare genetic deafness, autosomal recessive 22

OTOF
Deafness, Rare genetic deafness, autosomal recessive 9

OTOG
Deafness, Intellectual disability, Rare genetic deafness, Seizures, autosomal

recessive 18b

OTOGL
Rare genetic deafness

OTUD6B
Dysmorphic features, Epilepsy, Intellectual developmental disorder with

dysmorphic facies, Intellectual disability, and distal limb anomalies, seizures

OTX2
Syndromic microphthalmia type 5

P2RY12,
Platelet-type bleeding disorder 8

MED12L

P3H1
Osteogenesis imperfecta type 8

P3H2
Myopia, high, with cataract and vitreoretinal degeneration

P4HA2
Myopia 25, autosomal dominant

PAFAH1B1
Inborn genetic diseases, Lissencephaly due to LIS1 mutation

PAH
Phenylketonuria

PALB2
Basal cell carcinoma, Breast cancer, Cancer of the pancreas, Familial cancer of

breast, Fanconi anemia, Generalized hypopigmentation, Hereditary breast and

ovarian cancer syndrome, Hereditary cancer, Hereditary cancer-predisposing

syndrome, Neoplasm of the breast, Ovarian Neoplasms, PALB2-Related

Disorders, Pancreatic cancer 3, Pre-B-cell acute lymphoblastic leukemia,

Tracheoesophageal fistula, Tumor susceptibility linked to germline BAP1

mutations, complementation group N, susceptibility to

PANK2
Pigmentary pallidal degeneration

PAPSS2
Spondyloepimetaphyseal dysplasia, Pakistani type

PARN
Dyskeratosis congenita, autosomal recessive 6

PATL2
OOCYTE MATURATION DEFECT 4

PAX2
Focal segmental glomerulosclerosis 7, Renal coloboma syndrome

PAX3
Rare genetic deafness, Waardenburg syndrome, Waardenburg syndrome type 1

PAX6
Aniridia 1, Keratitis, autosomal dominant

PAX9
3, Tooth agenesis, selective

PC
Pyruvate carboxylase deficiency

PCCA
Propionic acidemia

PCCB
Propionic acidemia

PCDH15
DIGENIC, Deafness, Nonsyndromic Deafness, Rare genetic deafness, Retinal

dystrophy, TYPE ID/F, USHER SYNDROME, Usher syndrome, Usher syndrome

type 1, Usher syndrome type 1D, Usher syndrome type 1F, autosomal recessive

23, type 1G

PCDH19
Absence seizures, Delayed speech and language development, Early infantile

epileptic encephalopathy 9, Frontal cortical atrophy, Generalized seizures,

Generalized tonic-clonic seizures, Global developmental delay, Hand tremor, Long

palpebral fissure, Prominent fingertip pads, Strabismus, Temporal cortical atrophy

PCLO
Pontocerebellar hypoplasia type 3

PCNT
Microcephalic osteodysplastic primordial dwarfism type II

PCSK1,
Proprotein convertase ⅓ deficiency

LOC101929710

PCSK9
Familial hypercholesterolemia, Familial hypercholesterolemia 1, Low density

lipoprotein cholesterol level quantitative trait locus 1

PCYT1A
Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome

PDE11A
2, Pigmented nodular adrenocortical disease, primary

PDE6B
Retinal dystrophy, Retinitis pigmentosa, Retinitis pigmentosa 40

PDE6C
Achromatopsia 5

PDE8B
Striatal degeneration, autosomal dominant 1

PDHA1
Inborn genetic diseases, Pyruvate dehydrogenase E1-alpha deficiency

PDX1
DIABETES MELLITUS, Maturity-onset diabetes of the young type 4,

PERMANENT NEONATAL 1, Pancreatic agenesis 1

PDZD7
AUTOSOMAL RECESSIVE 57, DEAFNESS, Rare genetic deafness, Usher

syndrome, type 2A

PEPD
Prolidase deficiency

PEX1
Deafness enamel hypoplasia nail defects, Peroxisome biogenesis disorder 1A

(Zellweger), Peroxisome biogenesis disorder 1B, Peroxisome biogenesis disorders,

Retinal dystrophy, Zellweger syndrome spectrum

PEX1, GATAD1
Deafness enamel hypoplasia nail defects, Peroxisome biogenesis disorder 1A

(Zellweger), Peroxisome biogenesis disorder 1B, Peroxisome biogenesis disorders,

Zellweger syndrome spectrum

PEX10
Peroxisome biogenesis disorder, Peroxisome biogenesis disorder 6A, Peroxisome

biogenesis disorder 6B, Peroxisome biogenesis disorders, Zellweger syndrome

spectrum, complementation group 7

PEX10, PLCH2
Peroxisome biogenesis disorder 6B

PEX12
Infantile Refsums disease, Peroxisome biogenesis disorder 3A, Peroxisome

biogenesis disorders, Zellweger syndrome spectrum

PEX2
Peroxisome biogenesis disorder 5B, Peroxisome biogenesis disorder 5a

(zellweger), Peroxisome biogenesis disorders, Zellweger syndrome spectrum

PEX26
Peroxisome biogenesis disorder 7A, Peroxisome biogenesis disorder 7B,

Peroxisome biogenesis disorders, Zellweger syndrome spectrum

PEX6
Heimler syndrome 2, Peroxisome biogenesis disorder 4B, Peroxisome biogenesis

disorder 4a (zellweger), Peroxisome biogenesis disorders, Retinal dystrophy,

Zellweger syndrome spectrum

PEX7
PEX7-Related Disorders, Peroxisome biogenesis disorder 9B, Phytanic acid

storage disease, Rhizomelic chondrodysplasia punctata type 1

PGAM2, DBNL
Glycogen storage disease type X

PGAP1
Mental retardation, autosomal recessive 42

PGAP3
Hyperphosphatasia with mental retardation syndrome 4

PGM3, DOP1A
Immunodeficiency 23

PHEX
Familial X-linked hypophosphatemic vitamin D refractory rickets

PHEX, PTCHD1-
Familial X-linked hypophosphatemic vitamin D refractory rickets

AS

PHF3, EYS
Retinal dystrophy, Retinitis pigmentosa 25

PHF6
Borjeson-Forssman-Lehmann syndrome

PHGDH
Phosphoglycerate dehydrogenase deficiency

PHIP
Developmental delay, and dysmorphic features, intellectual disability, obesity

PHYH
1, Phytanic acid storage disease, Refsum disease, adult

PI4KA
Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

PIGA
Paroxysmal nocturnal hemoglobinuria 1

PIGN
Multiple congenital anomalies-hypotonia-seizures syndrome 1

PIGO
Hyperphosphatasia with mental retardation syndrome 2, Hyperphosphatasia-

intellectual disability syndrome

PIGT
Multiple congenital anomalies-hypotonia-seizures syndrome 3, PIGT-related

disorder

PIK3R1
SHORT syndrome

PINK1
Parkinson disease 6, autosomal recessive early-onset

PIRC66,
Aromatase deficiency

MIR4713HG,

CYP19A1

PITX3
Anterior segment mesenchymal dysgenesis, Cataract 11

PJVK
Deafness, Rare genetic deafness, autosomal recessive 59

PKD1
Autosomal recessive polycystic kidney disease, Polycystic kidney disease, adult

type

PKD1,
Polycystic kidney disease, adult type

LOC105371049

PKHD1
Autosomal recessive polycystic kidney disease, Polycystic kidney dysplasia,

Polycystic liver disease

PKP1
Epidermolysis bullosa simplex due to plakophilin deficiency

PKP2
Arrhythmogenic right ventricular cardiomyopathy, Arrhythmogenic right

ventricular dysplasia/cardiomyopathy, Arrhythmogenic ventricular

cardiomyopathy, Cardiac arrhythmia, Cardiomyopathy, Cardiovascular phenotype,

Sudden unexplained death, type 9

PLA2G5
Fleck retina, familial benign

PLA2G6
Infantile neuroaxonal dystrophy, Iron accumulation in brain, Neurodegeneration

with brain iron accumulation 2b, PLA2G6-associated neurodegeneration

PLCB1
Early infantile epileptic encephalopathy 12

PLCB4
Auriculocondylar syndrome 2

PLCD1
Leukonychia totalis

PLD1
Cardiac valvular defect, developmental

PLD3, PRX
Charcot-Marie-Tooth disease, SPINOCEREBELLAR ATAXIA 46

PLEC
Epidermolysis bullosa simplex with muscular dystrophy

PLN, CEP85L
Cardiac arrest, Cardiomyopathy, Cardiovascular phenotype, Dilated

cardiomyopathy 1P, Familial hypertrophic cardiomyopathy 18, Hypertrophic

cardiomyopathy, Primary dilated cardiomyopathy, Sudden cardiac death

PLOD1
Cardiovascular phenotype, Ehlers-Danlos syndrome, hydroxylysine-deficient

PLOD2
Bruck syndrome 2

PLP1, RAB9B
Hereditary spastic paraplegia 2

PLS3
Bone mineral density quantitative trait locus 18

PMFBP1
SPERMATOGENIC FAILURE 31

PMM2
Congenital disorder of glycosylation, type Ia

PMP22
Charcot-Marie-Tooth disease

PMS2
Acute lymphoid leukemia, Burkitt lymphoma, Colorectal cancer, Glioblastoma,

Hereditary cancer, Hereditary cancer-predisposing syndrome, Hereditary

nonpolyposis colon cancer, Hereditary nonpolyposis colorectal cancer type 4,

Lymphoma, Lynch syndrome, Lynch syndrome I, Pulmonary arterial hypertension,

Pulmonary insufficiency, Respiratory insufficiency, Tumor susceptibility linked to

germline BAP1 mutations, Turcot syndrome, non-polyposis

PNKD, CATIP-
Paroxysmal nonkinesigenic dyskinesia 1

AS2

PNKP
Ataxia-oculomotor apraxia 4, Early infantile epileptic encephalopathy 10, Early

infantile epileptic encephalopathy 12, History of neurodevelopmental disorder

PNPLA2
Neutral lipid storage myopathy

PNPLA6
Hereditary spastic paraplegia 39, Laurence-Moon syndrome, PNPLA6-related

disorders, Trichomegaly-retina pigmentary degeneration-dwarfism syndrome

PNPLA8
Mitochondrial myopathy-lactic acidosis-deafness syndrome

PNPO
Pyridoxal phosphate-responsive seizures

POC5
Retinitis pigmentosa, Syndromic retinitis pigmentosa

POGLUT1
Dowling-degos disease 4

POGZ
Global developmental delay, Speech apraxia, White-sutton syndrome, dysmorphy,

intellectual deficiency

POLA1
VAN ESCH-O DRISCOLL SYNDROME, Van Esch type, X-linked intellectual

disability

POLD1
Colorectal cancer 10, Hereditary cancer-predisposing syndrome, Mandibular

hypoplasia, and lipodystrophy syndrome, deafness, progeroid features

POLE
12, ADRENAL HYPOPLASIA CONGENITA, AND IMMUNODEFICIENCY,

Colorectal cancer, GENITAL ANOMALIES, Hereditary cancer-predisposing

syndrome, INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL

DYSPLASIA, susceptibility to

POLG
Generalized epilepsy, Global developmental delay, Obesity, Progressive sclerosing

poliodystrophy, Seizures

POLH
Xeroderma pigmentosum variant type

POLR1A
Acrofacial dysostosis, Cincinnati type

POLR1C
Treacher Collins syndrome 3

POLR1D
Treacher Collins syndrome 2

POLR2F, SOX10
Rare genetic deafness, Waardenburg syndrome type 4C

POLR3A
Hypomyelinating leukodystrophy 7, Neonatal pseudo-hydrocephalic progeroid

syndrome

POLR3B
Cerebellar hypoplasia with endosteal sclerosis, Hypogonadotropic hypogonadism

7 with or without anosmia, Hypomyelinating leukodystrophy 7, Hypomyelinating

leukodystrophy 8, with or without oligodontia and/or hypogonadotropic

hypogonadism

POMK
12, Muscular dystrophy-dystroglycanopathy (limb-girdle), type c

POMT1
1, Congenital muscular dystrophy-dystroglycanopathy with mental retardation,

Limb-girdle muscular dystrophy-dystroglycanopathy, Muscular dystrophy-

dystroglycanopathy (congenital with brain and eye anomalies), POMT1-Related

Disorders, Walker-Warburg congenital muscular dystrophy, type A, type B1, type

C1

POMT2
Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies,

Limb-girdle muscular dystrophy-dystroglycanopathy, type A2, type C2

POP1
Anauxetic dysplasia 2

POR
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis,

Disordered steroidogenesis due to cytochrome p450 oxidoreductase deficiency

PORCN
Focal dermal hypoplasia

POT1
10, Hereditary cancer-predisposing syndrome, Melanoma, cutaneous malignant,

susceptibility to

POU3F4
Deafness, Rare genetic deafness, X-linked 2

POU4F3
Rare genetic deafness

PPARG
Diabetes Mellitus, Diabetes mellitus, Noninsulin-Dependent, digenic, type II, with

Acanthosis Nigricans and Hypertension

PPIB
Osteogenesis imperfecta type 9

PPOX
Variegate porphyria

PPP1R12A
GENITOURINARY AND/OR BRAIN MALFORMATION SYNDROME

PPT1
History of neurodevelopmental disorder, Neuronal Ceroid-Lipofuscinosis,

Neuronal ceroid lipofuscinosis, Neuronal ceroid lipofuscinosis 1, Recessive

PQBP1
Delayed speech and language development, Hyperactivity, Inborn genetic diseases,

Intellectual disability, Microcephaly, Renpenning syndrome 1

PRB3
PRB3M(NULL)

PRDM16
Left ventricular noncompaction 8

PRDM5
Brittle cornea syndrome 2

PRDX1,
DIGENIC, METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC

MMACHC
TYPE

PRF1
Familial hemophagocytic lymphohistiocytosis, Familial hemophagocytic

lymphohistiocytosis 2

PRKAR1A
Carney complex, type 1

PRKAR1A,
Amelogenesis imperfecta type 1G

FAM20A

PRKAR1B,
18, Ciliary dyskinesia, primary

DNAAF5

PRKCSH
Polycystic liver disease 1

PRKN
Parkinson disease 2

PRMT7
Short stature, and seizures, brachydactyly, intellectual developmental disability

PROK2
Hypogonadotropic hypogonadism 4 with or without anosmia

PROKR2
Inborn genetic diseases, Kallmann syndrome 3

PROM1
Cone-rod dystrophy 12, PROM1-Related Disorders, Retinal dystrophy, Retinitis

pigmentosa, Retinitis pigmentosa 41

PROP1
Pituitary hormone deficiency, combined, combined 2

PRPH2
Macular dystrophy, Retinal dystrophy, Retinitis pigmentosa 7, Retinitis punctata

albescens, adult-onset, autosomal dominant, vitelliform

PRRT2
2, Episodic kinesigenic dyskinesia 1, History of neurodevelopmental disorder,

Infantile convulsions and choreoathetosis, Paroxysmal kinesigenic dyskinesia,

Paroxysmal nonkinesigenic dyskinesia 1, Seizures, benign familial infantile

PRSS12
Mental retardation, autosomal recessive 1

PRSS56
Microphthalmia, isolated 6

PRX
Charcot-Marie-Tooth disease, demyelinating, type 4F

PSAP
Combined saposin deficiency

PSEN1
3, Acne inversa, familial

PSENEN
2, Acne inversa, familial

PTCH1
Gorlin syndrome, Hereditary cancer-predisposing syndrome

PTCH2
Gorlin syndrome, Medulloblastoma

PTEN
Cowden syndrome, Cowden syndrome 1, Glioblastoma, Glioma susceptibility 2,

Hemangioma, Hereditary cancer-predisposing syndrome, Inborn genetic diseases,

Macrocephaly/autism syndrome, Malignant tumor of prostate, Meningioma,

Neoplasm of brain, Neoplasm of the breast, Neoplasm of the large intestine, Non-

small cell lung cancer, Ovarian Neoplasms, PTEN hamartoma tumor syndrome,

PTEN-related disorder, Proteus-like syndrome, VACTERL association with

hydrocephalus, familial

PTH1R
Chondrodysplasia Blomstrand type

PTPN11
Metachondromatosis

PTPRF
2, Breasts and/or nipples, aplasia or hypoplasia of

PTPRO
Nephrotic syndrome, type 6

PTS
BH4-deficient hyperphenylalaninemia A, Hyperphenylalaninemia, a, bh4-

deficient, due to partial pts deficiency

PUF60
Verheij syndrome

PURA
Apnea, Generalized hypotonia, Intellectual disability, Limb dystonia, Mental

retardation, PURA Syndrome, PURA-related severe neonatal hypotonia-seizures-

encephalopathy syndrome due to a point mutation, autosomal dominant 31

PUS7
AND SHORT STATURE, INTELLECTUAL DEVELOPMENTAL DISORDER

WITH ABNORMAL BEHAVIOR, MICROCEPHALY

PXDN
Anterior segment dysgenesis 7

PYCR1
Autosomal recessive cutis laxa type 2B

PYGL
Glycogen storage disease, type VI

PYGM
Glycogen storage disease, type V

RAB23
Carpenter syndrome, Carpenter syndrome 1

RAB27A
Griscelli syndrome, Griscelli syndrome type 2

RAB33B
Smith-McCort dysplasia 2

RAB3GAP1
Warburg micro syndrome 1

RABL3
5, PANCREATIC CANCER, SUSCEPTIBILITY TO

RAD50
Hereditary cancer-predisposing syndrome, Nijmegen breakage syndrome-like

disorder

RAD51C
Breast-ovarian cancer, Fanconi anemia, Hereditary breast and ovarian cancer

syndrome, Hereditary cancer-predisposing syndrome, Ovarian Neoplasms,

RAD51C-Related Disorders, complementation group O, familial 3

RAD51D,
Breast-ovarian cancer, Hereditary breast and ovarian cancer syndrome, Hereditary

RAD51L3-RFFL
cancer-predisposing syndrome, Ovarian Neoplasms, familial 4

RAD51L3-RFFL,
Breast-ovarian cancer, Hereditary cancer-predisposing syndrome, familial 4

RAD51D

RAI1
Smith-Magenis syndrome

RAPSN
11, Myasthenic syndrome, associated with acetylcholine receptor deficiency,

congenital

RARS1
9, Leukodystrophy, hypomyelinating

RASA1
Capillary malformation-arteriovenous malformation, Capillary malformation-

arteriovenous malformation 1

RB1
Hereditary cancer-predisposing syndrome, Neoplasm, Osteosarcoma,

Retinoblastoma, Small cell lung cancer, Urinary bladder cancer, trilateral

RBBP8
Microcephaly with mental retardation and digital anomalies

RBM20
Cardiovascular phenotype, Dilated cardiomyopathy 1DD, Primary dilated

cardiomyopathy

RBP3
Retinitis pigmentosa 66

RD3
Leber congenital amaurosis 12

RDH12
Retinitis pigmentosa 53

RDH5,
Fundus albipunctatus, Pigmentary retinal dystrophy, autosomal recessive

BLOC1S1-RDH5

RECQL
Hereditary cancer-predisposing syndrome

RECQL,
Hereditary cancer-predisposing syndrome

PYROXD1

RECQL4
B lymphoblastic leukemia lymphoma with t(12; 21)(p13; q22); TEL-AML1 (ETV6-

RUNX1), Baller-Gerold syndrome, High Grade Surface Osteosarcoma, Rapadilino

syndrome, Rothmund-Thomson syndrome, Rothmund-Thomson syndrome type 2

REEP6
Retinitis pigmentosa 77

RELT
AMELOGENESIS IMPERFECTA, TYPE IIIC

REN
Hyperproreninemia, familial

RET
Hirschsprung disease 1, Sensorineural hearing loss

RFX5
Bare lymphocyte syndrome, complementation group c, type II

RFXANK
Bare lymphocyte syndrome, complementation group B, type II

RFXAP
Bare Lymphocyte Syndrome, Bare lymphocyte syndrome 2, Complementation

Group D, Type II

RHAG
Rh-null, regulator type

RHCE
AMORPH TYPE, RH-NULL

RHO
Autosomal dominant retinitis pigmentosa

RIF1, NEB
Nemaline myopathy, Nemaline myopathy 2

RIN2
Macrocephaly, alopecia, and scoliosis, cutis laxa

RIPK1
IMMUNODEFICIENCY 57 WITH AUTOINFLAMMATION

RIPK4
Bartsocas-Papas syndrome

RNASEH2A
Aicardi Goutieres syndrome 4

RNASEH2B
Aicardi Goutieres syndrome 2

RNF113A
Trichothiodystrophy 5, nonphotosensitive

RNF216
Gordon Holmes syndrome

ROBO3
Gaze palsy, familial horizontal, with progressive scoliosis 1

RORA, RORA-
INTELLECTUAL DEVELOPMENTAL DISORDER WITH OR WITHOUT

AS1
EPILEPSY OR CEREBELLAR ATAXIA

RP1
Retinal dystrophy, Retinitis pigmentosa, Retinitis pigmentosa 1

RP1L1
RETINITIS PIGMENTOSA 88

RPE65
Leber congenital amaurosis 2, RETINITIS PIGMENTOSA 87 WITH

CHOROIDAL INVOLVEMENT, RPE65-Related Disorders, Retinal dystrophy,

Retinitis pigmentosa 20

RPGR
Inborn genetic diseases, Retinal dystrophy, Retinitis pigmentosa, Retinitis

pigmentosa 15, X-linked, and sinorespiratory infections, with deafness

RPGRIP1
Leber congenital amaurosis 6

RPGRIP1L
Joubert syndrome, Joubert syndrome 7

RPL36A-
Fabry disease

HNRNPH2, GLA

RPL5, DIPK1A
Diamond-Blackfan anemia, Diamond-Blackfan anemia 1

RPS10, RPS10-
Diamond-Blackfan anemia 9

NUDT3

RPS27
Diamond-Blackfan anemia 17

RPS6KA3
Coffin-Lowry syndrome, Mental retardation, X-linked 19

RSPH1
Kartagener syndrome, Primary ciliary dyskinesia, Primary ciliary dyskinesia 24

RSPH4A
11, Ciliary dyskinesia, Kartagener syndrome, Primary ciliary dyskinesia, primary

RSPO2
TETRAAMELIA SYNDROME 2

RTEL1, RTEL1-
3, 4, 5, Dyskeratosis congenita, Idiopathic fibrosing alveolitis, Pulmonary fibrosis

TNFRSF6B
and/or bone marrow failure, autosomal dominant, autosomal recessive, chronic

form, telomere-related

RTN2
Hereditary spastic paraplegia 12

RTTN
Congenital microcephaly, Microcephaly, and polymicrogyria with or without

seizures, short stature

RUNX1
Acute myeloid leukemia, Familial platelet disorder with associated myeloid

malignancy

RYR1
1, Central core myopathy, Malignant hyperthermia, Minicore myopathy, Multi-

minicore disease and atypical periodic paralysis, Neuromuscular disease, RYR1 -

Related Disorders, susceptibility to

SACS
Autosomal recessive spastic ataxia, Charlevoix-Saguenay spastic ataxia, Spastic

paraplegia

SAG
Oguchi s disease, Retinitis pigmentosa 47, SAG-Related Disorders

SALL1
Townes syndrome

SAMD9L
Ataxia-pancytopenia syndrome

SAMHD1
Aicardi Goutieres syndrome 5

SASH1
Dyschromatosis universalis hereditaria 1

SATB2
SATB2-Related Disorder

SBDS
Inborn genetic diseases, Shwachman-Diamond syndrome 1

SBF1
Charcot-Marie-Tooth disease type 4

SCAPER
Attention deficit hyperactivity disorder, INTELLECTUAL DEVELOPMENTAL

DISORDER AND RETINITIS PIGMENTOSA, Intellectual disability, Rod-cone

dystrophy, moderate

SCARB2
Epilepsy, progressive myoclonic 4, with or without renal failure

SCARF2
Van den Ende-Gupta syndrome

SCN1A
Autosomal dominant epilepsy, Early infantile epileptic encephalopathy, Familial

hemiplegic migraine type 3, Generalized epilepsy with febrile seizures plus,

History of neurodevelopmental disorder, Severe myoclonic epilepsy in infancy,

type 2, Dravet

SCN1A,
Autosomal dominant epilepsy, Early infantile epileptic encephalopathy, Epileptic

LOC102724058
encephalopathy, Generalized epilepsy with febrile seizures plus, Seizures, Severe

myoclonic epilepsy in infancy, type 2

SCN2A
SCN2A-related disorder

SCN5A
Brugada syndrome, Brugada syndrome (shorter-than-normal QT interval), Brugada

syndrome 1, Cardiovascular phenotype, Dilated cardiomyopathy 1E, Heart block,

Long QT syndrome 1, nonprogressive

SCN5A,
Brugada syndrome, Brugada syndrome (shorter-than-normal QT interval)

LOC110121269

SCN9A, SCN1A-
Generalized epilepsy with febrile seizures plus, Hereditary sensory and autonomic

AS1
neuropathy type IIA, Indifference to pain, autosomal recessive, congenital, type 7

SCNN1A
Autosomal recessive pseudohypoaldosteronism type 1, Idiopathic bronchiectasis

SCNN1B
Liddle syndrome 1

SCNN1G
Autosomal recessive pseudohypoaldosteronism type 1, LIDDLE SYNDROME 2

SCO1
Mitochondrial complex IV deficiency

SCP2
Leukoencephalopathy with dystonia and motor neuropathy

SDCCAG8
Bardet-Biedl syndrome, Bardet-Biedl syndrome 16, Senior-Loken syndrome 7

SDHA
Carney triad, Dilated cardiomyopathy 1GG, Hereditary cancer-predisposing

syndrome, Leigh syndrome, Mitochondrial complex II deficiency, Paragangliomas

5, Pilocytic astrocytoma

SDHAF2
Hereditary Paraganglioma-Pheochromocytoma Syndromes

SDHB
Carney-Stratakis syndrome, Gastrointestinal stromal tumor, Hereditary

Paraganglioma-Pheochromocytoma Syndromes, Hereditary cancer-predisposing

syndrome, Paragangliomas 4, Pheochromocytoma

SDHC
Gastrointestinal stromal tumor, Hereditary Paraganglioma-Pheochromocytoma

Syndromes, Hereditary cancer-predisposing syndrome, Paragangliomas 3

SDHD
Carney-Stratakis syndrome, Cowden syndrome 3, Hereditary Paraganglioma-

Pheochromocytoma Syndromes, Hereditary cancer-predisposing syndrome,

Paragangliomas 1, Paragangliomas 1 with sensorineural hearing loss,

Pheochromocytoma

SDR9C7
AUTOSOMAL RECESSIVE 13, CONGENITAL, ICHTHYOSIS

SEC23B
Congenital dyserythropoietic anemia

SEC24D
Cole-Carpenter syndrome 2

SECISBP2
Thyroid hormone metabolism, abnormal

SELENBP1
EXTRAORAL HALITOSIS DUE TO METHANETHIOL OXIDASE

DEFICIENCY, Extra oral halitosis

SELENON
Eichsfeld type congenital muscular dystrophy

SEMA3A
Hypogonadotropic hypogonadism 16 with or without anosmia

SEPSECS
Pontocerebellar hypoplasia type 2D

SEPTIN12
Spermatogenic failure 10

SERAC1
3-methylglutaconic aciduria with deafness, Mitochondrial oxidative

phosphorylation disorder, and Leigh-like syndrome, encephalopathy

SERPINA6
Corticosteroid-binding globulin deficiency

SERPINA7
Thyroxine-binding globulin quantitative trait locus

SERPINB6
Rare genetic deafness

SERPINB7
Palmoplantar keratoderma, nagashima type

SERPINC1
Antithrombin III deficiency

SERPINF1
Osteogenesis imperfecta, type VI

SERPING1
Hereditary angioedema type 1

SERPINH1
Osteogenesis imperfecta type 10

SETBP1
SETBP1-Related Disorder

SETD5
Inborn genetic diseases, Mental retardation, autosomal dominant 23

SF3B4
Hereditary hearing loss and deafness, Inborn genetic diseases, Nager syndrome

SFRP4
Pyle metaphyseal dysplasia

SFTPA1
Respiratory distress associated with prematurity

SFTPB
1, Surfactant metabolism dysfunction, pulmonary

SGCA
Autosomal recessive limb-girdle muscular dystrophy type 2D

SGCD
Neuromuscular disease

SGCE, CASD1
Myoclonic dystonia

SGCG
Severe autosomal recessive muscular dystrophy of childhood - North African type

SGSH
Developmental regression, Diarrhea, Gastrointestinal dysmotility, Global

developmental delay, MPS-III-A, Mucopolysaccharidosis, Nystagmus, Retinal

dystrophy, Sanfilippo syndrome, Severe visual impairment

SH2D1A
Lymphoproliferative syndrome 1, X-Linked Lymphoproliferative Syndrome, X-

linked

SH3PXD2B
Frank-Ter Haar syndrome

SH3TC2
Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 4, Inborn genetic

diseases, Mononeuropathy of the median nerve, SH3TC2-Related Disorders, mild,

type 4C

SHANK3
22q13.3 deletion syndrome, Autism spectrum disorder, History of

neurodevelopmental disorder, Inborn genetic diseases, SHANK3-Related Disorder

SHOX
Leri-Weill dyschondrosteosis

SI
Sucrase-isomaltase deficiency

SIX6
Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome

SKIV2L
Trichohepatoenteric syndrome 2

SLC10A7
AMELOGENESIS IMPERFECTA, AND SKELETAL DYSPLASIA WITH

SCOLIOSIS, SHORT STATURE

SLC12A1
Barrier syndrome, antenatal, type 1

SLC12A3
Familial hypokalemia-hypomagnesemia

SLC12A6
Agenesis of the corpus callosum with peripheral neuropathy, Charcot-Marie-Tooth

disease

SLC17A5
Salla disease, Sialic acid storage disease, severe infantile type

SLC19A1,
Knobloch syndrome 1

COL18A1

SLC19A2
Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and

sensorineural deafness

SLC19A3
Biotin-responsive basal ganglia disease

SLC22A5
Renal carnitine transport defect

SLC25A20
Carnitine acylcarnitine translocase deficiency

SLC26A2
3MC syndrome 2, Achondrogenesis, Atelosteogenesis type II, Diastrophic

dysplasia, Multiple epiphyseal dysplasia type 4, Osteochondrodysplasia,

SLC26A2-Related Disorders, type IB

SLC26A3
Congenital secretory diarrhea, chloride type

SLC26A4
Enlarged vestibular aqueduct, Pendred syndrome, Rare genetic deafness

SLC2A10
Arterial tortuosity syndrome, Cardiovascular phenotype

SLC2A2
Fanconi-Bickel syndrome

SLC30A8
Diabetes mellitus type 2

SLC33A1
Spastic paraplegia, Spastic paraplegia 42, autosomal dominant

SLC34A3
Autosomal recessive hypophosphatemic bone disease

SLC35A2
SLC35A2-CDG

SLC35D1
Schneckenbecken dysplasia

SLC37A4
Glucose-6-phosphate transport defect, Glycogen storage disease, Inborn genetic

diseases, Phosphate transport defect

SLC38A8
FOVEAL HYPOPLASIA 2 WITH OPTIC NERVE MISROUTING AND

ANTERIOR SEGMENT DYSGENESIS

SLC39A4
Hereditary acrodermatitis enteropathica

SLC45A2
Oculocutaneous albinism type 4

SLC4A1
Autosomal dominant distal renal tubular acidosis

SLC4A11
4, Corneal dystrophy, Corneal endothelial dystrophy, Fuchs endothelial

SLC52A3
Brown-Vialetto-Van Laere syndrome 1

SLC6A1
Myoclonic-atonic epilepsy, SLC6A1-Related Disorder

SLC9A3
Diarrhea 8, congenital, secretory sodium

SLC9A3,
Diarrhea 8, congenital, secretory sodium

SLC9A3-AS1

SLC9A6
Gastrostomy tube feeding in infancy, Global developmental delay, Recurrent

respiratory infections, Scoliosis, Seizures, Sleep disturbance

SLCO2A1
Primary hypertrophic osteoarthropathy, autosomal recessive 2

SLITRK1
Tourette Syndrome, Trichotillomania

SLURP1
Acroerythrokeratoderma

SMAD3
Familial thoracic aortic aneurysm and aortic dissection

SMAD4
Carcinoma of pancreas, Hereditary cancer-predisposing syndrome, Juvenile

polyposis syndrome, Juvenile polyposis/hereditary hemorrhagic telangiectasia

syndrome, Myhre syndrome

SMAD6
Aortic valve disease 2, Aortic valve disorder, CRANIOSYNOSTOSIS 7,

SUSCEPTIBILITY TO

SMARCA4
Neuroblastoma

SMARCAL1
Schimke immuno-osseous dysplasia

SMARCB1
Teratoid tumor, atypical

SMARCE1
Meningioma, familial

SMC1A
85, Congenital muscular hypertrophy-cerebral syndrome, EARLY INFANTILE,

EPILEPTIC ENCEPHALOPATHY, WITH OR WITHOUT MIDLINE BRAIN

DEFECTS

SMN1
Werdnig-Hoffmann disease

SMPD1
Niemann-Pick disease, Sphingomyelin/cholesterol lipidosis, type A, type B

SNAP29
2, CEDNIK syndrome, Leukodystrophy, hypomyelinating

SNRPB
Cerebro-costo-mandibular syndrome

SOHLH1
Nonsyndromic hypergonadotropic hypogonadism, OVARIAN DYSGENESIS 5

SON
Inborn genetic diseases, ZTTK syndrome

SOS1
Gingival fibromatosis 1

SOX2, SOX2-OT
Anophthalmia/microphthalmia-esophageal atresia syndrome

SOX9
Campomelic dysplasia with autosomal sex reversal, Camptomelic dysplasia

SOX9,
Campomelic dysplasia with autosomal sex reversal

LOC108021846

SP110, SP140
Hepatic veno-occlusive disease-immunodeficiency syndrome

SP7
Osteogenesis imperfecta type 12

SPART
Troyer syndrome

SPAST
Spastic paraplegia 4, autosomal dominant

SPEF2
Primary ciliary dyskinesia, SPERMATOGENIC FAILURE 43

SPEG
5, Myopathy, centronuclear

SPEG, ASIC4-
5, Myopathy, centronuclear

AS1

SPG11
Amyotrophic lateral sclerosis type 5, Hereditary spastic paraplegia, Spastic

paraplegia 11, autosomal recessive

SPG7
Hereditary spastic paraplegia, Hereditary spastic paraplegia 7, Mitochondrial

diseases

SPINK2
Spermatogenic failure 29

SPINK5
Netherton syndrome

SPNS2
AUTOSOMAL RECESSIVE 115, DEAFNESS, Inborn genetic diseases

SPRTN
Ruijs-Aalfs syndrome

SPTA1
Elliptocytosis 2, Hereditary pyropoikilocytosis

SPTB
Hereditary spherocytosis, Spherocytosis type 2

SQSTM1
Amyotrophic lateral sclerosis and/or frontotemporal dementia 1, Paget disease of

bone 2, SQSTM1-related disorder, early-onset

SRCAP
Floating-Harbor syndrome

SRPK2, KMT2E
See cases

SRY
46, XY sex reversal, type 1

ST14
Ichthyosis, autosomal recessive 11, congenital

STAG1
AUTOSOMAL DOMINANT 47, MENTAL RETARDATION

STAG3
Abnormality of the ovary, Female infertility, Premature ovarian failure 8,

Premature ovarian insufficiency

STAT1
Mycobacterial and viral infections, autosomal recessive, susceptibility to

STIM1
1, Combined immunodeficiency due to STIM1 deficiency, Myopathy, Stormorken

syndrome, tubular aggregate

STK11
Hereditary cancer-predisposing syndrome, Peutz-Jeghers syndrome

STRA6
Microphthalmia syndromic 9

STRC
Deafness, Rare genetic deafness, autosomal recessive 16

STXBP1
Early infantile epileptic encephalopathy, Early infantile epileptic encephalopathy

4, Epileptic encephalopathy

STXBP2
5, Hemophagocytic lymphohistiocytosis, familial

SUCLG1
Mitochondrial DNA depletion syndrome 9 (encephalomyopathic with

methylmalonic aciduria)

SUFU
Gorlin syndrome, Medulloblastoma, Medulloblastoma with extensive nodularity,

desmoplastic

SULT2B1
AUTOSOMAL RECESSIVE 14, Autosomal recessive congenital ichthyosis 2,

CONGENITAL, ICHTHYOSIS

SUMF1
Multiple sulfatase deficiency

SUN5
Spermatogenic failure 16

SURF1
Abnormal pyramidal signs, Cerebellar ataxia, Charcot-Marie-Tooth disease,

Dysarthria, Inborn genetic diseases, Leigh syndrome, Leigh syndrome due to COX

IV deficiency, Leigh syndrome due to mitochondrial complex IV deficiency,

Mitochondrial complex IV deficiency, Muscle weakness, type 4k

SUZ12
IMAGAWA-MATSUMOTO SYNDROME

SYCP2
Cryptozoospermia, Early spermatogenesis maturation arrest, Oligosynaptic

infertility

SYCP3
Spermatogenic failure 4

SYNE1
ARTHROGRYPOSIS MULTIPLEX CONGENITA, Cerebellar ataxia, Emery-

Dreifuss muscular dystrophy 4, MYOGENIC TYPE, Spinocerebellar ataxia,

autosomal dominant, autosomal recessive 8

SYNE4
Rare genetic deafness

SYNGAP1
Inborn genetic diseases, Mental retardation, autosomal dominant 5

SZT2
Early infantile epileptic encephalopathy 18

TAC3
Hypogonadotropic hypogonadism 10 with or without anosmia

TACO1
Mitochondrial complex IV deficiency

TALDO1
Deficiency of transaldolase

TANGO2
AND NEURODEGENERATION, Acute rhabdomyolysis, CARDIAC

ARRHYTHMIAS, Cardiac arrhythmia, Episodic flaccid weakness, Intellectual

functioning disability, METABOLIC CRISES, RECURRENT, Seizures, WITH

RHABDOMYOLYSIS

TAP1
Bare lymphocyte syndrome type 1

TAP2
Bare lymphocyte syndrome type 1, PEPTIDE TRANSPORTER PSF2

POLYMORPHISM

TAZ
3-Methylglutaconic aciduria type 2

TBC1D20
Warburg micro syndrome 4

TBC1D24
1, Caused by mutation in the TBC1 domain family, DOORS syndrome, Deafness,

Epileptic encephalopathy, Inborn genetic diseases, autosomal dominant 65, early

infantile, member 24

TBCK
Hypotonia, Inborn genetic diseases, Syndromic Infantile Encephalopathy, infantile,

with psychomotor retardation and characteristic facies 3

TBR1
Autism 5, Autistic behavior, Intellectual disability, Moderate global developmental

delay, Neurodevelopmental disorder, Severe global developmental delay

TBX19
Adrenocorticotropic hormone deficiency

TBX22
Cleft palate with ankyloglossia

TBX3
Ulnar-mammary syndrome

TBX4
Coxopodopatellar syndrome

TBX5
Congenital heart disease (variable), Holt-Oram syndrome

TBXAS1
Ghosal hematodiaphyseal dysplasia, Thromboxane synthetase deficiency

TCAP
Autosomal recessive limb-girdle muscular dystrophy type 2G, Dilated

cardiomyopathy 1N, Primary familial hypertrophic cardiomyopathy

TCF12
Craniosynostosis 3

TCF20
Neurodevelopmental abnormality

TCF4
Intellectual disability, Pitt-Hopkins syndrome

TCN2
Inborn genetic diseases, Transcobalamin II deficiency

TCOF1
Treacher Collins syndrome 1

TCTEX1D2
Short-rib thoracic dysplasia 17 with or without polydactyly

TCTEX1D2,
Short-rib thoracic dysplasia 17 with or without polydactyly

TM4SF19-

TCTEX1D2

TCTN2
Joubert syndrome, Meckel syndrome type 8

TCTN3
Orofacial-digital syndrome IV

TDO2
Hypertryptophanemia, familial

TDRD7
Cataract, autosomal recessive congenital 4

TDRD9
SPERMATOGENIC FAILURE 30

TECPR2
Spastic paraplegia 49, autosomal recessive

TECTA
Deafness, Nonsyndromic hearing loss and deafness, Rare genetic deafness,

autosomal dominant 12, autosomal recessive 21, neurosensory autosomal recessive

21

TENM3
MICROPHTHALMIA, SYNDROMIC 15

TENT5A
Osteogenesis imperfecta, type 18

TEX14
SPERMATOGENIC FAILURE 23

TEX15
SPERMATOGENIC FAILURE 25

TFAP2B
Patent ductus arteriosus 2

TFR2
Hemochromatosis type 3

TG
Iodotyrosyl coupling defect

TGFB2
Cardiovascular phenotype, Holt-Oram syndrome, Loeys-Dietz syndrome 4

TGFB3
Cardiovascular phenotype, Loeys-Dietz syndrome 5

TGFBR1
Familial thoracic aortic aneurysm and aortic dissection

TGFBR2
Familial thoracic aortic aneurysm and aortic dissection, Hereditary nonpolyposis

colorectal cancer type 6, Loeys-Dietz syndrome, Loeys-Dietz syndrome 2,

Malignant tumor of esophagus

TGM1
Autosomal recessive congenital ichthyosis 1, Ichthyosis (disease)

TGM5
Peeling skin syndrome 2

TH
Segawa syndrome, autosomal recessive

THRB
Thyroid hormone resistance, autosomal dominant, generalized

TICAM1
4, Herpes simplex encephalitis, susceptibility to

TIMM8A
Deafness dystonia syndrome

TIMMDC1
Leigh syndrome

TJP2
Progressive familial intrahepatic cholestasis 4

TK2
Mitochondrial DNA depletion syndrome 2

TLR5
1, Legionellosis, Melioidosis, Systemic lupus erythematosus, resistance to

TM4SF20
Specific language impairment 5

TMC1
Deafness, Dominant, Nonsyndromic Hearing Loss, Rare genetic deafness,

autosomal recessive 7

TMCO1
Craniofacial dysmorphism, and mental retardation syndrome, skeletal anomalies

TMCO6,
Cystic Leukoencephalopathy

NDUFA2

TMEM127
Hereditary Paraganglioma-Pheochromocytoma Syndromes, Hereditary cancer-

predisposing syndrome, Pheochromocytoma

TMEM216
Joubert syndrome, Joubert syndrome 2, Meckel syndrome, TMEM216-Related

Disorders, type 2

TMEM237
Joubert syndrome

TMEM260
Structural heart defects and renal anomalies syndrome

TMEM67
Cerebellar vermis hypoplasia, Generalized hypotonia, Iris coloboma, Joubert

syndrome, Joubert syndrome 6, Meckel syndrome, Meckel-Gruber syndrome,

Nystagmus, TMEM67-Related Disorders, type 3

TMEM70
Mitochondrial proton-transporting ATP synthase complex deficiency, Nuclearly-

encoded mitochondrial complex V (ATP synthase) deficiency 2

TMEM94
Intellectual developmental disorder with cardiac defects and dysmorphic facies

TMEM99, KRT10
Bullous ichthyosiform erythroderma

TMPRSS3
Deafness, Inborn genetic diseases, Rare genetic deafness, autosomal recessive 8

TNFRSF10B
Squamous cell carcinoma of the head and neck

TNFRSF11B
Hyperphosphatasemia with bone disease

TNFRSF13B
Absent epiphyses, Chronic lung disease, Cleft palate, Clubfoot, Coat hanger sign

of ribs, Common Variable Immune Deficiency, Common variable

immunodeficiency 2, Dominant, Hemivertebrae, Immunoglobulin A deficiency 2,

Interstitial pulmonary abnormality, Micrognathia, Patent ductus arteriosus,

Preaxial foot polydactyly, Pseudoarthrosis, Respiratory failure, Short femur,

Skeletal dysplasia, Vertebral hypoplasia, Vertebral segmentation defect

TNFRSF1A
5, Familial Periodic Fever, Multiple sclerosis, susceptibility to

TNFSF11
Autosomal recessive osteopetrosis 2

TNNI3
Cardiovascular phenotype

TNNI3K, FPGT-
Cardiac conduction disease with or without dilated cardiomyopathy

TNNI3K

TNNT2
Cardiomyopathy, Cardiovascular phenotype, Familial hypertrophic

cardiomyopathy 2, Familial restrictive cardiomyopathy 3, Hypertrophic

cardiomyopathy, Left ventricular noncompaction 6, Primary familial hypertrophic

cardiomyopathy

TNPO3
Limb-girdle muscular dystrophy, type 1F

TNXB
1, Ehlers-Danlos syndrome, Ehlers-Danlos syndrome due to tenascin-X deficiency,

classic-like

TONSL
Sponastrime dysplasia

TONSL, TONSL-
Sponastrime dysplasia

AS1

TOP3A
AND INCREASED SISTER CHROMATID EXCHANGE 2, GROWTH

RESTRICTION, MICROCEPHALY

TOPORS
Retinal dystrophy, Retinitis pigmentosa

TP53
Head and Neck Neoplasms, Hereditary cancer-predisposing syndrome, Li-

Fraumeni syndrome, Li-Fraumeni syndrome 1, Li-Fraumeni-like syndrome,

Multiple myeloma, Neoplasm of the large intestine, Ovarian Neoplasms

TP63
Ectrodactyly, Orofacial cleft 8, and cleft lip/palate syndrome 3, ectodermal

dysplasia

TPI1
Triosephosphate isomerase deficiency

TPM2
ARTHROGRYPOSIS, DISTAL, TYPE 2B4

TPO
Deficiency of iodide peroxidase

TPP1
Ceroid lipofuscinosis neuronal 2, Childhood-onset autosomal recessive slowly

progressive spinocerebellar ataxia, Inborn genetic diseases, Neuronal ceroid

lipofuscinosis

TPRN
Deafness, autosomal recessive 79

TRAPPC11
Limb-girdle muscular dystrophy, type 2S

TRAPPC2
Spondyloepiphyseal dysplasia tarda

TRDN
5, Catecholaminergic polymorphic ventricular tachycardia, Ventricular

tachycardia, catecholaminergic polymorphic, with or without muscle weakness

TREX1, ATRIP,
Aicardi Goutieres syndrome 1, Chilblain Lupus, Retinal vasculopathy with

ATRIP-TREX1
cerebral leukoencephalopathy and systemic manifestations, TREX1-Related

Disorders

TRIM14, NANS
Genevieve type, Spondyloepimetaphyseal dysplasia

TRIM32, ASTN2
Limb-girdle muscular dystrophy

TRIOBP
Nonsyndromic hearing loss and deafness

TRIP11
Achondrogenesis, Goldblatt hypertension, Osteochondrodysplasia, type IA

TRMU
Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins

TRNT1
Retinitis pigmentosa and erythrocytic microcytosis, Sideroblastic anemia with B-

cell immunodeficiency, and developmental delay, periodic fevers

TRPM4
Cardiomyopathy, Progressive familial heart block type IB, TRPM4-Related

Disorders

TRPS1
Trichorhinophalangeal dysplasia type I

TRPV4
Charcot-Marie-Tooth disease axonal type 2C

TRPV6
HYPERPARATHYROIDISM, TRANSIENT NEONATAL

TSC1
Cortical dysplasia, Cortical tubers, Focal cortical dysplasia type II, Hereditary

cancer-predisposing syndrome, Lymphangiomyomatosis, Multiple renal cysts,

Renal cortical cysts, Renal insufficiency, Seizures, Tuberous sclerosis 1, Tuberous

sclerosis syndrome, Urinary bladder cancer

TSC2
Focal cortical dysplasia type II, Lymphangiomyomatosis, Tuberous sclerosis 2,

Tuberous sclerosis syndrome

TSFM
Combined oxidative phosphorylation deficiency 3, Primary dilated

cardiomyopathy

TSHB
Secondary hypothyroidism

TSHR
1, Hypothyroidism, congenital, nongoitrous

TSHZ1
Aural atresia, congenital

TSPAN1,
Congenital muscular alpha-dystroglycanopathy with brain and eye anomalies,

POMGNT1
Congenital muscular dystrophy-dystroglycanopathy with mental retardation, Limb-

girdle muscular dystrophy-dystroglycanopathy, Muscle eye brain disease,

POMGNT1-Related Disorders, Retinitis pigmentosa 76, type B3, type C3

TSPAN12
Exudative vitreoretinopathy 5

TSPAN7
Mental retardation 58, X-linked

TSPEAR
ECTODERMAL DYSPLASIA 14, HAIR/TOOTH TYPE WITH

HYPOHIDROSIS

TSPEAR-AS1,
Deafness, ECTODERMAL DYSPLASIA 14, HAIR/TOOTH TYPE WITH

TSPEAR
HYPOHIDROSIS, autosomal recessive 98

TTC19
Mitochondrial complex III deficiency, nuclear type 2

TTC21A
SPERMATOGENIC FAILURE 37

TTC21B,
SHORT-RIB THORACIC DYSPLASIA 4 WITH POLYDACTYLY

TTC21B-AS1

TTC29
SPERMATOGENIC FAILURE 42

TTC37
Trichohepatoenteric syndrome, Trichohepatoenteric syndrome 1

TTC7A
Multiple gastrointestinal atresias

TTLL5
Cone-rod dystrophy 19

TTN
Cardiomyopathy, Cardiovascular phenotype, Dilated cardiomyopathy 1G, Limb-

girdle muscular dystrophy, Myotubular myopathy, Primary dilated

cardiomyopathy, Tibial muscular dystrophy, type 2J

TTN-AS1, TTN
Cardiovascular phenotype, Dilated cardiomyopathy 1G, Limb-girdle muscular

dystrophy, Primary dilated cardiomyopathy, TTN-Related Disorders, type 2J

TTN,
Primary dilated cardiomyopathy

LOC101927055

TTN, TTN-AS1
9, Broad-based gait, Cardiomyopathy, Cardiovascular phenotype, Congenital

muscular dystrophy, Decreased patellar reflex, Delayed gross motor development,

Dilated cardiomyopathy 1G, Dilated cardiomyopathy 1S, Distal muscle weakness,

Familial dilated cardiomyopathy, Familial hypertrophic cardiomyopathy 9, Gowers

sign, Heart murmur, Limb-girdle muscular dystrophy, Muscular dystrophy,

Myopathy, Primary dilated cardiomyopathy, Proximal lower limb amyotrophy,

Scoliosis, Severe muscular hypotonia, TTN-Related disorder, Tibial muscular

dystrophy, Waddling gait, early-onset, myofibrillar, type 2J, with early respiratory

failure, with fatal cardiomyopathy

TTPA
Ataxia, Familial isolated deficiency of vitamin E, Friedreich-like, with isolated

vitamin E deficiency

TUB, RIC3
Retinal dystrophy and obesity

TUBA3D,
KERATOCONUS 9

MZT2A

TUBB8
Oocyte maturation defect 2

TULP1
Leber congenital amaurosis, Retinitis pigmentosa

TWIST1
Craniosynostosis 1, Robinow-Sorauf syndrome, Saethre-Chotzen syndrome

TXNL4A
Burn-McKeown syndrome

TYK2
Tyrosine kinase 2 deficiency

TYR
3, Albinism, Inborn genetic diseases, Myopia (disease), Nonsyndromic

Oculocutaneous Albinism, Nystagmus, Oculocutaneous albinism, Oculocutaneous

albinism type 1B, Skin/hair/eye pigmentation, Tyrosinase-negative oculocutaneous

albinism, ocular, variation in, with sensorineural deafness

TYRP1,
Oculocutaneous albinism type 3

LURAP1L-AS1

UBAP1
AUTOSOMAL DOMINANT, SPASTIC PARAPLEGIA 80

UBE3A, SNHG14
Angelman syndrome, History of neurodevelopmental disorder, Inborn genetic

diseases

UBE3B
Kaufman oculocerebrofacial syndrome

UBR1
Johanson-Blizzard syndrome

UCP3
Obesity, and type II diabetes, severe

UGT1A,
Crigler-Najjar syndrome, Crigler-Najjar syndrome type 1, type II

UGT1A10,

UGT1A8,

UGT1A7,

UGT1A6,

UGT1A5,

UGT1A9,

UGT1A4,

UGT1A1,

UGT1A3

UNC13D
Familial hemophagocytic lymphohistiocytosis 3

UNC80
Hypotonia, Hypotonia-speech impairment-severe cognitive delay syndrome,

infantile, with psychomotor retardation and characteristic facies 2

UNG
Hyper-IgM syndrome type 5

UPF3B
Mental retardation, X-linked, syndromic 14

USH1C
Deafness, Rare genetic deafness, Retinal dystrophy, Retinitis pigmentosa, Usher

syndrome, Usher syndrome type 1, autosomal recessive 18, type 1C

USH2A
Abnormality of the upper limb, Abnormality of upper limb bone, Abnormality of

upper limb joint, Anxiety, Brisk reflexes, Chronic pain, Cognitive impairment,

Cone-rod dystrophy, Congenital sensorineural hearing impairment, Congenital

stationary night blindness, Dislocated radial head, Distal arthrogryposis,

Dysautonomia, Hearing impairment, High palate, Inborn genetic diseases, Macular

dystrophy, Multiple joint contractures, Rare genetic deafness, Retinal dystrophy,

Retinitis pigmentosa, Retinitis pigmentosa 39, Short stature, USH2A-Related

Disorders, Usher syndrome, Usher syndrome type 2, type 2A

USH2A, USH2A-
Rare genetic deafness, Retinal dystrophy, Retinitis pigmentosa 39, USH2A-

AS1
Related Disorders, Usher syndrome, type 2A

USH2A, USH2A-
Rare genetic deafness, Retinitis pigmentosa 39, Usher syndrome, type 2A

AS2

USP18
Pseudo-TORCH syndrome 2

USP27X
Mental retardation, X-linked 105

USP9X
Mental retardation, USP9X related disorders, X-linked 99, female-restricted,

syndromic

VCL
Dilated cardiomyopathy 1W, Familial hypertrophic cardiomyopathy 15, Primary

dilated cardiomyopathy

VHL
2, Erythrocytosis, Hereditary cancer-predisposing syndrome, Von Hippel-Lindau

syndrome, familial

VHL,
1, 2, Erythrocytosis, Hereditary cancer-predisposing syndrome, Renal cell

LOC107303340
carcinoma, Von Hippel-Lindau syndrome, familial, papillary

VIM, VIM-AS1
Cataract 30, Congenital cataract

VIPAS39
Arthrogryposis, and cholestasis 2, renal dysfunction

VPS13A
Choreoacanthocytosis

VPS13B
Abnormality of the eye, Cohen syndrome, Inborn genetic diseases, Intellectual

disability, Microcephaly, Neutropenia, Progressive visual loss, Recurrent aphthous

stomatitis, Retinal dystrophy, Short foot, Short stature, Small hand

VPS33B
Arthrogryposis, Inborn genetic diseases, and cholestasis 1, renal dysfunction

VRK2, FANCL
Fanconi anemia, complementation group A, complementation group L

VWF
von Willebrand disorder

WAC
Desanto-shinawi syndrome

WAS
Wiskott-Aldrich syndrome, X-linked severe congenital neutropenia, X-linked

thrombocytopenia with normal platelets

WDR35
Cranioectodermal dysplasia, Cranioectodermal dysplasia 2, Jeune thoracic

dystrophy, SHORT-RIB THORACIC DYSPLASIA 7 WITHOUT

POLYDACTYLY, Short Rib Polydactyly Syndrome, Short rib polydactyly

syndrome 5, Short-rib thoracic dysplasia 7/20 with polydactyly, WDR35-Related

Disorders, digenic

WDR45
Neurodegeneration with brain iron accumulation, Neurodegeneration with brain

iron accumulation 5

WDR72
Amelogenesis imperfecta

WDR73
Galloway-Mowat syndrome 1

WEE2-AS1,
OOCYTE MATURATION DEFECT 5

WEE2

WFS1
Autosomal dominant nonsyndromic deafness 6, Diabetes mellitus AND insipidus

with optic atrophy AND deafness, WFS1-Related Spectrum Disorders, Wolfram-

like syndrome, autosomal dominant

WHRN
Deafness, Rare genetic deafness, Usher syndrome, autosomal recessive 31, type

2D

WRN
Medulloblastoma, Werner syndrome

WT1
Drash syndrome, Frasier syndrome, Wilms tumor, Wilms tumor 1, and mental

retardation syndrome, aniridia, genitourinary anomalies

WT1,
Drash syndrome, Frasier syndrome, Pre-B-cell acute lymphoblastic leukemia,

LOC107982234
Wilms tumor, Wilms tumor 1, and mental retardation syndrome, aniridia,

genitourinary anomalies

XDH
Deficiency of xanthine oxidase

XIAP
Lymphoproliferative syndrome 2, X-linked

XK
McLeod neuroacanthocytosis syndrome

XPA
Xeroderma pigmentosum, Xeroderma pigmentosum group A

XPC
Xeroderma pigmentosum, group C

XRCC2
Fanconi anemia, Hereditary Cancer Syndrome, Hereditary breast and ovarian

cancer syndrome, Hereditary cancer-predisposing syndrome, Ovarian Neoplasms,

complementation group U

XRCC4
Short stature, and endocrine dysfunction, microcephaly

XYLT1
Desbuquois dysplasia 2

XYLT1,
Desbuquois dysplasia 2

LOC102723692

XYLT2
Inborn genetic diseases, Spondyloocular syndrome, autosomal recessive

YY1AP1
Grange syndrome

ZBTB18
Mental retardation, autosomal dominant 22

ZDBF2
Nasopalpebral lipoma-coloboma syndrome

ZEB2
Mowat-Wilson syndrome

ZFYVE26
Hereditary spastic paraplegia 15, Spastic paraplegia

ZFYVE26,
Abnormality of the eye, Leber congenital amaurosis 13, RDH12-Related

RDH12
Disorders, Retinal dystrophy, Retinitis pigmentosa

ZMPSTE24
Lethal tight skin contracture syndrome, Mandibuloacral dysplasia with type B

lipodystrophy, ZMPSTE24-Related Disorders

ZNF408
Retinitis pigmentosa 72

ZNF462
Craniosynostosis, Mental retardation, WEISS-KRUSZKA SYNDROME,

autosomal dominant

ZNF711
ZNF711-Related X-linked Mental Retardation

ZP1
Oocyte maturation defect 1

ZP2
OOCYTE MATURATION DEFECT 6

Use of TREMs

A TREM composition (e.g., a pharmaceutical TREM composition described herein) can modulate a function in a cell, tissue or subject having an endogenous ORF having a codon comprising a first sequence, e.g., a mutation, e.g., a premature termination codon.

In embodiments, a TREM composition (e.g., a pharmaceutical TREM composition) described herein is contacted with a cell or tissue, or administered to a subject in need thereof, in an amount and for a time sufficient to modulate expression of a protein encoded by an endogenous ORF having a first sequence, e.g., a mutation, e.g., a premature termination codon. In embodiments, a TREM composition (e.g., a pharmaceutical TREM composition described herein is contacted with a cell or tissue, or administered to a subject in need thereof, in an amount and for a time sufficient to treat a disease or disorder associated with a PTC, e.g., as described herein.

Methods of Modulating a Production Parameter of an RNA Corresponding to, or a Protein Encoded by an Endogenous ORF Having a PTC with a TREM Composition

A production parameter of an RNA corresponding to, or a protein encoded by a nucleic acid sequence comprising an endogenous ORF having a codon having a first sequence, e.g., a mutation, e.g., a premature termination codon, can be modulated by administration of a TREM composition comprising a TREM which pairs with, e.g., recognizes the codon having the first sequence.

In an aspect, provided herein is a method of modulating a production parameter of an RNA corresponding to, or a protein encoded by, a nucleic acid sequence comprising an endogenous ORF having a codon having a first sequence, e.g., a mutation, e.g., a premature termination codon, in a target cell or tissue, comprising:

providing, e.g., administering, to the target cell or tissue, or contacting the target cell or tissue with, an effective amount of a TREM composition, e.g., comprising a TREM, TREM fragment or TREM core fragment,

thereby modulating the production parameter of the RNA, or protein in the target cell or tissue.

The TREM composition can be administered to the subject or the target cell or tissue can be contacted ex vivo with the TREM composition.

Modulation of a production parameter of an RNA corresponding to, or a protein encoded by a nucleic acid sequence comprising an endogenous ORF having a codon having a first sequence, e.g., a mutation, e.g., a premature termination codon, by administration of a TREM composition, e.g., comprising a TREM, TREM fragment or TREM core fragment, comprises modulation of an expression parameter and/or a signaling parameter, e.g., as described herein.

For example, administration of a TREM composition to a target cell or tissue can result in an increase or decrease in any one or more of the following expression parameters for the RNA corresponding to, or protein encoded by a nucleic acid sequence comprising the endogenous ORF having the first sequence, e.g., mutation, e.g., PTC:

(a) protein translation;

(b) expression level (e.g., of polypeptide or protein, or mRNA);

(d) folding (e.g., of polypeptide or protein, or mRNA),

(e) structure (e.g., of polypeptide or protein, or mRNA),

(f) transduction (e.g., of polypeptide or protein),

(g) compartmentalization (e.g., of polypeptide or protein, or mRNA),

(h) incorporation (e.g., of polypeptide or protein, or mRNA) into a supermolecular structure, e.g., incorporation into a membrane, proteasome, or ribosome,

(i) incorporation into a multimeric polypeptide, e.g., a homo or heterodimer, and/or

(j) stability.

As another example, administration of a TREM composition to a target cell or tissue can result in an increase or decrease in any one or more of the following signaling parameters for the RNA corresponding to, or protein encoded by a nucleic acid sequence comprising the endogenous ORF having the first sequence, e.g., mutation, e.g., PTC:

(1) modulation of a signaling pathway, e.g., a cellular signaling pathway which is downstream or upstream of the protein encoded by the endogenous ORF comprising the PTC;

(2) cell fate modulation;

(3) ribosome occupancy modulation;

(4) protein translation modulation;

(5) mRNA stability modulation;

(6) protein folding and structure modulation;

(7) protein transduction or compartmentalization modulation; and/or

(8) protein stability modulation.

A production parameter (e.g., an expression parameter and/or a signaling parameter) may be modulated, e.g., increased, e.g., by at least 5% (e.g., at least 10%, 15%, 20%, 25%, 30%, 40%. 50%. 60%. 70%, 80%, 90%, 100%, 150%, 200% or more) compared to a reference, e.g., an RNA corresponding to or a polypeptide encoded by a nucleic acid sequence comprising an endogenous ORF having a non-mutated codon, e.g., wildtype codon. In some embodiments, the reference polypeptide encoded by the endogenous ORF having a non-mutated codon comprises a pre-mutation amino acid, e.g., wildtype amino acid, at the position corresponding to the non-mutated codon.

In some embodiments, the production parameter (e.g., an expression parameter and/or a signaling parameter) is increased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 2 50%, about 300%, about 3 50%, about 400%, about 4 50%, about 500%, about 600%, about 700%, about 800%, about 900%, about 1000%, or more compared to a reference, e.g., as described herein.

In some embodiments, the production parameter (e.g., an expression parameter and/or a signaling parameter) is increased from about 100% to about 1000%, about 100% to about 900%, about 100% to about 800%, about 100% to about 700%, about 100% to about 600%, about 100% to about 500%, about 100% to about 400%, about 100% to about 300%, about 100% to about 200%, about 200% to about 1000%, about 200% to about 900%, about 200% to about 800%, about 200% to about 700%, about 200% to about 600%, about 200% to about 500%, about 200% to about 400%, about 200% to about 300%, about 300% to about 1000%, about 300% to about 900%, about 300% to about 800%, about 300% to about 700%, about 300% to about 600%, about 300% to about 500%, about 300% to about 400%, about 400% to about 1000%, about 400% to about 900%, about 400% to about 800%, about 400% to about 700%, about 400% to about 600%, about 400% to about 500%, about 500% to about 1000%, about 500% to about 900%, about 500% to about 800%, about 500% to about 700%, about 500% to about 600%, about 600% to about 1000%, about 600% to about 900%, about 600% to about 800%, about 600% to about 700%, about 700% to about 1000%, about 700% to about 900%, about 700% to about 800%, about 800% to about 1000%, about 800% to about 900%, or about 900% to about 1000% compared to a reference, e.g., as described herein.

In some embodiments, the production parameter (e.g., an expression parameter and/or a signaling parameter) is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 2 50%, about 300%, about 3 50%, about 400%, about 4 50%, about 500%, about 600%, about 700%, about 800%, about 900%, about 1000%, or more compared to a reference, e.g., as described herein.

In some embodiments, the production parameter (e.g., an expression parameter and/or a signaling parameter) is decreased from about 100% to about 1000%, about 100% to about 900%, about 100% to about 800%, about 100% to about 700%, about 100% to about 600%, about 100% to about 500%, about 100% to about 400%, about 100% to about 300%, about 100% to about 200%, about 200% to about 1000%, about 200% to about 900%, about 200% to about 800%, about 200% to about 700%, about 200% to about 600%, about 200% to about 500%, about 200% to about 400%, about 200% to about 300%, about 300% to about 1000%, about 300% to about 900%, about 300% to about 800%, about 300% to about 700%, about 300% to about 600%, about 300% to about 500%, about 300% to about 400%, about 400% to about 1000%, about 400% to about 900%, about 400% to about 800%, about 400% to about 700%, about 400% to about 600%, about 400% to about 500%, about 500% to about 1000%, about 500% to about 900%, about 500% to about 800%, about 500% to about 700%, about 500% to about 600%, about 600% to about 1000%, about 600% to about 900%, about 600% to about 800%, about 600% to about 700%, about 700% to about 1000%, about 700% to about 900%, about 700% to about 800%, about 800% to about 1000%, about 800% to about 900%, or about 900% to about 1000% compared to a reference, e.g., as described herein.

A production parameter described herein may be measured by any method known in the art. For example Western blotting can be used to measure protein levels and quantitative RT-PCR or Northern blotting can be used to measure RNA levels.

Methods of Modulating Expression of a Protein Encoded by an Endogenous ORF Having a PTC with a TREM Composition

Expression and/or activity of a protein encoded by a nucleic acid sequence comprising an endogenous ORF having a codon having a first sequence, e.g., a mutation, e.g., a premature termination codon, can be modulated by administration of a TREM composition comprising a TREM which pairs with, e.g., recognizes the codon having the first sequence.

In an aspect, provided herein is a method of modulating the expression and/or activity of a protein encoded by a nucleic acid sequence comprising an endogenous ORF having a codon having a first sequence, e.g., a mutation, e.g., a premature termination codon, in a target cell or tissue, comprising:

thereby modulating the expression and/or activity of the protein in the target cell or tissue.

In some embodiments, the expression and/or activity of a polypeptide encoded by an endogenous ORF having a codon comprising a first sequence, e.g., a mutation, e.g., a PTC, is increased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 2 50%, about 300%, about 3 50%, about 400%, about 4 50%, about 500%, about 600%, about 700%, about 800%, about 900%, about 1000%, or more compared to a reference, e.g., as described herein.

In some embodiments, the expression and/or activity of a polypeptide encoded by the endogenous ORF having a codon comprising a first sequence, e.g., a mutation, e.g., a PTC, is increased from about 100% to about 1000%, about 100% to about 900%, about 100% to about 800%, about 100% to about 700%, about 100% to about 600%, about 100% to about 500%, about 100% to about 400%, about 100% to about 300%, about 100% to about 200%, about 200% to about 1000%, about 200% to about 900%, about 200% to about 800%, about 200% to about 700%, about 200% to about 600%, about 200% to about 500%, about 200% to about 400%, about 200% to about 300%, about 300% to about 1000%, about 300% to about 900%, about 300% to about 800%, about 300% to about 700%, about 300% to about 600%, about 300% to about 500%, about 300% to about 400%, about 400% to about 1000%, about 400% to about 900%, about 400% to about 800%, about 400% to about 700%, about 400% to about 600%, about 400% to about 500%, about 500% to about 1000%, about 500% to about 900%, about 500% to about 800%, about 500% to about 700%, about 500% to about 600%, about 600% to about 1000%, about 600% to about 900%, about 600% to about 800%, about 600% to about 700%, about 700% to about 1000%, about 700% to about 900%, about 700% to about 800%, about 800% to about 1000%, about 800% to about 900%, or about 900% to about 1000% compared to a reference, e.g., as described herein.

In some embodiments, the expression and/or activity of a polypeptide encoded by the endogenous ORF having a codon comprising a first sequence, e.g., a mutation, e.g., a PTC, is decreased from about 100% to about 1000%, about 100% to about 900%, about 100% to about 800%, about 100% to about 700%, about 100% to about 600%, about 100% to about 500%, about 100% to about 400%, about 100% to about 300%, about 100% to about 200%, about 200% to about 1000%, about 200% to about 900%, about 200% to about 800%, about 200% to about 700%, about 200% to about 600%, about 200% to about 500%, about 200% to about 400%, about 200% to about 300%, about 300% to about 1000%, about 300% to about 900%, about 300% to about 800%, about 300% to about 700%, about 300% to about 600%, about 300% to about 500%, about 300% to about 400%, about 400% to about 1000%, about 400% to about 900%, about 400% to about 800%, about 400% to about 700%, about 400% to about 600%, about 400% to about 500%, about 500% to about 1000%, about 500% to about 900%, about 500% to about 800%, about 500% to about 700%, about 500% to about 600%, about 600% to about 1000%, about 600% to about 900%, about 600% to about 800%, about 600% to about 700%, about 700% to about 1000%, about 700% to about 900%, about 700% to about 800%, about 800% to about 1000%, about 800% to about 900%, or about 900% to about 1000% compared to a reference, e.g., as described herein.

In some embodiments, the reference comprises a polypeptide encoded by an endogenous ORF having a non-mutated codon, e.g., wildtype codon. In some embodiments, the reference polypeptide encoded by the endogenous ORF having a non-mutated codon comprises a pre-mutation amino acid, e.g., wildtype amino acid, at the position corresponding to the non-mutated codon.

Methods of Treating a Subject Having an Endogenous ORF Having a PTC with a TREM Composition

In an aspect, provided herein is a method of treating a subject having an endogenous open reading frame (ORF) which comprises a codon having a first sequence, comprising:

providing a TREM composition comprising a TREM disclosed herein, wherein the TREM comprises a tRNA moiety having an anticodon that pairs with the codon of the ORF having the first sequence;

contacting the subject with the TREM composition in an amount and/or for a time sufficient to treat the subject,

thereby treating the subject.

In an embodiment, the subject has a disease or disorder associated with a PTC, e.g., as provided in any one of Tables 15-17.

In an embodiment, the subject has an ORF comprising a PTC in a gene disclosed in any one of Tables 15, 16 or 18.

TREM, TREM Core Fragment and TREM Fragment

A “tRNA-based effector molecule” or “TREM” refers to an RNA molecule comprising one or more of the properties described herein. A TREM can comprise a non-naturally occurring modification, e.g., as provided in Tables 4, 5, 6 or 7.

In an embodiment, a TREM includes a TREM comprising a sequence of Formula A; a TREM core fragment comprising a sequence of Formula B; or a TREM fragment comprising a portion of a TREM which TREM comprises a sequence of Formula A.

In an embodiment, a TREM comprises a sequence of Formula A: [L1]-[ASt Domain1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain2]. In an embodiment, [VL Domain] is optional. In an embodiment, [L1] is optional.

In an embodiment, a TREM core fragment comprises a sequence of Formula B: [L1]_y-[ASt Domain1]_x-[L2]_y-[DH Domain]_y-[L3]_y-[ACH Domain]_x-[VL Domain]_y-[TH Domain]_y-[L4]_y-[ASt Domain2]_x, wherein: x=1 and y=0 or 1. In an embodiment, y=0. In an embodiment, y=1.

In an embodiment, a TREM fragment comprises a portion of a TREM, wherein the TREM comprises a sequence of Formula A: [L1]-[ASt Domain1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain2], and wherein the TREM fragment comprises: one, two, three or all or any combination of the following: a TREM half (e.g., from a cleavage in the ACH Domain, e.g., in the anticodon sequence, e.g., a 5′half or a 3′ half); a 5′ fragment (e.g., a fragment comprising the 5′ end, e.g., from a cleavage in a DH Domain or the ACH Domain); a 3′ fragment (e.g., a fragment comprising the 3′ end, e.g., from a cleavage in the TH Domain); or an internal fragment (e.g., from a cleavage in any one of the ACH Domain, DH Domain or TH Domain). Exemplary TREM fragments include TREM halves (e.g., from a cleavage in the ACHD, e.g., 5′TREM halves or 3′ TREM halves), a 5′ fragment (e.g., a fragment comprising the 5′ end, e.g., from a cleavage in a DHD or the ACHD), a 3′ fragment (e.g., a fragment comprising the 3′ end of a TREM, e.g., from a cleavage in the THD), or an internal fragment (e.g., from a cleavage in one or more of the ACHD, DHD or THD).

In an embodiment, a TREM, a TREM core fragment or a TREM fragment can be charged with an amino acid (e.g., a cognate amino acid); charged with a non-cognate amino acid (e.g., a mischarged TREM (mTREM)); or not charged with an amino acid (e.g., an uncharged TREM (uTREM)). In an embodiment, a TREM, a TREM core fragment or a TREM fragment can be charged with an amino acid selected from alanine, arginine, asparagine, aspartate, cysteine, glutamine, glutamate, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

In an embodiment, the TREM, TREM core fragment or TREM fragment is a cognate TREM. In an embodiment, the TREM, TREM core fragment or TREM fragment is a non-cognate TREM. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes a codon provided in Table 7 or Table 8.

TABLE 7

List of codons

AAA

AAC

AAG

AAU

ACA

ACC

ACG

ACU

AGA

AGC

AGG

AGU

AUA

AUC

AUG

AUU

CAA

CAC

CAG

CAU

CCA

CCC

CCG

CCU

CGA

CGC

CGG

CGU

CUA

CUC

CUG

CUU

GAA

GAC

GAG

GAU

GCA

GCC

GCG

GCU

GGA

GGC

GGG

GGU

GUA

GUC

GUG

GUU

UAA

UAC

UAG

UAU

UCA

UCC

UCG

UCU

UGA

UGC

UGG

UGU

UUA

UUC

UUG

UUU

TABLE 8

Amino acids and corresponding codons

Amino Acid
mRNA codons

Alanine
GCU, GCC, GCA, GCG

Arginine
CGU, CGC, CGA, CGG, AGA, AGG

Asparagine
AAU, AAC

Aspartate
GAU, GAC

Cysteine
UGU, UGC

Glutamate
GAA, GAG

Glutamine
CAA, CAG

Glycine
GGU, GGC, GGA, GGG

Histidine
CAU, CAC

Isoleucine
AUU, AUC, AUA

Leucine
UUA, UUG, CUU, CUC, CUA, CUG

Lysine
AAA, AAG

Methionine
AUG

Phenylalanine
UUU, UUC

Proline
CCU, CCC, CCA, CCG

Serine
UCU, UCC, UCA, UCG, AGU, AGC

Stop
UAA, UAG, UGA

Threonine
ACU, ACC, ACA, ACG

Tryptophan
UGG

Tyrosine
UAU, UAC

Valine
GUU, GUC, GUA, GUG

In an embodiment, a TREM comprises a ribonucleic acid (RNA) sequence encoded by a deoxyribonucleic acid (DNA) sequence disclosed in Table 9, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 9. In an embodiment, a TREM comprises an RNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to an RNA sequence encoded by a DNA sequence provided in Table 9, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 9. In an embodiment, a TREM comprises an RNA sequence encoded by a DNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to a DNA sequence provided in Table 9, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 9.

In an embodiment, a TREM, a TREM core fragment, or TREM fragment comprises at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by a DNA sequence disclosed in Table 9, e.g., at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by any one of SEQ ID NOs: 1-451 disclosed in Table 9. In an embodiment, a TREM, a TREM core fragment, or TREM fragment comprises at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to an RNA sequence encoded by a DNA sequence provided in Table 9, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 9. In an embodiment, a TREM, a TREM core fragment, or TREM fragment comprises at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by a DNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to a DNA sequence provided in Table 9, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 9.

In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of an RNA sequence encoded by a DNA sequence provided in Table 9, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 9. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of an RNA sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to an RNA sequence encoded by a DNA sequence provided in Table 9, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 9. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of an RNA sequence encoded by a DNA sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to a DNA sequence provided in Table 9, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 9.

In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt or 60 nt (but less than the full length) of an RNA sequence encoded by a DNA sequence disclosed in Table 9, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 9. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt or 60 nt (but less than the full length) of an RNA sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to an RNA sequence encoded by a DNA sequence provided in Table 9, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 9. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt or 60 nt (but less than the full length) of an RNA sequence encoded by a DNA sequence with at least 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, 99% or 100% identity to a DNA sequence provided in Table 9, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 9.

In an embodiment, a TREM core fragment or a TREM fragment comprises a sequence of a length of between 10-90 ribonucleotides (rnt), between 10-80 rnt, between 10-70 rnt, between 10-60 rnt, between 10-50 rnt, between 10-40 rnt, between 10-30 rnt, between 10-20 rnt, between 20-90 rnt, between 20-80 rnt, 20-70 rnt, between 20-60 rnt, between 20-50 rnt, between 20-40 rnt, between 30-90 rnt, between 30-80 rnt, between 30-70 rnt, between 30-60 rnt, or between 30-50 rnt.

TABLE 9

List of tRNA sequences

SEQ

ID

NO
tRNA name
tRNA sequence

1
Ala_AGC_chr6: 28763741-28763812 (−)
GGGGGTATAGCTCAGTGGTAGAGCGCGTGCTTAGCATGCACGAGGTCC

TGGGTTCGATCCCCAGTACCTCCA

2
Ala_AGC_chr6: 26687485-26687557 (+)
GGGGAATTAGCTCAAGTGGTAGAGCGCTTGCTTAGCACGCAAGAGGTA

GTGGGATCGATGCCCACATTCTCCA

3
Ala_AGC_chr6: 26572092-26572164 (−)
GGGGAATTAGCTCAAATGGTAGAGCGCTCGCTTAGCATGCGAGAGGTA

GCGGGATCGATGCCCGCATTCTCCA

4
Ala_AGC_chr6: 26682715-26682787 (+)
GGGGAATTAGCTCAAGTGGTAGAGCGCTTGCTTAGCATGCAAGAGGTA

GTGGGATCGATGCCCACATTCTCCA

5
Ala_AGC_chr6: 26705606-26705678 (+)
GGGGAATTAGCTCAAGCGGTAGAGCGCTTGCTTAGCATGCAAGAGGTA

GTGGGATCGATGCCCACATTCTCCA

6
Ala_AGC_chr6: 26673590-26673662 (+)
GGGGAATTAGCTCAAGTGGTAGAGCGCTTGCTTAGCATGCAAGAGGTA

GTGGGATCAATGCCCACATTCTCCA

7
Ala_AGC_chr14: 89445442-89445514 (+)
GGGGAATTAGCTCAAGTGGTAGAGCGCTCGCTTAGCATGCGAGAGGTA

GTGGGATCGATGCCCGCATTCTCCA

8
Ala_AGC_chr6: 58196623-58196695 (−)
GGGGAATTAGCCCAAGTGGTAGAGCGCTTGCTTAGCATGCAAGAGGTA

GTGGGATCGATGCCCACATTCTCCA

9
Ala_AGC_chr6: 28806221-28806292 (−)
GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCTTAGCATGCACGAGGCCC

CGGGTTCAATCCCCGGCACCTCCA

10
Ala_AGC_chr6: 28574933-28575004 (+)
GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCTTAGCATGTACGAGGTCC

CGGGTTCAATCCCCGGCACCTCCA

11
Ala_AGC_chr6: 28626014-28626085 (−)
GGGGATGTAGCTCAGTGGTAGAGCGCATGCTTAGCATGCATGAGGTCC

CGGGTTCGATCCCCAGCATCTCCA

12
Ala_AGC_chr6: 28678366-28678437 (+)
GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCTTAGCATGCACGAGGCCC

TGGGTTCAATCCCCAGCACCTCCA

13
Ala_AGC_chr6: 28779849-28779920 (−)
GGGGGTATAGCTCAGCGGTAGAGCGCGTGCTTAGCATGCACGAGGTCC

TGGGTTCAATCCCCAATACCTCCA

14
Ala_AGC_chr6: 28687481-28687552 (+)
GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCTTAGCATGCACGAGGCCC

CGGGTTCAATCCCTGGCACCTCCA

15
Ala_AGC_chr2: 27274082-27274154 (+)
GGGGGATTAGCTCAAATGGTAGAGCGCTCGCTTAGCATGCGAGAGGTA

GCGGGATCGATGCCCGCATCCTCCA

16
Ala_AGC_chr6: 26730737-26730809 (+)
GGGGAATTAGCTCAGGCGGTAGAGCGCTCGCTTAGCATGCGAGAGGTA

GCGGGATCGACGCCCGCATTCTCCA

17
Ala_CGC_chr6: 26553731-26553802 (+)
GGGGATGTAGCTCAGTGGTAGAGCGCATGCTTCGCATGTATGAGGTCC

CGGGTTCGATCCCCGGCATCTCCA

18
Ala_CGC_chr6 28641613-28641684 (−)
GGGGATGTAGCTCAGTGGTAGAGCGCATGCTTCGCATGTATGAGGCCC

CGGGTTCGATCCCCGGCATCTCCA

19
Ala_CGC_chr2: 157257281-157257352
GGGGATGTAGCTCAGTGGTAGAGCGCGCGCTTCGCATGTGTGAGGTCC

(+)
CGGGTTCAATCCCCGGCATCTCCA

20
Ala_CGC_chr6: 28697092-28697163 (+)
GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCTTCGCATGTACGAGGCCC

CGGGTTCGACCCCCGGCTCCTCCA

21
Ala_TGC_chr6: 28757547-28757618 (−)
GGGGGTGTAGCTCAGTGGTAGAGCGCATGCTTTGCATGTATGAGGTCC

CGGGTTCGATCCCCGGCACCTCCA

22
Ala_TGC_chr6: 28611222-28611293 (+)
GGGGATGTAGCTCAGTGGTAGAGCGCATGCTTTGCATGTATGAGGTCC

CGGGTTCGATCCCCGGCATCTCCA

23
Ala_TGC_chr5: 180633868-180633939
GGGGATGTAGCTCAGTGGTAGAGCGCATGCTTTGCATGTATGAGGCCC

(+)
CGGGTTCGATCCCCGGCATCTCCA

24
Ala_TGC_chr12: 125424512-125424583
GGGGATGTAGCTCAGTGGTAGAGCGCATGCTTTGCACGTATGAGGCCC

(+)
CGGGTTCAATCCCCGGCATCTCCA

25
Ala_TGC_chr6: 28785012-28785083 (−)
GGGGGTGTAGCTCAGTGGTAGAGCGCATGCTTTGCATGTATGAGGCCT

CGGGTTCGATCCCCGACACCTCCA

26
Ala_TGC_chr6: 28726141-28726212 (−)
GGGGGTGTAGCTCAGTGGTAGAGCACATGCTTTGCATGTGTGAGGCCC

CGGGTTCGATCCCCGGCACCTCCA

27
Ala_TGC_chr6: 28770577-28770647 (−)
GGGGGTGTAGCTCAGTGGTAGAGCGCATGCTTTGCATGTATGAGGCCT

CGGTTCGATCCCCGACACCTCCA

28
Arg_ACG_chr6: 26328368-26328440 (+)
GGGCCAGTGGCGCAATGGATAACGCGTCTGACTACGGATCAGAAGATT

CCAGGTTCGACTCCTGGCTGGCTCG

29
Arg_ACG_chr3: 45730491-45730563 (−)
GGGCCAGTGGCGCAATGGATAACGCGTCTGACTACGGATCAGAAGATT

CTAGGTTCGACTCCTGGCTGGCTCG

30
Arg_CCG_chr6: 28710729-28710801 (−)
GGCCGCGTGGCCTAATGGATAAGGCGTCTGATTCCGGATCAGAAGATT

GAGGGTTCGAGTCCCTTCGTGGTCG

31
Arg_CCG_chr17: 66016013-66016085 (−)
GACCCAGTGGCCTAATGGATAAGGCATCAGCCTCCGGAGCTGGGGATT

GTGGGTTCGAGTCCCATCTGGGTCG

32
Arg_CCT_chr17: 73030001-73030073 (+)
GCCCCAGTGGCCTAATGGATAAGGCACTGGCCTCCTAAGCCAGGGATT

GTGGGTTCGAGTCCCACCTGGGGTA

33
Arg_CCT_chr17: 73030526-73030598 (−)
GCCCCAGTGGCCTAATGGATAAGGCACTGGCCTCCTAAGCCAGGGATT

GTGGGTTCGAGTCCCACCTGGGGTG

34
Arg_CCT_chr16: 3202901-3202973 (+)
GCCCCGGTGGCCTAATGGATAAGGCATTGGCCTCCTAAGCCAGGGATT

GTGGGTTCGAGTCCCACCCGGGGTA

35
Arg_CCT_chr7: 139025446-139025518
GCCCCAGTGGCCTAATGGATAAGGCATTGGCCTCCTAAGCCAGGGATT

(+)
GTGGGTTCGAGTCCCATCTGGGGTG

36
Arg_CCT_chr16: 3243918-3243990 (+)
GCCCCAGTGGCCTGATGGATAAGGTACTGGCCTCCTAAGCCAGGGATT

GTGGGTTCGAGTTCCACCTGGGGTA

37
Arg_TCG_chr15: 89878304-89878376 (+)
GGCCGCGTGGCCTAATGGATAAGGCGTCTGACTTCGGATCAGAAGATT

GCAGGTTCGAGTCCTGCCGCGGTCG

38
Arg_TCG_chr6: 26323046-26323118 (+)
GACCACGTGGCCTAATGGATAAGGCGTCTGACTTCGGATCAGAAGATT

GAGGGTTCGAATCCCTCCGTGGTTA

39
Arg_TCG_chr17: 73031208-73031280 (+)
GACCGCGTGGCCTAATGGATAAGGCGTCTGACTTCGGATCAGAAGATT

GAGGGTTCGAGTCCCTTCGTGGTCG

40
Arg_TCG_chr6: 26299905-26299977 (+)
GACCACGTGGCCTAATGGATAAGGCGTCTGACTTCGGATCAGAAGATT

GAGGGTTCGAATCCCTTCGTGGTTA

41
Arg_TCG_chr6: 28510891-28510963 (−)
GACCACGTGGCCTAATGGATAAGGCGTCTGACTTCGGATCAGAAGATT

GAGGGTTCGAATCCCTTCGTGGTTG

42
Arg_TCG_chr9: 112960803-112960875
GGCCGTGTGGCCTAATGGATAAGGCGTCTGACTTCGGATCAAAAGATT

(+)
GCAGGTTTGAGTTCTGCCACGGTCG

43
Arg_TCT_chr1: 94313129-94313213 (+)
GGCTCCGTGGCGCAATGGATAGCGCATTGGACTTCTAGAGGCTGAAGG

CATTCAAAGGTTCCGGGTTCGAGTCCCGGCGGAGTCG

44
Arg_TCT_chr17: 8024243-8024330 (+)
GGCTCTGTGGCGCAATGGATAGCGCATTGGACTTCTAGTGACGAATAG

AGCAATTCAAAGGTTGTGGGTTCGAATCCCACCAGAGTCG

45
Arg_TCT_chr9: 131102355-131102445 (−)
GGCTCTGTGGCGCAATGGATAGCGCATTGGACTTCTAGCTGAGCCTAG

TGTGGTCATTCAAAGGTTGTGGGTTCGAGTCCCACCAGAGTCG

46
Arg_TCT_chr11: 59318767-59318852 (+)
GGCTCTGTGGCGCAATGGATAGCGCATTGGACTTCTAGATAGTTAGAG

AAATTCAAAGGTTGTGGGTTCGAGTCCCACCAGAGTCG

47
Arg_TCT_chr1: 159111401-159111474 (−)
GTCTCTGTGGCGCAATGGACGAGCGCGCTGGACTTCTAATCCAGAGGT

TCCGGGTTCGAGTCCCGGCAGAGATG

48
Arg_TCT_chr6: 27529963-27530049 (+)
GGCTCTGTGGCGCAATGGATAGCGCATTGGACTTCTAGCCTAAATCAA

GAGATTCAAAGGTTGCGGGTTCGAGTCCCTCCAGAGTCG

49
Asn_GTT_chr1: 161510031-161510104
GTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACCGAAAGGT

(+)
TGGTGGTTCGATCCCACCCAGGGACG

50
Asn_GTT_chr1: 143879832-143879905 (−)
GTCTCTGTGGCGCAATCGGCTAGCGCGTTTGGCTGTTAACTAAAAGGTT

GGCGGTTCGAACCCACCCAGAGGCG

51
Asn_GTT_chr1: 144301611-144301684
GTCTCTGTGGTGCAATCGGTTAGCGCGTTCCGCTGTTAACCGAAAGCTT

(+)
GGTGGTTCGAGCCCACCCAGGGATG

52
Asn_GTT_chr1: 149326272-149326345 (−)
GTCTCTGTGGCGCAATCGGCTAGCGCGTTTGGCTGTTAACTAAAAAGTT

GGTGGTTCGAACACACCCAGAGGCG

53
Asn_GTT_chr1: 148248115-148248188
GTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACCGAAAGGT

(+)
TGGTGGTTCGAGCCCACCCAGGGACG

54
Asn_GTT_chr1: 148598314-148598387 (−)
GTCTCTGTGGCGCAATCGGTTAGCGCATTCGGCTGTTAACCGAAAGGT

TGGTGGTTCGAGCCCACCCAGGGACG

55
Asn_GTT_chr1: 17216172-17216245 (+)
GTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACCGAAAGAT

TGGTGGTTCGAGCCCACCCAGGGACG

56
Asn_GTT_chr1: 16847080-16847153 (−)
GTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACTGAAAGGTT

GGTGGTTCGAGCCCACCCAGGGACG

57
Asn_GTT_chr1: 149230570-149230643 (−)
GTCTCTGTGGCGCAATGGGTTAGCGCGTTCGGCTGTTAACCGAAAGGT

TGGTGGTTCGAGCCCATCCAGGGACG

58
Asn_GTT_chr1: 148000805-148000878
GTCTCTGTGGCGTAGTCGGTTAGCGCGTTCGGCTGTTAACCGAAAAGTT

(+)
GGTGGTTCGAGCCCACCCAGGAACG

59
Asn_GTT_chr1: 149711798-149711871 (−)
GTCTCTGTGGCGCAATCGGCTAGCGCGTTTGGCTGTTAACTAAAAGGTT

GGTGGTTCGAACCCACCCAGAGGCG

60
Asn_GTT_chr1: 145979034-145979107 (−)
GTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACTGAAAGGTT

AGTGGTTCGAGCCCACCCGGGGACG

61
Asp_GTC_chr12: 98897281-98897352 (+)
TCCTCGTTAGTATAGTGGTTAGTATCCCCGCCTGTCACGCGGGAGACCG

GGGTTCAATTCCCCGACGGGGAG

62
Asp_GTC_chr1: 161410615-161410686 (−)
TCCTCGTTAGTATAGTGGTGAGTATCCCCGCCTGTCACGCGGGAGACC

GGGGTTCGATTCCCCGACGGGGAG

63
Asp_GTC_chr6: 27551236-27551307 (−)
TCCTCGTTAGTATAGTGGTGAGTGTCCCCGTCTGTCACGCGGGAGACC

GGGGTTCGATTCCCCGACGGGGAG

64
Cys_GCA_chr7: 149007281-149007352
GGGGGCATAGCTCAGTGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

(+)
CTGGTTCAAATCCAGGTGCCCCCT

65
Cys_GCA_chr7: 149074601-149074672 (−)
GGGGGTATAGCTCAGGGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CTGGTTCAAATCCAGGTGCCCCCC

66
Cys_GCA_chr7: 149112229-149112300 (−)
GGGGGTATAGCTTAGCGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CCGGTTCAAATCCGGGTGCCCCCT

67
Cys_GCA_chr7: 149344046-149344117 (−)
GGGGGTATAGCTTAGGGGTAGAGCATTTGACTGCAGATCAAAAGGTCC

CTGGTTCAAATCCAGGTGCCCCTT

68
Cys_GCA_chr7: 149052766-149052837 (−)
GGGGGTATAGCTCAGGGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CCAGTTCAAATCTGGGTGCCCCCT

69
Cys_GCA_chr17: 37017937-37018008 (−)
GGGGGTATAGCTCAGGGGTAGAGCATTTGACTGCAGATCAAGAAGTCC

CCGGTTCAAATCCGGGTGCCCCCT

70
Cys_GCA_chr7: 149281816-149281887
GGGGGTATAGCTCAGGGGTAGAGCATTTGACTGCAGATCAAGAGGTCT

(+)
CTGGTTCAAATCCAGGTGCCCCCT

71
Cys_GCA_chr7: 149243631-149243702
GGGGGTATAGCTCAGGGGTAGAGCACTTGACTGCAGATCAAGAAGTCC

(+)
TTGGTTCAAATCCAGGTGCCCCCT

72
Cys_GCA_chr7: 149388272-149388343 (−)
GGGGATATAGCTCAGGGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CCGGTTCAAATCCGGGTGCCCCCC

73
Cys_GCA_chr7: 149072850-149072921 (−)
GGGGGTATAGTTCAGGGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CTGGTTCAAATCCAGGTGCCCCCT

74
Cys_GCA_chr7: 149310156-149310227 (−)
GGGGGTATAGCTCAGGGGTAGAGCATTTGACTGCAAATCAAGAGGTCC

CTGATTCAAATCCAGGTGCCCCCT

75
Cys_GCA_chr4: 124430005-124430076 (−)
GGGGGTATAGCTCAGTGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CCGGTTCAAATCCGGGTGCCCCCT

76
Cys_GCA_chr7: 149295046-149295117
GGGCGTATAGCTCAGGGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

(+)
CCAGTTCAAATCTGGGTGCCCCCT

77
Cys_GCA_chr7: 149361915-149361986
GGGGGTATAGCTCACAGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

(+)
CCGGTTCAAATCTGGGTGCCCCCT

78
Cys_GCA_chr7: 149253802-149253871
GGGCGTATAGCTCAGGGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

(+)
CCAGTTCAAATCTGGGTGCCCA

79
Cys_GCA_chr7: 149292305-149292376 (−)
GGGGGTATAGCTCACAGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CCGGTTCAAATCCGGTTACTCCCT

80
Cys_GCA_chr7: 149286164-149286235 (−)
GGGGGTATAGCTCAGGGGTAGAGCACTTGACTGCAGATCAAGAGGTCC

CTGGTTCAAATCCAGGTGCCCCCT

81
Cys_GCA_chr17: 37025545-37025616 (−)
GGGGGTATAGCTCAGTGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CTGGTTCAAATCCGGGTGCCCCCT

82
Cys_GCA_chr15: 80036997-80037069 (+)
GGGGGTATAGCTCAGTGGGTAGAGCATTTGACTGCAGATCAAGAGGTC

CCCGGTTCAAATCCGGGTGCCCCCT

83
Cys_GCA_chr3: 131947944-131948015 (−)
GGGGGTGTAGCTCAGTGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CTGGTTCAAATCCAGGTGCCCCCT

84
Cys_GCA_chr1: 93981834-93981906 (−)
GGGGGTATAGCTCAGGTGGTAGAGCATTTGACTGCAGATCAAGAGGTC

CCCGGTTCAAATCCGGGTGCCCCCT

85
Cys_GCA_chr14: 73429679-73429750 (+)
GGGGGTATAGCTCAGGGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CCGGTTCAAATCCGGGTGCCCCCT

86
Cys_GCA_chr3: 131950642-131950713 (−)
GGGGGTATAGCTCAGGGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CTGGTTCAAATCCAGGTGCCCCCT

87
Gln_CTG_chr6: 18836402-18836473 (+)
GGTTCCATGGTGTAATGGTTAGCACTCTGGACTCTGAATCCAGCGATCC

GAGTTCAAATCTCGGTGGAACCT

88
Gln_CTG_chr6: 27515531-27515602 (−)
GGTTCCATGGTGTAATGGTTAGCACTCTGGACTCTGAATCCAGCGATCC

GAGTTCAAGTCTCGGTGGAACCT

89
Gln_CTG_chr1: 145963304-145963375
GGTTCCATGGTGTAATGGTGAGCACTCTGGACTCTGAATCCAGCGATC

(+)
CGAGTTCGAGTCTCGGTGGAACCT

90
Gln_CTG_chr1: 147737382-147737453 (−)
GGTTCCATGGTGTAATGGTAAGCACTCTGGACTCTGAATCCAGCGATC

CGAGTTCGAGTCTCGGTGGAACCT

91
Gln_CTG_chr6: 27263212-27263283 (+)
GGTTCCATGGTGTAATGGTTAGCACTCTGGACTCTGAATCCGGTAATCC

GAGTTCAAATCTCGGTGGAACCT

92
Gln_CTG_chr6: 27759135-27759206 (−)
GGCCCCATGGTGTAATGGTCAGCACTCTGGACTCTGAATCCAGCGATC

CGAGTTCAAATCTCGGTGGGACCC

93
Gln_CTG_chr1: 147800937-147801008
GGTTCCATGGTGTAATGGTAAGCACTCTGGACTCTGAATCCAGCCATCT

(+)
GAGTTCGAGTCTCTGTGGAACCT

94
Gln_TTG_chr17: 47269890-47269961 (+)
GGTCCCATGGTGTAATGGTTAGCACTCTGGACTTTGAATCCAGCGATCC

GAGTTCAAATCTCGGTGGGACCT

95
Gln_TTG_chr6: 28557156-28557227 (+)
GGTCCCATGGTGTAATGGTTAGCACTCTGGACTTTGAATCCAGCAATCC

GAGTTCGAATCTCGGTGGGACCT

96
Gln_TTG_chr6: 26311424-26311495 (−)
GGCCCCATGGTGTAATGGTTAGCACTCTGGACTTTGAATCCAGCGATC

CGAGTTCAAATCTCGGTGGGACCT

97
Gln_TTG_chr6: 145503859-145503930
GGTCCCATGGTGTAATGGTTAGCACTCTGGGCTTTGAATCCAGCAATCC

(+)
GAGTTCGAATCTTGGTGGGACCT

98
Glu_CTC_chr1: 145399233-145399304 (−)
TCCCTGGTGGTCTAGTGGTTAGGATTCGGCGCTCTCACCGCCGCGGCCC

GGGTTCGATTCCCGGTCAGGGAA

99
Glu_CTC_chr1: 249168447-249168518
TCCCTGGTGGTCTAGTGGTTAGGATTCGGCGCTCTCACCGCCGCGGCCC

(+)
GGGTTCGATTCCCGGTCAGGAAA

100
Glu_TTC_chr2: 131094701-131094772 (−)
TCCCATATGGTCTAGCGGTTAGGATTCCTGGTTTTCACCCAGGTGGCCC

GGGTTCGACTCCCGGTATGGGAA

101
Glu_TTC_chr13: 45492062-45492133 (−)
TCCCACATGGTCTAGCGGTTAGGATTCCTGGTTTTCACCCAGGCGGCCC

GGGTTCGACTCCCGGTGTGGGAA

102
Glu_TTC_chr1: 17199078-17199149 (+)
TCCCTGGTGGTCTAGTGGCTAGGATTCGGCGCTTTCACCGCCGCGGCCC

GGGTTCGATTCCCGGCCAGGGAA

103
Glu_TTC_chr1: 16861774-16861845 (−)
TCCCTGGTGGTCTAGTGGCTAGGATTCGGCGCTTTCACCGCCGCGGCCC

GGGTTCGATTCCCGGTCAGGGAA

104
Gly_CCC_chr1: 16872434-16872504 (−)
GCATTGGTGGTTCAGTGGTAGAATTCTCGCCTCCCACGCGGGAGACCC

GGGTTCAATTCCCGGCCAATGCA

105
Gly_CCC_chr2: 70476123-70476193 (−)
GCGCCGCTGGTGTAGTGGTATCATGCAAGATTCCCATTCTTGCGACCCG

GGTTCGATTCCCGGGCGGCGCA

106
Gly_CCC_chr17: 19764175-19764245 (+)
GCATTGGTGGTTCAATGGTAGAATTCTCGCCTCCCACGCAGGAGACCC

AGGTTCGATTCCTGGCCAATGCA

107
Gly_GCC_chr1: 161413094-161413164
GCATGGGTGGTTCAGTGGTAGAATTCTCGCCTGCCACGCGGGAGGCCC

(+)
GGGTTCGATTCCCGGCCCATGCA

108
Gly_GCC_chr1: 161493637-161493707 (−)
GCATTGGTGGTTCAGTGGTAGAATTCTCGCCTGCCACGCGGGAGGCCC

GGGTTCGATTCCCGGCCAATGCA

109
Gly_GCC_chr16: 70812114-70812184 (−)
GCATTGGTGGTTCAGTGGTAGAATTCTCGCCTGCCACGCGGGAGGCCC

GGGTTTGATTCCCGGCCAGTGCA

110
Gly_GCC_chr1: 161450356-161450426
GCATAGGTGGTTCAGTGGTAGAATTCTTGCCTGCCACGCAGGAGGCCC

(+)
AGGTTTGATTCCTGGCCCATGCA

111
Gly_GCC_chr16: 70822597-70822667 (+)
GCATTGGTGGTTCAGTGGTAGAATTCTCGCCTGCCATGCGGGCGGCCG

GGCTTCGATTCCTGGCCAATGCA

112
Gly_TCC_chr19: 4724082-4724153 (+)
GCGTTGGTGGTATAGTGGTTAGCATAGCTGCCTTCCAAGCAGTTGACC

CGGGTTCGATTCCCGGCCAACGCA

113
Gly_TCC_chr1: 145397864-145397935 (−)
GCGTTGGTGGTATAGTGGTGAGCATAGCTGCCTTCCAAGCAGTTGACC

CGGGTTCGATTCCCGGCCAACGCA

114
Gly_TCC_chr17: 8124866-8124937(+)
GCGTTGGTGGTATAGTGGTAAGCATAGCTGCCTTCCAAGCAGTTGACC

CGGGTTCGATTCCCGGCCAACGCA

115
Gly_TCC_chr1: 161409961-161410032 (−)
GCGTTGGTGGTATAGTGGTGAGCATAGTTGCCTTCCAAGCAGTTGACC

CGGGCTCGATTCCCGCCCAACGCA

116
His_GTG_chr1: 145396881-145396952 (−)
GCCGTGATCGTATAGTGGTTAGTACTCTGCGTTGTGGCCGCAGCAACCT

CGGTTCGAATCCGAGTCACGGCA

117
His_GTG_chr1: 149155828-149155899 (−)
GCCATGATCGTATAGTGGTTAGTACTCTGCGCTGTGGCCGCAGCAACC

TCGGTTCGAATCCGAGTCACGGCA

118
Ile_AAT_chr6: 58149254-58149327 (+)
GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGCGCTAATAACGCCAAGGT

CGCGGGTTCGATCCCCGTACGGGCCA

119
Ile_AAT_chr6: 27655967-27656040 (+)
GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGTGCTAATAACGCCAAGGT

CGCGGGTTCGATCCCCGTACTGGCCA

120
Ile_AAT_chr6: 27242990-27243063 (−)
GGCTGGTTAGCTCAGTTGGTTAGAGCGTGGTGCTAATAACGCCAAGGT

CGCGGGTTCGATCCCCGTACTGGCCA

121
Ile AAT chr17: 8130309-8130382 (−)
GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGTGCTAATAACGCCAAGGT

CGCGGGTTCGAACCCCGTACGGGCCA

122
Ile_AAT_chr6: 26554350-26554423 (+)
GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGTGCTAATAACGCCAAGGT

CGCGGGTTCGATCCCCGTACGGGCCA

123
Ile_AAT_chr6: 26745255-26745328 (−)
GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGTGCTAATAACGCTAAGGT

CGCGGGTTCGATCCCCGTACTGGCCA

124
Ile_AAT_chr6: 26721221-26721294 (−)
GGCCGGTTAGCTCAGTTGGTCAGAGCGTGGTGCTAATAACGCCAAGGT

CGCGGGTTCGATCCCCGTACGGGCCA

125
Ile_AAT_chr6: 27636362-27636435 (+)
GGCCGGTTAGCTCAGTCGGCTAGAGCGTGGTGCTAATAACGCCAAGGT

CGCGGGTTCGATCCCCGTACGGGCCA

126
Ile_AAT_chr6: 27241739-27241812 (+)
GGCTGGTTAGTTCAGTTGGTTAGAGCGTGGTGCTAATAACGCCAAGGT

CGTGGGTTCGATCCCCATATCGGCCA

127
Ile_GAT_chrX: 3756418-3756491 (−)
GGCCGGTTAGCTCAGTTGGTAAGAGCGTGGTGCTGATAACACCAAGGT

CGCGGGCTCGACTCCCGCACCGGCCA

128
Ile_TAT_chr19: 39902808-39902900 (−)
GCTCCAGTGGCGCAATCGGTTAGCGCGCGGTACTTATATGACAGTGCG

AGCGGAGCAATGCCGAGGTTGTGAGTTCGATCCTCACCTGGAGCA

129
Ile_TAT_chr2: 43037676-43037768 (+)
GCTCCAGTGGCGCAATCGGTTAGCGCGCGGTACTTATACAGCAGTACA

TGCAGAGCAATGCCGAGGTTGTGAGTTCGAGCCTCACCTGGAGCA

130
Ile_TAT_chr6: 26988125-26988218 (+)
GCTCCAGTGGCGCAATCGGTTAGCGCGCGGTACTTATATGGCAGTATG

TGTGCGAGTGATGCCGAGGTTGTGAGTTCGAGCCTCACCTGGAGCA

131
Ile_TAT_chr6: 27599200-27599293 (+)
GCTCCAGTGGCGCAATCGGTTAGCGCGCGGTACTTATACAACAGTATA

TGTGCGGGTGATGCCGAGGTTGTGAGTTCGAGCCTCACCTGGAGCA

132
Ile_TAT_chr6: 28505367-28505460 (+)
GCTCCAGTGGCGCAATCGGTTAGCGCGCGGTACTTATAAGACAGTGCA

CCTGTGAGCAATGCCGAGGTTGTGAGTTCAAGCCTCACCTGGAGCA

133
Leu_AAG_chr5: 180524474-180524555 (−)
GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGGATTAAGGCTCCAGTCTC

TTCGGAGGCGTGGGTTCGAATCCCACCGCTGCCA

134
Leu_AAG_chr5: 180614701-180614782
GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGGATTAAGGCTCCAGTCTC

(+)
TTCGGGGGCGTGGGTTCGAATCCCACCGCTGCCA

135
Leu_AAG_chr6: 28956779-28956860 (+)
GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGGATTAAGGCTCCAGTCTC

TTCGGGGGCGTGGGTTCAAATCCCACCGCTGCCA

136
Leu_AAG_chr6: 28446400-28446481 (−)
GGTAGCGTGGCCGAGTGGTCTAAGACGCTGGATTAAGGCTCCAGTCTC

TTCGGGGGCGTGGGTTTGAATCCCACCGCTGCCA

137
Leu_CAA_chr6: 28864000-28864105 (−)
GTCAGGATGGCCGAGTGGTCTAAGGCGCCAGACTCAAGCTAAGCTTCC

TCCGCGGTGGGGATTCTGGTCTCCAATGGAGGCGTGGGTTCGAATCCC

138
Leu_CAA_chr6: 28908830-28908934 (+)
GTCAGGATGGCCGAGTGGTCTAAGGCGCCAGACTCAAGCTTGGCTTCC

TCGTGTTGAGGATTCTGGTCTCCAATGGAGGCGTGGGTTCGAATCCCA

139
Leu_CAA_chr6: 27573417-27573524 (−)
GTCAGGATGGCCGAGTGGTCTAAGGCGCCAGACTCAAGCTTACTGCTT

CCTGTGTTCGGGTCTTCTGGTCTCCGTATGGAGGCGTGGGTTCGAATCC

140
Leu_CAA_chr6: 27570348-27570454 (−)
GTCAGGATGGCCGAGTGGTCTAAGGCGCCAGACTCAAGTTGCTACTTC

CCAGGTTTGGGGCTTCTGGTCTCCGCATGGAGGCGTGGGTTCGAATCC

141
Leu_CAA_chr1: 249168054-249168159
GTCAGGATGGCCGAGTGGTCTAAGGCGCCAGACTCAAGGTAAGCACCT

(+)
TGCCTGCGGGCTTTCTGGTCTCCGGATGGAGGCGTGGGTTCGAATCCC

142
Leu_CAA_chr11: 9296790-9296863 (+)
GCCTCCTTAGTGCAGTAGGTAGCGCATCAGTCTCAAAATCTGAATGGT

CCTGAGTTCAAGCCTCAGAGGGGGCA

143
Leu_CAA_chr1: 161581736-161581819 (−)
GTCAGGATGGCCGAGCAGTCTTAAGGCGCTGCGTTCAAATCGCACCCT

CCGCTGGAGGCGTGGGTTCGAATCCCACTTTTGACA

144
Leu_CAG_chr1: 161411323-161411405
GTCAGGATGGCCGAGCGGTCTAAGGCGCTGCGTTCAGGTCGCAGTCTC

(+)
CCCTGGAGGCGTGGGTTCGAATCCCACTCCTGACA

145
Leu_CAG chr16: 57333863-57333945 (+)
GTCAGGATGGCCGAGCGGTCTAAGGCGCTGCGTTCAGGTCGCAGTCTC

CCCTGGAGGCGTGGGTTCGAATCCCACTTCTGACA

146
Leu_TAA_chr6: 144537684-144537766
ACCAGGATGGCCGAGTGGTTAAGGCGTTGGACTTAAGATCCAATGGAC

(+)
ATATGTCCGCGTGGGTTCGAACCCCACTCCTGGTA

147
Leu_TAA_chr6: 27688898-27688980 (−)
ACCGGGATGGCCGAGTGGTTAAGGCGTTGGACTTAAGATCCAATGGGC

TGGTGCCCGCGTGGGTTCGAACCCCACTCTCGGTA

148
Leu_TAA_chr11: 59319228-59319310 (+)
ACCAGAATGGCCGAGTGGTTAAGGCGTTGGACTTAAGATCCAATGGAT

TCATATCCGCGTGGGTTCGAACCCCACTTCTGGTA

149
Leu_TAA_chr6: 27198334-27198416 (−)
ACCGGGATGGCTGAGTGGTTAAGGCGTTGGACTTAAGATCCAATGGAC

AGGTGTCCGCGTGGGTTCGAGCCCCACTCCCGGTA

150
Leu_TAG_chr17: 8023632-8023713 (−)
GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGGATTTAGGCTCCAGTCTC

TTCGGAGGCGTGGGTTCGAATCCCACCGCTGCCA

151
Leu_TAG_chr14: 21093529-21093610 (+)
GGTAGTGTGGCCGAGCGGTCTAAGGCGCTGGATTTAGGCTCCAGTCTC

TTCGGGGGCGTGGGTTCGAATCCCACCACTGCCA

152
Leu_TAG_chr16: 22207032-22207113 (−)
GGTAGCGTGGCCGAGTGGTCTAAGGCGCTGGATTTAGGCTCCAGTCAT

TTCGATGGCGTGGGTTCGAATCCCACCGCTGCCA

153
Lys_CTT_chr14: 58706613-58706685 (−)
GCCCGGCTAGCTCAGTCGGTAGAGCATGGGACTCTTAATCCCAGGGTC

GTGGGTTCGAGCCCCACGTTGGGCG

154
Lys_CTT_chr19: 36066750-36066822 (+)
GCCCAGCTAGCTCAGTCGGTAGAGCATAAGACTCTTAATCTCAGGGTT

GTGGATTCGTGCCCCATGCTGGGTG

155
Lys_CTT_chr19: 52425393-52425466 (−)
GCAGCTAGCTCAGTCGGTAGAGCATGAGACTCTTAATCTCAGGGTCAT

GGGTTCGTGCCCCATGTTGGGTGCCA

156
Lys_CTT_chr1: 145395522-145395594 (−)
GCCCGGCTAGCTCAGTCGGTAGAGCATGAGACTCTTAATCTCAGGGTC

GTGGGTTCGAGCCCCACGTTGGGCG

157
Lys_CTT_chr16: 3207406-3207478 (−)
GCCCGGCTAGCTCAGTCGGTAGAGCATGAGACCCTTAATCTCAGGGTC

GTGGGTTCGAGCCCCACGTTGGGCG

158
Lys_CTT_chr16: 3241501-3241573 (+)
GCCCGGCTAGCTCAGTCGGTAGAGCATGGGACTCTTAATCTCAGGGTC

GTGGGTTCGAGCCCCACGTTGGGCG

159
Lys_CTT_chr16: 3230555-3230627 (−)
GCCCGGCTAGCTCAGTCGATAGAGCATGAGACTCTTAATCTCAGGGTC

GTGGGTTCGAGCCGCACGTTGGGCG

160
Lys_CTT_chr1: 55423542-55423614 (−)
GCCCAGCTAGCTCAGTCGGTAGAGCATGAGACTCTTAATCTCAGGGTC

ATGGGTTTGAGCCCCACGTTTGGTG

161
Lys_CTT_chr16: 3214939-3215011 (+)
GCCTGGCTAGCTCAGTCGGCAAAGCATGAGACTCTTAATCTCAGGGTC

GTGGGCTCGAGCTCCATGTTGGGCG

162
Lys_CTT_chr5: 26198539-26198611 (−)
GCCCGACTACCTCAGTCGGTGGAGCATGGGACTCTTCATCCCAGGGTT

GTGGGTTCGAGCCCCACATTGGGCA

163
Lys_TTT_chr16: 73512216-73512288 (−)
GCCTGGATAGCTCAGTTGGTAGAGCATCAGACTTTTAATCTGAGGGTC

CAGGGTTCAAGTCCCTGTTCAGGCA

164
Lys_TTT_chr12: 27843306-27843378 (+)
ACCCAGATAGCTCAGTCAGTAGAGCATCAGACTTTTAATCTGAGGGTC

CAAGGTTCATGTCCCTTTTTGGGTG

165
Lys_TTT_chr11: 122430655-122430727
GCCTGGATAGCTCAGTTGGTAGAGCATCAGACTTTTAATCTGAGGGTC

(+)
CAGGGTTCAAGTCCCTGTTCAGGCG

166
Lys_TTT_chr1: 204475655-204475727 (+)
GCCCGGATAGCTCAGTCGGTAGAGCATCAGACTTTTAATCTGAGGGTC

CAGGGTTCAAGTCCCTGTTCGGGCG

167
Lys_TTT_chr6: 27559593-27559665 (−)
GCCTGGATAGCTCAGTCGGTAGAGCATCAGACTTTTAATCTGAGGGTC

CAGGGTTCAAGTCCCTGTTCAGGCG

168
Lys_TTT_chr11: 59323902-59323974 (+)
GCCCGGATAGCTCAGTCGGTAGAGCATCAGACTTTTAATCTGAGGGTC

CGGGGTTCAAGTCCCTGTTCGGGCG

169
Lys_TTT_chr6: 27302769-27302841 (−)
GCCTGGGTAGCTCAGTCGGTAGAGCATCAGACTTTTAATCTGAGGGTC

CAGGGTTCAAGTCCCTGTCCAGGCG

170
Lys_TTT_chr6: 28715521-28715593 (+)
GCCTGGATAGCTCAGTTGGTAGAACATCAGACTTTTAATCTGACGGTG

CAGGGTTCAAGTCCCTGTTCAGGCG

171
Met_CAT_chr8: 124169470-124169542 (−)
GCCTCGTTAGCGCAGTAGGTAGCGCGTCAGTCTCATAATCTGAAGGTC

GTGAGTTCGATCCTCACACGGGGCA

172
Met_CAT_chr16: 71460396-71460468 (+)
GCCCTCTTAGCGCAGTGGGCAGCGCGTCAGTCTCATAATCTGAAGGTC

CTGAGTTCGAGCCTCAGAGAGGGCA

173
Met_CAT_chr6: 28912352-28912424 (+)
GCCTCCTTAGCGCAGTAGGCAGCGCGTCAGTCTCATAATCTGAAGGTC

CTGAGTTCGAACCTCAGAGGGGGCA

174
Met_CAT_chr6: 26735574-26735646 (−)
GCCCTCTTAGCGCAGCGGGCAGCGCGTCAGTCTCATAATCTGAAGGTC

CTGAGTTCGAGCCTCAGAGAGGGCA

175
Met_CAT_chr6: 26701712-26701784 (+)
GCCCTCTTAGCGCAGCTGGCAGCGCGTCAGTCTCATAATCTGAAGGTC

CTGAGTTCAAGCCTCAGAGAGGGCA

176
Met_CAT_chr16: 87417628-87417700 (−)
GCCTCGTTAGCGCAGTAGGCAGCGCGTCAGTCTCATAATCTGAAGGTC

GTGAGTTCGAGCCTCACACGGGGCA

177
Met_CAT_chr6: 58168492-58168564 (−)
GCCCTCTTAGTGCAGCTGGCAGCGCGTCAGTTTCATAATCTGAAAGTCC

TGAGTTCAAGCCTCAGAGAGGGCA

178
Phe_GAA_chr6: 28758499-28758571 (−)
GCCGAAATAGCTCAGTTGGGAGAGCGTTAGACTGAAGATCTAAAGGTC

CCTGGTTCGATCCCGGGTTTCGGCA

179
Phe_GAA_chr11: 59333853-59333925 (−)
GCCGAAATAGCTCAGTTGGGAGAGCGTTAGACTGAAGATCTAAAGGTC

CCTGGTTCAATCCCGGGTTTCGGCA

180
Phe_GAA_chr6: 28775610-28775682 (−)
GCCGAGATAGCTCAGTTGGGAGAGCGTTAGACTGAAGATCTAAAGGTC

CCTGGTTCAATCCCGGGTTTCGGCA

181
Phe_GAA_chr6: 28791093-28791166 (−)
GCCGAAATAGCTCAGTTGGGAGAGCGTTAGACCGAAGATCTTAAAGGT

CCCTGGTTCAATCCCGGGTTTCGGCA

182
Phe_GAA_chr6: 28731374-28731447 (−)
GCTGAAATAGCTCAGTTGGGAGAGCGTTAGACTGAAGATCTTAAAGTT

CCCTGGTTCAACCCTGGGTTTCAGCC

183
Pro_AGG_chr16: 3241989-3242060 (+)
GGCTCGTTGGTCTAGGGGTATGATTCTCGCTTAGGATGCGAGAGGTCC

CGGGTTCAAATCCCGGACGAGCCC

184
Pro_AGG_chr1: 167684725-167684796 (−)
GGCTCGTTGGTCTAGGGGTATGATTCTCGCTTAGGGTGCGAGAGGTCC

CGGGTTCAAATCCCGGACGAGCCC

185
Pro_CGG_chr1: 167683962-167684033
GGCTCGTTGGTCTAGGGGTATGATTCTCGCTTCGGGTGCGAGAGGTCC

(+)
CGGGTTCAAATCCCGGACGAGCCC

186
Pro_CGG_chr6: 27059521-27059592 (+)
GGCTCGTTGGTCTAGGGGTATGATTCTCGCTTCGGGTGTGAGAGGTCCC

GGGTTCAAATCCCGGACGAGCCC

187
Pro_TGG_chr14: 21101165-21101236 (+)
GGCTCGTTGGTCTAGTGGTATGATTCTCGCTTTGGGTGCGAGAGGTCCC

GGGTTCAAATCCCGGACGAGCCC

188
Pro_TGG_chr11: 75946869-75946940 (−)
GGCTCGTTGGTCTAGGGGTATGATTCTCGGTTTGGGTCCGAGAGGTCCC

GGGTTCAAATCCCGGACGAGCCC

189
Pro_TGG_chr5: 180615854-180615925 (−)
GGCTCGTTGGTCTAGGGGTATGATTCTCGCTTTGGGTGCGAGAGGTCCC

GGGTTCAAATCCCGGACGAGCCC

190
SeC_TCA_chr19: 45981859-45981945 (−)
GCCCGGATGATCCTCAGTGGTCTGGGGTGCAGGCTTCAAACCTGTAGC

TGTCTAGCGACAGAGTGGTTCAATTCCACCTTTCGGGCG

191
SeC_TCA_chr22: 44546537-44546620 (+)
GCTCGGATGATCCTCAGTGGTCTGGGGTGCAGGCTTCAAACCTGTAGC

TGTCTAGTGACAGAGTGGTTCAATTCCACCTTTGTA

192
Ser_AGA_chr6: 27509554-27509635 (−)
GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTAGAAATCCATTGGGG

TTTCCCCGCGCAGGTTCGAATCCTGCCGACTACG

193
Ser_AGA_chr6: 26327817-26327898 (+)
GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTAGAAATCCATTGGGG

TCTCCCCGCGCAGGTTCGAATCCTGCCGACTACG

194
Ser_AGA_chr6: 27499987-27500068 (+)
GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTAGAAATCCATTGGGG

TTTCCCCACGCAGGTTCGAATCCTGCCGACTACG

195
Ser_AGA_chr6: 27521192-27521273 (−)
GTAGTCGTGGCCGAGTGGTTAAGGTGATGGACTAGAAACCCATTGGGG

TCTCCCCGCGCAGGTTCGAATCCTGCCGACTACG

196
Ser_CGA_chr17: 8042199-8042280 (−)
GCTGTGATGGCCGAGTGGTTAAGGCGTTGGACTCGAAATCCAATGGGG

TCTCCCCGCGCAGGTTCGAATCCTGCTCACAGCG

197
Ser_CGA_chr6: 27177628-27177709 (+)
GCTGTGATGGCCGAGTGGTTAAGGCGTTGGACTCGAAATCCAATGGGG

TCTCCCCGCGCAGGTTCAAATCCTGCTCACAGCG

198
Ser_CGA_chr6: 27640229-27640310 (−)
GCTGTGATGGCCGAGTGGTTAAGGTGTTGGACTCGAAATCCAATGGGG

GTTCCCCGCGCAGGTTCAAATCCTGCTCACAGCG

199
Ser_CGA_chr12: 56584148-56584229 (+)
GTCACGGTGGCCGAGTGGTTAAGGCGTTGGACTCGAAATCCAATGGGG

TTTCCCCGCACAGGTTCGAATCCTGTTCGTGACG

200
Ser_GCT_chr6: 27065085-27065166 (+)
GACGAGGTGGCCGAGTGGTTAAGGCGATGGACTGCTAATCCATTGTGC

TCTGCACGCGTGGGTTCGAATCCCACCCTCGTCG

201
Ser_GCT_chr6: 27265775-27265856 (+)
GACGAGGTGGCCGAGTGGTTAAGGCGATGGACTGCTAATCCATTGTGC

TCTGCACGCGTGGGTTCGAATCCCACCTTCGTCG

202
Ser_GCT_chr11: 66115591-66115672 (+)
GACGAGGTGGCCGAGTGGTTAAGGCGATGGACTGCTAATCCATTGTGC

TTTGCACGCGTGGGTTCGAATCCCATCCTCGTCG

203
Ser_GCT_chr6: 28565117-28565198 (−)
GACGAGGTGGCCGAGTGGTTAAGGCGATGGACTGCTAATCCATTGTGC

TCTGCACGCGTGGGTTCGAATCCCATCCTCGTCG

204
Ser_GCT_chr6: 28180815-28180896 (+)
GACGAGGTGGCCGAGTGGTTAAGGCGATGGACTGCTAATCCATTGTGC

TCTGCACACGTGGGTTCGAATCCCATCCTCGTCG

205
Ser_GCT_chr6: 26305718-26305801(−)
GGAGAGGCCTGGCCGAGTGGTTAAGGCGATGGACTGCTAATCCATTGT

GCTCTGCACGCGTGGGTTCGAATCCCATCCTCGTCG

206
Ser_TGA_chr10: 69524261-69524342 (+)
GCAGCGATGGCCGAGTGGTTAAGGCGTTGGACTTGAAATCCAATGGGG

TCTCCCCGCGCAGGTTCGAACCCTGCTCGCTGCG

207
Ser_TGA_chr6: 27513468-27513549 (+)
GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTTGAAATCCATTGGGG

TTTCCCCGCGCAGGTTCGAATCCTGCCGACTACG

208
Ser_TGA_chr6: 26312824-26312905 (−)
GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTTGAAATCCATTGGGG

TCTCCCCGCGCAGGTTCGAATCCTGCCGACTACG

209
Ser_TGA_chr6: 27473607-27473688 (−)
GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTTGAAATCCATTGGGG

TTTCCCCGCGCAGGTTCGAATCCTGTCGGCTACG

210
Thr_AGT_chr17: 8090478-8090551 (+)
GGCGCCGTGGCTTAGTTGGTTAAAGCGCCTGTCTAGTAAACAGGAGAT

CCTGGGTTCGAATCCCAGCGGTGCCT

211
Thr_AGT_chr6: 26533145-26533218 (−)
GGCTCCGTGGCTTAGCTGGTTAAAGCGCCTGTCTAGTAAACAGGAGAT

CCTGGGTTCGAATCCCAGCGGGGCCT

212
Thr_AGT_chr6: 28693795-28693868 (+)
GGCTCCGTAGCTTAGTTGGTTAAAGCGCCTGTCTAGTAAACAGGAGAT

CCTGGGTTCGACTCCCAGCGGGGCCT

213
Thr_AGT_chr6: 27694473-27694546 (+)
GGCTTCGTGGCTTAGCTGGTTAAAGCGCCTGTCTAGTAAACAGGAGAT

CCTGGGTTCGAATCCCAGCGAGGCCT

214
Thr_AGT_chr17: 8042770-8042843 (−)
GGCGCCGTGGCTTAGCTGGTTAAAGCGCCTGTCTAGTAAACAGGAGAT

CCTGGGTTCGAATCCCAGCGGTGCCT

215
Thr_AGT_chr6: 27130050-27130123 (+)
GGCCCTGTGGCTTAGCTGGTCAAAGCGCCTGTCTAGTAAACAGGAGAT

CCTGGGTTCGAATCCCAGCGGGGCCT

216
Thr_CGT_chr6: 28456770-28456843 (−)
GGCTCTATGGCTTAGTTGGTTAAAGCGCCTGTCTCGTAAACAGGAGAT

CCTGGGTTCGACTCCCAGTGGGGCCT

217
Thr_CGT_chr16: 14379750-14379821(+)
GGCGCGGTGGCCAAGTGGTAAGGCGTCGGTCTCGTAAACCGAAGATCA

CGGGTTCGAACCCCGTCCGTGCCT

218
Thr_CGT_chr6: 28615984-28616057 (−)
GGCTCTGTGGCTTAGTTGGCTAAAGCGCCTGTCTCGTAAACAGGAGAT

CCTGGGTTCGAATCCCAGCGGGGCCT

219
Thr_CGT_chr17: 29877093-29877164 (+)
GGCGCGGTGGCCAAGTGGTAAGGCGTCGGTCTCGTAAACCGAAGATCG

CGGGTTCGAACCCCGTCCGTGCCT

220
Thr_CGT_chr6: 27586135-27586208 (+)
GGCCCTGTAGCTCAGCGGTTGGAGCGCTGGTCTCGTAAACCTAGGGGT

CGTGAGTTCAAATCTCACCAGGGCCT

221
Thr_TGT_chr6: 28442329-28442402 (−)
GGCTCTATGGCTTAGTTGGTTAAAGCGCCTGTCTTGTAAACAGGAGAT

CCTGGGTTCGAATCCCAGTAGAGCCT

222
Thr_TGT_chr1: 222638347-222638419 (+)
GGCTCCATAGCTCAGTGGTTAGAGCACTGGTCTTGTAAACCAGGGGTC

GCGAGTTCGATCCTCGCTGGGGCCT

223
Thr_TGT_chr14 21081949-21082021 (−)
GGCTCCATAGCTCAGGGGTTAGAGCGCTGGTCTTGTAAACCAGGGGTC

GCGAGTTCAATTCTCGCTGGGGCCT

224
Thr_TGT_chr14: 21099319-21099391 (−)
GGCTCCATAGCTCAGGGGTTAGAGCACTGGTCTTGTAAACCAGGGGTC

GCGAGTTCAAATCTCGCTGGGGCCT

225
Thr_TGT_chr14: 21149849-21149921 (+)
GGCCCTATAGCTCAGGGGTTAGAGCACTGGTCTTGTAAACCAGGGGTC

GCGAGTTCAAATCTCGCTGGGGCCT

226
Thr_TGT_chr5: 180618687-180618758 (−)
GGCTCCATAGCTCAGGGGTTAGAGCACTGGTCTTGTAAACCAGGGTCG

CGAGTTCAAATCTCGCTGGGGCCT

227
Trp_CCA_chr17: 8124187-8124258 (−)
GGCCTCGTGGCGCAACGGTAGCGCGTCTGACTCCAGATCAGAAGGTTG

CGTGTTCAAATCACGTCGGGGTCA

228
Trp_CCA_chr17: 19411494-19411565 (+)
GACCTCGTGGCGCAATGGTAGCGCGTCTGACTCCAGATCAGAAGGTTG

CGTGTTCAAGTCACGTCGGGGTCA

229
Trp_CCA_chr6: 26319330-26319401 (−)
GACCTCGTGGCGCAACGGTAGCGCGTCTGACTCCAGATCAGAAGGTTG

CGTGTTCAAATCACGTCGGGGTCA

230
Trp_CCA_chr12: 98898030-98898101 (+)
GACCTCGTGGCGCAACGGTAGCGCGTCTGACTCCAGATCAGAAGGCTG

CGTGTTCGAATCACGTCGGGGTCA

231
Trp_CCA_chr7: 99067307-99067378 (+)
GACCTCGTGGCGCAACGGCAGCGCGTCTGACTCCAGATCAGAAGGTTG

CGTGTTCAAATCACGTCGGGGTCA

232
Tyr_ATA_chr2: 219110549-219110641
CCTTCAATAGTTCAGCTGGTAGAGCAGAGGACTATAGCTACTTCCTCA

(+)
GTAGGAGACGTCCTTAGGTTGCTGGTTCGATTCCAGCTTGAAGGA

233
Tyr_GTA_chr6: 26569086-26569176 (+)
CCTTCGATAGCTCAGTTGGTAGAGCGGAGGACTGTAGTTGGCTGTGTC

CTTAGACATCCTTAGGTCGCTGGTTCGAATCCGGCTCGAAGGA

234
Tyr_GTA_chr2: 27273650-27273738 (+)
CCTTCGATAGCTCAGTTGGTAGAGCGGAGGACTGTAGTGGATAGGGCG

TGGCAATCCTTAGGTCGCTGGTTCGATTCCGGCTCGAAGGA

235
Tyr_GTA_chr6: 26577332-26577420 (+)
CCTTCGATAGCTCAGTTGGTAGAGCGGAGGACTGTAGGCTCATTAAGC

AAGGTATCCTTAGGTCGCTGGTTCGAATCCGGCTCGGAGGA

236
Tyr_GTA_chr14: 21125623-21125716 (−)
CCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGATTGTATAGAC

ATTTGCGGACATCCTTAGGTCGCTGGTTCGATTCCAGCTCGAAGGA

237
Tyr_GTA_chr8: 67025602-67025694 (+)
CCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGCTACTTCCTCA

GCAGGAGACATCCTTAGGTCGCTGGTTCGATTCCGGCTCGAAGGA

238
Tyr_GTA_chr8: 67026223-67026311 (+)
CCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGGCGCGCGCCCG

TGGCCATCCTTAGGTCGCTGGTTCGATTCCGGCTCGAAGGA

239
Tyr_GTA_chr14: 21121258-21121351 (−)
CCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGCCTGTAGAAAC

ATTTGTGGACATCCTTAGGTCGCTGGTTCGATTCCGGCTCGAAGGA

240
Tyr GTA_chr14: 21131351-21131444 (−)
CCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGATTGTACAGAC

ATTTGCGGACATCCTTAGGTCGCTGGTTCGATTCCGGCTCGAAGGA

241
Tyr_GTA_chr14: 21151432-21151520 (+)
CCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGTACTTAATGTG

TGGTCATCCTTAGGTCGCTGGTTCGATTCCGGCTCGAAGGA

242
Tyr_GTA_chr6: 26595102-26595190 (+)
CCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGGGGTTTGAATG

TGGTCATCCTTAGGTCGCTGGTTCGAATCCGGCTCGGAGGA

243
Tyr_GTA_chr14: 21128117-21128210 (−)
CCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGACTGCGGAAAC

GTTTGTGGACATCCTTAGGTCGCTGGTTCAATTCCGGCTCGAAGGA

244
Tyr_GTA_chr6: 26575798-26575887 (+)
CTTTCGATAGCTCAGTTGGTAGAGCGGAGGACTGTAGGTTCATTAAAC

TAAGGCATCCTTAGGTCGCTGGTTCGAATCCGGCTCGAAGGA

245
Tyr GTA_chr8: 66609532-66609619 (−)
TCTTCAATAGCTCAGCTGGTAGAGCGGAGGACTGTAGGTGCACGCCCG

TGGCCATTCTTAGGTGCTGGTTTGATTCCGACTTGGAGAG

246
Val_AAC_chr3: 169490018-169490090
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTAACACGCGAAAGGTCC

(+)
CCGGTTCGAAACCGGGCGGAAACA

247
Val_AAC_chr5: 180615416-180615488 (−)
GTTTCCGTAGTGTAGTGGTCATCACGTTCGCCTAACACGCGAAAGGTC

CCCGGTTCGAAACCGGGCGGAAACA

248
Val_AAC_chr6: 27618707-27618779 (−)
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTAACACGCGAAAGGTCC

CTGGATCAAAACCAGGCGGAAACA

249
Val_AAC_chr6: 27648885-27648957 (−)
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTAACACGCGAAAGGTCC

GCGGTTCGAAACCGGGCGGAAACA

250
Val_AAC_chr6: 27203288-27203360 (+)
GTTTCCGTAGTGTAGTGGTTATCACGTTTGCCTAACACGCGAAAGGTCC

CCGGTTCGAAACCGGGCAGAAACA

251
Val_AAC_chr6: 28703206-28703277 (−)
GGGGGTGTAGCTCAGTGGTAGAGCGTATGCTTAACATTCATGAGGCTC

TGGGTTCGATCCCCAGCACTTCCA

252
Val_CAC_chr1: 161369490-161369562 (−)
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTCACACGCGAAAGGTCC

CCGGTTCGAAACCGGGCGGAAACA

253
Val_CAC_chr6: 27248049-27248121 (−)
GCTTCTGTAGTGTAGTGGTTATCACGTTCGCCTCACACGCGAAAGGTCC

CCGGTTCGAAACCGGGCAGAAGCA

254
Val_CAC_chr19: 4724647-4724719 (−)
GTTTCCGTAGTGTAGCGGTTATCACATTCGCCTCACACGCGAAAGGTCC

CCGGTTCGATCCCGGGCGGAAACA

255
Val_CAC_chr1: 149298555-149298627 (−)
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTCACACGCGAAAGGTCC

CCGGTTCGAAACTGGGCGGAAACA

256
Val_CAC_chrl: 149684088-149684161 (−)
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTCACACGCGTAAAGGTC

CCCGGTTCGAAACCGGGCGGAAACA

257
Val_CAC_chr6: 27173867-27173939 (−)
GTTTCCGTAGTGGAGTGGTTATCACGTTCGCCTCACACGCGAAAGGTC

CCCGGTTTGAAACCAGGCGGAAACA

258
Val_TAC_chr11: 59318102-59318174 (−)
GGTTCCATAGTGTAGTGGTTATCACGTCTGCTTTACACGCAGAAGGTCC

TGGGTTCGAGCCCCAGTGGAACCA

259
Val_TAC_chr11: 59318460-59318532 (−)
GGTTCCATAGTGTAGCGGTTATCACGTCTGCTTTACACGCAGAAGGTCC

TGGGTTCGAGCCCCAGTGGAACCA

260
Val_TAC_chr10: 5895674-5895746 (−)
GGTTCCATAGTGTAGTGGTTATCACATCTGCTTTACACGCAGAAGGTCC

TGGGTTCAAGCCCCAGTGGAACCA

261
Val_TAC_chr6: 27258405-27258477 (+)
GTTTCCGTGGTGTAGTGGTTATCACATTCGCCTTACACGCGAAAGGTCC

TCGGGTCGAAACCGAGCGGAAACA

262
iMet_CAT_chr1: 153643726-153643797
AGCAGAGTGGCGCAGCGGAAGCGTGCTGGGCCCATAACCCAGAGGTC

(+)
GATGGATCGAAACCATCCTCTGCTA

263
iMet_CAT_chr6: 27745664-27745735 (+)
AGCAGAGTGGCGCAGCGGAAGCGTGCTGGGCCCATAACCCAGAGGTC

GATGGATCTAAACCATCCTCTGCTA

264
Glu_TTC_chr1: 16861773-16861845 (−)
TCCCTGGTGGTCTAGTGGCTAGGATTCGGCGCTTTCACCGCCGCGGCCC

GGGTTCGATTCCCGGTCAGGGAAT

265
Gly_CCC_chr1: 17004765-17004836 (−)
GCGTTGGTGGTTTAGTGGTAGAATTCTCGCCTCCCATGCGGGAGACCC

GGGTTCAATTCCCGGCCACTGCAC

266
Gly_CCC_chr1: 17053779-17053850 (+)
GGCCTTGGTGGTGCAGTGGTAGAATTCTCGCCTCCCACGTGGGAGACC

CGGGTTCAATTCCCGGCCAATGCA

267
Glu_TTC_chr1: 17199077-17199149 (+)
GTCCCTGGTGGTCTAGTGGCTAGGATTCGGCGCTTTCACCGCCGCGGCC

CGGGTTCGATTCCCGGCCAGGGAA

268
Asn_GTT_chr1: 17216171-17216245 (+)
TGTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACCGAAAGA

TTGGTGGTTCGAGCCCACCCAGGGACG

269
Arg_TCT_chr1: 94313128-94313213 (+)
TGGCTCCGTGGCGCAATGGATAGCGCATTGGACTTCTAGAGGCTGAAG

GCATTCAAAGGTTCCGGGTTCGAGTCCCGGCGGAGTCG

270
Lys_CTT_chr1: 145395521-145395594 (−)
GCCCGGCTAGCTCAGTCGGTAGAGCATGAGACTCTTAATCTCAGGGTC

GTGGGTTCGAGCCCCACGTTGGGCGC

271
His_GTG_chr1: 145396880-145396952 (−)
GCCGTGATCGTATAGTGGTTAGTACTCTGCGTTGTGGCCGCAGCAACCT

CGGTTCGAATCCGAGTCACGGCAG

272
Gly_TCC_chr1: 145397863-145397935 (−)
GCGTTGGTGGTATAGTGGTGAGCATAGCTGCCTTCCAAGCAGTTGACC

CGGGTTCGATTCCCGGCCAACGCAG

273
Glu_CTC_chr1: 145399232-145399304 (−)
TCCCTGGTGGTCTAGTGGTTAGGATTCGGCGCTCTCACCGCCGCGGCCC

GGGTTCGATTCCCGGTCAGGGAAA

274
Gln_CTG_chr1: 145963303-145963375
AGGTTCCATGGTGTAATGGTGAGCACTCTGGACTCTGAATCCAGCGAT

(+)
CCGAGTTCGAGTCTCGGTGGAACCT

275
Asn_GTT_chr1: 148000804-148000878
TGTCTCTGTGGCGTAGTCGGTTAGCGCGTTCGGCTGTTAACCGAAAAGT

(+)
TGGTGGTTCGAGCCCACCCAGGAACG

276
Asn_GTT_chr1: 148248114-148248188
TGTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACCGAAAGG

(+)
TTGGTGGTTCGAGCCCACCCAGGGACG

277
Asn_GTT_chr1: 148598313-148598387 (−)
GTCTCTGTGGCGCAATCGGTTAGCGCATTCGGCTGTTAACCGAAAGGT

TGGTGGTTCGAGCCCACCCAGGGACGC

278
Asn_GTT_chr1: 149230569-149230643 (−)
GTCTCTGTGGCGCAATGGGTTAGCGCGTTCGGCTGTTAACCGAAAGGT

TGGTGGTTCGAGCCCATCCAGGGACGC

279
Val_CAC_chr1: 149294665-149294736 (−)
GCACTGGTGGTTCAGTGGTAGAATTCTCGCCTCACACGCGGGACACCC

GGGTTCAATTCCCGGTCAAGGCAA

280
Val_CAC_chr1: 149298554-149298627 (−)
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTCACACGCGAAAGGTCC

CCGGTTCGAAACTGGGCGGAAACAG

281
Gly_CCC_chr1: 149680209-149680280 (−)
GCACTGGTGGTTCAGTGGTAGAATTCTCGCCTCCCACGCGGGAGACCC

GGGTTTAATTCCCGGTCAAGATAA

282
Val_CAC_chrl: 149684087-149684161 (−)
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTCACACGCGTAAAGGTC

CCCGGTTCGAAACCGGGCGGAAACAT

283
Met_CAT_chr1: 153643725-153643797
TAGCAGAGTGGCGCAGCGGAAGCGTGCTGGGCCCATAACCCAGAGGT

(+)
CGATGGATCGAAACCATCCTCTGCTA

284
Val_CAC_chr1: 161369489-161369562 (−)
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTCACACGCGAAAGGTCC

CCGGTTCGAAACCGGGCGGAAACAA

285
Asp_GTC_chr1: 161410614-161410686 (−)
TCCTCGTTAGTATAGTGGTGAGTATCCCCGCCTGTCACGCGGGAGACC

GGGGTTCGATTCCCCGACGGGGAGG

286
Gly_GCC_chr1: 161413093-161413164
TGCATGGGTGGTTCAGTGGTAGAATTCTCGCCTGCCACGCGGGAGGCC

(+)
CGGGTTCGATTCCCGGCCCATGCA

287
Glu_CTC_chr1: 161417017-161417089 (−)
TCCCTGGTGGTCTAGTGGTTAGGATTCGGCGCTCTCACCGCCGCGGCCC

GGGTTCGATTCCCGGTCAGGGAAG

288
Asp_GTC_chr1: 161492934-161493006
ATCCTTGTTACTATAGTGGTGAGTATCTCTGCCTGTCATGCGTGAGAGA

(+)
GGGGGTCGATTCCCCGACGGGGAG

289
Gly_GCC_chr1: 161493636-161493707 (−)
GCATTGGTGGTTCAGTGGTAGAATTCTCGCCTGCCACGCGGGAGGCCC

GGGTTCGATTCCCGGCCAATGCAC

290
Leu_CAG_chr1: 161500131-161500214 (−)
GTCAGGATGGCCGAGCGGTCTAAGGCGCTGCGTTCAGGTCGCAGTCTC

CCCTGGAGGCGTGGGTTCGAATCCCACTCCTGACAA

291
Gly_TCC_chr1: 161500902-161500974
CGCGTTGGTGGTATAGTGGTGAGCATAGCTGCCTTCCAAGCAGTTGAC

(+)
CCGGGTTCGATTCCCGGCCAACGCA

292
Asn_GTT_chr1: 161510030-161510104
CGTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACCGAAAGG

(+)
TTGGTGGTTCGATCCCACCCAGGGACG

293
Glu TTC chr1: 161582507-161582579 (+)
CGCGTTGGTGGTGTAGTGGTGAGCACAGCTGCCTTTCAAGCAGTTAAC

GCGGGTTCGATTCCCGGGTAACGAA

294
Pro_CGG_chr1: 167683961-167684033
CGGCTCGTTGGTCTAGGGGTATGATTCTCGCTTCGGGTGCGAGAGGTC

(+)
CCGGGTTCAAATCCCGGACGAGCCC

295
Pro_AGG_chr1: 167684724-167684796 (−)
GGCTCGTTGGTCTAGGGGTATGATTCTCGCTTAGGGTGCGAGAGGTCC

CGGGTTCAAATCCCGGACGAGCCCT

296
Lys_TTT_chr1: 204475654-204475727 (+)
CGCCCGGATAGCTCAGTCGGTAGAGCATCAGACTTTTAATCTGAGGGT

CCAGGGTTCAAGTCCCTGTTCGGGCG

297
Lys_TTT_chr1: 204476157-204476230 (−)
GCCCGGATAGCTCAGTCGGTAGAGCATCAGACTTTTAATCTGAGGGTC

CAGGGTTCAAGTCCCTGTTCGGGCGT

298
Leu_CAA_chr1: 249168053-249168159
TGTCAGGATGGCCGAGTGGTCTAAGGCGCCAGACTCAAGGTAAGCACC

(+)
TTGCCTGCGGGCTTTCTGGTCTCCGGATGGAGGCGTGGGTTCGAATCCC

299
Glu_CTC_chr1: 249168446-249168518
TTCCCTGGTGGTCTAGTGGTTAGGATTCGGCGCTCTCACCGCCGCGGCC

(+)
CGGGTTCGATTCCCGGTCAGGAAA

300
Tyr_GTA_chr2: 27273649-27273738 (+)
GCCTTCGATAGCTCAGTTGGTAGAGCGGAGGACTGTAGTGGATAGGGC

GTGGCAATCCTTAGGTCGCTGGTTCGATTCCGGCTCGAAGGA

301
Ala_AGC_chr2: 27274081-27274154 (+)
CGGGGGATTAGCTCAAATGGTAGAGCGCTCGCTTAGCATGCGAGAGGT

AGCGGGATCGATGCCCGCATCCTCCA

302
Ile_TAT_chr2: 43037675-43037768 (+)
AGCTCCAGTGGCGCAATCGGTTAGCGCGCGGTACTTATACAGCAGTAC

ATGCAGAGCAATGCCGAGGTTGTGAGTTCGAGCCTCACCTGGAGCA

303
Gly_CCC_chr2: 70476122-70476193 (−)
GCGCCGCTGGTGTAGTGGTATCATGCAAGATTCCCATTCTTGCGACCCG

GGTTCGATTCCCGGGCGGCGCAT

304
Glu_TTC_chr2: 131094700-131094772 (−)
TCCCATATGGTCTAGCGGTTAGGATTCCTGGTTTTCACCCAGGTGGCCC

GGGTTCGACTCCCGGTATGGGAAC

305
Ala_CGC_chr2: 157257280-157257352
GGGGGATGTAGCTCAGTGGTAGAGCGCGCGCTTCGCATGTGTGAGGTC

(+)
CCGGGTTCAATCCCCGGCATCTCCA

306
Gly_GCC_chr2: 157257658-157257729 (−)
GCATTGGTGGTTCAGTGGTAGAATTCTCGCCTGCCACGCGGGAGGCCC

GGGTTCGATTCCCGGCCAATGCAA

307
Arg_ACG_chr3: 45730490-45730563 (−)
GGGCCAGTGGCGCAATGGATAACGCGTCTGACTACGGATCAGAAGATT

CTAGGTTCGACTCCTGGCTGGCTCGC

308
Val_AAC_chr3: 169490017-169490090
GGTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTAACACGCGAAAGGT

(+)
CCCCGGTTCGAAACCGGGCGGAAACA

309
Val_AAC_chr5: 180596609-180596682
AGTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTAACACGCGAAAGGT

(+)
CCCCGGTTCGAAACCGGGCGGAAACA

310
Leu_AAG_chr5: 180614700-180614782
AGGTAGCGTGGCCGAGCGGTCTAAGGCGCTGGATTAAGGCTCCAGTCT

(+)
CTTCGGGGGCGTGGGTTCGAATCCCACCGCTGCCA

311
Val_AAC_chr5: 180615415-180615488 (−)
GTTTCCGTAGTGTAGTGGTCATCACGTTCGCCTAACACGCGAAAGGTC

CCCGGTTCGAAACCGGGCGGAAACAT

312
Pro_TGG_chr5: 180615853-180615925 (−)
GGCTCGTTGGTCTAGGGGTATGATTCTCGCTTTGGGTGCGAGAGGTCCC

GGGTTCAAATCCCGGACGAGCCCA

313
Thr_TGT_chr5: 180618686-180618758 (−)
GGCTCCATAGCTCAGGGGTTAGAGCACTGGTCTTGTAAACCAGGGTCG

CGAGTTCAAATCTCGCTGGGGCCTG

314
Ala_TGC_chr5: 180633867-180633939
TGGGGATGTAGCTCAGTGGTAGAGCGCATGCTTTGCATGTATGAGGCC

(+)
CCGGGTTCGATCCCCGGCATCTCCA

315
Lys_CTT_chr5: 180634754-180634827 (+)
CGCCCGGCTAGCTCAGTCGGTAGAGCATGAGACTCTTAATCTCAGGGT

CGTGGGTTCGAGCCCCACGTTGGGCG

316
Val_AAC_chr5: 180645269-180645342 (−)
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTAACACGCGAAAGGTCC

CCGGTTCGAAACCGGGCGGAAACAA

317
Lys_CTT_chr5: 180648978-180649051 (−)
GCCCGGCTAGCTCAGTCGGTAGAGCATGAGACTCTTAATCTCAGGGTC

GTGGGTTCGAGCCCCACGTTGGGCGT

318
Val_CAC_chr5: 180649394-180649467 (−)
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTCACACGCGAAAGGTCC

CCGGTTCGAAACCGGGCGGAAACAC

319
Met_CAT_chr6: 26286753-26286825 (+)
CAGCAGAGTGGCGCAGCGGAAGCGTGCTGGGCCCATAACCCAGAGGT

CGATGGATCGAAACCATCCTCTGCTA

320
Ser_GCT_chr6: 26305717-26305801 (−)
GGAGAGGCCTGGCCGAGTGGTTAAGGCGATGGACTGCTAATCCATTGT

GCTCTGCACGCGTGGGTTCGAATCCCATCCTCGTCGC

321
Gln_TTG_chr6: 26311423-26311495 (−)
GGCCCCATGGTGTAATGGTTAGCACTCTGGACTTTGAATCCAGCGATC

CGAGTTCAAATCTCGGTGGGACCTG

322
Gln_TTG_chr6: 26311974-26312046 (−)
GGCCCCATGGTGTAATGGTTAGCACTCTGGACTTTGAATCCAGCGATC

CGAGTTCAAATCTCGGTGGGACCTA

323
Ser_TGA_chr6: 26312823-26312905 (−)
GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTTGAAATCCATTGGGG

TCTCCCCGCGCAGGTTCGAATCCTGCCGACTACGG

324
Met_CAT_chr6: 26313351-26313423 (−)
AGCAGAGTGGCGCAGCGGAAGCGTGCTGGGCCCATAACCCAGAGGTC

GATGGATCGAAACCATCCTCTGCTAT

325
Arg_TCG_chr6: 26323045-26323118 (+)
GGACCACGTGGCCTAATGGATAAGGCGTCTGACTTCGGATCAGAAGAT

TGAGGGTTCGAATCCCTCCGTGGTTA

326
Ser_AGA_chr6: 26327816-26327898 (+)
TGTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTAGAAATCCATTGGG

GTCTCCCCGCGCAGGTTCGAATCCTGCCGACTACG

327
Met_CAT_chr6: 26330528-26330600 (−)
AGCAGAGTGGCGCAGCGGAAGCGTGCTGGGCCCATAACCCAGAGGTC

GATGGATCGAAACCATCCTCTGCTAG

328
Leu_CAG_chr6: 26521435-26521518 (+)
CGTCAGGATGGCCGAGCGGTCTAAGGCGCTGCGTTCAGGTCGCAGTCT

CCCCTGGAGGCGTGGGTTCGAATCCCACTCCTGACA

329
Thr_AGT_chr6: 26533144-26533218 (−)
GGCTCCGTGGCTTAGCTGGTTAAAGCGCCTGTCTAGTAAACAGGAGAT

CCTGGGTTCGAATCCCAGCGGGGCCTG

330
Arg_ACG_chr6: 26537725-26537798 (+)
AGGGCCAGTGGCGCAATGGATAACGCGTCTGACTACGGATCAGAAGA

TTCCAGGTTCGACTCCTGGCTGGCTCG

331
Val_CAC_chr6: 26538281-26538354 (+)
GGTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTCACACGCGAAAGGTC

CCCGGTTCGAAACCGGGCGGAAACA

332
Ala_CGC_chr6: 26553730-26553802 (+)
AGGGGATGTAGCTCAGTGGTAGAGCGCATGCTTCGCATGTATGAGGTC

CCGGGTTCGATCCCCGGCATCTCCA

333
Ile_AAT_chr6: 26554349-26554423 (+)
TGGCCGGTTAGCTCAGTTGGTTAGAGCGTGGTGCTAATAACGCCAAGG

TCGCGGGTTCGATCCCCGTACGGGCCA

334
Pro_AGG_chr6: 26555497-26555569 (+)
CGGCTCGTTGGTCTAGGGGTATGATTCTCGCTTAGGGTGCGAGAGGTC

CCGGGTTCAAATCCCGGACGAGCCC

335
Lys_CTT_chr6: 26556773-26556846 (+)
AGCCCGGCTAGCTCAGTCGGTAGAGCATGAGACTCTTAATCTCAGGGT

CGTGGGTTCGAGCCCCACGTTGGGCG

336
Tyr_GTA_chr6: 26569085-26569176 (+)
TCCTTCGATAGCTCAGTTGGTAGAGCGGAGGACTGTAGTTGGCTGTGT

CCTTAGACATCCTTAGGTCGCTGGTTCGAATCCGGCTCGAAGGA

337
Ala_AGC_chr6: 26572091-26572164 (−)
GGGGAATTAGCTCAAATGGTAGAGCGCTCGCTTAGCATGCGAGAGGTA

GCGGGATCGATGCCCGCATTCTCCAG

338
Met_CAT_chr6: 26766443-26766516 (+)
CGCCCTCTTAGCGCAGCGGGCAGCGCGTCAGTCTCATAATCTGAAGGT

CCTGAGTTCGAGCCTCAGAGAGGGCA

339
Ile_TAT_chr6: 26988124-26988218 (+)
TGCTCCAGTGGCGCAATCGGTTAGCGCGCGGTACTTATATGGCAGTAT

GTGTGCGAGTGATGCCGAGGTTGTGAGTTCGAGCCTCACCTGGAGCA

340
His_GTG_chr6: 27125905-27125977 (+)
TGCCGTGATCGTATAGTGGTTAGTACTCTGCGTTGTGGCCGCAGCAACC

TCGGTTCGAATCCGAGTCACGGCA

341
Ile_AAT_chr6: 27144993-27145067 (−)
GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGTGCTAATAACGCCAAGGT

CGCGGGTTCGATCCCCGTACGGGCCAC

342
Val_AAC_chr6: 27203287-27203360 (+)
AGTTTCCGTAGTGTAGTGGTTATCACGTTTGCCTAACACGCGAAAGGTC

CCCGGTTCGAAACCGGGCAGAAACA

343
Val_CAC_chr6: 27248048-27248121 (−)
GCTTCTGTAGTGTAGTGGTTATCACGTTCGCCTCACACGCGAAAGGTCC

CCGGTTCGAAACCGGGCAGAAGCAA

344
Asp_GTC_chr6: 27447452-27447524 (+)
TTCCTCGTTAGTATAGTGGTGAGTATCCCCGCCTGTCACGCGGGAGACC

GGGGTTCGATTCCCCGACGGGGAG

345
Ser_TGA_chr6: 27473606-27473688 (−)
GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTTGAAATCCATTGGGG

TTTCCCCGCGCAGGTTCGAATCCTGTCGGCTACGG

346
Gln_CTG_chr6: 27487307-27487379 (+)
AGGTTCCATGGTGTAATGGTTAGCACTCTGGACTCTGAATCCAGCGAT

CCGAGTTCAAATCTCGGTGGAACCT

347
Asp_GTC_chr6: 27551235-27551307 (−)
TCCTCGTTAGTATAGTGGTGAGTGTCCCCGTCTGTCACGCGGGAGACC

GGGGTTCGATTCCCCGACGGGGAGA

348
Val_AAC_chr6 27618706-27618779 (−)
GTTTCCGTAGTGTAGTGGTTATCACGTTCGCCTAACACGCGAAAGGTCC

CTGGATCAAAACCAGGCGGAAACAA

349
Ile_AAT_chr6: 27655966-27656040 (+)
CGGCCGGTTAGCTCAGTTGGTTAGAGCGTGGTGCTAATAACGCCAAGG

TCGCGGGTTCGATCCCCGTACTGGCCA

350
Gln_CTG_chr6: 27759134-27759206 (−)
GGCCCCATGGTGTAATGGTCAGCACTCTGGACTCTGAATCCAGCGATC

CGAGTTCAAATCTCGGTGGGACCCA

351
Gln_TTG_chr6: 27763639-27763711 (−)
GGCCCCATGGTGTAATGGTTAGCACTCTGGACTTTGAATCCAGCGATC

CGAGTTCAAATCTCGGTGGGACCTT

352
Ala_AGC_chr6: 28574932-28575004 (+)
TGGGGGTGTAGCTCAGTGGTAGAGCGCGTGCTTAGCATGTACGAGGTC

CCGGGTTCAATCCCCGGCACCTCCA

353
Ala_AGC_chr6 28626013-28626085 (−)
GGGGATGTAGCTCAGTGGTAGAGCGCATGCTTAGCATGCATGAGGTCC

CGGGTTCGATCCCCAGCATCTCCAG

354
Ala_CGC_chr6 28697091-28697163 (+)
AGGGGGTGTAGCTCAGTGGTAGAGCGCGTGCTTCGCATGTACGAGGCC

CCGGGTTCGACCCCCGGCTCCTCCA

355
Ala_AGC_chr6: 28806220-28806292 (−)
GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCTTAGCATGCACGAGGCCC

CGGGTTCAATCCCCGGCACCTCCAT

356
Ala_AGC_chr6: 28831461-28831533 (−)
GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCTTAGCATGCACGAGGCCC

CGGGTTCAATCCCCGGCACCTCCAG

357
Leu_CAA_chr6: 28863999-28864105 (−)
GTCAGGATGGCCGAGTGGTCTAAGGCGCCAGACTCAAGCTAAGCTTCC

TCCGCGGTGGGGATTCTGGTCTCCAATGGAGGCGTGGGTTCGAATCCC

358
Leu_CAA_chr6: 28908829-28908934 (+)
TGTCAGGATGGCCGAGTGGTCTAAGGCGCCAGACTCAAGCTTGGCTTC

CTCGTGTTGAGGATTCTGGTCTCCAATGGAGGCGTGGGTTCGAATCCC

359
Gln_CTG_chr6: 28909377-28909449 (−)
GGTTCCATGGTGTAATGGTTAGCACTCTGGACTCTGAATCCAGCGATCC

GAGTTCAAATCTCGGTGGAACCTT

360
Leu_AAG_chr6: 28911398-28911480 (−)
GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGGATTAAGGCTCCAGTCTC

TTCGGGGGCGTGGGTTCGAATCCCACCGCTGCCAG

361
Met_CAT_chr6 28912351-28912424 (+)
TGCCTCCTTAGCGCAGTAGGCAGCGCGTCAGTCTCATAATCTGAAGGT

CCTGAGTTCGAACCTCAGAGGGGGCA

362
Lys_TTT_chr6: 28918805-28918878 (+)
AGCCCGGATAGCTCAGTCGGTAGAGCATCAGACTTTTAATCTGAGGGT

CCAGGGTTCAAGTCCCTGTTCGGGCG

363
Met_CAT_chr6: 28921041-28921114 (−)
GCCTCCTTAGCGCAGTAGGCAGCGCGTCAGTCTCATAATCTGAAGGTC

CTGAGTTCGAACCTCAGAGGGGGCAG

364
Glu_CTC_chr6: 28949975-28950047 (+)
TTCCCTGGTGGTCTAGTGGTTAGGATTCGGCGCTCTCACCGCCGCGGCC

CGGGTTCGATTCCCGGTCAGGGAA

365
Leu_TAA_chr6: 144537683-144537766
CACCAGGATGGCCGAGTGGTTAAGGCGTTGGACTTAAGATCCAATGGA

(+)
CATATGTCCGCGTGGGTTCGAACCCCACTCCTGGTA

366
Pro_AGG_chr7: 128423503-128423575
TGGCTCGTTGGTCTAGGGGTATGATTCTCGCTTAGGGTGCGAGAGGTC

(+)
CCGGGTTCAAATCCCGGACGAGCCC

367
Arg_CCT_chr7: 139025445-139025518
AGCCCCAGTGGCCTAATGGATAAGGCATTGGCCTCCTAAGCCAGGGAT

(+)
TGTGGGTTCGAGTCCCATCTGGGGTG

368
Cys_GCA_chr7: 149388271-149388343 (−)
GGGGATATAGCTCAGGGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CCGGTTCAAATCCGGGTGCCCCCCC

369
Tyr_GTA_chr8: 67025601-67025694 (+)
CCCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGCTACTTCCTC

AGCAGGAGACATCCTTAGGTCGCTGGTTCGATTCCGGCTCGAAGGA

370
Tyr_GTA_chr8: 67026222-67026311 (+)
CCCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGGCGCGCGCCC

GTGGCCATCCTTAGGTCGCTGGTTCGATTCCGGCTCGAAGGA

371
Ala_AGC_chr8: 67026423-67026496 (+)
TGGGGGATTAGCTCAAATGGTAGAGCGCTCGCTTAGCATGCGAGAGGT

AGCGGGATCGATGCCCGCATCCTCCA

372
Ser_AGA_chr8: 96281884-96281966 (−)
GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTAGAAATCCATTGGGG

TCTCCCCGCGCAGGTTCGAATCCTGCCGACTACGG

373
Met_CAT_chr8: 124169469-124169542 (−)
GCCTCGTTAGCGCAGTAGGTAGCGCGTCAGTCTCATAATCTGAAGGTC

GTGAGTTCGATCCTCACACGGGGCAC

374
Arg_TCT_chr9: 131102354-131102445 (−)
GGCTCTGTGGCGCAATGGATAGCGCATTGGACTTCTAGCTGAGCCTAG

TGTGGTCATTCAAAGGTTGTGGGTTCGAGTCCCACCAGAGTCGA

375
Asn_GTT_chr10: 22518437-22518511 (−)
GTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACCGAAAGGT

TGGTGGTTCGAGCCCACCCAGGGACGC

376
Ser_TGA_chr10: 69524260-69524342 (+)
GGCAGCGATGGCCGAGTGGTTAAGGCGTTGGACTTGAAATCCAATGGG

GTCTCCCCGCGCAGGTTCGAACCCTGCTCGCTGCG

377
Val_TAC_chr11: 59318101-59318174 (−)
GGTTCCATAGTGTAGTGGTTATCACGTCTGCTTTACACGCAGAAGGTCC

TGGGTTCGAGCCCCAGTGGAACCAT

378
Val_TAC_chr11: 59318459-59318532 (−)
GGTTCCATAGTGTAGCGGTTATCACGTCTGCTTTACACGCAGAAGGTCC

TGGGTTCGAGCCCCAGTGGAACCAC

379
Arg_TCT_chr11: 59318766-59318852 (+)
TGGCTCTGTGGCGCAATGGATAGCGCATTGGACTTCTAGATAGTTAGA

GAAATTCAAAGGTTGTGGGTTCGAGTCCCACCAGAGTCG

380
Leu_TAA_chr11: 59319227-59319310 (+)
TACCAGAATGGCCGAGTGGTTAAGGCGTTGGACTTAAGATCCAATGGA

TTCATATCCGCGTGGGTTCGAACCCCACTTCTGGTA

381
Lys_TTT_chr11: 59323901-59323974 (+)
GGCCCGGATAGCTCAGTCGGTAGAGCATCAGACTTTTAATCTGAGGGT

CCGGGGTTCAAGTCCCTGTTCGGGCG

382
Phe_GAA_chr11: 59324969-59325042 (−)
GCCGAAATAGCTCAGTTGGGAGAGCGTTAGACTGAAGATCTAAAGGTC

CCTGGTTCGATCCCGGGTTTCGGCAG

383
Lys_TTT_chr11: 59327807-59327880 (−)
GCCCGGATAGCTCAGTCGGTAGAGCATCAGACTTTTAATCTGAGGGTC

CAGGGTTCAAGTCCCTGTTCGGGCGG

384
Phe_GAA_chr11: 59333852-59333925 (−)
GCCGAAATAGCTCAGTTGGGAGAGCGTTAGACTGAAGATCTAAAGGTC

CCTGGTTCAATCCCGGGTTTCGGCAG

385
Ser_GCT_chr11: 66115590-66115672 (+)
GGACGAGGTGGCCGAGTGGTTAAGGCGATGGACTGCTAATCCATTGTG

CTTTGCACGCGTGGGTTCGAATCCCATCCTCGTCG

386
Pro_TGG_chr11: 75946868-75946940 (−)
GGCTCGTTGGTCTAGGGGTATGATTCTCGGTTTGGGTCCGAGAGGTCCC

GGGTTCAAATCCCGGACGAGCCCC

387
Ser_CGA_chr12: 56584147-56584229 (+)
AGTCACGGTGGCCGAGTGGTTAAGGCGTTGGACTCGAAATCCAATGGG

GTTTCCCCGCACAGGTTCGAATCCTGTTCGTGACG

388
Asp_GTC_chr12: 98897280-98897352 (+)
CTCCTCGTTAGTATAGTGGTTAGTATCCCCGCCTGTCACGCGGGAGACC

GGGGTTCAATTCCCCGACGGGGAG

389
Trp_CCA_chr12: 98898029-98898101 (+)
GGACCTCGTGGCGCAACGGTAGCGCGTCTGACTCCAGATCAGAAGGCT

GCGTGTTCGAATCACGTCGGGGTCA

390
Ala_TGC_chr12: 125406300-125406372 (−)
GGGGATGTAGCTCAGTGGTAGAGCGCATGCTTTGCATGTATGAGGCCC

CGGGTTCGATCCCCGGCATCTCCAT

391
Phe_GAA_chr12: 125412388-125412461
GCCGAAATAGCTCAGTTGGGAGAGCGTTAGACTGAAGATCTAAAGGTC

(−)
CCTGGTTCGATCCCGGGTTTCGGCAG

392
Ala_TGC_chr12: 125424511-125424583
AGGGGATGTAGCTCAGTGGTAGAGCGCATGCTTTGCACGTATGAGGCC

(+)
CCGGGTTCAATCCCCGGCATCTCCA

393
Asn_GTT_chr13: 31248100-31248174 (−)
GTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACCGAAAGGT

TGGTGGTTCGAGCCCACCCAGGGACGG

394
Glu_TTC_chr13: 45492061-45492133 (−)
TCCCACATGGTCTAGCGGTTAGGATTCCTGGTTTTCACCCAGGCGGCCC

GGGTTCGACTCCCGGTGTGGGAAC

395
Thr_TGT_chr14: 21081948-21082021 (−)
GGCTCCATAGCTCAGGGGTTAGAGCGCTGGTCTTGTAAACCAGGGGTC

GCGAGTTCAATTCTCGCTGGGGCCTG

396
Leu_TAG_chr14: 21093528-21093610 (+)
TGGTAGTGTGGCCGAGCGGTCTAAGGCGCTGGATTTAGGCTCCAGTCT

CTTCGGGGGCGTGGGTTCGAATCCCACCACTGCCA

397
Thr_TGT_chr14: 21099318-21099391 (−)
GGCTCCATAGCTCAGGGGTTAGAGCACTGGTCTTGTAAACCAGGGGTC

GCGAGTTCAAATCTCGCTGGGGCCTC

398
Pro_TGG_chr14: 21101164-21101236 (+)
TGGCTCGTTGGTCTAGTGGTATGATTCTCGCTTTGGGTGCGAGAGGTCC

CGGGTTCAAATCCCGGACGAGCCC

399
Tyr_GTA_chr14: 21131350-21131444 (−)
CCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGATTGTACAGAC

ATTTGCGGACATCCTTAGGTCGCTGGTTCGATTCCGGCTCGAAGGAA

400
Thr_TGT_chr14: 21149848-21149921 (+)
AGGCCCTATAGCTCAGGGGTTAGAGCACTGGTCTTGTAAACCAGGGGT

CGCGAGTTCAAATCTCGCTGGGGCCT

401
Tyr_GTA_chr14: 21151431-21151520 (+)
TCCTTCGATAGCTCAGCTGGTAGAGCGGAGGACTGTAGTACTTAATGT

GTGGTCATCCTTAGGTCGCTGGTTCGATTCCGGCTCGAAGGA

402
Pro_TGG_chr14: 21152174-21152246 (+)
TGGCTCGTTGGTCTAGGGGTATGATTCTCGCTTTGGGTGCGAGAGGTCC

CGGGTTCAAATCCCGGACGAGCCC

403
Lys_CTT_chr14: 58706612-58706685 (−)
GCCCGGCTAGCTCAGTCGGTAGAGCATGGGACTCTTAATCCCAGGGTC

GTGGGTTCGAGCCCCACGTTGGGCGC

404
Ile_AAT_chr14: 102783428-102783502
CGGCCGGTTAGCTCAGTTGGTTAGAGCGTGGTGCTAATAACGCCAAGG

(+)
TCGCGGGTTCGATCCCCGTACGGGCCA

405
Glu_TTC_chr15: 26327380-26327452 (−)
TCCCACATGGTCTAGCGGTTAGGATTCCTGGTTTTCACCCAGGCGGCCC

GGGTTCGACTCCCGGTGTGGGAAT

406
Ser_GCT_chr15: 40886022-40886104 (−)
GACGAGGTGGCCGAGTGGTTAAGGCGATGGACTGCTAATCCATTGTGC

TCTGCACGCGTGGGTTCGAATCCCATCCTCGTCGA

407
His_GTG_chr15: 45490803-45490875 (−)
GCCGTGATCGTATAGTGGTTAGTACTCTGCGTTGTGGCCGCAGCAACCT

CGGTTCGAATCCGAGTCACGGCAT

408
His_GTG_chr15: 45493348-45493420 (+)
CGCCGTGATCGTATAGTGGTTAGTACTCTGCGTTGTGGCCGCAGCAAC

CTCGGTTCGAATCCGAGTCACGGCA

409
Gln_CTG_chr15: 66161399-66161471 (−)
GGTTCCATGGTGTAATGGTTAGCACTCTGGACTCTGAATCCAGCGATCC

GAGTTCAAATCTCGGTGGAACCTG

410
Lys_CTT_chr15: 79152903-79152976 (+)
TGCCCGGCTAGCTCAGTCGGTAGAGCATGGGACTCTTAATCCCAGGGT

CGTGGGTTCGAGCCCCACGTTGGGCG

411
Arg_TCG_chr15: 89878303-89878376 (+)
GGGCCGCGTGGCCTAATGGATAAGGCGTCTGACTTCGGATCAGAAGAT

TGCAGGTTCGAGTCCTGCCGCGGTCG

412
Gly_CCC_chr16: 686735-686806 (−)
GCGCCGCTGGTGTAGTGGTATCATGCAAGATTCCCATTCTTGCGACCCG

GGTTCGATTCCCGGGCGGCGCAC

413
Arg_CCG_chr16: 3200674-3200747 (+)
GGGCCGCGTGGCCTAATGGATAAGGCGTCTGATTCCGGATCAGAAGAT

TGAGGGTTCGAGTCCCTTCGTGGTCG

414
Arg_CCT_chr16: 3202900-3202973 (+)
CGCCCCGGTGGCCTAATGGATAAGGCATTGGCCTCCTAAGCCAGGGAT

TGTGGGTTCGAGTCCCACCCGGGGTA

415
Lys_CTT_chr16: 3207405-3207478 (−)
GCCCGGCTAGCTCAGTCGGTAGAGCATGAGACCCTTAATCTCAGGGTC

GTGGGTTCGAGCCCCACGTTGGGCGT

416
Thr_CGT_chr16: 14379749-14379821 (+)
AGGCGCGGTGGCCAAGTGGTAAGGCGTCGGTCTCGTAAACCGAAGATC

ACGGGTTCGAACCCCGTCCGTGCCT

417
Leu_TAG_chr16 22207031-22207113 (−)
GGTAGCGTGGCCGAGTGGTCTAAGGCGCTGGATTTAGGCTCCAGTCAT

TTCGATGGCGTGGGTTCGAATCCCACCGCTGCCAC

418
Leu_AAG_chr16: 22308460-22308542 (+)
GGGTAGCGTGGCCGAGCGGTCTAAGGCGCTGGATTAAGGCTCCAGTCT

CTTCGGGGGCGTGGGTTCGAATCCCACCGCTGCCA

419
Leu_CAG_chr16: 57333862-57333945 (+)
AGTCAGGATGGCCGAGCGGTCTAAGGCGCTGCGTTCAGGTCGCAGTCT

CCCCTGGAGGCGTGGGTTCGAATCCCACTTCTGACA

420
Leu_CAG_chr16: 57334391-57334474 (−)
GTCAGGATGGCCGAGCGGTCTAAGGCGCTGCGTTCAGGTCGCAGTCTC

CCCTGGAGGCGTGGGTTCGAATCCCACTTCTGACAG

421
Met_CAT_chr16: 87417627-87417700 (−)
GCCTCGTTAGCGCAGTAGGCAGCGCGTCAGTCTCATAATCTGAAGGTC

GTGAGTTCGAGCCTCACACGGGGCAG

422
Leu_TAG_chr17: 8023631-8023713 (−)
GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGGATTTAGGCTCCAGTCTC

TTCGGAGGCGTGGGTTCGAATCCCACCGCTGCCAG

423
Arg_TCT_chr17: 8024242-8024330 (+)
TGGCTCTGTGGCGCAATGGATAGCGCATTGGACTTCTAGTGACGAATA

GAGCAATTCAAAGGTTGTGGGTTCGAATCCCACCAGAGTCG

424
Gly_GCC_chr17: 8029063-8029134 (+)
CGCATTGGTGGTTCAGTGGTAGAATTCTCGCCTGCCACGCGGGAGGCC

CGGGTTCGATTCCCGGCCAATGCA

425
Ser_CGA_chr17: 8042198-8042280 (−)
GCTGTGATGGCCGAGTGGTTAAGGCGTTGGACTCGAAATCCAATGGGG

TCTCCCCGCGCAGGTTCGAATCCTGCTCACAGCGT

426
Thr_AGT_chr17: 8042769-8042843 (−)
GGCGCCGTGGCTTAGCTGGTTAAAGCGCCTGTCTAGTAAACAGGAGAT

CCTGGGTTCGAATCCCAGCGGTGCCTG

427
Trp_CCA_chr17: 8089675-8089747 (+)
CGACCTCGTGGCGCAACGGTAGCGCGTCTGACTCCAGATCAGAAGGTT

GCGTGTTCAAATCACGTCGGGGTCA

428
Ser_GCT_chr17: 8090183-8090265 (+)
AGACGAGGTGGCCGAGTGGTTAAGGCGATGGACTGCTAATCCATTGTG

CTCTGCACGCGTGGGTTCGAATCCCATCCTCGTCG

429
Thr_AGT_chr17: 8090477-8090551 (+)
CGGCGCCGTGGCTTAGTTGGTTAAAGCGCCTGTCTAGTAAACAGGAGA

TCCTGGGTTCGAATCCCAGCGGTGCCT

430
Trp_CCA_chr17: 8124186-8124258 (−)
GGCCTCGTGGCGCAACGGTAGCGCGTCTGACTCCAGATCAGAAGGTTG

CGTGTTCAAATCACGTCGGGGTCAA

431
Gly_TCC_chr17: 8124865-8124937 (+)
AGCGTTGGTGGTATAGTGGTAAGCATAGCTGCCTTCCAAGCAGTTGAC

CCGGGTTCGATTCCCGGCCAACGCA

432
Asp_GTC_chr17: 8125555-8125627 (−)
TCCTCGTTAGTATAGTGGTGAGTATCCCCGCCTGTCACGCGGGAGACC

GGGGTTCGATTCCCCGACGGGGAGA

433
Pro_CGG_chr17: 8126150-8126222 (−)
GGCTCGTTGGTCTAGGGGTATGATTCTCGCTTCGGGTGCGAGAGGTCC

CGGGTTCAAATCCCGGACGAGCCCT

434
Thr_AGT_chr17: 8129552-8129626 (−)
GGCGCCGTGGCTTAGTTGGTTAAAGCGCCTGTCTAGTAAACAGGAGAT

CCTGGGTTCGAATCCCAGCGGTGCCTT

435
Ser_AGA_chr17: 8129927-8130009 (−)
GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTAGAAATCCATTGGGG

TCTCCCCGCGCAGGTTCGAATCCTGCCGACTACGT

436
Trp_CCA_chr17: 19411493-19411565 (+)
TGACCTCGTGGCGCAATGGTAGCGCGTCTGACTCCAGATCAGAAGGTT

GCGTGTTCAAGTCACGTCGGGGTCA

437
Thr_CGT_chr17: 29877092-29877164 (+)
AGGCGCGGTGGCCAAGTGGTAAGGCGTCGGTCTCGTAAACCGAAGATC

GCGGGTTCGAACCCCGTCCGTGCCT

438
Cys_GCA_chr17: 37023897-37023969 (+)
AGGGGGTATAGCTCAGTGGTAGAGCATTTGACTGCAGATCAAGAGGTC

CCCGGTTCAAATCCGGGTGCCCCCT

439
Cys_GCA_chr17: 37025544-37025616 (−)
GGGGGTATAGCTCAGTGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CTGGTTCAAATCCGGGTGCCCCCTC

440
Cys_GCA_chr17: 37309986-37310058 (−)
GGGGGTATAGCTCAGTGGTAGAGCATTTGACTGCAGATCAAGAGGTCC

CCGGTTCAAATCCGGGTGCCCCCTC

441
Gln_TTG_chr17: 47269889-47269961 (+)
AGGTCCCATGGTGTAATGGTTAGCACTCTGGACTTTGAATCCAGCGAT

CCGAGTTCAAATCTCGGTGGGACCT

442
Arg_CCG_chr17: 66016012-66016085 (−)
GACCCAGTGGCCTAATGGATAAGGCATCAGCCTCCGGAGCTGGGGATT

GTGGGTTCGAGTCCCATCTGGGTCGC

443
Arg_CCT_chr17: 73030000-73030073 (+)
AGCCCCAGTGGCCTAATGGATAAGGCACTGGCCTCCTAAGCCAGGGAT

TGTGGGTTCGAGTCCCACCTGGGGTA

444
Arg_CCT_chr17: 73030525-73030598 (−)
GCCCCAGTGGCCTAATGGATAAGGCACTGGCCTCCTAAGCCAGGGATT

GTGGGTTCGAGTCCCACCTGGGGTGT

445
Arg_TCG_chr17: 73031207-73031280 (+)
AGACCGCGTGGCCTAATGGATAAGGCGTCTGACTTCGGATCAGAAGAT

TGAGGGTTCGAGTCCCTTCGTGGTCG

446
Asn_GTT_chr19: 1383561-1383635 (+)
CGTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACCGAAAGG

TTGGTGGTTCGAGCCCACCCAGGGACG

447
Gly_TCC_chr19: 4724081-4724153 (+)
GGCGTTGGTGGTATAGTGGTTAGCATAGCTGCCTTCCAAGCAGTTGAC

CCGGGTTCGATTCCCGGCCAACGCA

448
Val_CAC_chr19: 4724646-4724719 (−)
GTTTCCGTAGTGTAGCGGTTATCACATTCGCCTCACACGCGAAAGGTCC

CCGGTTCGATCCCGGGCGGAAACAG

449
Thr_AGT_chr19: 33667962-33668036 (+)
TGGCGCCGTGGCTTAGTTGGTTAAAGCGCCTGTCTAGTAAACAGGAGA

TCCTGGGTTCGAATCCCAGCGGTGCCT

450
Ile_TAT_chr19: 39902807-39902900 (−)
GCTCCAGTGGCGCAATCGGTTAGCGCGCGGTACTTATATGACAGTGCG

AGCGGAGCAATGCCGAGGTTGTGAGTTCGATCCTCACCTGGAGCAC

451
Gly_GCC_chr21: 18827106-18827177 (−)
GCATGGGTGGTTCAGTGGTAGAATTCTCGCCTGCCACGCGGGAGGCCC

GGGTTCGATTCCCGGCCCATGCAG

Non-Naturally Occurring Modification

A TREM, a TREM core fragment or a TREM fragment described herein may comprise a non-naturally occurring modification, e.g., a modification described in any one of Tables 10-14. A non-naturally occurring modification can be made according to methods known in the art. Methods of making non-naturally occurring modifications are known in the art; for example, several methods are provided in the Examples described herein.

In an embodiment, a non-naturally occurring modification is a modification that a cell, e.g., a human cell, does not make on an endogenous tRNA.

In an embodiment, a non-naturally occurring modification is a modification that a cell, e.g., a human cell, can make on an endogenous tRNA, but wherein such modification is in a location in which it does not occur on a native tRNA. In an embodiment, the non-naturally occurring modification is in a domain, linker or arm which does not have such modification in nature. In an embodiment, the non-naturally occurring modification is at a position within a domain, linker or arm, which does not have such modification in nature. In an embodiment, the non-naturally occurring modification is on a nucleotide which does not have such modification in nature. In an embodiment, the non-naturally occurring modification is on a nucleotide at a position within a domain, linker or arm, which does not have such modification in nature.

In an embodiment, a TREM, a TREM core fragment or a TREM fragment described herein comprises a non-naturally occurring modification provided in Table 10 or a combination thereof.

TABLE 10

Exemplary non-naturally occurring modifications

Modification

7-deaza-adenosine

N1-methyl-adenosine

N6, N6 (dimethyl)adenine

N6-cis-hydroxy-isopentenyl-adenosine

thio-adenosine

2-(amino)adenine

2-(aminopropyl)adenine

2-(methylthio) N6 (isopentenyl)adenine

2-(alkyl)adenine

2-(aminoalkyl)adenine

2-(aminopropyl)adenine

2-(halo)adenine

2-(propyl)adenine

2′-azido-2′-deoxy-adenosine

2′-Deoxy-2′-alpha-aminoadenosine

2′-Deoxy-2′-alpha-azidoadenosine

6-(alkyl)adenine

6-(methyl)adenine

6-(alkyl)adenine

6-(methyl)adenine

7-(deaza)adenine

8-(alkenyl)adenine

8-(alkynyl)adenine

8-(amino)adenine

8-(thioalkyl)adenine

8-(alkenyl)adenine

8-(alkyl)adenine

8-(alkynyl)adenine

8-(amino)adenine

8-(halo)adenine

8-(hydroxyl)adenine

8-(thioalkyl)adenine

8-(thiol)adenine

8-azido-adenosine

azaadenine

deazaadenine

N6-(methyl)adenine

N6-(isopentyl)adenine

7-deaza-8-aza-adenosine

7-methyladenine

1-deazaadenosine

2′-Fluoro-N6-Bz-deoxyadenosine

2′-OMe-2-Amino-adenosine

2′O-methyl-N6-Bz-deoxyadenosine

2′-alpha-ethynyladenosine

2-aminoadenine

2-Aminoadenosine

2-Amino-adenosine

2′-alpha-Trifluoromethyladenosine

2-Azidoadenosine

2′-beta-Ethynyladenosine

2-Bromoadenosine

2′-beta-Trifluoromethyladenosine

2-Chloroadenosine

2′-Deoxy-2′,2′-difluoroadenosine

2′-Deoxy-2′-alpha-mercaptoadenosine

2′-Deoxy-2′-alpha-

thiomethoxyadenosine

2′-Deoxy-2′-beta-aminoadenosine

2′-Deoxy-2′-beta-azidoadenosine

2′-Deoxy-2′-beta-bromoadenosine

2′-Deoxy-2′-beta-chloroadenosine

2′-Deoxy-2′-beta-fluoroadenosine

2′-Deoxy-2′-beta-iodoadenosine

2′-Deoxy-2′-beta-mercaptoadenosine

2′-Deoxy-2′-beta-thiomethoxyadenosine

2-Fluoroadenosine

2-Iodoadenosine

2-Mercaptoadenosine

2-methoxy-adenine

2-methylthio-adenine

2-Trifluoromethyladenosine

3-Deaza-3-bromoadenosine

3-Deaza-3-chloroadenosine

3-Deaza-3-fluoroadenosine

3-Deaza-3-iodoadenosine

3-Deazaadenosine

4′-Azidoadenosine

4′-Carbocyclic adenosine

4′-Ethynyladenosine

5′-Homo-adenosine

8-Aza-adenosine

8-bromo-adenosine

8-Trifluoromethyladenosine

9-Deazaadenosine

2-aminopurine

7-deaza-2,6-diaminopurine

7-deaza-8-aza-2,6-diaminopurine

7-deaza-8-aza-2-aminopurine

2,6-diaminopurine

7-deaza-8-aza-adenine, 7-deaza-2-

aminopurine

4-methylcytidine

5-aza-cytidine

Pseudo-iso-cytidine

pyrrolo-cytidine

alpha-thio-cytidine

2-(thio)cytosine

2′-Amino-2′-deoxy-cytosine

2′-Azido-2′-deoxy-cytosine

2′-Deoxy-2′-alpha-aminocytidine

2′-Deoxy-2′-alpha-azidocytidine

3 (deaza) 5 (aza)cytosine

3 (methyl)cytosine

3-(alkyl)cytosine

3-(deaza) 5 (aza)cytosine

3-(methyl)cytidine

4,2′-O-dimethylcytidine

5 (halo)cytosine

5 (methyl)cytosine

5 (propynyl)cytosine

5 (trifluoromethyl)cytosine

5-(alkyl)cytosine

5-(alkynyl)cytosine

5-(halo)cytosine

5-(propynyl)cytosine

5-(trifluoromethyl)cytosine

5-bromo-cytidine

5-iodo-cytidine

5-propynyl cytosine

6-(azo)cytosine

6-aza-cytidine

aza cytosine

deaza cytosine

N4 (acetyl)cytosine

1-methyl-1-deaza-pseudoisocytidine

1-methyl-pseudoisocytidine

2-methoxy-5-methyl-cytidine

2-methoxy-cytidine

2-thio-5-methyl-cytidine

4-methoxy-1-methyl-pseudoisocytidine

4-methoxy-pseudoisocytidine

4-thio-1-methyl-1-deaza-

pseudoisocytidine

4-thio-1-methyl-pseudoisocytidine

4-thio-pseudoisocytidine

5-aza-zebularine

5-methyl-zebularine

pyrrolo-pseudoisocytidine

zebularine

(E)-5-(2-Bromo-vinyl)cytidine

2,2′-anhydro-cytidine

2′-Fluor-N4-Bz-cytidine

2′-Fluoro-N4-Acetyl-cytidine

2′-O-Methyl-N4-Acetyl-cytidine

2′-O-methyl-N4-Bz-cytidine

2′-a-Ethynylcytidine

2′-a-Trifluoromethylcytidine

2′-b-Ethynylcytidine

2′-b-Trifluoromethylcytidine

2′-Deoxy-2′,2′-difluorocytidine

2′-Deoxy-2′-alpha-mercaptocytidine

2′-Deoxy-2′-alpha-thiomethoxycytidine

2′-Deoxy-2′-betab-aminocytidine

2′-Deoxy-2′-beta-azidocytidine

2′-Deoxy-2′-beta-bromocytidine

2′-Deoxy-2′-beta-chlorocytidine

2′-Deoxy-2′-beta-fluorocytidine

2′-Deoxy-2′-beta-iodocytidine

2′-Deoxy-2′-beta-mercaptocytidine

2′-Deoxy-2′-beta-thiomethoxycytidine

TP

2′-O-Methyl-5-(1-propynyl)cytidine

3′-Ethynylcytidine

4′-Azidocytidine

4′-Carbocyclic cytidine

4′-Ethynylcytidine

5-(1-Propynyl)ara-cytidine

5-(2-Chloro-phenyl)-2-thiocytidine

5-(4-Amino-phenyl)-2-thiocytidine

5-Aminoallyl-cytosine

5-Cyanocytidine

5-Ethynylara-cytidine

5-Ethynylcytidine

5′-Homo-cytidine

5-Methoxycytidine

5-Trifluoromethyl-Cytidine

N4-Amino-cytidine

N4-Benzoyl-cytidine

pseudoisocytidine

6-thio-guanosine

7-deaza-guanosine

8-oxo-guanosine

N1-methyl-guanosine

alpha-thio-guanosine

2-(propyl)guanine

2-(alky1)guanine

2′-Amino-2′-deoxy-guanosine

2′-Azido-2′-deoxy-guanosine

2′-Deoxy-2′-alpha-aminoguanosine

2′-Deoxy-2′-alpha-azidoguanosine

6-(methyl)guanine

6-(alky1)guanine

6-(methyl)guanine

6-methyl-guanosine

7-(alkyl)guanine

7-(deaza)guanine

7-(methyl)guanine

7-(alkyl)guanine

7-(deaza)guanine

7-(methyl)guanine

8-(alkyl)guanine

8-(alkynyl)guanine

8-(halo)guanine

8-(thioalkyl)guanine

8-(alkenyl)guanine

8-(alkyl)guanine

8-(alkynyl)guanine

8-(amino)guanine

8-(halo)guanine

8-(hydroxyl)guanine

8-(thioalkyl)guanine

8-(thiol)guanine

azaguanine

deaza guanine

N (methyl)guanine

N-(methyl)guanine

1-methyl-6-thio-guanosine

6-methoxy-guanosine

6-thio-7-deaza-8-aza-guanosine

6-thio-7-deaza-guanosine

6-thio-7-methyl-guanosine

7-deaza-8-aza-guanosine

7-methyl-8-oxo-guanosine

N2,N2-dimethyl-6-thio-guanosine

N2-methyl-6-thio-guanosine

1-Me-guanosine

2′Fluoro-N2-isobutyl-guanosine

2′O-methyl-N2-isobutyl-guanosine

2′-alpha-Ethynylguanosine

2′-alpha-Trifluoromethylguanosine

2′-beta-Ethynylguanosine

2′-beta-Trifluoromethylguanosine

2′-Deoxy-2′,2′-difluoroguanosine

2′-Deoxy-2′-alpha-mercaptoguanosine

2′-Deoxy-2′-alpha-

thiomethoxyguanosine

2′-Deoxy-2′-beta-aminoguanosine

2′-Deoxy-2′-beta-azidoguanosine

2′-Deoxy-2′-beta-bromoguanosine

2′-Deoxy-2′-beta-chloroguanosine

2′-Deoxy-2′-beta-fluoroguanosine

2′-Deoxy-2′-beta-iodoguanosine

2′-Deoxy-2′-beta-mercaptoguanosine

2′-Deoxy-2′-beta-thiomethoxyguanosine

4′-Azidoguanosine

4′-Carbocyclic guanosine

4′-Ethynylguanosine

5′-Homo-guanosine

8-bromo-guanosine

9-Deazaguanosine

N2-isobutyl-guanosine

7-methylinosine

allyamino-thymidine

aza thymidine

deaza thymidine

deoxy-thymidine

5-propynyl uracil

alpha-thio-uridine

1-(aminoalkylamino-carbonylethylenyl)-

2(thio)-pseudouracil

1-(aminoalkylaminocarbonylethylenyl)-

2,4-(dithio)pseudouracil

1-(aminoalkylaminocarbonylethylenyl)-4

(thio)pseudouracil

1-(aminoalkylaminocarbonylethylenyl)-

pseudouracil

1-(aminocarbonylethylenyl)-2(thio)-

pseudouracil

1-(aminocarbonylethylenyl)-2,4-

(dithio)pseudouracil

1-(aminocarbonylethylenyl)-4

(thio)pseudouracil

1-(aminocarbonylethylenyl)-pseudouracil

1-substituted 2-(thio)-pseudouracil

1-substituted 2,4-(dithio)pseudouracil

1-substituted 4 (thio)pseudouracil

1-substituted pseudouracil

1-(aminoalkylamino-carbonylethylenyl)-

2-(thio)-pseudouracil

1-Methyl-3-(3-amino-3-carboxypropyl)

pseudouridine

l-Methyl-3-(3-amino-3-

carboxyproovl)pseudo-Uradine

1-Methyl-pseudo-UTP

2 (thio)pseudouracil

2′ deoxy uridine

2′ fluorouridine

2-(thio)uracil

2,4-(dithio)psuedouracil

2′-methyl, 2′-amino, 2′azido, 2′fluro-

guanosine

2′-Amino-2′-deoxy-uridine

2′-Azido-2′-deoxy-uridine

2′-Azido-deoxyuridine

2′-O-methylpseudouridine

2′ deoxyuridine

2′ fluorouridine

2′-Deoxy-2′-alpha-aminouridine TP

2′-Deoxy-2′-alpha-azidouridine TP

2-methylpseudouridine

3-(3amino-3-carboxypropyl)uracil

4-(thio)pseudouracil

4-(thio)pseudouracil

4-(thio)uracil

4-thiouracil

5-(1,3-diazole-1-alkyl)uracil

5-(2-aminopropyl)uracil

5-(aminoalkyl)uracil

5-(dimethylaminoalkyl)uracil

5-(guanidiniumalkyl)uracil

5-(methoxycarbonylmethyl)-2-

(thio)uracil

5-(methoxycarbonyl-methyl)uracil

5-(methyl)-2-(thio)uracil

5-(methyl)-2,4-(dithio)uracil

5 (methyl) 4 (thio)uracil

5 (methylaminomethyl)-2 (thio)uracil

5 (methylaminomethyl)-2,4 (dithio)uracil

5 (methylaminomethyl)-4 (thio)uracil

5 (propynyl)uracil

5 (trifluoromethyl)uracil

5-(2-aminopropyl)uracil

5-(alkyl)-2-(thio)pseudouracil

5-(alkyl)-2,4 (dithio)pseudouracil

5-(alkyl)-4 (thio)pseudouracil

5-(alkyl)pseudouracil

5-(alkyl)uracil

5-(alkynyl)uracil

5-(allylamino)uracil

5-(cyanoalkyl)uracil

5-(dialkylaminoalkyl)uracil

5-(dimethylaminoalkyl)uracil

5-(guanidiniumalkyl)uracil

5-(halo)uracil

5-(1,3-diazole-1-alkyl)uracil

5-(methoxy)uracil

5-(methoxycarbonylmethyl)-2-

(thio)uracil

5-(methoxycarbonyl-methyl)uracil

5-(methyl) 2(thio)uracil

5-(methyl) 2,4 (dithio)uracil

5-(methyl) 4 (thio)uracil

5-(methyl)-2-(thio)pseudouracil

5-(methyl)-2,4 (dithio)pseudouracil

5-(methyl)-4 (thio)pseudouracil

5-(methyl)pseudouracil

5-(methylaminomethyl)-2 (thio)uracil

5-(methylaminomethyl)-2,4(dithio)uracil

5-(methylaminomethyl)-4-(thio)uracil

5-(propynyl)uracil

5-(trifluoromethyl)uracil

5-aminoallyl-uridine

5-bromo-uridine

5-iodo-uridine

5-uracil

6 (azo)uracil

6-(azo)uracil

6-aza-uridine

allyamino-uracil

aza uracil

deaza uracil

N3 (methyl)uracil

Pseudo-uridine-1-2-ethanoic acid

pseudouracil

4-Thio-pseudouridine

1-carboxymethyl-pseudouridine

1-methyl-1-deaza-pseudouridine

1-propynyl-uridine

1-taurinomethyl-1-methyl-uridine

1-taurinomethyl-4-thio-uridine

1-taurinomethyl-pseudouridine

2-methoxy-4-thio-pseudouridine

2-thio-1-methyl-1-deaza-pseudouridine

2-thio-1-methyl-pseudouridine

2-thio-5-aza-uridine

2-thio-dihydropseudouridine

2-thio-dihydrouridine

2-thio-pseudouridine

4-methoxy-2-thio-pseudouridine

4-methoxy-pseudouridine

4-thio-1-methyl-pseudouridine

4-thio-pseudouridine

5-aza-uridine

dihydropseudouridine

(±)1-(2-Hydroxypropyl)pseudouridine

(2R)-1-(2-Hydroxypropyl)pseudouridine

(2S)-1-(2-Hydroxypropyl)pseudouridine

(E)-5-(2-Bromo-vinyl)ara-uridine

(E)-5-(2-Bromo-vinyl)uridine

(Z)-5-(2-Bromo-vinyl)ara-uridine

(Z)-5-(2-Bromo-vinyl)uridine

1-(2,2,2-Trifluoroethyl)-pseudouridine

1-(2,2,3,3,3-

Pentafluoropropyl)pseudouridine

1-(2,2-Diethoxyethyl)pseudouridine

1-(2,4,6-Trimethylbenzyl)pseudouridine

1-(2,4,6-Trimethyl-benzyl)pseudo-uridine

1-(2,4,6-Trimethyl-phenyl)pseudo-

uridine

1-(2-Amino-2-carboxyethyl)pseudo-

uridine

1-(2-Amino-ethyl)pseudouridine

1-(2-Hydroxyethyl)pseudouridine

1-(2-Methoxyethyl)pseudouridine

1-(3,4-Bis-

trifluoromethoxvbenzvl)pseudouridine

1-(3,4-Dimethoxybenzyl)pseudouridine

1-(3-Amino-3-carboxypropyl)pseudo-

uridine

1-(3-Amino-propyl)pseudouridine

1-(3-Cyclopropyl-prop-2-

ynyl)pseudouridine TP

1-(4-Amino-4-

carboxybutyl)pseudouridine

1-(4-Amino-benzyl)pseudouridine

1-(4-Amino-butyl)pseudouridine

1-(4-Amino-phenyl)pseudouridine

1-(4-Azidobenzyl)pseudouridine

1-(4-Bromobenzyl)pseudouridine

1-(4-Chlorobenzyl)pseudouridine

1-(4-Fluorobenzyl)pseudouridin

1-(4-Iodobenzyl)pseudouridine

1-4-

Methanesulfonvlbenzvl)pseudouridine

1-(4-Methoxybenzyl)pseudouridine

1-(4-Methoxy-benzyl)pseudouridine

1-(4-Methoxy-phenyl)pseudouridine

1-(4-Methylbenzyl)pseudouridine

1-(4-Methyl-benzyl)pseudouridine

1-(4-Nitrobenzyl)pseudouridine

1-(4-Nitro-benzyl)pseudouridine

1(4-Nitro-phenyl)pseudouridine

1-(4-Thiomethoxybenzyl)pseudouridine

1-4-

Trifluoromethoxybenzvl)pseudouridine

1-(4-

Trifluoromethylbenzyl)pseudouridine

1-(5-Amino-pentyl)pseudouridine

1-(6-Amino-hexyl)pseudouridine

1,6-Dimethyl-pseudouridine

1-[3-(2-{2-[2-(2-Aminoethoxy)-ethoxy]-

ethoxy}-ethoxy)-propionyl]pseudouridine

1-{3-[2-(2-Aminoethoxy)-ethoxy]-

propionvl} pseudouridine

1-Acetylpseudouridine

1-Alkyl-6-(1-propynyl)-pseudo-uridine

1-Alkyl-6-(2-propynyl)-pseudo-uridine

1-Alkyl-6-allyl-pseudo-uridine

1-Alkyl-6-ethynyl-pseudo-uridine

1-Alkyl-6-homoallyl-pseudo-uridine

1-Alkyl-6-vinyl-pseudo-uridine

1-Allylpseudouridine

1-Aminomethyl-pseudo-uridine

1-Benzoylpseudouridine

1-Benzyloxymethylpseudouridine

1-Benzyl-pseudo-uridine

1-Biotinyl-PEG2-pseudouridine

1-Biotinylpseudouridine

1-Butyl-pseudo-uridine

1-Cyanomethylpseudouridine

1-Cyclobutylmethyl-pseudo-uridine

1-Cyclobutyl-pseudo-uridine

1-Cycloheptylmethyl-pseudo-uridine

1-Cycloheptyl-pseudo-uridine

1-Cyclohexylmethyl-pseudo-uridine

1-Cyclohexyl-pseudo-uridine

1-Cyclooctylmethyl-pseudo-uridine

1-Cyclooctyl-pseudo-uridine

1-Cyclopentylmethyl-pseudo-uridine

1-Cyclopentyl-pseudo-uridine

1-Cyclopropylmethyl-pseudo-uridine

1-Cyclopropyl-pseudo-uridine

1-Ethyl-pseudo-uridine

1-Hexyl-pseudo-uridine

1-Homoallylpseudouridine

1-Hydroxymethylpseudouridine

1-iso-propyl-pseudo-uridine

1-Me-2-thio-pseudo-uridine

1-Me-4-thio-pseudo-uridine

1-Me-alpha-thio-pseudo-uridine

1-Methanesulfonylmethylpseudouridine

1-Methoxymethylpseudouridine uridine

1-Methyl-6-(2,2,2-Trifluoroethyl)pseudo-

uridine

1-Methyl-6-(4-morpholino)-pseudo-

uridine

1-Methyl-6-(4-thiomorpholino)-pseudo-

uridine

1-Methyl-6-(substituted phenyl)pseudo-

uridine

1-Methyl-6-amino-pseudo-uridine

1-Methyl-6-azido-pseudo-uridine

1-Methyl-6-bromo-pseudo-uridine

1-Methyl-6-butyl-pseudo-uridine

1-Methyl-6-chloro-pseudo-uridine

1-Methyl-6-cyano-pseudo-uridine

1-Methyl-6-dimethylamino-pseudo-

uridine

1-Methyl-6-ethoxy-pseudo-uridine

1-Methyl-6-ethylcarboxylate-pseudo-

uridine

1-Methyl-6-ethyl-pseudo-uridine

1-Methyl-6-fluoro-pseudo-uridine

1-Methyl-6-formyl-pseudo-uridine

1-Methyl-6-hydroxyamino-pseudo-

uridine

1-Methyl-6-hydroxy-pseudo-uridine

1-Methyl-6-iodo-pseudo-uridine

1-Methyl-6-iso-propyl-pseudo-uridine

1-Methyl-6-methoxy-pseudo-uridine

1-Methyl-6-methylamino-pseudo-uridine

1-Methyl-6-phenyl-pseudo-uridine

1-Methyl-6-propyl-pseudo-uridine

1-Methyl-6-tert-butyl-pseudo-uridine

1-Methyl-6-trifluoromethoxy-pseudo-

uridine

1-Methyl-6-trifluoromethyl-pseudo-

uridine

1-Morpholinomethylpseudouridine

1-Pentyl-pseudo-uridineuridine

1-Phenyl-pseudo-uridine

1-Pivaloylpseudouridine

1-Propargylpseudouridine

1-Propyl-pseudo-uridine

1-propynyl-pseudouridine

1-p-tolyl-pseudo-uridine

1-tert-Butyl-pseudo-uridine

1-Thiomethoxymethylpseudouridine

1-Thiomorpholinomethylpseudouridine

1-Trifluoroacetylpseudouridine

1-Trifluoromethyl-pseudouridine

1-Vinylpseudouridine

2,2′-anhydro-uridine

2′-bromo-deoxyuridine

2′-F-5-Methyl-2′-deoxy-uridine

2′-OMe-5-Me-uridine

2′-OMe-pseudouridine

2′-alpha-Ethynyluridine

2′-alpha-Trifluoromethyluridine

2′-beta-Ethynyluridine

2′-beta-Trifluoromethyluridiner

2′-Deoxy-2′,2′-difluorouridine

2′-Deoxy-2′-a-mercaptouridin

2′-Deoxy-2′-alpha-thiomethoxyuridine

2′-Deoxy-2′-beta-aminouridine

2′-Deoxy-2′-beta-azidouridine

2′-Deoxy-2′-beta-bromouridine

2′-Deoxy-2′-beta-chlorouridine

2′-Deoxy-2′-beta-fluorouridine

2′-Deoxy-2′-beta-iodouridine

2′-Deoxy-2′-beta-mercaptouridine

2′-Deoxy-2′-beta-thiomethoxyuridine

2-methoxy-4-thio-uridine

2-methoxyuridine

2′-O-Methyl-5-(1-propynyl)uridine

3-Alkyl-pseudo-uridine

4′-Azidouridine

4′-Carbocyclic uridine

4′-Ethynyluridine

5-(1-Propynyl)ara-uridine

5-(2-Furanyl)uridine

5-Cyanouridine

5-Dimethylaminouridine

5′-Homo-uridine

5-iodo-2′-fluoro-deoxyuridine

5-Phenylethynyluridine

5-Trideuteromethyl-6-deuterouridine

5-Trifluoromethyl-Uridine

5-Vinylarauridine

6-(2,2,2-Trifluoroethyl)-pseudo-uridine

6-(4-Morpholino)-pseudo-uridine

6-(4-Thiomorpholino)-pseudo-uridine

6-(Substituted-Phenyl)-pseudo-uridine

6-Amino-pseudo-uridine

6-Azido-pseudo-uridine

6-Bromo-pseudo-uridine

6-Butyl-pseudo-uridine

6-Chloro-pseudo-uridine

6-Cyano-pseudo-uridine

6-Dimethylamino-pseudo-uridine

6-Ethoxy-pseudo-uridine

6-Ethylcarboxylate-pseudo-uridine

6-Ethyl-pseudo-uridine

6-Fluoro-pseudo-uridine

6-Formyl-pseudo-uridine

6-Hydroxyamino-pseudo-uridine

6-Hydroxy-pseudo-uridine

6-Iodo-pseudo-uridine

6-iso-Propyl-pseudo-uridine

6-Methoxy-pseudo-uridine

6-Methylamino-pseudo-uridine

6-Methyl-pseudo-uridine

6-Phenyl-pseudo-uridine

6-Phenyl-pseudo-uridine

6-Propyl-pseudo-uridine

6-tert-Butyl-pseudo-uridine

6-Trifluoromethoxy-pseudo-uridine

6-Trifluoromethyl-pseudo-uridine

alpha-thio-pseudo-uridine

Pseudouridine 1-(4-

methylbenzenesulfonic

acid)

Pseudouridine 1-(4-methylbenzoic acid)

TP

Pseudouridine 1-[3-(2-

ethoxy)]propionic acid

Pseudouridine 1-[3-{2-(2-[2-(2-ethoxy)-

ethoxy]-ethoxy)-ethoxy}]propionic

acid

Pseudouridine 1-[3-{2-(2-[2-{2(2-

ethoxy}ipropionic acid

ethoxy)-ethoxy}-ethoxy]-ethoxy)-

Pseudouridine 1-[3-{2-(2-[2-ethoxy]-

ethoxy)-ethoxv}]propionic acid

Pseudouridine 1-[3-{2-(2-ethoxy)-

ethoxv}] propionic acid

Pseudouridine 1-methylphosphonic

acid

Pseudouridine TP 1-methylphosphonic

acid diethyl ester

Pseudo-uridine-N1-3-propionic acid

Pseudo-uridine-N1-4-butanoic acid

Pseudo-uridine-N1-5-pentanoic acid

Pseudo-uridine-N1-6-hexanoic acid

Pseudo-uridine-N1-7-heptanoic acid

Pseudo-uridine-N1-methyl-p-benzoic

acid

Pseudo-uridine-N1-p-benzoic acid

In an embodiment, a TREM, a TREM core fragment or a TREM fragment described herein comprises a modification provided in Table 11, or a combination thereof. The modifications provided in Table 6 occur naturally in RNAs, and are used herein on a synthetic TREM, a TREM core fragment or a TREM fragment at a position that does not occur in nature.

TABLE 11

Additional exemplary modifications

Modification

2-methylthio-N6-(cis-

hvdroxvisopentenvl)adenosine

2-methylthio-N6-methyladenosine

2-methylthio-N6-

threonyl

carbamoyladenosine

N6-glycinylcarbamoyladenosine

N6-isopentenyladenosine

N6-methyladenosine

N6-threonylcarbamoyladenosine

1,2′-O-dimethyladenosine

1-methyladenosine

2′-O-methyladenosine

2′-O-ribosyladenosine (phosphate)

2-methyladenosine

2-methylthio-N6 isopentenyladenosine

2-methylthio-N6-

hydroxynorvalyl

carbamoyladenosine

2′-O-methyladenosine

2′-O-ribosyladenosine (phosphate)

isopenteny ladenosine

N6-(cis-hydroxyisopentenyl)adenosine

N6,2′-O-dimethyladenosine

N6,2′-O-dimethyladenosine

N6,N6,2′-O-trimethyladenosine

N6,N6-dimethyladenosine

N6-acetyladenosine

N6-hydroxynorvalylcarbamoyladenosine

N6-methyl-N6-

threonylcarbamoyladenosine

2-methyladenosine

2-methylthio-N⁶-isopentenyladenosine

2-thiocytidine

3-methylcytidine

5-formylcytidine

5-hydroxymethylcytidine

5-methylcytidine

N4-acetylcytidine

2′-O-methylcytidine

2′-O-methylcytidine

5,2′-O-dimethylcytidine

5-formyl-2′-O-methylcytidine

lysidine

N4,2′-O-dimethylcytidine

N4-acetyl-2′-O-methylcytidine

N4-methylcytidine

N4,N4-Dimethyl-2′-OMe-Cytidine

7-methylguanosine

N2,2′-O-dimethylguanosine

N2-methylguanosine

wyosme

1,2′-O-dimethylguanosine

1-methylguanosine

2′-O-methylguanosine

2′-O-ribosylguanosine (phosphate)

2′-O-methylguanosine

2′-O-ribosylguanosine (phosphate)

7-aminomethyl-7-deazaguanosine

7-cyano-7-deazaguanosine

archaeosine

methylwyosine

N2,7-dimethylguanosine

N2,N2,2′-O-trimethylguanosine

N2,N2,7-trimethylguanosine

N2,N2-dimethylguanosine

N2,7,2′-O-trimethylguanosine

1-methylinosine

mosme

1,2′-O-dimethylinosine

2′-O-methylinosine

2′-O-methylinosine

epoxyqueuosine

galactosyl-queuosine

mannosyl-queuosine

2′-O-methyluridine

2-thiouridine

3-methyluridine

5-carboxymethyluridine

5-hydroxyuridine

5-methyluridine

5-taurinomethyl-2-thiouridine

5-taurinomethyluridine

dihydrouridine

pseudouridine

(3-(3-amino-3-carboxypropyl)uridine

1-methyl-3-(3-amino-5-

carboxypropyl)pseudouridine

1-methylpseduouridine

1-methyl-pseudouridine

2′-O-methyluridine

2′-O-methylpseudouridine

2′-O-methyluridine

2-thio-2′-O-methyluridine

3-(3-amino-3-carboxypropyl)uridine

3,2′-O-dimethyluridine

3-Methyl-pseudo-Uridine

4-thiouridine

5-(carboxyhydroxymethyl)uridine

5-(carboxyhydroxymethyl)uridine methyl

ester

5,2′-O-dimethyluridine

5,6-dihydro-uridine

5-aminomethyl-2-thiouridine

5-carbamoylmethyl-2′-O-methyluridine

5-carbamoylmethyluridine

5-carboxyhydroxymethyluridine

5-carboxyhydroxymethyluridine methyl

ester

5-carboxymethylaminomethyl-2′-O-

methyluridine

5-carboxymethylaminomethyl-2-

thiouridine

5-carboxymethylaminomethyl-2-

thiouridine

5-carboxymethylaminomethyluridine

5-carboxymethylaminomethyluridine

5-Carbamoylmethyluridine

5-methoxycarbonylmethyl-2′-O-

methyluridine

5-methoxycarbonylmethyl-2-thiouridine

5-methoxy carbonylmethyluridine

5-methoxyuridine

5-methyl-2-thiouridine

5-methylaminomethyl-2-selenouridine

5-methylaminomethyl-2-thiouridine

5-methylaminomethyluridine

5-Methyldihydrouridine

5-Oxyacetic acid-Uridine

5-Oxyacetic acid-methyl ester-Uridin

N1-methyl-pseudo-uridine

uridine 5-oxyacetic acid

uridine 5-oxyacetic acid methyl ester

3-(3-Amino-3-carboxypropyl)-Uridine

5-(iso-Pentenylaminomethyl)-2-

thiouridine

5-(iso-Pentenylaminomethyl)-2′-O-

methyluridine

5-(iso-Pentenylaminomethyl)uridine

wybutosine

hydroxywybutosine

isowyosme

peroxywybutosine

undermodified hydroxywybutosine

4-demethylwyosine

altriol

In an embodiment, a TREM, a TREM core fragment or a TREM fragment described herein comprises a non-naturally occurring modification provided in Table 12, or a combination thereof.

TABLE 12

Additional exemplary non-naturally occurring modifications

Modification

2,6-(diamino)purine

1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl

l,3-(diaza)-2-(oxo)-phenthiazin-1-yl

1,3^-(diaza)-2-(oxo)-phenoxazin-1-yl

1,3,5-(triaza)-2,6-(dioxa)-naphthalene

2 (amino)purine

2,4,5-(trimethyl)phenyl

2′ methyl, 2′amino, 2′azido, 2′fluro-

cytidine

2′ methyl, 2′amino, 2′azido, 2′fluro-

adenine

2′methyl, 2′amino, 2′azido, 2′fluro-

uridine

2′-amino-2′-deoxyribose

2-amino-6-Chloro-purine

2-aza-inosinyl

2′-azido-2′-deoxyribose

2′fluoro-2′-deoxyribose

2′-fluoro-modified bases

2′-O-methyl-ribose

2-oxo-7-aminopyridopyrimidin-3-yl

2-oxo-pyridopyrimidine-3-yl

2-pyridinone

3 nitropyrrole

3-(methyl)-7-(propynyl)isocarbostyrilyl

3-(methyl)isocarbostyrilyl

4-(fluoro)-6-(methyl)benzimidazole

4-(methyl)benzimidazole

4-(methyl)indolyl

4,6-(dimethyl)indolyl

5 nitroindole

5 substituted pyrimidines

5-(methyl)isocarbostyrilyl

5-nitroindole

6-(aza)pyrimidine

6-(azo)thymine

6-(methyl)-7-(aza)indolyl

6-chloro-purine

6-phenyl-pyrrolo-pyrimidin-2-on-3-yl

7-(aminoalkylhydroxy)-1-(aza)-2-(thio)-

3-(aza)-phenthiazin-1-yl

7-(aminoalkylhydroxy)-1-(aza)-2-(thio)-

3-(aza)-phenoxazin-1-yl

7-(aminoalkylhydroxy)-1,3-(diaza)-2-

(oxo)-phenoxazin-1-yl

7-(aminoalkylhydroxy)-1,3-(diaza)-2-

(oxo-phenthiazin-1-yl

7-(aminoalkylhydroxy)-1,3-(diaza)-2-

(oxo)-phenoxazin-l-yl

7-(aza)indolyl

7-(guanidiniumalkylhydroxy)-1-(aza)-2-

(thio)-3-(aza)-phenoxazinl-yl

7-(guanidiniumalkylhydroxy)-1-(aza)-2-

(thio)-3-(aza)-

phenthiazin-1-yl

7-(guanidiniumalkylhydroxy)-1-(aza)-2-

(thio)-3-(aza)-phenoxazin-1-yl

7-(guanidiniumalkylhydroxy)-1,3-

(diaza)-2-(oxo)-phenoxazin-1-yl

7-(guanidiniumalkyl-hydroxy)-1,3-

(diaza)-2-(oxo)-

phenthiazin-1-yl

7-(guanidiniumalkylhydroxy)-1,3-

(diaza)-2-(oxo)-phenoxazin-1-yl

7-(propynyl)isocarbostyrilyl

7-(propynyl)isocarbostyrilyl, propynyl-

7-(aza)indolyl

7-deaza-inosinyl

7-substituted 1-(aza)-2-(thio)-3-(aza)-

phenoxazin-1-yl

7-substituted 1,3-(diaza)-2-(oxo)-

phenoxazin-1-yl

9-(methyl)-imidizopyridinyl

aminoindolyl

anthracenyl

bis-ortho-(aminoalkylhydroxy)-6-

phenyl-pyrrolo-nvrimidin-2-on-3-yl

bis-ortho-substituted-6-phenyl-pyrrolo-

pyrimidin-2-on-3-yl

difluorotolyl

hypoxanthine

imidizopyridinyl

inosinyl

isocarbostyrilyl

isoguanosine

N2-substituted purines

N6-methyl-2-amino-purine

N6-substituted purines

N-alkylated derivative

napthalenyl

nitrobenzimidazolyl

nitroimidazolyl

nitroindazolyl

nitropyrazolyl

nubularine

O6-substituted purines

O-alkylated derivative

ortho-(aminoalkylhydroxy)-6-phenyl-

pyrrolo-pyrimidin-2-on-3-yl

ortho-substituted-6-phenyl-pyrrolo-

pyrimidin-2-on-3-yl

Oxoformycin TP

para-(aminoalkylhydroxy)-6-phenyl-

pyrrolo-pyrimidin-2-on-3-yl

para-substituted-6-phenyl-pyrrolo-

pyrimidin-2-on-3-yl

pentacenyl

phenanthracenyl

phenyl

propynyl-7-(aza)indolyl

pyrenyl

pyridopyrimidin-3-yl

pyridopyrimidin-3-yl, 2-oxo-7-amino-

pyridopyrimidin-3-yl

pyrrolo-pyrimidin-2-on-3-yl

pyrrolopyrimidinyl

pyrrolopyrizinyl

stilbenzyl

substituted 1,2,4-triazoles

tetracenyl

tubercidine

xanthine

Xanthosine

2-thio-zebularine

5-aza-2-thio-zebularine

7-deaza-2-amino-purine

pyridin-4-one ribonucleoside

2-Amino-riboside

Formycin A

Formycin B

Pyrrolosine

2′-OH-ara-adenosine

2′-OH-ara-cytidine

2′-OH-ara-uridine

2′-OH-ara-guanosine

5-(2-carbomethoxyvinyl)uridine

N6-(19-Amino-pentaoxanonadecyl)adenosine

In an embodiment, a TREM, a TREM core fragment or a TREM fragment described herein comprises a non-naturally occurring modification provided in Table 13, or a combination thereof.

TABLE 13

Exemplary backbone modifications

Modification

3′-alkylene phosphonates

3′-amino phosphoramidate

alkene containing backbones

aminoalkylphosphoramidates

aminoalkylphosphotriesters

boranophosphates

—CH2—O—N(CH3)—CH2—

—CH2—N(CH3)—N(CH3)—CH2—

—CH2—NH—CH2—

chiral phosphonates

chiral phosphorothioates

formacetyl and thioformacetyl

backbones

methylene (methylimino)

methylene formacetyl and

thioformacetyl backbones

methyleneimino and

methylenehydrazino backbones

morpholino linkages

—N(CH3)—CH2—CH2—

oligonucleosides with heteroatom

intenucleoside linkage

phosphinates

phosphoramidates

phosphorodithioates

phosphorothioate intenucleoside

linkages

phosphorothioates

phosphotriesters

Peptide nucleic acid (PNA)

siloxane backbones

sulfamate backbones

Sulfide, sulfoxide, and sulfone

backbones

sulfonate and sulfonamide backbones

thionoalkylphosphonates

thionoalkylphosphotriesters

thionophosphoramidates

methylphosphonates

phosphonoacetates

Phosphorothioate

Constrained nucleic acid (CNA)

2′-O-methyl

2′-O-methoxyethyl (MOE)

2′ Fluoro

Locked nucleic acid (LNA)

(S)-constrained ethyl (cEt)

Fluoro hexitol nucleic acid (FHNA)

5′-phosphorothioate

Phosphorodiamidate Morpholino Oligomer

(PMO)

Tricyclo-DNA (tcDNA)

(S) 5′-C-methyl

(E)-vinylphosphonate

Methyl phosphonate

(S) 5′-C-methyl with phosphate

(R) 5′-C-methyl with phosphate

DNA

(R) 5′-C-methyl

GNA (glycol nucleic acid)

alkyl phosphonates

Phosphorothioate

Constrained nucleic acid (CNA)

2′-O-methyl

2′-O-methoxyethyl (MOE)

2′ Fluoro

Locked nucleic acid (LNA)

(S)-constrained ethyl (cEt)

Fluoro hexitol nucleic acid (FHNA)

5′-phosphorothioate

Phosphorodiamidate Morpholino Oligomer

(PMO)

Tricyclo-DNA (tcDNA)

(S) 5′-C-methyl

(E)-vinylphosphonate

Methyl phosphonate

(S) 5′-C-methyl with phosphate

(R) 5′-C-methyl with phosphate

DNA

GNA (glycol nucleic acid)

alkyl phosphonates

In an embodiment, a TREM, a TREM core fragment or a TREM fragment described herein comprises a non-naturally occurring modification provided in Table 14, or a combination thereof.

TABLE 14

Exemplary non-naturally occurring backbone modificiations

Name of synthetic backbone modifications

Phosphorothioate

Constrained nucleic acid (CNA)

2′ O′-methylation

2-O-methoxyethyl ribose (MOE)

2 Fluoro

Locked nucleic acid (LNA)

(S)-const rained ethyl (cEt)

Fluoro hexitol nucleic acid (FHNA)

5 phosphorothioate

Phosphorodiamidate Morpholino Oligomer (PMO)

Tricyclo-DNA (tcDNA)

(5) 5-C-methyl

(E)-vinylphosphonate

Methyl phosphonate

(S) 5-C-methyl with phosphate

TREM, TREM Core Fragment and TREM Fragment Fusions

In an embodiment, a TREM, a TREM core fragment or a TREM fragment disclosed herein comprises an additional moiety, e.g., a fusion moiety. In an embodiment, the fusion moiety can be used for purification, to alter folding of the TREM, TREM core fragment or TREM fragment, or as a targeting moiety. In an embodiment, the fusion moiety can comprise a tag, a linker, can be cleavable or can include a binding site for an enzyme. In an embodiment, the fusion moiety can be disposed at the N terminal of the TREM or at the C terminal of the TREM, TREM core fragment or TREM fragment. In an embodiment, the fusion moiety can be encoded by the same or different nucleic acid molecule that encodes the TREM, TREM core fragment or TREM fragment.

TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises a consensus sequence provided herein.

In an embodiment, a TREM disclosed herein comprises a consensus sequence of Formula I_ZZZ, wherein _ZZZindicates any of the twenty amino acids and Formula I corresponds to all species.

In an embodiment, a TREM disclosed herein comprises a consensus sequence of Formula II_ZZZ, wherein _ZZZindicates any of the twenty amino acids and Formula II corresponds to mammals.

In an embodiment, a TREM disclosed herein comprises a consensus sequence of Formula III_ZZZ, wherein _ZZZindicates any of the twenty amino acids and Formula III corresponds to humans.

In an embodiment, _ZZZindicates any of the twenty amino acids: alanine, arginine, asparagine, aspartate, cysteine, glutamine, glutamate, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

In an embodiment, a TREM disclosed herein comprises a property selected from the following:

a) under physiological conditions residue R₀forms a linker region, e.g., a Linker 1 region;

b) under physiological conditions residues R₁-R₂-R₃-R₄-R₅-R₆-R₇and residues R₆₅-R₆₆-R₆₇-R₆₈-R₆₉-R₇₀-R₇₁form a stem region, e.g., an AStD stem region;

c) under physiological conditions residues R₈-R₉forms a linker region, e.g., a Linker 2 region;

d) under physiological conditions residues -R₁₀-R₁₁-R₁₂-R₁₃-R₁₄R₁₅-R₁₆-R₁₇-R₁₈-R₁₉-R₂₀-R₂₁-R₂₂-R₂₃-R₂₄-R₂₅-R₂₆-R₂₇-R₂₈form a stem-loop region, e.g., a D arm Region;

e) under physiological conditions residue -R₂₉forms a linker region, e.g., a Linker 3 Region;

f) under physiological conditions residues -R₃₀-R₃₁-R₃₂-R₃₃-R₃₄-R₃₅-R₃₆-R₃₇-R₃₈-R₃₉-R₄₀-R₄₁-R₄₂-R₄₃-R₄₄-R₄₅-R₄₆form a stem-loop region, e.g., an AC arm region;

g) under physiological conditions residue -[R₄₇]_xcomprises a variable region, e.g., as described herein;

h) under physiological conditions residues -R₄₈-R₄₉-R₅₀-R₅₁-R₅₂-R₅₃-R₅₄-R₅₅-R₅₆-R₅₇-R₅₈-R₅₉-R₆₀-R₆₁-R₆₂-R₆₃-R₆₄form a stem-loop region, e.g., a T arm Region; or

i) under physiological conditions residue R₇₂forms a linker region, e.g., a Linker 4 region.

Alanine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_ALA(SEQ ID NO: 562),

R₀-R₁-R₂-R₃-R₄-R₅-R₆-R₇-R₈-R₉-R₁₀-R₁₁-R₁₂-R₁₃-R₁₄-R₁₅-R₁₆-R₁₇-R₁₈-R₁₉-R₂₀-R₂₁-R₂₂-R₂₃-R₂₄-R₂₅-R₂₆-R₂₇-R₂₈-R₂₉-R₃₀-R₃₁-R₃₂-R₃₃-R₃₄-R₃₅-R₃₆-R₃₇-R₃₈-R₃₉-R₄₀-R₄₁-R₄₂-R₄₃-R₄₄-R₄₅-R₄₆-[R₄₇]_x-R₄₈-R₄₉-R₅₀-R₅₁-R₅₂-R₅₃-R₅₄-R₅₅-R₅₆-R₅₇-R₅₈-R₅₉-R₆₀-R₆₁-R₆₂-R₆₃-R₆₄-R₆₅-R₆₆-R₆₇-R₆₈-R₆₉-R₇₀-R₇₁-R₇₂

wherein R is a ribonucleotide residue and the consensus for Ala is:

- R₀=absent;
- R₁₄, R₅₇=are independently A or absent;
- R₂₆=A, C, G or absent;
- R₅, R₆, R₁₅, R₁₆, R₂₁, R₃₀, R₃₁, R₃₂, R₃₄, R₃₇, R₄₁, R₄₂, R₄₃, R₄₄, R₄₅, R₄₈, R₄₉, R₅₀, R₅₈, R₅₉, R₆₃, R₆₄, R₆₆, R₆₇=are independently N or absent;
- R₁₁, R₃₅, R₆₅=are independently A, C, U or absent;
- R₁, R₉, R₂₀, R₃₈, R₄₀, R₅₁, R₅₂, R₅₆=are independently A, G or absent;
- R₇, R₂₂, R₂₅, R₂₇, R₂₉, R₄₆, R₅₃, R₇₂=are independently A, G, U or absent;
- R₂₄, R₆₉=are independently A, U or absent;
- R₇₀, R₇₁=are independently C or absent;
- R₃, R₄=are independently C, G or absent;
- R₁₂, R₃₃, R₃₆, R₆₂, R₆₈=are independently C, G, U or absent;
- R₁₃, R₁₇, R₂₈, R₃₉, R₅₅, R₆₀, R₆₁=are independently C, U or absent;
- R₁₀, R₁₉, R₂₃=are independently G or absent;
- R₂=G, U or absent;
- R₈, R₁₈, R₅₄=are independently U or absent;
- [R₄₇]_x=N or absent;

wherein, e.g., x=1-271 (e.g., x=1-250, x=1-225, x=1-200, x=1-175, x=1-150, x=1-125, x=1-100, x=1-75, x=1-50, x=1-40, x=1-30, x=1-29, x=1-28, x=1-27, x=1-26, x=1-25, x=1-24, x=1-23, x=1-22, x=1-21, x=1-20, x=1-19, x=1-18, x=1-17, x=1-16, x=1-15, x=1-14, x=1-13, x=1-12, x=1-11, x=1-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70-271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_ALA(SEQ ID NO: 563),

wherein R is a ribonucleotide residue and the consensus for Ala is:

R₀, R₁₈=are absent;

R₁₄, R₂₄, R₅₇=are independently A or absent;

R₁₅, R₂₆, R₆₄=are independently A, C, G or absent;

R₁₆, R₃₁, R₅₀, R₅₉=are independently N or absent;

R₁₁, R₃₂, R₃₇, R₄₁, R₄₃, R₄₅, R₄₉, R₆₅, R₆₆=are independently A, C, U or absent;

R₁, R₅, R₉, R₂₅, R₂₇, R₃₈, R₄₀, R₄₆, R₅₁, R₅₆=are independently A, G or absent;

R₇, R₂₂, R₂₉, R₄₂, R₄₄, R₅₃, R₆₃, R₇₂=are independently A, G, U or absent;

R₆, R₃₅, R₆₉=are independently A, U or absent;

R₅₅, R₆₀, R₇₀, R₇₁=are independently C or absent;

R₃=C, G or absent;

R₁₂, R₃₆, R₄₈=are independently C, G, U or absent;

R₁₃, R₁₇, R₂₈, R₃₀, R₃₄, R₃₉, R₅₈, R₆₁, R₆₂, R₆₇, R₆₈=are independently C, U or absent;

R₄, R₁₀, R₁₉, R₂₀, R₂₃, R₅₂=are independently G or absent;

R₂, R₈, R₃₃=are independently G, U or absent;

R₂₁, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_ALA(SEQ ID NO: 564),

wherein R is a ribonucleotide residue and the consensus for Ala is:

R₀, R₁₈=are absent;

R₁₄, R₂₄, R₅₇, R₇₂=are independently A or absent;

R₁₅, R₂₆, R₆₄=are independently A, C, G or absent;

R₁₆, R₃₁, R₅₀=are independently N or absent;

R₁₁, R₃₂, R₃₇, R₄₁, R₄₃, R₄₅, R₄₉, R₆₅, R₆₆=are independently A, C, U or absent;

R₅, R₉, R₂₅, R₂₇, R₃₈, R₄₀, R₄₆, R₅₁, R₅₆=are independently A, G or absent;

R₇, R₂₂, R₂₉, R₄₂, R₄₄, R₅₃, R₆₃=are independently A, G, U or absent;

R₆, R₃₅=are independently A, U or absent;

R₅₅, R₆₀, R₆₁, R₇₀, R₇₁=are independently C or absent;

R₁₂, R₄₈, R₅₉=are independently C, G, U or absent;

R₁₃, R₁₇, R₂₈, R₃₀, R₃₄, R₃₉, R₅₈, R₆₂, R₆₇, R₆₈=are independently C, U or absent;

R₁, R₂, R₃, R₄, R₁₀, R₁₉, R₂₀, R₂₃, R₅₂=are independently G or absent;

R₃₃, R₃₆=are independently G, U or absent;

R₈, R₂₁, R₅₄, R₆₉=are independently U or absent;

[R₄₇]_x=N or absent;

Arginine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_ARG(SEQ ID NO: 565),

wherein R is a ribonucleotide residue and the consensus for Arg is:

R₅₇=A or absent;

R₉, R₂₇=are independently A, C, G or absent;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₁, R₁₂, R₁₆, R₂₁, R₂₂, R₂₃, R₂₅, R₂₆, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₇, R₄₂, R₄₄, R₄₅, R₄₆, R₄₈, R₄₉, R₅₀, R₅₁, R₅₈, R₆₂, R₆₃, R₆₄, R₆₅, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀, R₇₁=are independently N or absent;

R₁₃, R₁₇, R₄₁=are independently A, C, U or absent;

R₁₉, R₂₀, R₂₄, R₄₀, R₅₆=are independently A, G or absent;

R₁₄, R₁₅, R₇₂=are independently A, G, U or absent;

R₁₈=A, U or absent;

R₃₈=C or absent;

R₃₅, R₄₃, R₆₁=are independently C, G, U or absent;

R₂₈, R₅₅, R₅₉, R₆₀=are independently C, U or absent;

R₀, R₁₀, R₅₂=are independently G or absent;

R₈, R₃₉=are independently G, U or absent;

R₃₆, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_ARG(SEQ ID NO: 566),

wherein R is a ribonucleotide residue and the consensus for Arg is:

R₁₈=absent;

R₂₄, R₅₇=are independently A or absent;

R₄₁=A, C or absent;

R₃, R₇, R₃₄, R₅₀=are independently A, C, G or absent;

R₂, R₅, R₆, R₁₂, R₂₆, R₃₂, R₃₇, R₄₄, R₅₈, R₆₆, R₆₇, R₆₈, R₇₀=are independently N or absent;

R₄₉, R₇₁=are independently A, C, U or absent;

R₁, R₁₅, R₁₉, R₂₅, R₂₇, R₄₀, R₄₅, R₄₆, R₅₆, R₇₂=are independently A, G or absent;

R₁₄, R₂₉, R₆₃=are independently A, G, U or absent;

R₁₆, R₂₁=are independently A, U or absent;

R₃₈, R₆₁=are independently C or absent;

R₃₃, R₄₈=are independently C, G or absent;

R₄, R₉, R₁₁, R₄₃, R₆₂, R₆₄, R₆₉=are independently C, G, U or absent;

R₁₃, R₂₂, R₂₈, R₃₀, R₃₁, R₃₅, R₅₅, R₆₀, R₆₅=are independently C, U or absent;

R₀, R₁₀, R₂₀, R₂₃, R₅₁, R₅₂=are independently G or absent;

R₈, R₃₉, R₄₂=are independently G, U or absent;

R₁₇, R₃₆, R₅₃, R₅₄, R₅₉=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_ARG(SEQ ID NO: 567),

wherein R is a ribonucleotide residue and the consensus for Arg is:

R₁₈=is absent;

R₁₅, R₂₁, R₂₄, R₄₁, R₅₇=are independently A or absent;

R₃₄, R₄₄=are independently A, C or absent;

R₃, R₅, R₅₈=are independently A, C, G or absent;

R₂, R₆, R₆₆, R₇₀=are independently N or absent;

R₃₇, R₄₉=are independently A, C, U or absent;

R₁, R₂₅, R₂₉, R₄₀, R₄₅, R₄₆, R₅₀=are independently A, G or absent;

R₁₄, R₆₃, R₆₈=are independently A, G, U or absent;

R₁₆=A, U or absent;

R₃₈, R₆₁=are independently C or absent;

R₇, R₁₁, R₁₂, R₂₆, R₄₈=are independently C, G or absent;

R₆₄, R₆₇, R₆₉=are independently C, G, U or absent;

R₄, R₁₃, R₂₂, R₂₈, R₃₀, R₃₁, R₃₅, R₄₃, R₅₅, R₆₀, R₆₂, R₆₅, R₇₁=are independently C, U or absent;

R₀, R₁₀, R₁₉, R₂₀, R₂₃, R₂₇, R₃₃, R₅₁, R₅₂, R₅₆, R₇₂=are independently G or absent;

R₈, R₉, R₃₂, R₃₉, R₄₂=are independently G, U or absent;

R₁₇, R₃₆, R₅₃, R₅₄, R₅₉=are independently U or absent;

[R₄₇]_x=N or absent;

Asparagine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_ASN(SEQ ID NO: 568),

wherein R is a ribonucleotide residue and the consensus for Asn is:

R₀, R₁₈=are absent;

R₄₁=A or absent;

R₁₄, R₄₈, R₅₆=are independently A, C, G or absent;

R₂, R₄, R₅, R₆, R₁₂, R₁₇, R₂₆, R₂₉, R₃₀, R₃₁, R₄₄, R₄₅, R₄₆, R₄₉, R₅₀, R₅₈, R₆₂, R₆₃, R₆₅, R₆₆, R₆₇, R₆₈, R₇₀, R₇₁=are independently N or absent;

R₁₁, R₁₃, R₂₂, R₄₂, R₅₅, R₅₉=are independently A, C, U or absent;

R₉, R₁₅, R₂₄, R₂₇, R₃₄, R₃₇, R₅₁, R₇₂=are independently A, G or absent;

R₁, R₇, R₂₅, R₆₉=are independently A, G, U or absent;

R₄₀, R₅₇=are independently A, U or absent;

R₆₀=C or absent;

R₃₃=C, G or absent;

R₂₁, R₃₂, R₄₃, R₆₄=are independently C, G, U or absent;

R₃, R₁₆, R₂₈, R₃₅, R₃₆, R₆₁=are independently C, U or absent;

R₁₀, R₁₉, R₂₀, R₅₂=are independently G or absent;

R₅₄=G, U or absent;

R₈, R₂₃, R₃₈, R₃₉, R₅₃=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_ASN(SEQ ID NO: 569),

wherein R is a ribonucleotide residue and the consensus for Asn is:

R₀, R₁₈=are absent

R₂₄, R₄₁, R₄₆, R₆₂=are independently A or absent;

R₅₉=A, C or absent;

R₁₄, R₅₆, R₆₆=are independently A, C, G or absent;

R₁₇, R₂₉=are independently N or absent;

R₁₁, R₂₆, R₄₂, R₅₅=are independently A, C, U or absent;

R₁, R₉, R₁₂, R₁₅, R₂₅, R₃₄, R₃₇, R₄₈, R₅₁, R₆₇, R₆₈, R₆₉, R₇₀, R₇₂=are independently A, G or absent;

R₄₄, R₄₅, R₅₅=are independently A, G, U or absent;

R₄₀, R₅₇=are independently A, U or absent;

R₅, R₂₈, R₆₀=are independently C or absent;

R₃₃, R₆₅=are independently C, G or absent;

R₂₁, R₄₃, R₇₁=are independently C, G, U or absent;

R₃, R₆, R₁₃, R₂₂, R₃₂, R₃₅, R₃₆, R₆₁, R₆₃, R₆₄=are independently C, U or absent;

R₇, R₁₀, R₁₉, R₂₀, R₂₇, R₄₉, R₅₂=are independently G or absent;

R₅₄=G, U or absent;

R₂, R₄, R₈, R₁₆, R₂₃, R₃₀, R₃₁, R₃₈, R₃₉, R₅₀, R₅₃=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_ASN(SEQ ID NO: 570),

wherein R is a ribonucleotide residue and the consensus for Asn is:

R₀, R₁₈=are absent

R₂₄, R₄₀, R₄₁, R₄₆, R₆₂=are independently A or absent;

R₅₉=A, C or absent;

R₁₄, R₅₆, R₆₆=are independently A, C, G or absent;

R₁₁, R₂₆, R₄₂, R₅₅=are independently A, C, U or absent;

R₁, R₉, R₁₂, R₁₅, R₃₄, R₃₇, R₄₈, R₅₁, R₆₇, R₆₈, R₆₉, R₇₀=are independently A, G or absent;

R₄₄, R₄₅, R₅₈=are independently A, G, U or absent;

R₅₇=A, U or absent;

R₅, R₂₈, R₆₀=are independently C or absent;

R₃₃, R₆₅=are independently C, G or absent;

R₁₇, R₂₁, R₂₉=are independently C, G, U or absent;

R₃, R₆, R₁₃, R₂₂, R₃₂, R₃₅, R₃₆, R₄₃, R₆₁, R₆₃, R₆₄, R₇₁=are independently C, U or absent;

R₇, R₁₀, R₁₉, R₂₀, R₂₅, R₂₇, R₄₉, R₅₂, R₇₂=are independently G or absent;

R₅₄=G, U or absent;

R₂, R₄, R₈, R₁₆, R₂₃, R₃₀, R₃₁, R₃₈, R₃₉, R₅₀, R₅₃=are independently U or absent;

[R₄₇]_x=N or absent;

Aspartate TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_ASP(SEQ ID NO: 571),

wherein R is a ribonucleotide residue and the consensus for Asp is:

R₀=absent

R₂₄, R₇₁=are independently A, C or absent;

R₃₃, R₄₆=are independently A, C, G or absent;

R₂, R₃, R₄, R₅, R₆, R₁₂, R₁₆, R₂₂, R₂₆, R₂₉, R₃₁, R₃₂, R₄₄, R₄₈, R₄₉, R₅₈, R₆₃, R₆₄, R₆₆, R₆₇, R₆₈, R₆₉=are independently N or absent;

R₁₃, R₂₁, R₃₄, R₄₁, R₅₇, R₆₅=are independently A, C, U or absent;

R₉, R₁₀, R₁₄, R₁₅, R₂₀, R₂₇, R₃₇, R₄₀, R₅₁, R₅₆, R₇₂=are independently A, G or absent;

R₇, R₂₅, R₄₂=are independently A, G, U or absent;

R₃₉=C or absent;

R₅₀, R₆₂=are independently C, G or absent;

R₃₀, R₄₃, R₄₅, R₅₅, R₇₀=are independently C, G, U or absent;

R₈, R₁₁, R₁₇, R₁₈, R₂₈, R₃₅, R₅₃, R₅₉, R₆₀, R₆₁=are independently C, U or absent;

R₁₉, R₅₂=are independently G or absent;

R₁=G, U or absent;

R₂₃, R₃₆, R₃₈, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_ASP(SEQ ID NO: 572),

wherein R is a ribonucleotide residue and the consensus for Asp is:

R₀, R₁₇, R₁₈, R₂₃=are independently absent;

R₉, R₄₀=are independently A or absent;

R₂₄, R₇₁=are independently A, C or absent;

R₆₇, R₆₈=are independently A, C, G or absent;

R₂, R₆, R₆₆=are independently N or absent;

R₅₇, R₆₃=are independently A, C, U or absent;

R₁₀, R₁₄, R₂₇, R₃₃, R₃₇, R₄₄, R₄₆, R₅₁, R₅₆, R₆₄, R₇₂=are independently A, G or absent;

R₇, R₁₂, R₂₆, R₆₅=are independently A, U or absent;

R₃₉, R₆₁, R₆₂=are independently C or absent;

R₃, R₃₁, R₄₅, R₇₀=are independently C, G or absent;

R₄, R₅, R₂₉, R₄₃, R₅₅=are independently C, G, U or absent;

R₈, R₁₁, R₁₃, R₃₀, R₃₂, R₃₄, R₃₅, R₄₁, R₄₈, R₅₃, R₅₉, R₆₀=are independently C, U or absent;

R₁₅, R₁₉, R₂₀, R₂₅, R₄₂, R₅₀, R₅₂=are independently G or absent;

R₁, R₂₂, R₄₉, R₅₈, R₆₉=are independently G, U or absent;

R₁₆, R₂₁, R₂₈, R₃₆, R₃₈, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_ASP(SEQ ID NO: 573),

wherein R is a ribonucleotide residue and the consensus for Asp is:

R₀, R₁₇, R₁₈, R₂₃=are absent

R₉, R₁₂, R₄₀, R₆₅, R₇₁=are independently A or absent;

R₂, R₂₄, R₅₇=are independently A, C or absent;

R₆, R₁₄, R₂₇, R₄₆, R₅₁, R₅₆, R₆₄, R₆₇, R₆₈=are independently A, G or absent;

R₃, R₃₁, R₃₅, R₃₉, R₆₁, R₆₂=are independently C or absent;

R₆₆=C, G or absent;

R₅, R₈, R₂₉, R₃₀, R₃₂, R₃₄, R₄₁, R₄₃, R₄₈, R₅₅, R₅₉, R₆₀, R₆₃=are independently C, U or absent;

R₁₀, R₁₅, R₁₉, R₂₀, R₂₅, R₃₃, R₃₇, R₄₂, R₄₄, R₄₅, R₄₉, R₅₀, R₅₂, R₆₉, R₇₀, R₇₂=are independently G or absent;

R₂₂, R₅₈=are independently G, U or absent;

R₁, R₄, R₇, R₁₁, R₁₃, R₁₆, R₂₁, R₂₆, R₂₈, R₃₆, R₃₈, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

Cysteine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_CYS(SEQ ID NO: 574),

wherein R is a ribonucleotide residue and the consensus for Cys is:

R₀=absent

R₁₄, R₃₉, R₅₇=are independently A or absent;

R₄₁=A, C or absent;

R₁₀, R₁₅, R₂₇, R₃₃, R₆₂=are independently A, C, G or absent;

R₃, R₄, R₅, R₆, R₁₂, R₁₃, R₁₆, R₂₄, R₂₆, R₂₉, R₃₀, R₃₁, R₃₂, R₃₄, R₄₂, R₄₄, R₄₅, R₄₆, R₄₈, R₄₉, R₅₈, R₆₃, R₆₄, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀=are independently N or absent;

R₆₅=A, C, U or absent;

R₉, R₂₅, R₃₇, R₄₀, R₅₂, R₅₆=are independently A, G or absent;

R₇, R₂₀, R₅₁=are independently A, G, U or absent;

R₁₈, R₃₈, R₅₅=are independently C or absent;

R₂=C, G or absent;

R₂₁, R₂₈, R₄₃, R₅₀=are independently C, G, U or absent;

R₁₁, R₂₂, R₂₃, R₃₅, R₃₆, R₅₉, R₆₀, R₆₁, R₇₁, R₇₂=are independently C, U or absent;

R₁, R₁₉=are independently G or absent;

R₁₇=G, U or absent;

R₈, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_CYS(SEQ ID NO: 575),

wherein R is a ribonucleotide residue and the consensus for Cys is:

R₀, R₁₈, R₂₃=are absent;

R₁₄, R₂₄, R₂₆, R₂₉, R₃₉, R₄₁, R₄₅, R₅₇=are independently A or absent;

R₄₄=A, C or absent;

R₂₇, R₆₂=are independently A, C, G or absent;

R₁₆=A, C, G, U or absent;

R₃₀, R₇₀=are independently A, C, U or absent;

R₅, R₇, R₉, R₂₅, R₃₄, R₃₇, R₄₀, R₄₆, R₅₂, R₅₆, R₅₈, R₆₆=are independently A, G or absent;

R₂₀, R₅₁=are independently A, G, U or absent;

R₃₅, R₃₈, R₄₃, R₅₅, R₆₉=are independently C or absent;

R₂, R₄, R₁₅=are independently C, G or absent;

R₁₃=C, G, U or absent;

R₆, R₁₁, R₂₈, R₃₆, R₄₈, R₄₉, R₅₀, R₆₀, R₆₁, R₆₇, R₆₈, R₇₁, R₇₂=are independently C, U or absent;

R₁, R₃, R₁₀, R₁₉, R₃₃, R₆₃=are independently G or absent;

R₈, R₁₇, R₂₁, R₆₄=are independently G, U or absent;

R₁₂, R₂₂, R₃₁, R₃₂, R₄₂, R₅₃, R₅₄, R₆₅=are independently U or absent;

R₅₉=U, or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_CYS(SEQ ID NO: 576),

wherein R is a ribonucleotide residue and the consensus for Cys is:

R₀, R₁₈, R₂₃=are absent

R₁₄, R₂₄, R₂₆, R₂₉, R₃₄, R₃₉, R₄₁, R₄₅, R₅₇, R₅₈=are independently A or absent;

R₄₄, R₇₀=are independently A, C or absent;

R₆₂=A, C, G or absent;

R₁₆=N or absent;

R₅, R₇, R₉, R₂₀, R₄₀, R₄₆, R₅₁, R₅₂, R₅₆, R₆₆=are independently A, G or absent;

R₂₈, R₃₅, R₃₈, R₄₃, R₅₅, R₆₇, R₆₉=are independently C or absent;

R₄, R₁₅=are independently C, G or absent;

R₆, R₁₁, R₁₃, R₃₀, R₄₈, R₄₉, R₅₀, R₆₀, R₆₁, R₆₈, R₇₁, R₇₂=are independently C, U or absent;

R₁, R₂, R₃, R₁₀, R₁₉, R₂₅, R₂₇, R₃₃, R₃₇, R₆₃=are independently G or absent;

R₈, R₂₁, R₆₄=are independently G, U or absent;

R₁₂, R₁₇, R₂₂, R₃₁, R₃₂, R₃₆, R₄₂, R₅₃, R₅₄, R₅₉, R₆₅=are independently U or absent;

[R₄₇]_x=N or absent;

Glutamine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_GLN(SEQ ID NO: 577),

wherein R is a ribonucleotide residue and the consensus for Gln is:

R₀, R₁₈=are absent;

R₁₄, R₂₄, R₅₇=are independently A or absent;

R₉, R₂₆, R₂₇, R₃₃, R₅₆=are independently A, C, G or absent;

R₂, R₄, R₅, R₆, R₁₂, R₁₃, R₁₆, R₂₁, R₂₂, R₂₅, R₂₉, R₃₀, R₃₁, R₃₂, R₃₄, R₄₁, R₄₂, R₄₄, R₄₅, R₄₆, R₄₈, R₄₉, R₅₀, R₅₈, R₆₂, R₆₃, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀=are independently N or absent;

R₁₇, R₂₃, R₄₃, R₆₅, R₇₁=are independently A, C, U or absent;

R₁₅, R₄₀, R₅₁, R₅₂=are independently A, G or absent;

R₁, R₇, R₇₂=are independently A, G, U or absent;

R₃, R₁₁, R₃₇, R₆₀, R₆₄=are independently C, G, U or absent;

R₂₈, R₃₅, R₅₅, R₅₉, R₆₁=are independently C, U or absent;

R₁₀, R₁₉, R₂₀=are independently G or absent;

R₃₉=G, U or absent;

R₈, R₃₆, R₃₈, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_GLN(SEQ ID NO: 578),

wherein R is a ribonucleotide residue and the consensus for Gln is:

R₀, R₁₈, R₂₃=are absent

R₁₄, R₂₄, R₅₇=are independently A or absent;

R₁₇, R₇₁=are independently A, C or absent;

R₂₅, R₂₆, R₃₃, R₄₄, R₄₆, R₅₆, R₆₉=are independently A, C, G or absent;

R₄, R₅, R₁₂, R₂₂, R₂₉, R₃₀, R₄₈, R₄₉, R₆₃, R₆₇, R₆₈=are independently N or absent;

R₃₁, R₄₃, R₆₂, R₆₅, R₇₀=are independently A, C, U or absent;

R₁₅, R₂₇, R₃₄, R₄₀, R₄₁, R₅₁, R₅₂=are independently A, G or absent;

R₂, R₇, R₂₁, R₄₅, R₅₀, R₅₈, R₆₆, R₇₂=are independently A, G, U or absent;

R₃, R₁₃, R₃₂, R₃₇, R₄₂, R₆₀, R₆₄=are independently C, G, U or absent;

R₆, R₁₁, R₂₈, R₃₅, R₅₅, R₅₉, R₆₁=are independently C, U or absent;

R₉, R₁₀, R₁₉, R₂₀=are independently G or absent;

R₁, R₁₆, R₃₉=are independently G, U or absent;

R₈, R₃₆, R₃₈, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_GLN(SEQ ID NO: 579),

wherein R is a ribonucleotide residue and the consensus for Gln is:

R₀, R₁₈, R₂₃=are absent

R₁₄, R₂₄, R₄₁, R₅₇=are independently A or absent;

R₁₇, R₇₁=are independently A, C or absent;

R₅, R₂₅, R₂₆, R₄₆, R₅₆, R₆₉=are independently A, C, G or absent;

R₄, R₂₂, R₂₉, R₃₀, R₄₈, R₄₉, R₆₃, R₆₈=are independently N or absent;

R₄₃, R₆₂, R₆₅, R₇₀=are independently A, C, U or absent;

R₁₅, R₂₇, R₃₃, R₃₄, R₄₀, R₅₁, R₅₂=are independently A, G or absent;

R₂, R₇, R₁₂, R₄₅, R₅₀, R₅₈, R₆₆=are independently A, G, U or absent;

R₃₁=A, U or absent;

R₃₂, R₄₄, R₆₀=are independently C, G or absent;

R₃, R₁₃, R₃₇, R₄₂, R₆₄, R₆₇=are independently C, G, U or absent;

R₆, R₁₁, R₂₈, R₃₅, R₅₅, R₅₉, R₆₁=are independently C, U or absent;

R₉, R₁₀, R₁₉, R₂₀=are independently G or absent;

R₁, R₂₁, R₃₉, R₇₂=are independently G, U or absent;

R₈, R₁₆, R₃₆, R₃₈, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

Glutamate TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_GLU(SEQ ID NO: 580),

wherein R is a ribonucleotide residue and the consensus for Glu is:

R₀=absent;

R₃₄, R₄₃, R₆₈, R₆₉=are independently A, C, G or absent;

R₁, R₂, R₅, R₆, R₉, R₁₂, R₁₆, R₂₀, R₂₁, R₂₆, R₂₇, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₄₁, R₄₄, R₄₅, R₄₆, R₄₈, R₅₀, R₅₁, R₅₈, R₆₃, R₆₄, R₆₅, R₆₆, R₇₀, R₇₁=are independently N or absent;

R₁₃, R₁₇, R₂₃, R₆₁=are independently A, C, U or absent;

R₁₀, R₁₄, R₂₄, R₄₀, R₅₂, R₅₆=are independently A, G or absent;

R₇, R₁₅, R₂₅, R₆₇, R₇₂=are independently A, G, U or absent;

R₁₁, R₅₇=are independently A, U or absent;

R₃₉=C, G or absent;

R₃, R₄, R₂₂, R₄₂, R₄₉, R₅₅, R₆₂=are independently C, G, U or absent;

R₁₈, R₂₈, R₃₅, R₃₇, R₅₃, R₅₉, R₆₀=are independently C, U or absent;

R₁₉=G or absent;

R₈, R₃₆, R₃₈, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_GLU(SEQ ID NO: 581),

wherein R is a ribonucleotide residue and the consensus for Glu is:

R₀, R₁₈, R₂₃=are absent

R₁₇, R₄₀=are independently A or absent;

R₂₆, R₂₇, R₃₄, R₄₃, R₆₈, R₆₉, R₇₁=are independently A, C, G or absent;

R₁, R₂, R₅, R₁₂, R₂₁, R₃₁, R₃₃, R₄₁, R₄₅, R₄₈, R₅₁, R₅₈, R₆₆, R₇₀=are independently N or absent;

R₄₄, R₆₁=are independently A, C, U or absent;

R₉, R₁₄, R₂₄, R₂₅, R₅₂, R₅₆, R₆₃=are independently A, G or absent;

R₇, R₁₅, R₄₆, R₅₀, R₆₇, R₇₂=are independently A, G, U or absent;

R₂₉, R₅₇=are independently A, U or absent;

R₆₀=C or absent;

R₃₉=C, G or absent;

R₃, R₆, R₂₀, R₃₀, R₃₂, R₄₂, R₅₅, R₆₂, R₆₅=are independently C, G, U or absent;

R₄, R₅, R₁₆, R₂₈, R₃₅, R₃₇, R₄₉, R₅₃, R₅₉=are independently C, U or absent;

R₁₀, R₁₉=are independently G or absent;

R₂₂, R₆₄=are independently G, U or absent;

R₁₁, R₁₃, R₃₆, R₃₈, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_GLU(SEQ ID NO: 582),

wherein R is a ribonucleotide residue and the consensus for Glu is:

R₀, R₁₇, R₁₈, R₂₃=are absent

R₁₄, R₂₇, R₄₀, R₇₁=are independently A or absent;

R₄₄=A, C or absent;

R₄₃=A, C, G or absent;

R₁, R₃₁, R₃₃, R₄₅, R₅₁, R₆₆=are independently N or absent;

R₂₁, R₄₁=are independently A, C, U or absent;

R₇, R₂₄, R₂₅, R₅₀, R₅₂, R₅₆, R₆₃, R₆₈, R₇₀=are independently A, G or absent;

R₅, R₄₆=are independently A, G, U or absent;

R₂₉, R₅₇, R₆₇, R₇₂=are independently A, U or absent;

R₂, R₃₉, R₆₀=are independently C or absent;

R₃, R₁₂, R₂₀, R₂₆, R₃₄, R₆₉=are independently C, G or absent;

R₆, R₃₀, R₄₂, R₄₈, R₆₅=are independently C, G, U or absent;

R₄, R₁₆, R₂₈, R₃₅, R₃₇, R₄₉, R₅₃, R₅₅, R₅₈, R₆₁, R₆₂=are independently C, U or absent;

R₉, R₁₀, R₁₉, R₆₄=are independently G or absent;

R₁₅, R₂₂, R₃₂=are independently G, U or absent;

R₈, R₁₁, R₁₃, R₃₆, R₃₈, R₅₄, R₅₉=are independently U or absent;

[R₄₇]_x=N or absent;

Glycine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_GLY(SEQ ID NO: 583),

wherein R is a ribonucleotide residue and the consensus for Gly is:

R₀=absent;

R₂₄=A or absent;

R₃, R₉, R₄₀, R₅₀, R₅₁=are independently A, C, G or absent;

R₄, R₅, R₆, R₇, R₁₂, R₁₆, R₂₁, R₂₂, R₂₆, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₄₁, R₄₂, R₄₃, R₄₄, R₄₅, R₄₆, R₄₈, R₄₉, R₅₈, R₆₃, R₆₄, R₆₅, R₆₆, R₆₇, R₆₈=are independently N or absent;

R₅₉=A, C, U or absent;

R₁, R₁₀, R₁₄, R₁₅, R₂₇, R₅₆=are independently A, G or absent;

R₂₀, R₂₅=are independently A, G, U or absent;

R₅₇, R₇₂=are independently A, U or absent;

R₃₈, R₃₉, R₆₀=are independently C or absent;

R₅₂=C, G or absent;

R₂, R₁₉, R₃₇, R₅₄, R₅₅, R₆₁, R₆₂, R₆₉, R₇₀=are independently C, G, U or absent; R₁₁, R₁₃, R₁₇, R₂₈, R₃₅, R₃₆, R₇₁=are independently C, U or absent;

R₈, R₁₈, R₂₃, R₅₃=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_GLY(SEQ ID NO: 584),

wherein R is a ribonucleotide residue and the consensus for Gly is:

R₀, R₁₈, R₂₃=are absent

R₂₄, R₂₇, R₄₀, R₇₂=are independently A or absent;

R₂₆=A, C or absent;

R₃, R₇, R₆₈=are independently A, C, G or absent;

R₅, R₃₀, R₄₁, R₄₂, R₄₄, R₄₉, R₆₇=are independently A, C, G, U or absent;

R₃₁, R₃₂, R₃₄=are independently A, C, U or absent;

R₉, R₁₀, R₁₄, R₁₅, R₃₃, R₅₀, R₅₆=are independently A, G or absent;

R₁₂, R₁₆, R₂₂, R₂₅, R₂₉, R₄₆=are independently A, G, U or absent;

R₅₇=A, U or absent;

R₁₇, R₃₈, R₃₉, R₆₀, R₆₁, R₇₁=are independently C or absent;

R₆, R₅₂, R₆₄, R₆₆=are independently C, G or absent;

R₂, R₄, R₃₇, R₄₈, R₅₅, R₆₅=are independently C, G, U or absent;

R₁₃, R₃₅, R₄₃, R₆₂, R₆₉=are independently C, U or absent;

R₁, R₁₉, R₂₀, R₅₁, R₇₀=are independently G or absent;

R₂₁, R₄₅, R₆₃=are independently G, U or absent;

R₈, R₁₁, R₂₈, R₃₆, R₅₃, R₅₄, R₅₈, R₅₉=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_GLY(SEQ ID NO: 585),

wherein R is a ribonucleotide residue and the consensus for Gly is:

R₀, R₁₈, R₂₃=are absent

R₂₄, R₂₇, R₄₀, R₇₂=are independently A or absent;

R₂₆=A, C or absent;

R₃, R₇, R₄₉, R₆₈=are independently A, C, G or absent;

R₅, R₃₀, R₄₁, R₄₄, R₆₇=are independently N or absent;

R₃₁, R₃₂, R₃₄=are independently A, C, U or absent;

R₉, R₁₀, R₁₄, R₁₅, R₃₃, R₅₀, R₅₆=are independently A, G or absent;

R₁₂, R₂₅, R₂₉, R₄₂, R₄₆=are independently A, G, U or absent;

R₁₆, R₅₇=are independently A, U or absent;

R₁₇, R₃₈, R₃₉, R₆₀, R₆₁, R₇₁=are independently C or absent;

R₆, R₅₂, R₆₄, R₆₆=are independently C, G or absent;

R₃₇, R₄₈, R₆₅=are independently C, G, U or absent;

R₂, R₄, R₁₃, R₃₅, R₄₃, R₅₅, R₆₂, R₆₉=are independently C, U or absent;

R₁, R₁₉, R₂₀, R₅₁, R₇₀=are independently G or absent;

R₂₁, R₂₂, R₄₅, R₆₃=are independently G, U or absent;

R₈, R₁₁, R₂₈, R₃₆, R₅₃, R₅₄, R₅₈, R₅₉=are independently U or absent;

[R₄₇]_x=N or absent;

Histidine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_HIS(SEQ ID NO: 586),

wherein R is a ribonucleotide residue and the consensus for His is:

R₂₃=absent;

R₁₄, R₂₄, R₅₇=are independently A or absent;

R₇₂=A, C or absent;

R₉, R₂₇, R₄₃, R₄₈, R₆₉=are independently A, C, G or absent;

R₃, R₄, R₅, R₆, R₁₂, R₂₅, R₂₆, R₂₉, R₃₀, R₃₁, R₃₄, R₄₂, R₄₅, R₄₆, R₄₉, R₅₀, R₅₈, R₆₂, R₆₃, R₆₆, R₆₇, R₆₈=are independently N or absent;

R₁₃, R₂₁, R₄₁, R₄₄, R₆₅=are independently A, C, U or absent;

R₄₀, R₅₁, R₅₆, R₇₀=are independently A, G or absent;

R₇, R₃₂=are independently A, G, U or absent;

R₅₅, R₆₀=are independently C or absent;

R₁₁, R₁₆, R₃₃, R₆₄=are independently C, G, U or absent;

R₂, R₁₇, R₂₂, R₂₈, R₃₅, R₅₃, R₅₉, R₆₁, R₇₁=are independently C, U or absent;

R₁, R₁₀, R₁₅, R₁₉, R₂₀, R₃₇, R₃₉, R₅₂=are independently G or absent;

R₀=G, U or absent;

R₈, R₁₈, R₃₆, R₃₈, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_HIS(SEQ ID NO: 587),

wherein R is a ribonucleotide residue and the consensus for His is:

R₀, R₁₇, R₁₈, R₂₃=are absent;

R₇, R₁₂, R₁₄, R₂₄, R₂₇, R₄₅, R₅₇, R₅₈, R₆₃, R₆₇, R₇₂=are independently A or absent;

R₃=A, C, U or absent;

R₄, R₄₃, R₅₆, R₇₀=are independently A, G or absent;

R₄₉=A, U or absent;

R₂, R₂₈, R₃₀, R₄₁, R₄₂, R₄₄, R₄₈, R₅₅, R₆₀, R₆₆, R₇₁=are independently C or absent;

R₂₅=C, G or absent;

R₉=C, G, U or absent;

R₈, R₁₃, R₂₆, R₃₃, R₃₅, R₅₀, R₅₃, R₆₁, R₆₈=are independently C, U or absent;

R₁, R₆, R₁₀, R₁₅, R₁₉, R₂₀, R₃₂, R₃₄, R₃₇, R₃₉, R₄₀, R₄₆, R₅₁, R₅₂, R₆₂, R₆₄, R₆₉=are independently G or absent;

R₁₆=G, U or absent;

R₅, R₁₁, R₂₁, R₂₂, R₂₉, R₃₁, R₃₆, R₃₈, R₅₄, R₅₉, R₆₅=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_HIS(SEQ ID NO: 588),

wherein R is a ribonucleotide residue and the consensus for His is:

R₀, R₁₇, R₁₈, R₂₃=are absent

R₇, R₁₂, R₁₄, R₂₄, R₂₇, R₄₅, R₅₇, R₅₈, R₆₃, R₆₇, R₇₂=are independently A or absent;

R₃=A, C or absent;

R₄, R₄₃, R₅₆, R₇₀=are independently A, G or absent;

R₄₉=A, U or absent;

R₂, R₂₈, R₃₀, R₄₁, R₄₂, R₄₄, R₄₈, R₅₅, R₆₀, R₆₆, R₇₁=are independently C or absent;

R₈, R₉, R₂₆, R₃₃, R₃₅, R₅₀, R₆₁, R₆₈=are independently C, U or absent;

R₁, R₆, R₁₀, R₁₅, R₁₉, R₂₀, R₂₅, R₃₂, R₃₄, R₃₇, R₃₉, R₄₀, R₄₆, R₅₁, R₅₂, R₆₂, R₆₄, R₆₉=are independently G or absent;

R₅, R₁₁, R₁₃, R₁₆, R₂₁, R₂₂, R₂₉, R₃₁, R₃₆, R₃₈, R₅₃, R₅₄, R₅₉, R₆₅=are independently U or absent;

[R₄₇]_x=N or absent;

Isoleucine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_ILE(SEQ ID NO: 589),

wherein R is a ribonucleotide residue and the consensus for Ile is:

R₂₃=absent;

R₃₈, R₄₁, R₅₇, R₇₂=are independently A or absent;

R₁, R₂₆=are independently A, C, G or absent;

R₀, R₃, R₄, R₆, R₁₆, R₃₁, R₃₂, R₃₄, R₃₇, R₄₂, R₄₃, R₄₄, R₄₅, R₄₆, R₄₈, R₄₉, R₅₀, R₅₈, R₅₉, R₆₂, R₆₃, R₆₄, R₆₆, R₆₇, R₆₈, R₆₉=are independently N or absent;

R₂₂, R₆₁, R₆₅=are independently A, C, U or absent;

R₉, R₁₄, R₁₅, R₂₄, R₂₇, R₄₀=are independently A, G or absent;

R₇, R₂₅, R₂₉, R₅₁, R₅₆=are independently A, G, U or absent;

R₁₈, R₅₄=are independently A, U or absent;

R₆₀=C or absent;

R₂, R₅₂, R₇₀=are independently C, G or absent;

R₅, R₁₂, R₂₁, R₃₀, R₃₃, R₇₁=are independently C, G, U or absent;

R₁₁, R₁₃, R₁₇, R₂₈, R₃₅, R₅₃, R₅₅=are independently C, U or absent;

R₁₀, R₁₉, R₂₀=are independently G or absent;

R₈, R₃₆, R₃₉=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_ILE(SEQ ID NO: 590),

wherein R is a ribonucleotide residue and the consensus for Ile is:

R₀, R₁₈, R₂₃=are absent

R₂₄, R₃₈, R₄₀, R₄₁, R₅₇, R₇₂=are independently A or absent;

R₂₆, R₆₅=are independently A, C or absent;

R₅₈, R₅₉, R₆₇=are independently N or absent;

R₂₂=A, C, U or absent;

R₆, R₉, R₁₄, R₁₅, R₂₉, R₃₄, R₄₃, R₄₆, R₄₈, R₅₀, R₅₁, R₆₃, R₆₉=are independently A, G or absent;

R₃₇, R₅₆=are independently A, G, U or absent;

R₅₄=A, U or absent;

R₂₈, R₃₅, R₆₀, R₆₂, R₇₁=are independently C or absent;

R₂, R₅₂, R₇₀=are independently C, G or absent;

R₅=C, G, U or absent;

R₃, R₄, R₁₁, R₁₃, R₁₇, R₂₁, R₃₀, R₄₂, R₄₄, R₄₅, R₄₉, R₅₃, R₅₅, R₆₁, R₆₄, R₆₆=are independently C, U or absent;

R₁, R₁₀, R₁₉, R₂₀, R₂₅, R₂₇, R₃₁, R₆₈=are independently G or absent;

R₇, R₁₂, R₃₂=are independently G, U or absent;

R₈, R₁₆, R₃₃, R₃₆, R₃₉=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_ILE(SEQ ID NO: 591),

wherein R is a ribonucleotide residue and the consensus for Ile is:

R₀, R₁₈, R₂₃=are absent

R₁₄, R₂₄, R₃₈, R₄₀, R₄₁, R₅₇, R₇₂=are independently A or absent;

R₂₆, R₆₅=are independently A, C or absent;

R₂₂, R₅₉=are independently A, C, U or absent;

R₆, R₉, R₁₅, R₃₄, R₄₃, R₄₆, R₅₁, R₅₆, R₆₃, R₆₉=are independently A, G or absent;

R₃₇=A, G, U or absent;

R₁₃, R₂₈, R₃₅, R₄₄, R₅₅, R₆₀, R₆₂, R₇₁=are independently C or absent;

R₂, R₅, R₇₀=are independently C, G or absent;

R₅₈, R₆₇=are independently C, G, U or absent;

R₃, R₄, R₁₁, R₁₇, R₂₁, R₃₀, R₄₂, R₄₅, R₄₉, R₅₃, R₆₁, R₆₄, R₆₆=are independently C, U or absent;

R₁, R₁₀, R₁₉, R₂₀, R₂₅, R₂₇, R₂₉, R₃₁, R₃₂, R₄₈, R₅₀, R₅₂, R₆₈=are independently G or absent;

R₇, R₁₂=are independently G, U or absent;

R₈, R₁₆, R₃₃, R₃₆, R₃₉, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

Methionine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_MET(SEQ ID NO: 592),

wherein R is a ribonucleotide residue and the consensus for Met is:

R₀, R₂₃=are absent;

R₁₄, R₃₈, R₄₀, R₅₇=are independently A or absent;

R₆₀=A, C or absent;

R₃₃, R₄₈, R₇₀=are independently A, C, G or absent;

R₁, R₃, R₄, R₅, R₆, R₁₁, R₁₂, R₁₆, R₁₇, R₂₁, R₂₂, R₂₆, R₂₇, R₂₉, R₃₀, R₃₁, R₃₂, R₄₂, R₄₄, R₄₅, R₄₆, R₄₉, R₅₀, R₅₈, R₆₂, R₆₃, R₆₆, R₆₇, R₆₈, R₆₉, R₇₁=are independently N or absent;

R₁₈, R₃₅, R₄₁, R₅₉, R₆₅=are independently A, C, U or absent;

R₉, R₁₅, R₅₁=are independently A, G or absent;

R₇, R₂₄, R₂₅, R₃₄, R₅₃, R₅₆=are independently A, G, U or absent;

R₇₂=A, U or absent;

R₃₇=C or absent;

R₁₀, R₅₅=are independently C, G or absent;

R₂, R₁₃, R₂₈, R₄₃, R₆₄=are independently C, G, U or absent;

R₃₆, R₆₁=are independently C, U or absent;

R₁₉, R₂₀, R₅₂=are independently G or absent;

R₈, R₃₉, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_MET(SEQ ID NO: 593),

wherein R is a ribonucleotide residue and the consensus for Met is:

R₀, R₁₈, R₂₂, R₂₃=are absent

R₁₄, R₂₄, R₃₈, R₄₀, R₄₁, R₅₇, R₇₂=are independently A or absent;

R₅₉, R₆₀, R₆₂, R₆₅=are independently A, C or absent;

R₆, R₄₅, R₆₇=are independently A, C, G or absent;

R₄=N or absent;

R₂₁, R₄₂=are independently A, C, U or absent;

R₁, R₉, R₂₇, R₂₉, R₃₂, R₄₆, R₅₁=are independently A, G or absent;

R₁₇, R₄₉, R₅₃, R₅₆, R₅₈=are independently A, G, U or absent;

R₆₃=A, U or absent;

R₃, R₁₃, R₃₇=are independently C or absent;

R₄₈, R₅₅, R₆₄, R₇₀=are independently C, G or absent;

R₂, R₅, R₆₆, R₆₈=are independently C, G, U or absent;

R₁₁, R₁₆, R₂₆, R₂₈, R₃₀, R₃₁, R₃₅, R₃₆, R₄₃, R₄₄, R₆₁, R₇₁=are independently C, U or absent;

R₁₀, R₁₂, R₁₅, R₁₉, R₂₀, R₂₅, R₃₃, R₅₂, R₆₉=are independently G or absent;

R₇, R₃₄, R₅₀=are independently G, U or absent;

R₈, R₃₉, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_MET(SEQ ID NO: 594),

wherein R is a ribonucleotide residue and the consensus for Met is:

R₀, R₁₈, R₂₂, R₂₃=are absent

R₁₄, R₂₄, R₃₈, R₄₀, R₄₁, R₅₇, R₇₂=are independently A or absent;

R₅₉, R₆₂, R₆₅=are independently A, C or absent;

R₆, R₆₇=are independently A, C, G or absent;

R₄, R₂₁=are independently A, C, U or absent;

R₁, R₉, R₂₇, R₂₉, R₃₂, R₄₅, R₄₆, R₅₁=are independently A, G or absent;

R₁₇, R₅₆, R₅₈=are independently A, G, U or absent;

R₄₉, R₅₃, R₆₃=are independently A, U or absent;

R₃, R₁₃, R₂₆, R₃₇, R₄₃, R₆₀=are independently C or absent;

R₂, R₄₈, R₅₅, R₆₄, R₇₀=are independently C, G or absent;

R₅, R₆₆=are independently C, G, U or absent;

R₁₁, R₁₆, R₂₈, R₃₀, R₃₁, R₃₅, R₃₆, R₄₂, R₄₄, R₆₁, R₇₁=are independently C, U or absent;

R₁₀, R₁₂, R₁₅, R₁₉, R₂₀, R₂₅, R₃₃, R₅₂, R₆₉=are independently G or absent;

R₇, R₃₄, R₅₀, R₆₈=are independently G, U or absent;

R₈, R₃₉, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

Leucine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_LEU(SEQ ID NO: 595),

wherein R is a ribonucleotide residue and the consensus for Leu is:

R₀=absent;

R₃₈, R₅₇=are independently A or absent;

R₆₀=A, C or absent;

R₁, R₁₃, R₂₇, R₄₈, R₅₁, R₅₆=are independently A, C, G or absent;

R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁, R₁₂, R₁₆, R₂₃, R₂₆, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₇, R₄₁, R₄₂, R₄₃, R₄₄, R₄₅, R₄₆, R₄₉, R₅₀, R₅₈, R₆₂, R₆₃, R₆₅, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀=are independently N or absent;

R₁₇, R₁₈, R₂₁, R₂₂, R₂₅, R₃₅, R₅₅=are independently A, C, U or absent;

R₁₄, R₁₅, R₃₉, R₇₂=are independently A, G or absent;

R₂₄, R₄₀=are independently A, G, U or absent;

R₅₂, R₆₁, R₆₄, R₇₁=are independently C, G, U or absent;

R₃₆, R₅₃, R₅₉=are independently C, U or absent;

R₁₉=G or absent;

R₂₀=G, U or absent;

R₈, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_LEU(SEQ ID NO: 596),

wherein R is a ribonucleotide residue and the consensus for Leu is:

R₀=absent

R₃₈, R₅₇, R₇₂=are independently A or absent;

R₆₀=A, C or absent;

R₄, R₅, R₄₈, R₅₀, R₅₆, R₆₉=are independently A, C, G or absent;

R₆, R₃₃, R₄₁, R₄₃, R₄₆, R₄₉, R₅₈, R₆₃, R₆₆, R₇₀=are independently N or absent;

R₁₁, R₁₂, R₁₇, R₂₁, R₂₂, R₂₈, R₃₁, R₃₇, R₄₄, R₅₅=are independently A, C, U or absent;

R₁, R₉, R₁₄, R₁₅, R₂₄, R₂₇, R₃₄, R₃₉=are independently A, G or absent;

R₇, R₂₉, R₃₂, R₄₀, R₄₅=are independently A, G, U or absent;

R₂₅=A, U or absent;

R₁₃=C, G or absent;

R₂, R₃, R₁₆, R₂₆, R₃₀, R₅₂, R₆₂, R₆₄, R₆₅, R₆₇, R₆₈=are independently C, G, U or absent; R₁₈, R₃₅, R₄₂, R₅₃, R₅₉, R₆₁, R₇₁=are independently C, U or absent;

R₁₉, R₅₁=are independently G or absent;

R₁₀, R₂₀=are independently G, U or absent;

R₈, R₂₃, R₃₆, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_LEU(SEQ ID NO: 597),

wherein R is a ribonucleotide residue and the consensus for Leu is:

R₀=absent

R₃₈, R₅₇, R₇₂=are independently A or absent;

R₆₀=A, C or absent;

R₄, R₅, R₄₈, R₅₀, R₅₆, R₅₈, R₆₉=are independently A, C, G or absent;

R₆, R₃₃, R₄₃, R₄₆, R₄₉, R₆₃, R₆₆, R₇₀=are independently N or absent;

R₁₁, R₁₂, R₁₇, R₂₁, R₂₂, R₂₈, R₃₁, R₃₇, R₄₁, R₄₄, R₅₅=are independently A, C, U or absent;

R₁, R₉, R₁₄, R₁₅, R₂₄, R₂₇, R₃₄, R₃₉=are independently A, G or absent;

R₇, R₂₉, R₃₂, R₄₀, R₄₅=are independently A, G, U or absent;

R₂₅=A, U or absent;

R₁₃=C, G or absent;

R₂, R₃, R₁₆, R₃₀, R₅₂, R₆₂, R₆₄, R₆₇, R₆₈=are independently C, G, U or absent;

R₁₈, R₃₅, R₄₂, R₅₃, R₅₉, R₆₁, R₆₅, R₇₁=are independently C, U or absent;

R₁₉, R₅₁=are independently G or absent;

R₁₀, R₂₀, R₂₆=are independently G, U or absent;

R₈, R₂₃, R₃₆, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

Lysine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_LYS(SEQ ID NO: 598),

wherein R is a ribonucleotide residue and the consensus for Lys is:

R₀=absent

R₁₄=A or absent;

R₄₀, R₄₁=are independently A, C or absent;

R₃₄, R₄₃, R₅₁=are independently A, C, G or absent;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₁, R₁₂, R₁₆, R₂₁, R₂₆, R₃₀, R₃₁, R₃₂, R₄₄, R₄₅, R₄₆, R₄₈, R₄₉, R₅₀, R₅₈, R₆₂, R₆₃, R₆₅, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀=are independently N or absent;

R₁₃, R₁₇, R₅₉, R₇₁=are independently A, C, U or absent;

R₉, R₁₅, R₁₉, R₂₀, R₂₅, R₂₇, R₅₂, R₅₆=are independently A, G or absent;

R₂₄, R₂₉, R₇₂=are independently A, G, U or absent;

R₁₈, R₅₇=are independently A, U or absent;

R₁₀, R₃₃=are independently C, G or absent;

R₄₂, R₆₁, R₆₄=are independently C, G, U or absent;

R₂₈, R₃₅, R₃₆, R₃₇, R₅₃, R₅₅, R₆₀=are independently C, U or absent;

R₈, R₂₂, R₂₃, R₃₈, R₃₉, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_LYS(SEQ ID NO: 599),

wherein R is a ribonucleotide residue and the consensus for Lys is:

R₀, R₁₈, R₂₃=are absent

R₁₄=A or absent;

R₄₀, R₄₁, R₄₃=are independently A, C or absent;

R₃, R₇=are independently A, C, G or absent;

R₁, R₆, R₁₁, R₃₁, R₄₅, R₄₈, R₄₉, R₆₃, R₆₅, R₆₆, R₆₈=are independently N or absent;

R₂, R₁₂, R₁₃, R₁₇, R₄₄, R₆₇, R₇₁=are independently A, C, U or absent;

R₉, R₁₅, R₁₉, R₂₀, R₂₅, R₂₇, R₃₄, R₅₀, R₅₂, R₅₆, R₇₀, R₇₂=are independently A, G or absent;

R₅, R₂₄, R₂₆, R₂₉, R₃₂, R₄₆, R₆₉=are independently A, G, U or absent;

R₅=A, U or absent;

R₁₀, R₆₁=are independently C, G or absent;

R₄, R₁₆, R₂₁, R₃₀, R₅₈, R₆₄=are independently C, G, U or absent;

R₂₁, R₃₅, R₃₆, R₃₇, R₄₂, R₅₃, R₅₅, R₅₉, R₆₀, R₆₂=are independently C, U or absent;

R₃₃, R₅₁=are independently G or absent;

R₈=G, U or absent;

R₂₂, R₃₈, R₃₉, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_LYS(SEQ ID NO: 600),

wherein R is a ribonucleotide residue and the consensus for Lys is:

R₀, R₁₈, R₂₃=absent

R₉, R₁₄, R₃₄, R₄₁=are independently A or absent;

R₄₀=A, C or absent;

R₁, R₃, R₇, R₃₁=are independently A, C, G or absent;

R₄₈, R₆₅, R₆₈=are independently N or absent;

R₂, R₁₃, R₁₇, R₄₄, R₆₃, R₆₆=are independently A, C, U or absent;

R₅, R₁₅, R₁₉, R₂₀, R₂₅, R₂₇, R₂₉, R₅₀, R₅₂, R₅₆, R₇₀, R₇₂=are independently A, G or absent;

R₆, R₂₄, R₃₂, R₄₉=are independently A, G, U or absent;

R₁₂, R₂₆, R₄₆, R₅₇=are independently A, U or absent;

R₁₁, R₂₈, R₃₅, R₄₃=are independently C or absent;

R₁₀, R₄₅, R₆₁=are independently C, G or absent;

R₄, R₂₁, R₆₄=are independently C, G, U or absent;

R₃₇, R₅₃, R₅₅, R₅₉, R₆₀, R₆₂, R₆₇, R₇₁=are independently C, U or absent;

R₃₃, R₅₁=are independently G or absent;

R₈, R₃₀, R₅₃, R₆₉=are independently G, U or absent;

R₁₆, R₂₂, R₃₆, R₃₈, R₃₉, R₄₂, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

Phenylalanine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_PHE(SEQ ID NO: 601),

wherein R is a ribonucleotide residue and the consensus for Phe is:

R₀, R₂₃=are absent

R₉, R₁₄, R₃₈, R₃₉, R₅₇, R₇₂=are independently A or absent;

R₇₁=A, C or absent;

R₄₁, R₇₀=are independently A, C, G or absent;

R₄, R₅, R₆, R₃₀, R₃₁, R₃₂, R₃₄, R₄₂, R₄₄, R₄₅, R₄₆, R₄₈, R₄₉, R₅₈, R₆₂, R₆₃, R₆₆, R₆₇, R₆₈, R₆₉=are independently N or absent;

R₁₆, R₆₁, R₆₅=are independently A, C, U or absent;

R₁₅, R₂₆, R₂₇, R₂₉, R₄₀, R₅₆=are independently A, G or absent;

R₇, R₅₁=are independently A, G, U or absent;

R₂₂, R₂₄=are independently A, U or absent;

R₅₅, R₆₀=are independently C or absent;

R₂, R₃, R₂₁, R₃₃, R₄₃, R₅₀, R₆₄=are independently C, G, U or absent;

R₁₁, R₁₂, R₁₃, R₁₇, R₂₈, R₃₅, R₃₆, R₅₉=are independently C, U or absent;

R₁₀, R₁₉, R₂₀, R₂₅, R₃₇, R₅₂=are independently G or absent;

R₁=G, U or absent;

R₈, R₁₈, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_PHE(SEQ ID NO: 602),

wherein R is a ribonucleotide residue and the consensus for Phe is:

R₀, R₁₈, R₂₃=absent

R₁₄, R₂₄, R₃₈, R₃₉, R₅₇, R₇₂=are independently A or absent;

R₄₆, R₇₁=are independently A, C or absent;

R₄, R₇₀=are independently A, C, G or absent;

R₄₅=A, C, U or absent;

R₆, R₇, R₁₅, R₂₆, R₂₇, R₃₂, R₃₄, R₄₀, R₄₁, R₅₆, R₆₉=are independently A, G or absent;

R₂₉=A, G, U or absent;

R₅, R₉, R₆₇=are independently A, U or absent;

R₃₅, R₄₉, R₅₅, R₆₀=are independently C or absent;

R₂₁, R₄₃, R₆₂=are independently C, G or absent;

R₂, R₃₃, R₆₈=are independently C, G, U or absent;

R₃, R₁₁, R₁₂, R₁₃, R₂₈, R₃₀, R₃₆, R₄₂, R₄₄, R₄₈, R₅₈, R₅₉, R₆₁, R₆₆=are independently C, U or absent;

R₁₀, R₁₉, R₂₀, R₂₅, R₃₇, R₅₁, R₅₂, R₆₃, R₆₄=are independently G or absent;

R₁, R₃₁, R₅₀=are independently G, U or absent;

R₈, R₁₆, R₁₇, R₂₂, R₅₃, R₅₄, R₆₅=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_PHE(SEQ ID NO: 603),

wherein R is a ribonucleotide residue and the consensus for Phe is:

R₀, R₁₈, R₂₂, R₂₃=absent

R₅, R₇, R₁₄, R₂₄, R₂₆, R₃₂, R₃₄, R₃₈, R₃₉, R₄₁, R₅₇, R₇₂=are independently A or absent;

R₄₆=A, C or absent;

R₇₀=A, C, G or absent;

R₄, R₆, R₁₅, R₅₆, R₆₉=are independently A, G or absent;

R₉, R₄₅=are independently A, U or absent;

R₂, R₁₁, R₁₃, R₃₅, R₄₃, R₄₉, R₅₅, R₆₀, R₆₈, R₇₁=are independently C or absent;

R₃₃=C, G or absent;

R₃, R₂₈, R₃₆, R₄₈, R₅₈, R₅₉, R₆₁=are independently C, U or absent;

R₁, R₁₀, R₁₉, R₂₀, R₂₁, R₂₅, R₃₇, R₂₉, R₃₇, R₄₀, R₅₁, R₅₂, R₆₂, R₆₃, R₆₄=are independently G or absent;

R₈, R₁₂, R₁₆, R₁₇, R₃₀, R₃₁, R₄₂, R₄₄, R₅₀, R₅₃, R₅₄, R₆₅, R₆₆, R₆₇=are independently U or absent;

[R₄₇]_x=N or absent;

Proline TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_PRO(SEQ ID NO: 604),

wherein R is a ribonucleotide residue and the consensus for Pro is:

R₀=absent

R₁₄, R₅₇=are independently A or absent;

R₇₀, R₇₂=are independently A, C or absent;

R₉, R₂₆, R₂₇=are independently A, C, G or absent;

R₄, R₅, R₆, R₁₆, R₂₁, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₇, R₄₁, R₄₂, R₄₃, R₄₄, R₄₅, R₄₆, R₄₈, R₄₉, R₅₀, R₅₈, R₆₁, R₆₂, R₆₃, R₆₄, R₆₆, R₆₇, R₆₈=are independently N or absent;

R₃₅, R₆₅=are independently A, C, U or absent;

R₂₄, R₄₀, R₅₆=are independently A, G or absent;

R₇, R₂₅, R₅₁=are independently A, G, U or absent;

R₅₅, R₆₀=are independently C or absent;

R₁, R₃, R₇₁=are independently C, G or absent;

R₁₁, R₁₂, R₂₀, R₆₉=are independently C, G, U or absent;

R₁₃, R₁₇, R₁₈, R₂₂, R₂₃, R₂₈, R₅₉=are independently C, U or absent;

R₁₀, R₁₅, R₁₉, R₃₈, R₃₉, R₅₂=are independently G or absent;

R₂=are independently G, U or absent;

R₈, R₃₆, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_PRO(SEQ ID NO: 605),

wherein R is a ribonucleotide residue and the consensus for Pro is:

R₀, R₁₇, R₁₈, R₂₂, R₂₃=absent;

R₁₄, R₄₅, R₅₆, R₅₇, R₅₈, R₆₅, R₆₈=are independently A or absent;

R₆₁=A, C, G or absent;

R₄₃=N or absent;

R₃₇=A, C, U or absent;

R₂₄, R₂₇, R₃₃, R₄₀, R₄₄, R₆₃=are independently A, G or absent;

R₃, R₁₂, R₃₀, R₃₂, R₄₈, R₅₅, R₆₀, R₇₀, R₇₁, R₇₂=are independently C or absent;

R₅, R₃₄, R₄₂, R₆₆=are independently C, G or absent;

R₂₀=C, G, U or absent;

R₃₅, R₄₁, R₄₉, R₆₂=are independently C, U or absent;

R₁, R₂, R₆, R₉, R₁₀, R₁₅, R₁₉, R₂₆, R₃₈, R₃₉, R₄₆, R₅₀, R₅₁, R₅₂, R₆₄, R₆₇, R₆₉=are independently G or absent;

R₁₁, R₁₆=are independently G, U or absent;

R₄, R₇, R₈, R₁₃, R₂₁, R₂₅, R₂₈, R₂₉, R₃₁, R₃₆, R₅₃, R₅₄, R₅₉=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_PRO(SEQ ID NO: 606),

wherein R is a ribonucleotide residue and the consensus for Pro is:

R₀, R₁₇, R₁₈, R₂₂, R₂₃=absent

R₁₄, R₄₅, R₅₆, R₅₇, R₅₈, R₆₅, R₆₈=are independently A or absent;

R₃₇=A, C, U or absent;

R₂₄, R₂₇, R₄₀=are independently A, G or absent;

R₃, R₅, R₁₂, R₃₀, R₃₂, R₄₈, R₄₉, R₅₅, R₆₀, R₆₁, R₆₂, R₆₆, R₇₀, R₇₁, R₇₂=are independently C or absent;

R₃₄, R₄₂=are independently C, G or absent;

R₄₃=C, G, U or absent;

R₄₁=C, U or absent;

R₁, R₂, R₆, R₉, R₁₀, R₁₅, R₁₉, R₂₀, R₂₆, R₃₃, R₃₈, R₃₉, R₄₄, R₄₆, R₅₀, R₅₁, R₅₂, R₆₃, R₆₄, R₆₇, R₆₉=are independently G or absent;

R₁₆=G, U or absent;

R₄, R₇, R₈, R₁₁, R₁₃, R₂₁, R₂₅, R₂₈, R₂₉, R₃₁, R₃₅, R₃₆, R₅₃, R₅₄, R₅₉=are independently U or absent;

[R₄₇]_x=N or absent;

Serine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_SER(SEQ ID NO: 607),

wherein R is a ribonucleotide residue and the consensus for Ser is:

R₀=absent;

R₁₄, R₂₄, R₅₇=are independently A or absent;

R₄₁=A, C or absent;

R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₆, R₂₁, R₂₅, R₂₆, R₂₇, R₂₈, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₇, R₄₂, R₄₃, R₄₄, R₄₅, R₄₆, R₄₈, R₄₉, R₅₀, R₆₂, R₆₃, R₆₄, R₆₅, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀=are independently N or absent;

R₁₈=A, C, U or absent;

R₁₅, R₄₀, R₅₁, R₅₆=are independently A, G or absent;

R₁, R₂₉, R₅₈, R₇₂=are independently A, G, U or absent;

R₃₉=A, U or absent;

R₆₀=C or absent;

R₃₈=C, G or absent;

R₁₇, R₂₂, R₂₃, R₇₁=are independently C, G, U or absent;

R₈, R₃₅, R₃₆, R₅₅, R₅₉, R₆₁=are independently C, U or absent;

R₁₉, R₂₀=are independently G or absent;

R₅₂=G, U or absent;

R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_SER(SEQ ID NO: 608),

wherein R is a ribonucleotide residue and the consensus for Ser is:

R₀, R₂₃=absent

R₁₄, R₂₄, R₄₁, R₅₇=are independently A or absent;

R₄₄=A, C or absent;

R₂₅, R₄₅, R₄₈=are independently A, C, G or absent;

R₂, R₃, R₄, R₅, R₃₇, R₅₀, R₆₂, R₆₆, R₆₇, R₆₉, R₇₀=are independently N or absent;

R₁₂, R₂₈, R₆₅=are independently A, C, U or absent;

R₉, R₁₅, R₂₉, R₃₄, R₄₀, R₅₆, R₆₃=are independently A, G or absent;

R₇, R₂₆, R₃₀, R₃₃, R₄₆, R₅₈, R₇₂=are independently A, G, U or absent;

R₃₉=A, U or absent;

R₁₁, R₃₅, R₆₀, R₆₁=are independently C or absent;

R₁₃, R₃₈=are independently C, G or absent;

R₆, R₁₇, R₃₁, R₄₃, R₆₄, R₆₈=are independently C, G, U or absent;

R₃₆, R₄₂, R₄₉, R₅₅, R₅₉, R₇₁=are independently C, U or absent;

R₁₀, R₁₉, R₂₀, R₂₇, R₅₁=are independently G or absent;

R₁, R₁₆, R₃₂, R₅₂=are independently G, U or absent;

R₈, R₁₈, R₂₁, R₂₂, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_SER(SEQ ID NO: 609),

wherein R is a ribonucleotide residue and the consensus for Ser is:

R₀, R₂₃=absent

R₁₄, R₂₄, R₄₁, R₅₇, R₅₈=are independently A or absent;

R₄₄=A, C or absent;

R₂₅, R₄₈=are independently A, C, G or absent;

R₂, R₃, R₅, R₃₇, R₆₆, R₆₇, R₆₉, R₇₀=are independently N or absent;

R₁₂, R₂₈, R₆₂=are independently A, C, U or absent;

R₇, R₉, R₁₅, R₂₉, R₃₃, R₃₄, R₄₀, R₄₅, R₅₆, R₆₃=are independently A, G or absent;

R₄, R₂₆, R₄₆, R₅₀=are independently A, G, U or absent;

R₃₀, R₃₉=are independently A, U or absent;

R₁₁, R₁₇, R₃₅, R₆₀, R₆₁=are independently C or absent;

R₁₃, R₃₈=are independently C, G or absent;

R₆, R₆₄=are independently C, G, U or absent;

R₃₁, R₄₂, R₄₃, R₄₉, R₅₅, R₅₉, R₆₅, R₆₈, R₇₁=are independently C, U or absent;

R₁₀, R₁₉, R₂₀, R₂₇, R₅₁, R₅₂=are independently G or absent;

R₁, R₁₆, R₃₂, R₇₂=are independently G, U or absent;

R₈, R₁₈, R₂₁, R₂₂, R₃₆, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

Threonine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_THR(SEQ ID NO: 610),

R₀-R₁-R₂-R₃-R₄-R₅-R₆-R₇-R₈-R₉-R₁₀-R₁₁-R₁₂-R₁₃-R₁₄-R₁₅-R₁₆-R₁₇-R₁₈-R₁₉-R₂₀-R₂₁-R₂₂-R₂₃-R₂₄-R₂₅-R₂₆-R₂₇-R₂₈-R₂₉-R₃₀-R₃₁-R₃₂-R₃₃-R₃₄-R₃₅-R₃₆-R₃₇R₃₈-R₃₉-R₄₀-R₄₁-R₄₂-R₄₃-R₄₄-R₄₅-R₄₆-[R₄₇]_x-R₄₈-R₄₉-R₅₀-R₅₁-R₅₂-R₅₃-R₅₄-R₅₅-R₅₆-R₅₇-R₅₈-R₅₉-R₆₀-R₆₁-R₆₂-R₆₃-R₆₄-R₆₅-R₆₆-R₆₇-R₆₈-R₆₉-R₇₀-R₇₁-R₇₂

wherein R is a ribonucleotide residue and the consensus for Thr is:

R₀, R₂₃=absent

R₁₄, R₄₁, R₅₇=are independently A or absent;

R₅₆, R₇₀=are independently A, C, G or absent;

R₄, R₅, R₆, R₇, R₁₂, R₁₆, R₂₆, R₃₀, R₃₁, R₃₂, R₃₄, R₃₇, R₄₂, R₄₄, R₄₅, R₄₆, R₄₈, R₄₉, R₅₀, R₅₈, R₆₂, R₆₃, R₆₄, R₆₅, R₆₆, R₆₇, R₆₈, R₇₂=are independently N or absent;

R₁₃, R₁₇, R₂₁, R₃₅, R₆₁=are independently A, C, U or absent;

R₁, R₉, R₂₄, R₂₇, R₂₉, R₆₉=are independently A, G or absent;

R₁₅, R₂₅, R₅₁=are independently A, G, U or absent;

R₄₀, R₅₃=are independently A, U or absent;

R₃₃, R₄₃=are independently C, G or absent;

R₂, R₃, R₅₉=are independently C, G, U or absent;

R₁₁, R₁₈, R₂₂, R₂₈, R₃₆, R₅₄, R₅₅, R₆₀, R₇₁=are independently C, U or absent;

R₁₀, R₂₀, R₃₈, R₅₂=are independently G or absent;

R₁₉=G, U or absent;

R₈, R₃₉=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_THR(SEQ ID NO: 611),

wherein R is a ribonucleotide residue and the consensus for Thr is:

R₀, R₁₈, R₂₃=absent

R₁₄, R₄₁, R₅₇=are independently A or absent;

R₉, R₄₂, R₄₄, R₄₈, R₅₆, R₇₀=are independently A, C, G or absent;

R₄, R₆, R₁₂, R₂₆, R₄₉, R₅₈, R₆₃, R₆₄, R₆₆, R₆₈=are independently N or absent;

R₁₃, R₂₁, R₃₁, R₃₇, R₆₂=are independently A, C, U or absent;

R₁, R₁₅, R₂₄, R₂₇, R₂₉, R₄₆, R₅₁, R₆₉=are independently A, G or absent;

R₇, R₂₅, R₄₅, R₅₀, R₆₇=are independently A, G, U or absent;

R₄₀, R₅₃=are independently A, U or absent;

R₃₅=C or absent;

R₃₃, R₄₃=are independently C, G or absent;

R₂, R₃, R₅, R₁₆, R₃₂, R₃₄, R₅₉, R₆₅, R₇₂=are independently C, G, U or absent;

R₁₁, R₁₇, R₂₂, R₂₈, R₃₀, R₃₆, R₅₅, R₆₀, R₆₁, R₇₁=are independently C, U or absent;

R₁₀, R₁₉, R₂₀, R₃₈, R₅₂=are independently G or absent;

R₈, R₃₉, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_THR(SEQ ID NO: 612),

wherein R is a ribonucleotide residue and the consensus for Thr is:

R₀, R₁₈, R₂₃=absent

R₁₄, R₄₀, R₄₁, R₅₇=are independently A or absent;

R₄₄=A, C or absent;

R₉, R₄₂, R₄₈, R₅₆=are independently A, C, G or absent;

R₄, R₆, R₁₂, R₂₆, R₅₈, R₆₄, R₆₆, R₆₈=are independently N or absent;

R₁₃, R₂₁, R₃₁, R₃₇, R₄₉, R₆₂=are independently A, C, U or absent;

R₁, R₁₅, R₂₄, R₂₇, R₂₉, R₄₆, R₅₁, R₆₉=are independently A, G or absent;

R₇, R₂₅, R₄₅, R₅₀, R₆₃, R₆₇=are independently A, G, U or absent;

R₅₃=A, U or absent;

R₃₅=C or absent;

R₂, R₃₃, R₄₃, R₇₀=are independently C, G or absent;

R₅, R₁₆, R₃₄, R₅₉, R₆₅=are independently C, G, U or absent;

R₃, R₁₁, R₂₂, R₂₈, R₃₀, R₃₆, R₅₅, R₆₀, R₆₁, R₇₁=are independently C, U or absent;

R₁₀, R₁₉, R₂₀, R₃₈, R₅₂=are independently G or absent;

R₃₂=G, U or absent;

R₈, R₁₇, R₃₉, R₅₄, R₇₂=are independently U or absent;

[R₄₇]_x=N or absent;

Tryptophan TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_TRP(SEQ ID NO: 613),

wherein R is a ribonucleotide residue and the consensus for Trp is:

R₀=absent;

R₂₄, R₃₉, R₄₁, R₅₇=are independently A or absent;

R₂, R₃, R₂₆, R₂₇, R₄₀, R₄₈=are independently A, C, G or absent;

R₄, R₅, R₆, R₂₉, R₃₀, R₃₁, R₃₂, R₃₄, R₄₂, R₄₄, R₄₅, R₄₆, R₄₉, R₅₁, R₅₈, R₆₃, R₆₆, R₆₇, R₆₈=are independently N or absent;

R₁₃, R₁₄, R₁₆, R₁₈, R₂₁, R₆₁, R₆₅, R₇₁=are independently A, C, U or absent;

R₁, R₉, R₁₀, R₁₅, R₃₃, R₅₀, R₅₆=are independently A, G or absent;

R₇, R₂₅, R₇₂=are independently A, G, U or absent;

R₃₇, R₃₈, R₅₅, R₆₀=are independently C or absent;

R₁₂, R₃₅, R₄₃, R₆₄, R₆₉, R₇₀=are independently C, G, U or absent;

R₁₁, R₁₇, R₂₂, R₂₈, R₅₉, R₆₂=are independently C, U or absent;

R₁₉, R₂₀, R₅₂=are independently G or absent;

R₈, R₂₃, R₃₆, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_UP(SEQ ID NO: 614),

wherein R is a ribonucleotide residue and the consensus for Trp is:

R₀, R₁₈, R₂₂, R₂₃=absent

R₁₄, R₂₄, R₃₉, R₄₁, R₅₇, R₇₂=are independently A or absent;

R₃, R₄, R₁₃, R₆₁, R₇₁=are independently A, C or absent;

R₆, R₄₄=are independently A, C, G or absent;

R₂₁=A, C, U or absent;

R₂, R₇, R₁₅, R₂₅, R₃₃, R₃₄, R₄₅, R₅₆, R₆₃=are independently A, G or absent;

R₅₈=A, G, U or absent;

R₄₆=A, U or absent;

R₃₇, R₃₈, R₅₅, R₆₀, R₆₂=are independently C or absent;

R₁₂, R₂₆, R₂₇, R₃₅, R₄₀, R₄₈, R₆₇=are independently C, G or absent;

R₃₂, R₄₃, R₆₈=are independently C, G, U or absent;

R₁₁, R₁₆, R₂₈, R₃₁, R₄₉, R₅₉, R₆₅, R₇₀=are independently C, U or absent;

R₁, R₉, R₁₀, R₁₉, R₂₀, R₅₀, R₅₂, R₆₉=are independently G or absent;

R₅, R₈, R₂₉, R₃₀, R₄₂, R₅₁, R₆₄, R₆₆=are independently G, U or absent;

R₁₇, R₃₆, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_TRP(SEQ ID NO: 615),

wherein R is a ribonucleotide residue and the consensus for Trp is:

R₀, R₁₈, R₂₂, R₂₃=absent

R₁₄, R₂₄, R₃₉, R₄₁, R₅₇, R₇₂=are independently A or absent;

R₃, R₄, R₁₃, R₆₁, R₇₁=are independently A, C or absent;

R₆, R₄₄=are independently A, C, G or absent;

R₂₁=A, C, U or absent;

R₂, R₇, R₁₅, R₂₅, R₃₃, R₃₄, R₄₅, R₅₆, R₆₃=are independently A, G or absent;

R₅₈=A, G, U or absent;

R₄₆=A, U or absent;

R₃₇, R₃₈, R₅₅, R₆₀, R₆₂=are independently C or absent;

R₁₂, R₂₆, R₂₇, R₃₅, R₄₀, R₄₈, R₆₇=are independently C, G or absent;

R₃₂, R₄₃, R₆₈=are independently C, G, U or absent;

R₁₁, R₁₆, R₂₈, R₃₁, R₄₉, R₅₉, R₆₅, R₇₀=are independently C, U or absent;

R₁, R₉, R₁₀, R₁₉, R₂₀, R₅₀, R₅₂, R₆₉=are independently G or absent;

R₅, R₈, R₂₉, R₃₀, R₄₂, R₅₁, R₆₄, R₆₆=are independently G, U or absent;

R₁₇, R₃₆, R₅₃, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

Tyrosine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_TYR(SEQ ID NO: 616),

wherein R is a ribonucleotide residue and the consensus for Tyr is:

R₀=absent

R₁₄, R₃₉, R₅₇=are independently A or absent;

R₄₁, R₄₈, R₅₁, R₇₁=are independently A, C, G or absent;

R₃, R₄, R₅, R₆, R₉, R₁₀, R₁₂, R₁₃, R₁₆, R₂₅, R₂₆, R₃₀, R₃₁, R₃₂, R₄₂, R₄₄, R₄₅, R₄₆, R₄₉, R₅₀, R₅₈, R₆₂, R₆₃, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀=are independently N or absent;

R₂₂, R₆₅=are independently A, C, U or absent;

R₁₅, R₂₄, R₂₇, R₃₃, R₃₇, R₄₀, R₅₆=are independently A, G or absent;

R₇, R₂₉, R₃₄, R₇₂=are independently A, G, U or absent;

R₂₃, R₅₃=are independently A, U or absent;

R₃₅, R₆₀=are independently C or absent;

R₂₀=C, G or absent;

R₁, R₂, R₂₈, R₆₁, R₆₄=are independently C, G, U or absent;

R₁₁, R₁₇, R₂₁, R₄₃, R₅₅=are independently C, U or absent;

R₁₉, R₅₂=are independently G or absent;

R₈, R₁₈, R₃₆, R₃₈, R₅₄, R₅₉=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_TYR(SEQ ID NO: 617),

wherein R is a ribonucleotide residue and the consensus for Tyr is:

R₀, R₁₈, R₂₃=absent

R₇, R₉, R₁₄, R₂₄, R₂₆, R₃₄, R₃₉, R₅₇=are independently A or absent;

R₄₄, R₆₉=are independently A, C or absent;

R₇₁=A, C, G or absent;

R₆₈=N or absent;

R₅₈=A, C, U or absent;

R₃₃, R₃₇, R₄₁, R₅₆, R₆₂, R₆₃=are independently A, G or absent;

R₆, R₂₉, R₇₂=are independently A, G, U or absent;

R₃₁, R₄₅, R₅₃=are independently A, U or absent;

R₁₃, R₃₅, R₄₉, R₆₀=are independently C or absent;

R₂₀, R₄₈, R₆₄, R₆₇, R₇₀=are independently C, G or absent;

R₁, R₂, R₅, R₁₆, R₆₆=are independently C, G, U or absent;

R₁₁, R₂₁, R₂₈, R₄₃, R₅₅, R₆₁=are independently C, U or absent;

R₁₀, R₁₅, R₁₉, R₂₅, R₂₇, R₄₀, R₅₁, R₅₂=are independently G or absent;

R₃, R₄, R₃₀, R₃₂, R₄₂, R₄₆=are independently G, U or absent;

R₈, R₁₂, R₁₇, R₂₂, R₃₆, R₃₈, R₅₀, R₅₄, R₅₉, R₆₅=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III_TYR(SEQ ID NO: 618),

wherein R is a ribonucleotide residue and the consensus for Tyr is:

R₀, R₁₈, R₂₃=absent

R₇, R₉, R₁₄, R₂₄, R₂₆, R₃₄, R₃₉, R₅₇, R₇₂=are independently A or absent;

R₄₄, R₆₉=are independently A, C or absent;

R₇₁=A, C, G or absent;

R₃₇, R₄₁, R₅₆, R₆₂, R₆₃=are independently A, G or absent;

R₆, R₂₉, R₆₈=are independently A, G, U or absent;

R₃₁, R₄₅, R₅₈=are independently A, U or absent;

R₁₃, R₂₈, R₃₅, R₄₉, R₆₀, R₆₁=are independently C or absent;

R₅, R₄₈, R₆₄, R₆₇, R₇₀=are independently C, G or absent;

R₁, R₂=are independently C, G, U or absent;

R₁₁, R₁₆, R₂₁, R₄₃, R₅₅, R₆₆=are independently C, U or absent;

R₁₀, R₁₅, R₁₉, R₂₀, R₂₅, R₂₇, R₃₃, R₄₀, R₅₁, R₅₂=are independently G or absent;

R₃, R₄, R₃₀, R₃₂, R₄₂, R₄₆=are independently G, U or absent;

R₈, R₁₂, R₁₇, R₂₂, R₃₆, R₃₈, R₅₀, R₅₃, R₅₄, R₅₉, R₆₅=are independently U or absent;

[R₄₇]_x=N or absent;

Valine TREM Consensus Sequence

In an embodiment, a TREM disclosed herein comprises the sequence of Formula I_VAL(SEQ ID NO: 619),

wherein R is a ribonucleotide residue and the consensus for Val is:

R₀, R₂₃=absent;

R₂₄, R₃₅, R₅₇=are independently A or absent;

R₉, R₇₂=are independently A, C, G or absent;

R₂, R₄, R₅, R₆, R₇, R₁₂, R₁₅, R₁₆, R₂₁, R₂₅, R₂₆, R₂₉, R₃₁, R₃₂, R₃₃, R₃₄, R₃₇, R₄₁, R₄₂, R₄₃, R₄₄, R₄₅, R₄₆, R₄₈, R₄₉, R₅₀, R₅₈, R₆₁, R₆₂, R₆₃, R₆₄, R₆₅, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀=are independently N or absent;

R₁₇, R₃₅, R₅₉=are independently A, C, U or absent;

R₁₀, R₁₄, R₂₇, R₄₀, R₅₂, R₅₆=are independently A, G or absent;

R₁, R₃, R₅₁, R₅₃=are independently A, G, U or absent;

R₃₉=C or absent;

R₁₃, R₃₀, R₅₅=are independently C, G, U or absent;

R₁₁, R₂₂, R₂₈, R₆₀, R₇₁=are independently C, U or absent;

R₁₉=G or absent;

R₂₀=G, U or absent;

R₈, R₁₈, R₃₆, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula II_VAL(SEQ ID NO: 620),

wherein R is a ribonucleotide residue and the consensus for Val is:

R₀, R₁₈, R₂₃=absent;

R₂₄, R₃₈, R₅₇=are independently A or absent;

R₆₄, R₇₀, R₇₂=are independently A, C, G or absent;

R₁₅, R₁₆, R₂₆, R₂₉, R₃₁, R₃₂, R₄₃, R₄₄, R₄₅, R₄₉, R₅₀, R₅₈, R₆₂, R₆₅=are independently N or absent;

R₆, R₁₇, R₃₄, R₃₇, R₄₁, R₅₉=are independently A, C, U or absent;

R₉, R₁₀, R₁₄, R₂₇, R₄₀, R₄₆, R₅₁, R₅₂, R₅₆=are independently A, G or absent;

R₇, R₁₂, R₂₅, R₃₃, R₅₃, R₆₃, R₆₆, R₆₈=are independently A, G, U or absent;

R₆₉=A, U or absent;

R₃₉=C or absent;

R₅, R₆₇=are independently C, G or absent;

R₂, R₄, R₁₃, R₄₈, R₅₅, R₆₁=are independently C, G, U or absent;

R₁₁, R₂₂, R₂₈, R₃₀, R₃₅, R₆₀, R₇₁=are independently C, U or absent;

R₁₉=G or absent;

R₁, R₃, R₂₀, R₄₂=are independently G, U or absent;

R₈, R₂₁, R₃₆, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III v_AL(SEQ ID NO: 621),

wherein R is a ribonucleotide residue and the consensus for Val is:

R₀, R₁₈, R₂₃=absent

R₂₄, R₃₈, R₄₀, R₅₇, R₇₂=are independently A or absent;

R₂₉, R₆₄, R₇₀=are independently A, C, G or absent;

R₄₉, R₅₀, R₆₂=are independently N or absent;

R₁₆, R₂₆, R₃₁, R₃₂, R₃₇, R₄₁, R₄₃, R₅₉, R₆₅=are independently A, C, U or absent;

R₉, R₁₄, R₂₇, R₄₆, R₅₂, R₅₆, R₆₆=are independently A, G or absent;

R₇, R₁₂, R₂₅, R₃₃, R₄₄, R₄₅, R₅₃, R₅₈, R₆₃, R₆₈=are independently A, G, U or absent;

R₆₉=A, U or absent;

R₃₉=C or absent;

R₅, R₆₇=are independently C, G or absent;

R₂, R₄, R₁₃, R₁₅, R₄₈, R₅₅=are independently C, G, U or absent;

R₆, R₁₁, R₂₂, R₂₈, R₃₀, R₃₄, R₃₅, R₆₀, R₆₁, R₇₁=are independently C, U or absent;

R₁₀, R₁₉, R₅₁=are independently G or absent;

R₁, R₃, R₂₀, R₄₂=are independently G, U or absent;

R₈, R₁₇, R₂₁, R₃₆, R₅₄=are independently U or absent;

[R₄₇]_x=N or absent;

Variable Region Consensus Sequence

In an embodiment, a TREM disclosed herein comprises a variable region at position R₄₇.

In an embodiment, the variable region is 1-271 ribonucleotides in length (e.g. 1-250, 1-225, 1-200, 1-175, 1-150, 1-125, 1-100, 1-75, 1-50, 1-40, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 10-271, 20-271, 30-271, 40-271, 50-271, 60-271, 70-271, 80-271, 100-271, 125-271, 150-271, 175-271, 200-271, 225-271, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 110, 125, 150, 175, 200, 225, 250, or 271 ribonucleotides). In an embodiment, the variable region comprises any one, all or a combination of Adenine, Cytosine, Guanine or Uracil.

In an embodiment, the variable region comprises a ribonucleic acid (RNA) sequence encoded by a deoxyribonucleic acid (DNA) sequence disclosed in Table 15, e.g., any one of SEQ ID NOs: 452-561 disclosed in Table 15.

TABLE 15

Exemplary variable region sequences.

SEQ ID NO
SEQUENCE

1
452
AAAATATAAATATATTTC

2
453
AAGCT

3
454
AAGTT

4
455
AATTCTTCGGAATGT

5
456
AGA

6
457
AGTCC

7
458
CAACC

8
459
CAATC

9
460
CAGC

10
461
CAGGCGGGTTCTGCCCGCGC

11
462
CATACCTGCAAGGGTATC

12
463
CGACCGCAAGGTTGT

13
464
CGACCTTGCGGTCAT

14
465
CGATGCTAATCACATCGT

15
466
CGATGGTGACATCAT

16
467
CGATGGTTTACATCGT

17
468
CGCCGTAAGGTGT

18
469
CGCCTTAGGTGT

19
470
CGCCTTTCGACGCGT

20
471
CGCTTCACGGCGT

21
472
CGGCAGCAATGCTGT

22
473
CGGCTCCGCCTTC

23
474
CGGGTATCACAGGGTC

24
475
CGGTGCGCAAGCGCTGT

25
476
CGTACGGGTGACCGTACC

26
477
CGTCAAAGACTTC

27
478
CGTCGTAAGACTT

28
479
CGTTGAATAAACGT

29
480
CTGTC

30
481
GGCC

31
482
GGGGATT

32
483
GGTC

33
484
GGTTT

34
485
GTAG

35
486
TAACTAGATACTTTCAGAT

36
487
TACTCGTATGGGTGC

37
488
TACTTTGCGGTGT

38
489
TAGGCGAGTAACATCGTGC

39
490
TAGGCGTGAATAGCGCCTC

40
491
TAGGTCGCGAGAGCGGCGC

41
492
TAGGTCGCGTAAGCGGCGC

42
493
TAGGTGGTTATCCACGC

43
494
TAGTC

44
495
TAGTT

45
496
TATACGTGAAAGCGTATC

46
497
TATAGGGTCAAAAACTCTATC

47
498
TATGCAGAAATACCTGCATC

48
499
TCCCCATACGGGGGC

49
500
TCCCGAAGGGGTTC

50
501
TCTACGTATGTGGGC

51
502
TCTCATAGGAGTTC

52
503
TCTCCTCTGGAGGC

53
504
TCTTAGCAATAAGGT

54
505
TCTTGTAGGAGTTC

55
506
TGAACGTAAGTTCGC

56
507
TGAACTGCGAGGTTCC

57
508
TGAC

58
509
TGACCGAAAGGTCGT

59
510
TGACCGCAAGGTCGT

60
511
TGAGCTCTGCTCTC

61
512
TGAGGCCTCACGGCCTAC

62
513
TGAGGGCAACTTCGT

63
514
TGAGGGTCATACCTCC

64
515
TGAGGGTGCAAATCCTCC

65
516
TGCCGAAAGGCGT

66
517
TGCCGTAAGGCGT

67
518
TGCGGTCTCCGCGC

68
519
TGCTAGAGCAT

69
520
TGCTCGTATAGAGCTC

70
521
TGGACAATTGTCTGC

71
522
TGGACAGATGTCCGT

72
523
TGGACAGGTGTCCGC

73
524
TGGACGGTTGTCCGC

74
525
TGGACTTGTGGTC

75
526
TGGAGATTCTCTCCGC

76
527
TGGCATAGGCCTGC

77
528
TGGCTTATGTCTAC

78
529
TGGGAGTTAATCCCGT

79
530
TGGGATCTTCCCGC

80
531
TGGGCAGAAATGTCTC

81
532
TGGGCGTTCGCCCGC

82
533
TGGGCTTCGCCCGC

83
534
TGGGGGATAACCCCGT

84
535
TGGGGGTTTCCCCGT

85
536
TGGT

86
537
TGGTGGCAACACCGT

87
538
TGGTTTATAGCCGT

88
539
TGTACGGTAATACCGTACC

89
540
TGTCCGCAAGGACGT

90
541
TGTCCTAACGGACGT

91
542
TGTCCTATTAACGGACGT

92
543
TGTCCTTCACGGGCGT

93
544
TGTCTTAGGACGT

94
545
TGTGCGTTAACGCGTACC

95
546
TGTGTCGCAAGGCACC

96
547
TGTTCGTAAGGACTT

97
548
TTCACAGAAATGTGTC

98
549
TTCCCTCGTGGAGT

99
550
TTCCCTCTGGGAGC

100
551
TTCCCTTGTGGATC

101
552
TTCCTTCGGGAGC

102
553
TTCTAGCAATAGAGT

103
554
TTCTCCACTGGGGAGC

104
555
TTCTCGAGAGGGAGC

105
556
TTCTCGTATGAGAGC

106
557
TTTAAGGTTTTCCCTTAAC

107
558
TTTCATTGTGGAGT

108
559
TTTCGAAGGAATCC

109
560
TTTCTTCGGAAGC

110
561
TTTGGGGCAACTCAAC

Method of Making TREMs, TREM Core Fragments, and TREM Fragments

In vitro methods for synthesizing oligonucleotides are known in the art and can be used to make a TREM, a TREM core fragment or a TREM fragment disclosed herein. For example, a TREM, TREM core fragment or TREM fragment can be synthesized using a synthetic method, e.g., solid state synthesis or liquid phase synthesis. In an embodiment, a synthetic method of making a TREM, TREM core fragment or TREM fragment comprises linking a first nucleotide to a second nucleotide to form the TREM TREM core fragment or TREM fragment.

In an embodiment, a TREM, a TREM core fragment or a TREM fragment made according to an in vitro synthesis method disclosed herein has a different modification profile compared to a TREM expressed and isolated from a cell, or compared to a naturally occurring tRNA.

An exemplary method for making a synthetic TREM via 5 custom-character Silyl-2Orthoester (2ACE) Chemistry is provided in Example 3. The method provided in Example 3 can also be used to make a synthetic TREM core fragment or synthetic TREM fragment. Additional synthetic methods are disclosed in Hartsel S A et al., (2005) Oligonucleotide Synthesis, 033-050, the entire contents of which are hereby incorporated by reference.

TREM Composition

In an embodiment, a TREM composition, e.g., a TREM pharmaceutical composition, comprises a pharmaceutically acceptable excipient. Exemplary excipients include those provided in the FDA Inactive Ingredient Database (https://www.accessdata.fda.gov/scripts/cder/iig/index.Cfm).

In an embodiment, a TREM composition, e.g., a TREM pharmaceutical composition, comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100 or 150 grams of TREM, TREM core fragment or TREM fragment. In an embodiment, a TREM composition, e.g., a TREM pharmaceutical composition, comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50 or 100 milligrams of TREM, TREM core fragment or TREM fragment.

In an embodiment, a TREM composition, e.g., a TREM pharmaceutical composition, is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 or 99% dry weight TREMs, TREM core fragments or TREM fragments.

In an embodiment, a TREM composition comprises at least 1×10⁶TREM molecules, at least 1×10⁷TREM molecules, at least 1×10⁸TREM molecules or at least 1×10⁹TREM molecules.

In an embodiment, a TREM composition comprises at least 1×10⁶TREM core fragment molecules, at least 1×10⁷TREM core fragment molecules, at least 1×10⁸TREM core fragment molecules or at least 1×10⁹TREM core fragment molecules.

In an embodiment, a TREM composition comprises at least 1×10⁶TREM fragment molecules, at least 1×10⁷TREM fragment molecules, at least 1×10⁸TREM fragment molecules or at least 1×10⁹TREM fragment molecules.

In an embodiment, a TREM composition produced by any of the methods of making disclosed herein can be charged with an amino acid using an in vitro charging reaction as known in the art.

In an embodiment, a TREM composition comprise one or more species of TREMs, TREM core fragments, or TREM fragments. In an embodiment, a TREM composition comprises a single species of TREM, TREM core fragment, or TREM fragment. In an embodiment, a TREM composition comprises a first TREM, TREM core fragment, or TREM fragment species and a second TREM, TREM core fragment, or TREM fragment species. In an embodiment, the TREM composition comprises X TREM, TREM core fragment, or TREM fragment species, wherein X=2, 3, 4, 5, 6, 7, 8, 9, or 10.

In an embodiment, the TREM, TREM core fragment, or TREM fragment has at least 70, 75, 80, 85, 90, or 95, or has 100%, identity with a sequence encoded by a nucleic acid in Table 9.

In an embodiment, the TREM comprises a consensus sequence provided herein.

A TREM composition can be formulated as a liquid composition, as a lyophilized composition or as a frozen composition.

In some embodiments, a TREM composition can be formulated to be suitable for pharmaceutical use, e.g., a pharmaceutical TREM composition. In an embodiment, a pharmaceutical TREM composition is substantially free of materials and/or reagents used to separate and/or purify a TREM, TREM core fragment, or TREM fragment.

In some embodiments, a TREM composition can be formulated with water for injection. In some embodiments, a TREM composition formulated with water for injection is suitable for pharmaceutical use, e.g., comprises a pharmaceutical TREM composition.

TREM Characterization

A TREM, TREM core fragment, or TREM fragment, or a TREM composition, e.g., a pharmaceutical TREM composition, produced by any of the methods disclosed herein can be assessed for a characteristic associated with the TREM, TREM core fragment, or TREM fragment or the TREM composition, such as purity, sterility, concentration, structure, or functional activity of the TREM, TREM core fragment, or TREM fragment. Any of the above-mentioned characteristics can be evaluated by providing a value for the characteristic, e.g., by evaluating or testing the TREM, TREM core fragment, or TREM fragment, or the TREM composition, or an intermediate in the production of the TREM composition. The value can also be compared with a standard or a reference value. Responsive to the evaluation, the TREM composition can be classified, e.g., as ready for release, meets production standard for human trials, complies with ISO standards, complies with cGMP standards, or complies with other pharmaceutical standards. Responsive to the evaluation, the TREM composition can be subjected to further processing, e.g., it can be divided into aliquots, e.g., into single or multi-dosage amounts, disposed in a container, e.g., an end-use vial, packaged, shipped, or put into commerce. In embodiments, in response to the evaluation, one or more of the characteristics can be modulated, processed or re-processed to optimize the TREM composition. For example, the TREM composition can be modulated, processed or re-processed to (i) increase the purity of the TREM composition; (ii) decrease the amount of fragments in the composition; (iii) decrease the amount of endotoxins in the composition; (iv) increase the in vitro translation activity of the composition; (v) increase the TREM concentration of the composition; or (vi) inactivate or remove any viral contaminants present in the composition, e.g., by reducing the pH of the composition or by filtration.

In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) has a purity of at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, i.e., by mass.

In an embodiment, the TREM (e.g., TREM composition or an intermediate in the production of the TREM composition) has less than 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25% TREM fragments relative to full length TREMs.

In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) has low levels or absence of endotoxins, e.g., a negative result as measured by the Limulus amebocyte lysate (LAL) test.

In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) has in-vitro translation activity, e.g., as measured by an assay described in Examples 12-13.

In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) has a TREM concentration of at least 0.1 ng/mL, 0.5 ng/mL, 1 ng/mL, 5 ng/mL, 10 ng/mL, 50 ng/mL, 0.1 ug/mL, 0.5 ug/mL, 1 ug/mL, 2 ug/mL, 5 ug/mL, 10 ug/mL, 20 ug/mL, 30 ug/mL, 40 ug/mL, 50 ug/mL, 60 ug/mL, 70 ug/mL, 80 ug/mL, 100 ug/mL, 200 ug/mL, 300 ug/mL, 500 ug/mL, 1000 ug/mL, 5000 ug/mL, 10,000 ug/mL, or 100,000 ug/mL.

In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) is sterile, e.g., the composition or preparation supports the growth of fewer than 100 viable microorganisms as tested under aseptic conditions, the composition or preparation meets the standard of USP <71>, and/or the composition or preparation meets the standard of USP <85>.

In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) has an undetectable level of viral contaminants, e.g., no viral contaminants. In an embodiment, any viral contaminant, e.g., residual virus, present in the composition is inactivated or removed. In an embodiment, any viral contaminant, e.g., residual virus, is inactivated, e.g., by reducing the pH of the composition. In an embodiment, any viral contaminant, e.g., residual virus, is removed, e.g., by filtration or other methods known in the field.

TREM Administration

Any TREM composition or pharmaceutical composition described herein can be administered to a cell, tissue or subject, e.g., by direct administration to a cell, tissue and/or an organ in vitro, ex-vivo or in vivo. In-vivo administration may be via, e.g., by local, systemic and/or parenteral routes, for example intravenous, subcutaneous, intraperitoneal, intrathecal, intramuscular, ocular, nasal, urogenital, intradermal, dermal, enteral, intravitreal, intracerebral, intrathecal, or epidural.

Vectors and Carriers

In some embodiments the TREM, TREM core fragment, or TREM fragment or TREM composition described herein, is delivered to cells, e.g. mammalian cells or human cells, using a vector. The vector may be, e.g., a plasmid or a viral vector. In some embodiments, delivery is in vivo, in vitro, ex vivo, or in situ. In some embodiments, the viral vector is an adeno associated virus (AAV) vector, a lentivirus vector, an adenovirus or an anellovector. In some embodiments, the system or components of the system are delivered to cells with a viral-like particle or a virosome. In some embodiments, the delivery uses more than one virus, viral-like particle or virosome.

A TREM, a TREM composition or a pharmaceutical TREM composition described herein may comprise, may be formulated with, or may be delivered in, a carrier.

Viral Vectors

The carrier may be a viral vector (e.g., a viral vector comprising a sequence encoding a TREM, a TREM core fragment or a TREM fragment). The viral vector may be administered to a cell or to a subject (e.g., a human subject or animal model) to deliver a TREM, a TREM core fragment or a TREM fragment, a TREM composition or a pharmaceutical TREM composition.

A viral vector may be systemically or locally administered (e.g., injected). Viral genomes provide a rich source of vectors that can be used for the efficient delivery of exogenous genes into a mammalian cell. Viral genomes are known in the art as useful vectors for delivery because the polynucleotides contained within such genomes are typically incorporated into the nuclear genome of a mammalian cell by generalized or specialized transduction. These processes occur as part of the natural viral replication cycle, and do not require added proteins or reagents in order to induce gene integration. Examples of viral vectors include a retrovirus (e.g., Retroviridae family viral vector), adenovirus (e.g., Ad5, Ad26, Ad34, Ad35, and Ad48), parvovirus (e.g., adeno-associated viruses), coronavirus, negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g., measles and Sendai), positive strand RNA viruses, such as picornavirus and alphavirus, and double stranded DNA viruses including adenovirus, herpesvirus (e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus, replication deficient herpes virus), and poxvirus (e.g., vaccinia, modified vaccinia Ankara (MVA), fowlpox and canarypox). Other viruses include Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, human papilloma virus, human foamy virus, and hepatitis virus, for example. Examples of retroviruses include: avian leukosis-sarcoma, avian C-type viruses, mammalian C-type, B-type viruses, D-type viruses, oncoretroviruses, HTLV-BLV group, lentivirus, alpharetrovirus, gammaretrovirus, spumavirus (Coffin, J. M., Retroviridae: The viruses and their replication, Virology (Third Edition) Lippincott-Raven, Philadelphia, 1996). Other examples include murine leukemia viruses, murine sarcoma viruses, mouse mammary tumor virus, bovine leukemia virus, feline leukemia virus, feline sarcoma virus, avian leukemia virus, human T-cell leukemia virus, baboon endogenous virus, Gibbon ape leukemia virus, Mason Pfizer monkey virus, simian immunodeficiency virus, simian sarcoma virus, Rous sarcoma virus and lentiviruses. In some embodiments, a viral vector is used which does not integrate into the genome, e.g., an anellovector (see, e.g., US20200188456). Other examples of vectors are described, for example, in U.S. Pat. No. 5,801,030, the teachings of which are incorporated herein by reference. In some embodiments the system or components of the system are delivered to cells with a viral-like particle or a virosome.

Cell and Vesicle-Based Carriers

A TREM, a TREM core fragment or a TREM fragment, a TREM composition or a pharmaceutical TREM composition described herein can be administered to a cell in a vesicle or other membrane-based carrier.

In embodiments, a TREM, a TREM core fragment or a TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein is administered in or via a cell, vesicle or other membrane-based carrier. In one embodiment, the TREM, TREM core fragment, TREM fragment, or TREM composition or pharmaceutical TREM composition can be formulated in liposomes or other similar vesicles. Liposomes are spherical vesicle structures composed of a uni- or multilamellar lipid bilayer surrounding internal aqueous compartments and a relatively impermeable outer lipophilic phospholipid bilayer. Liposomes may be anionic, neutral or cationic. Liposomes are biocompatible, nontoxic, can deliver both hydrophilic and lipophilic drug molecules, protect their cargo from degradation by plasma enzymes, and transport their load across biological membranes and the blood brain barrier (BBB) (see, e.g., Spuch and Navarro, Journal of Drug Delivery, vol. 2011, Article ID 469679, 12 pages, 2011. doi:10.1155/2011/469679 for review).

Vesicles can be made from several different types of lipids; however, phospholipids are most commonly used to generate liposomes as drug carriers. Methods for preparation of multilamellar vesicle lipids are known in the art (see for example U.S. Pat. No. 6,693,086, the teachings of which relating to multilamellar vesicle lipid preparation are incorporated herein by reference). Although vesicle formation can be spontaneous when a lipid film is mixed with an aqueous solution, it can also be expedited by applying force in the form of shaking by using a homogenizer, sonicator, or an extrusion apparatus (see, e.g., Spuch and Navarro, Journal of Drug Delivery, vol. 2011, Article ID 469679, 12 pages, 2011. doi:10.1155/2011/469679 for review). Extruded lipids can be prepared by extruding through filters of decreasing size, as described in Templeton et al., Nature Biotech, 15:647-652, 1997, the teachings of which relating to extruded lipid preparation are incorporated herein by reference.

Lipid nanoparticles are another example of a carrier that provides a biocompatible and biodegradable delivery system for the TREM, TREM core fragment, TREM fragment, or TREM composition or pharmaceutical TREM composition described herein. Nanostructured lipid carriers (NLCs) are modified solid lipid nanoparticles (SLNs) that retain the characteristics of the SLN, improve drug stability and loading capacity, and prevent drug leakage. Polymer nanoparticles (PNPs) are an important component of drug delivery. These nanoparticles can effectively direct drug delivery to specific targets and improve drug stability and controlled drug release. Lipid-polymer nanoparticles (PLNs), a new type of carrier that combines liposomes and polymers, may also be employed. These nanoparticles possess the complementary advantages of PNPs and liposomes. A PLN is composed of a core-shell structure; the polymer core provides a stable structure, and the phospholipid shell offers good biocompatibility. As such, the two components increase the drug encapsulation efficiency rate, facilitate surface modification, and prevent leakage of water-soluble drugs. For a review, see, e.g., Li et al. 2017, Nanomaterials 7, 122; doi:10.3390/nano7060122.

Exemplary lipid nanoparticles are disclosed in International Application PCT/US2014/053907, the entire contents of which are hereby incorporated by reference. For example, an LNP described in paragraphs [403-406] or [410-413] of PCT/US2014/053907 can be used as a carrier for the TREM, TREM core fragment, TREM fragment, or TREM composition or pharmaceutical TREM composition described herein.

Additional exemplary lipid nanoparticles are disclosed in U.S. Pat. No. 10,562,849 the entire contents of which are hereby incorporated by reference. For example, an LNP of formula (I) as described in columns 1-3 of U.S. Pat. No. 10,562,849 can be used as a carrier for the TREM, TREM core fragment, TREM fragment, or TREM composition or pharmaceutical TREM composition described herein.

Lipids that can be used in nanoparticle formations (e.g., lipid nanoparticles) include, for example those described in Table 4 of WO2019217941, which is incorporated by reference, e.g., a lipid-containing nanoparticle can comprise one or more of the lipids in Table 4 of WO2019217941. Lipid nanoparticles can include additional elements, such as polymers, such as the polymers described in Table 5 of WO2019217941, incorporated by reference.

In some embodiments, conjugated lipids, when present, can include one or more of PEG-diacylglycerol (DAG) (such as 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG)), PEG-dialkyloxypropyl (DAA), PEG-phospholipid, PEG-ceramide (Cer), a pegylated phosphatidylethanoloamine (PEG-PE), PEG succinate diacylglycerol (PEGS-DAG) (such as 4-0-(2 custom-character 3di(tetradecanoyloxy)propyl-1-0-(w-methoxy(polyethoxy)ethyl) butanedioate (PEG-S-DMG)), PEG dialkoxypropylcarbam, N-(carbonyl-methoxypoly ethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt, and those described in Table 2 of WO2019051289 (incorporated by reference), and combinations of the foregoing.

In some embodiments, sterols that can be incorporated into lipid nanoparticles include one or more of cholesterol or cholesterol derivatives, such as those in WO2009/127060 or US2010/0130588, which are incorporated by reference. Additional exemplary sterols include phytosterols, including those described in Eygeris et al (2020), incorporated herein by reference.

In some embodiments, the lipid particle comprises an ionizable lipid, a non-cationic lipid, a conjugated lipid that inhibits aggregation of particles, and a sterol. The amounts of these components can be varied independently and to achieve desired properties. For example, in some embodiments, the lipid nanoparticle comprises an ionizable lipid is in an amount from about 20 mol % to about 90 mol % of the total lipids (in other embodiments it may be 20-70% (mol), 30-60% (mol) or 40-50% (mol); about 50 mol % to about 90 mol % of the total lipid present in the lipid nanoparticle), a non-cationic lipid in an amount from about 5 mol % to about 30 mol % of the total lipids, a conjugated lipid in an amount from about 0.5 mol % to about 20 mol % of the total lipids, and a sterol in an amount from about 20 mol % to about 50 mol % of the total lipids. The ratio of total lipid to nucleic acid can be varied as desired. For example, the total lipid to nucleic acid (mass or weight) ratio can be from about 10:1 to about 30:1.

In some embodiments, the lipid to nucleic acid ratio (mass/mass ratio; w/w ratio) can be in the range of from about 1:1 to about 25:1, from about 10:1 to about 14:1, from about 3:1 to about 15:1, from about 4:1 to about 10:1, from about 5:1 to about 9:1, or about 6:1 to about 9:1. The amounts of lipids and nucleic acid can be adjusted to provide a desired N/P ratio, for example, N/P ratio of 3, 4, 5, 6, 7, 8, 9, 10 or higher. Generally, the lipid nanoparticle formulation's overall lipid content can range from about 5 mg/ml to about 30 mg/mL.

Some non-limiting example of lipid compounds that may be used (e.g., in combination with other lipid components) to form lipid nanoparticles for the delivery of compositions described herein, e.g., nucleic acid (e.g., RNA) described herein includes,

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In some embodiments an LNP comprising Formula (i) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

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In some embodiments an LNP comprising Formula (ii) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

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In some embodiments an LNP comprising Formula (iii) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

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In some embodiments an LNP comprising Formula (v) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

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In some embodiments an LNP comprising Formula (vi) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

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In some embodiments an LNP comprising Formula (viii) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

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In some embodiments an LNP comprising Formula (ix) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

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wherein X¹is O, NR¹, or a direct bond, X²is C2-5 alkylene, X³is C(═O) or a direct bond, R¹is H or Me, R¹is Ci-3 alkyl, R²is Ci-3 alkyl, or R²taken together with the nitrogen atom to which it is attached and 1-3 carbon atoms of X²form a 4-, 5-, or 6-membered ring, or X¹is NR¹, R¹and R²taken together with the nitrogen atoms to which they are attached form a 5- or 6-membered ring, or R²taken together with R³and the nitrogen atom to which they are attached form a 5-, 6-, or 7-membered ring, Y¹is C2-12 alkylene, Y²is selected from

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n is 0 to 3, R⁴is Ci-15 alkyl, Z¹is Ci-6 alkylene or a direct bond, Z²is

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(in either orientation) or absent, provided that if Z¹is a direct bond, Z²is absent; R⁵is C5-9 alkyl or C6-10 alkoxy, R⁶is C5-9 alkyl or C6-10 alkoxy, W is methylene or a direct bond, and R⁷is H or Me, or a salt thereof, provided that if R³and R²are C2 alkyls, X¹is O, X²is linear C3 alkylene, X³is C(=0), Y¹is linear Ce alkylene, (Y²)n-R⁴is:

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R⁴is linear C5 alkyl, Z¹is C2 alkylene, Z²is absent, W is methylene, and R⁷is H, then R⁵and R⁶are not Cx alkoxy.

In some embodiments an LNP comprising Formula (xii) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

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In some embodiments an LNP comprising Formula (xi) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

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In some embodiments an LNP comprises a compound of Formula (xiii) and a compound of Formula (xiv).

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In some embodiments, an LNP comprising Formula (xv) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

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In some embodiments an LNP comprising a formulation of Formula (xvi) is used to deliver a TREM composition described herein to the lung endothelial cells.

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In some embodiments, a lipid compound used to form lipid nanoparticles for the delivery of compositions described herein, e.g., a TREM described herein is made by one of the following reactions:

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In some embodiments, a composition described herein (e.g., TREM composition) is provided in an LNP that comprises an ionizable lipid. In some embodiments, the ionizable lipid is heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate (SM-102); e.g., as described in Example 1 of U.S. Pat. No. 9,867,888 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is 9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-dienoate (LP01), e.g., as synthesized in Example 13 of WO2015/095340 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is Di((Z)-non-2-en-1-yl) 9-((4-dimethylamino)-butanoyl)oxy)heptadecanedioate (L319), e.g. as synthesized in Example 7, 8, or 9 of US2012/0027803 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is 1,1 custom-character ((2-(4-(2-((2-(Bis(2-hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl) amino)ethyl)piperazin-1-yl)ethyl)azanediyl)bis(dodecan-2-ol) (C12-200), e.g., as synthesized in Examples 14 and 16 of WO2010/053572 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is Imidazole cholesterol ester (ICE) lipid (3S, 10R, 13R, 17R)-10, 13-dimethyl-17-((R)-6-methylheptan-2-yl)-2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-3-yl 3-(1H-imidazol-4-yl)propanoate, e.g., Structure (I) from WO2020/106946 (incorporated by reference herein in its entirety).

In some embodiments, an ionizable lipid may be a cationic lipid, an ionizable cationic lipid, e.g., a cationic lipid that can exist in a positively charged or neutral form depending on pH, or an amine-containing lipid that can be readily protonated. In some embodiments, the cationic lipid is a lipid capable of being positively charged, e.g., under physiological conditions. Exemplary cationic lipids include one or more amine group(s) which bear the positive charge. In some embodiments, the lipid particle comprises a cationic lipid in formulation with one or more of neutral lipids, ionizable amine-containing lipids, biodegradable alkyne lipids, steroids, phospholipids including polyunsaturated lipids, structural lipids (e.g., sterols), PEG, cholesterol and polymer conjugated lipids. In some embodiments, the cationic lipid may be an ionizable cationic lipid. An exemplary cationic lipid as disclosed herein may have an effective pKa over 6.0. In embodiments, a lipid nanoparticle may comprise a second cationic lipid having a different effective pKa (e.g., greater than the first effective pKa), than the first cationic lipid. A lipid nanoparticle may comprise between 40 and 60 mol percent of a cationic lipid, a neutral lipid, a steroid, a polymer conjugated lipid, and a therapeutic agent, e.g., a TREM described herein, encapsulated within or associated with the lipid nanoparticle. In some embodiments, the TREM is co-formulated with the cationic lipid. The TREM may be adsorbed to the surface of an LNP, e.g., an LNP comprising a cationic lipid. In some embodiments, the TREM may be encapsulated in an LNP, e.g., an LNP comprising a cationic lipid. In some embodiments, the lipid nanoparticle may comprise a targeting moiety, e.g., coated with a targeting agent. In embodiments, the LNP formulation is biodegradable. In some embodiments, a lipid nanoparticle comprising one or more lipid described herein, e.g., Formula (i), (ii), (ii), (vii) and/or (ix) encapsulates at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 92%, at least 95%, at least 97%, at least 98% or 100% of a TREM.

Exemplary ionizable lipids that can be used in lipid nanoparticle formulations include, without limitation, those listed in Table 1 of WO2019051289, incorporated herein by reference. Additional exemplary lipids include, without limitation, one or more of the following formulae: X of US2016/0311759; I of US20150376115 or in US2016/0376224; I, II or III of US20160151284; I, IA, II, or IIA of US20170210967; I-c of US20150140070; A of US2013/0178541; I of US2013/0303587 or US2013/0123338; I of US2015/0141678; II, III, IV, or V of US2015/0239926; I of US2017/0119904; I or II of WO2017/117528; A of US2012/0149894; A of US2015/0057373; A of WO2013/116126; A of US2013/0090372; A of US2013/0274523; A of US2013/0274504; A of US2013/0053572; A of WO2013/016058; A of WO2012/162210; I of US2008/042973; I, II, III, or IV of US2012/01287670; I or II of US2014/0200257; I, II, or III of US2015/0203446; I or III of US2015/0005363; I, IA, IB, IC, ID, II, IIA, IIB, IIC, IID, or III-XXIV of US2014/0308304; of US2013/0338210; I, II, III, or IV of WO2009/132131; A of US2012/01011478; I or XXXV of US2012/0027796; XIV or XVII of US2012/0058144; of US2013/0323269; I of US2011/0117125; 1, II, or III of US2011/0256175; I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII of US2012/0202871; I, II, III, IV, V, VI, VII, VIII, X, XII, XIII, XIV, XV, or XVI of US2011/0076335; I or II of US2006/008378; I of US2013/0123338; I or X-A-Y-Z of US2015/0064242; XVI, XVII, or XVIII of US2013/0022649; I, II, or III of US2013/0116307; I, II, or III of US2013/0116307; I or II of US2010/0062967; I-X of US2013/0189351; I of US2014/0039032; V of US2018/0028664; I of US2016/0317458; I of US2013/0195920; 5, 6, or 10 of U.S. Pat. No. 10,221,127; III-3 of WO2018/081480; I-5 or I-8 of WO2020/081938; 18 or 25 of U.S. Pat. No. 9,867,888; A of US2019/0136231; II of WO2020/219876; 1 of US2012/0027803; OF-02 of US2019/0240349; 23 of U.S. Pat. No. 10,086,013; cKK-E12/A6 of Miao et al (2020); C12-200 of WO2010/053572; 7C1 of Dahlman et al (2017); 304-013 or 503-013 of Whitehead et al; TS-P4C2 of U.S. Pat. No. 9,708,628; I of WO2020/106946; I of WO2020/106946.

In some embodiments, the ionizable lipid is MC3 (6Z,9Z,28Z,3 lZ)-heptatriaconta-6,9,28,3 l-tetraen-19-yl-4-(dimethylamino) butanoate (DLin-MC3-DMA or MC3), e.g., as described in Example 9 of WO2019051289A9 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is the lipid ATX-002, e.g., as described in Example 10 of WO2019051289A9 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is (13Z,16Z)-A,A-dimethyl-3-nonyldocosa-13, 16-dien-1-amine (Compound 32), e.g., as described in Example 11 of WO2019051289A9 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is Compound 6 or Compound 22, e.g., as described in Example 12 of WO2019051289A9 (incorporated by reference herein in its entirety).

Exemplary non-cationic lipids include, but are not limited to, distearoyl-sn-glycero-phosphoethanolamine, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidyl-ethanolamine (DSPE), monomethyl-phosphatidylethanolamine (such as 16-O-monomethyl PE), dimethyl-phosphatidylethanolamine (such as 16-O-dimethyl PE), l8-l-trans PE, 1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), hydrogenated soy phosphatidylcholine (HSPC), egg phosphatidylcholine (EPC), dioleoylphosphatidylserine (DOPS), sphingomyelin (SM), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), distearoylphosphatidylglycerol (DSPG), dierucoylphosphatidylcholine (DEPC), palmitoyloleyolphosphatidylglycerol (POPG), dielaidoyl-phosphatidylethanolamine (DEPE), lecithin, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, egg sphingomyelin (ESM), cephalin, cardiolipin, phosphatidicacid,cerebrosides, dicetylphosphate, lysophosphatidylcholine, dilinoleoylphosphatidylcholine, or mixtures thereof. It is understood that other diacylphosphatidylcholine and diacylphosphatidylethanolamine phospholipids can also be used. The acyl groups in these lipids are preferably acyl groups derived from fatty acids having C10-C24 carbon chains, e.g., lauroyl, myristoyl, palmitoyl, stearoyl, or oleoyl. Additional exemplary lipids, in certain embodiments, include, without limitation, those described in Kim et al. (2020) dx.doi.org/10.1021/acs.nanolett.0c01386, incorporated herein by reference. Such lipids include, in some embodiments, plant lipids found to improve liver transfection with mRNA (e.g., DGTS).

Other examples of non-cationic lipids suitable for use in the lipid nanoparticles include, without limitation, nonphosphorous lipids such as, e.g., stearylamine, dodeeylamine, hexadecylamine, acetyl palmitate, glycerol ricinoleate, hexadecyl stereate, isopropyl myristate, amphoteric acrylic polymers, triethanolamine-lauryl sulfate, alkyl-aryl sulfate polyethyloxylated fatty acid amides, dioctadecyl dimethyl ammonium bromide, ceramide, sphingomyelin, and the like. Other non-cationic lipids are described in WO2017/099823 or US patent publication US2018/0028664, the contents of which is incorporated herein by reference in their entirety.

In some embodiments, the non-cationic lipid is oleic acid or a compound of Formula I, II, or IV of US2018/0028664, incorporated herein by reference in its entirety. The non-cationic lipid can comprise, for example, 0-30% (mol) of the total lipid present in the lipid nanoparticle. In some embodiments, the non-cationic lipid content is 5-20% (mol) or 10-15% (mol) of the total lipid present in the lipid nanoparticle. In embodiments, the molar ratio of ionizable lipid to the neutral lipid ranges from about 2:1 to about 8:1 (e.g., about 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1).

In some embodiments, the lipid nanoparticles do not comprise any phospholipids.

In some aspects, the lipid nanoparticle can further comprise a component, such as a sterol, to provide membrane integrity. One exemplary sterol that can be used in the lipid nanoparticle is cholesterol and derivatives thereof. Non-limiting examples of cholesterol derivatives include polar analogues such as 5a-choiestanol, 53-coprostanol, choiesteryl-(2′-hydroxy)-ethyl ether, choiesteryl-(4 custom-character hydroxy)-butyl ether, and 6-ketocholestanol; non-polar analogues such as 5a-cholestane, cholestenone, 5a-cholestanone, 5p-cholestanone, and cholesteryl decanoate; and mixtures thereof. In some embodiments, the cholesterol derivative is a polar analogue, e.g., choiesteryl-(4hydroxy)-butyl ether. Exemplary cholesterol derivatives are described in PCT publication WO2009/127060 and US patent publication US2010/0130588, each of which is incorporated herein by reference in its entirety.

In some embodiments, the component providing membrane integrity, such as a sterol, can comprise 0-50% (mol) (e.g., 0-10%, 10-20%, 20-30%, 30-40%, or 40-50%) of the total lipid present in the lipid nanoparticle. In some embodiments, such a component is 20-50% (mol) 30-40% (mol) of the total lipid content of the lipid nanoparticle.

In some embodiments, the lipid nanoparticle can comprise a polyethylene glycol (PEG) or a conjugated lipid molecule. Generally, these are used to inhibit aggregation of lipid nanoparticles and/or provide steric stabilization. Exemplary conjugated lipids include, but are not limited to, PEG-lipid conjugates, polyoxazoline (POZ)-lipid conjugates, polyamide-lipid conjugates (such as ATTA-lipid conjugates), cationic-polymer lipid (CPL) conjugates, and mixtures thereof. In some embodiments, the conjugated lipid molecule is a PEG-lipid conjugate, for example, a (methoxy polyethylene glycol)-conjugated lipid.

Exemplary PEG-lipid conjugates include, but are not limited to, PEG-diacylglycerol (DAG) (such as 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG)), PEG-dialkyloxypropyl (DAA), PEG-phospholipid, PEG-ceramide (Cer), a pegylated phosphatidylethanoloamine (PEG-PE), PEG succinate diacylglycerol (PEGS-DAG) (such as 4-0-(2 custom-character 3di(tetradecanoyloxy)propyl-1-0-(w-methoxy(polyethoxy)ethyl) butanedioate (PEG-S-DMG)), PEG dialkoxypropylcarbam, N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt, or a mixture thereof. Additional exemplary PEG-lipid conjugates are described, for example, in U.S. Pat. Nos. 5,885,613, 6,287,591, US2003/0077829, US2003/0077829, US2005/0175682, US2008/0020058, US2011/0117125, US2010/0130588, US2016/0376224, US2017/0119904, and US/099823, the contents of all of which are incorporated herein by reference in their entirety. In some embodiments, a PEG-lipid is a compound of Formula III, III-a-I, III-a-2, III-b-1, III-b-2, or V of US2018/0028664, the content of which is incorporated herein by reference in its entirety. In some embodiments, a PEG-lipid is of Formula II of US20150376115 or US2016/0376224, the content of both of which is incorporated herein by reference in its entirety. In some embodiments, the PEG-DAA conjugate can be, for example, PEG-dilauryloxypropyl, PEG-dimyristyloxypropyl, PEG-dipalmityloxypropyl, or PEG-distearyloxypropyl. The PEG-lipid can be one or more of PEG-DMG, PEG-dilaurylglycerol, PEG-dipalmitoylglycerol, PEG-disterylglycerol, PEG-dilaurylglycamide, PEG-dimyristylglycamide, PEG-dipalmitoylglycamide, PEG-disterylglycamide, PEG-cholesterol (1-[8 custom-character (Cholest-5-en-3[beta]-oxy)carboxamido-36dioxaoctanyl] carbamoyl-[omega]-methyl-poly(ethylene glycol), PEG-DMB (3,4-Ditetradecoxylbenzyl-[omega]-methyl-poly(ethylene glycol) ether), and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. In some embodiments, the PEG-lipid comprises PEG-DMG, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. In some embodiments, the PEG-lipid comprises a structure selected from:

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In some embodiments, lipids conjugated with a molecule other than a PEG can also be used in place of PEG-lipid. For example, polyoxazoline (POZ)-lipid conjugates, polyamide-lipid conjugates (such as ATTA-lipid conjugates), and cationic-polymer lipid (GPL) conjugates can be used in place of or in addition to the PEG-lipid.

Exemplary conjugated lipids, i.e., PEG-lipids, (POZ)-lipid conjugates, ATTA-lipid conjugates and cationic polymer-lipids are described in the PCT and LIS patent applications listed in Table 2 of WO2019051289A9, the contents of all of which are incorporated herein by reference in their entirety.

In some embodiments, the PEG or the conjugated lipid can comprise 0-20% (mol) of the total lipid present in the lipid nanoparticle. In some embodiments, PEG or the conjugated lipid content is 0.5-10% or 2-5% (mol) of the total lipid present in the lipid nanoparticle. Molar ratios of the ionizable lipid, non-cationic-lipid, sterol, and PEG/conjugated lipid can be varied as needed. For example, the lipid particle can comprise 30-70% ionizable lipid by mole or by total weight of the composition, 0-60% cholesterol by mole or by total weight of the composition, 0-30% non-cationic-lipid by mole or by total weight of the composition and 1-10% conjugated lipid by mole or by total weight of the composition. Preferably, the composition comprises 30-40% ionizable lipid by mole or by total weight of the composition, 40-50% cholesterol by mole or by total weight of the composition, and 10-20% non-cationic-lipid by mole or by total weight of the composition. In some other embodiments, the composition is 50-75% ionizable lipid by mole or by total weight of the composition, 20-40% cholesterol by mole or by total weight of the composition, and 5 to 10% non-cationic-lipid, by mole or by total weight of the composition and 1-10% conjugated lipid by mole or by total weight of the composition. The composition may contain 60-70% ionizable lipid by mole or by total weight of the composition, 25-35% cholesterol by mole or by total weight of the composition, and 5-10% non-cationic-lipid by mole or by total weight of the composition. The composition may also contain up to 90% ionizable lipid by mole or by total weight of the composition and 2 to 15% non-cationic lipid by mole or by total weight of the composition. The formulation may also be a lipid nanoparticle formulation, for example comprising 8-30% ionizable lipid by mole or by total weight of the composition, 5-30% non-cationic lipid by mole or by total weight of the composition, and 0-20% cholesterol by mole or by total weight of the composition; 4-25% ionizable lipid by mole or by total weight of the composition, 4-25% non-cationic lipid by mole or by total weight of the composition, 2 to 25% cholesterol by mole or by total weight of the composition, 10 to 35% conjugate lipid by mole or by total weight of the composition, and 5% cholesterol by mole or by total weight of the composition; or 2-30% ionizable lipid by mole or by total weight of the composition, 2-30% non-cationic lipid by mole or by total weight of the composition, 1 to 15% cholesterol by mole or by total weight of the composition, 2 to 35% conjugate lipid by mole or by total weight of the composition, and 1-20% cholesterol by mole or by total weight of the composition; or even up to 90% ionizable lipid by mole or by total weight of the composition and 2-10% non-cationic lipids by mole or by total weight of the composition, or even 100% cationic lipid by mole or by total weight of the composition. In some embodiments, the lipid particle formulation comprises ionizable lipid, phospholipid, cholesterol and a PEG-ylated lipid in a molar ratio of 50:10:38.5:1.5. In some other embodiments, the lipid particle formulation comprises ionizable lipid, cholesterol and a PEG-ylated lipid in a molar ratio of 60:38.5:1.5.

In some embodiments, the lipid particle comprises ionizable lipid, non-cationic lipid (e.g. phospholipid), a sterol (e.g., cholesterol) and a PEG-ylated lipid, where the molar ratio of lipids ranges from 20 to 70 mole percent for the ionizable lipid, with a target of 40-60, the mole percent of non-cationic lipid ranges from 0 to 30, with a target of 0 to 15, the mole percent of sterol ranges from 20 to 70, with a target of 30 to 50, and the mole percent of PEG-ylated lipid ranges from 1 to 6, with a target of 2 to 5.

In some embodiments, the lipid particle comprises ionizable lipid/non-cationic-lipid/sterol/conjugated lipid at a molar ratio of 50:10:38.5:1.5.

In an aspect, the disclosure provides a lipid nanoparticle formulation comprising phospholipids, lecithin, phosphatidylcholine and phosphatidylethanolamine.

In some embodiments, one or more additional compounds can also be included. Those compounds can be administered separately, or the additional compounds can be included in the lipid nanoparticles of the invention. In other words, the lipid nanoparticles can contain other compounds in addition to the nucleic acid or at least a second nucleic acid, different than the first. Without limitations, other additional compounds can be selected from the group consisting of small or large organic or inorganic molecules, monosaccharides, disaccharides, trisaccharides, oligosaccharides, polysaccharides, peptides, proteins, peptide analogs and derivatives thereof, peptidomimetics, nucleic acids, nucleic acid analogs and derivatives, an extract made from biological materials, or any combinations thereof.

In some embodiments, LNPs are directed to specific tissues by the addition of targeting domains. For example, biological ligands may be displayed on the surface of LNPs to enhance interaction with cells displaying cognate receptors, thus driving association with and cargo delivery to tissues wherein cells express the receptor. In some embodiments, the biological ligand may be a ligand that drives delivery to the liver, e.g., LNPs that display GalNAc result in delivery of nucleic acid cargo to hepatocytes that display asialoglycoprotein receptor (ASGPR). The work of Akinc et al. Mol Ther 18(7):1357-1364 (2010) teaches the conjugation of a trivalent GalNAc ligand to a PEG-lipid (GalNAc-PEG-DSG) to yield LNPs dependent on ASGPR for observable LNP cargo effect (see, e.g., FIG. 6 of Akinc et al. 2010, supra). Other ligand-displaying LNP formulations, e.g., incorporating folate, transferrin, or antibodies, are discussed in WO2017223135, which is incorporated herein by reference in its entirety, in addition to the references used therein, namely Kolhatkar et al., Curr Drug Discov Technol. 2011 8:197-206; Musacchio and Torchilin, Front Biosci. 2011 16:1388-1412; Yu et al., Mol Membr Biol. 2010 27:286-298; Patil et al., Crit Rev Ther Drug Carrier Syst. 2008 25:1-61; Benoit et al., Biomacromolecules. 2011 12:2708-2714; Zhao et al., Expert Opin Drug Deliv. 2008 5:309-319; Akinc et al., Mol Ther. 2010 18:1357-1364; Srinivasan et al., Methods Mol Biol. 2012 820:105-116; Ben-Arie et al., Methods Mol Biol. 2012 757:497-507; Peer 2010 J Control Release. 20:63-68; Peer et al., Proc Natl Acad Sci USA. 2007 104:4095-4100; Kim et al., Methods Mol Biol. 2011 721:339-353; Subramanya et al., Mol Ther. 2010 18:2028-2037; Song et al., Nat Biotechnol. 2005 23:709-717; Peer et al., Science. 2008 319:627-630; and Peer and Lieberman, Gene Ther. 2011 18:1127-1133.

In some embodiments, LNPs are selected for tissue-specific activity by the addition of a Selective ORgan Targeting (SORT) molecule to a formulation comprising traditional components, such as ionizable cationic lipids, amphipathic phospholipids, cholesterol and poly(ethylene glycol) (PEG) lipids. The teachings of Cheng et al. Nat Nanotechnol 15(4):313-320 (2020) demonstrate that the addition of a supplemental “SORT” component precisely alters the in vivo RNA delivery profile and mediates tissue-specific (e.g., lungs, liver, spleen) gene delivery and editing as a function of the percentage and biophysical property of the SORT molecule.

In some embodiments, the LNPs comprise biodegradable, ionizable lipids. In some embodiments, the LNPs comprise (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-dienoate, also called 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z,12Z)-octadeca-9,12-dienoate) or another ionizable lipid. See, e.g, lipids of WO2019/067992, WO/2017/173054, WO2015/095340, and WO2014/136086, as well as references provided therein. In some embodiments, the term cationic and ionizable in the context of LNP lipids is interchangeable, e.g., wherein ionizable lipids are cationic depending on the pH.

In some embodiments, the average LNP diameter of the LNP formulation may be between 10s of nm and 100s of nm, e.g., measured by dynamic light scattering (DLS). In some embodiments, the average LNP diameter of the LNP formulation may be from about 40 nm to about 150 nm, such as about 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, or 150 nm. In some embodiments, the average LNP diameter of the LNP formulation may be from about 50 nm to about 100 nm, from about 50 nm to about 90 nm, from about 50 nm to about 80 nm, from about 50 nm to about 70 nm, from about 50 nm to about 60 nm, from about 60 nm to about 100 nm, from about 60 nm to about 90 nm, from about 60 nm to about 80 nm, from about 60 nm to about 70 nm, from about 70 nm to about 100 nm, from about 70 nm to about 90 nm, from about 70 nm to about 80 nm, from about 80 nm to about 100 nm, from about 80 nm to about 90 nm, or from about 90 nm to about 100 nm. In some embodiments, the average LNP diameter of the LNP formulation may be from about 70 nm to about 100 nm. In a particular embodiment, the average LNP diameter of the LNP formulation may be about 80 nm. In some embodiments, the average LNP diameter of the LNP formulation may be about 100 nm. In some embodiments, the average LNP diameter of the LNP formulation ranges from about 1 mm to about 500 mm, from about 5 mm to about 200 mm, from about 10 mm to about 100 mm, from about 20 mm to about 80 mm, from about 25 mm to about 60 mm, from about 30 mm to about 55 mm, from about 35 mm to about 50 mm, or from about 38 mm to about 42 mm.

A LNP may, in some instances, be relatively homogenous. A polydispersity index may be used to indicate the homogeneity of a LNP, e.g., the particle size distribution of the lipid nanoparticles. A small (e.g., less than 0.3) polydispersity index generally indicates a narrow particle size distribution. A LNP may have a polydispersity index from about 0 to about 0.25, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, or 0.25. In some embodiments, the polydispersity index of a LNP may be from about 0.10 to about 0.20.

The zeta potential of a LNP may be used to indicate the electrokinetic potential of the composition. In some embodiments, the zeta potential may describe the surface charge of an LNP. Lipid nanoparticles with relatively low charges, positive or negative, are generally desirable, as more highly charged species may interact undesirably with cells, tissues, and other elements in the body. In some embodiments, the zeta potential of a LNP may be from about −10 mV to about +20 mV, from about −10 mV to about +15 mV, from about −10 mV to about +10 mV, from about −10 mV to about +5 mV, from about −10 mV to about 0 mV, from about −10 mV to about −5 mV, from about −5 mV to about +20 mV, from about −5 mV to about +15 mV, from about −5 mV to about +10 mV, from about −5 mV to about +5 mV, from about −5 mV to about 0 mV, from about 0 mV to about +20 mV, from about 0 mV to about +15 mV, from about 0 mV to about +10 mV, from about 0 mV to about +5 mV, from about +5 mV to about +20 mV, from about +5 mV to about +15 mV, or from about +5 mV to about +10 mV.

The efficiency of encapsulation of a TREM describes the amount of TREM that is encapsulated or otherwise associated with a LNP after preparation, relative to the initial amount provided. The encapsulation efficiency is desirably high (e.g., close to 100%). The encapsulation efficiency may be measured, for example, by comparing the amount of TREM in a solution containing the lipid nanoparticle before and after breaking up the lipid nanoparticle with one or more organic solvents or detergents. An anion exchange resin may be used to measure the amount of free protein or nucleic acid (e.g., RNA) in a solution. Fluorescence may be used to measure the amount of free TREM in a solution. For the lipid nanoparticles described herein, the encapsulation efficiency of a TREM may be at least 50%, for example 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the encapsulation efficiency may be at least 80%. In some embodiments, the encapsulation efficiency may be at least 90%. In some embodiments, the encapsulation efficiency may be at least 95%.

A LNP may optionally comprise one or more coatings. In some embodiments, a LNP may be formulated in a capsule, film, or table having a coating. A capsule, film, or tablet including a composition described herein may have any useful size, tensile strength, hardness or density.

Additional exemplary lipids, formulations, methods, and characterization of LNPs are taught by WO2020061457, which is incorporated herein by reference in its entirety.

In some embodiments, in vitro or ex vivo cell lipofections are performed using Lipofectamine MessengerMax (Thermo Fisher) or TransIT-mRNA Transfection Reagent (Mirus Bio). In certain embodiments, LNPs are formulated using the GenVoy_ILM ionizable lipid mix (Precision NanoSystems). In certain embodiments, LNPs are formulated using 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA) or dilinoleylmethyl-4-dimethylaminobutyrate (DLin-MC3-DMA or MC3), the formulation and in vivo use of which are taught in Jayaraman et al. Angew Chem Int Ed Engl 51(34):8529-8533 (2012), incorporated herein by reference in its entirety.

LNP formulations optimized for the delivery of CRISPR-Cas systems, e.g., Cas9-gRNA RNP, gRNA, Cas9 mRNA, are described in WO2019067992 and WO2019067910, both incorporated by reference.

Additional specific LNP formulations useful for delivery of nucleic acids are described in U.S. Pat. Nos. 8,158,601 and 8,168,775, both incorporated by reference, which include formulations used in patisiran, sold under the name ONPATTRO.

Exosomes can also be used as drug delivery vehicles for the TREM, TREM core fragment, TREM fragment, or TREM compositions or pharmaceutical TREM composition described herein. For a review, see Ha et al. July 2016. Acta Pharmaceutica Sinica B. Volume 6, Issue 4, Pages 287-296; https://doi.org/10.1016/j.apsb.2016.02.001.

Ex vivo differentiated red blood cells can also be used as a carrier for a TREM, TREM core fragment, TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein. See, e.g., WO2015073587; WO2017123646; WO2017123644; WO2018102740; WO2016183482; WO2015153102; WO2018151829; WO2018009838; Shi et al. 2014. Proc Natl Acad Sci USA. 111(28): 10131-10136; U.S. Pat. No. 9,644,180; Huang et al. 2017. Nature Communications 8: 423; Shi et al. 2014. Proc Natl Acad Sci USA. 111(28): 10131-10136.

Fusosome compositions, e.g., as described in WO2018208728, can also be used as carriers to deliver the TREM, TREM core fragment, TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein.

Virosomes and virus-like particles (VLPs) can also be used as carriers to deliver a TREM, TREM core fragment, TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein to targeted cells.

Plant nanovesicles, e.g., as described in WO2011097480A1, WO2013070324A1, or WO2017004526A1 can also be used as carriers to deliver the TREM, TREM core fragment, TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein.

Delivery without a Carrier

A TREM, a TREM core fragment or a TREM fragment, a TREM composition or a pharmaceutical TREM composition described herein can be administered to a cell without a carrier, e.g., via naked delivery of the TREM, a TREM core fragment or a TREM fragment, a TREM composition or a pharmaceutical TREM composition.

In some embodiments, naked delivery as used herein refers to delivery without a carrier. In some embodiments, delivery without a carrier, e.g., naked delivery, comprises delivery with a moiety, e.g., a targeting peptide.

In some embodiments, a TREM, a TREM core fragment or a TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein is delivered to a cell without a carrier, e.g., via naked delivery. In some embodiments, the delivery without a carrier, e.g., naked delivery, comprises delivery with a moiety, e.g., a targeting peptide.

ENUMERATED EMBODIMENTS

1. A TREM comprising a sequence of Formula A:

[L1]-[ASt Domain1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain2],

wherein:

- independently, [L1] and [VL Domain], are optional;
- one of [L1], [ASt Domain1], [L2]-[DH Domain], [L3], [ACH Domain], [VL Domain], [TH Domain], [L4], and [ASt Domain2] comprises a nucleotide having a non-naturally occurring modification; and

wherein:

- (a) the TREM retains the ability to: support protein synthesis, be charged by a synthetase, be bound by an elongation factor, introduce an amino acid into a peptide chain, support elongation, or support initiation;
- (b) the TREM comprises at least X contiguous nucleotides without a non-naturally occurring modification, wherein X is greater than 10;
- (c) at least 3, but less than all of the nucleotides of a type (e.g., A, T, C, G or U) comprise the same non-naturally occurring modification;
- (d) at least X nucleotides of a type (e.g., A, T, C, G or U) do not comprise a non-naturally occurring modification, wherein X=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50;
- (e) no more than 5, 10, or 15 nucleotides of a type (e.g., A, T, C, G or U) comprise a non-naturally occurring modification; and/or
- (f) no more than 5, 10, or 15 nucleotides of a type (e.g., A, T, C, G or U) do not comprise a non-naturally occurring modification.
  
  2. The TREM of embodiment 1, comprising the feature provided in embodiment 1(a).
  
  3. The TREM of embodiment 1, comprising the feature provided in embodiment 1(b).
  
  4. The TREM of embodiment 1, comprising the feature provided in embodiment 1(c).
  
  5. The TREM of embodiment 1, comprising the feature provided in embodiment 1(d).
  
  6. The TREM of embodiment 1, comprising the feature provided in embodiment 1(e).
  
  7. The TREM of embodiment 1, comprising the feature provided in embodiment 1(f).
  
  8. The TREM of embodiment 1, comprising all of the features provided in embodiments 1(a)-(f).
  
  9. The TREM of any one of embodiments 1-8, wherein the Domain comprising the non-naturally occurring modification retains a function, e.g., a domain function described herein.
  
  10. The TREM of any one of embodiments 1-8, comprising an [L1].
  
  11. The TREM of any one of embodiments 1-8, comprising a [VL Domain].
  
  12. The TREM of any one of embodiments 1-8, wherein: [L1] is a linker comprising a nucleotide having a non-naturally occurring modification.
  
  13. The TREM of any one of embodiments 1-8, wherein [ASt Domain1 (AstD1)] comprises a nucleotide having a non-naturally occurring modification.
  
  14. The TREM of any one of embodiments 1-8, wherein [L2] is a linker comprising a nucleotide having a non-naturally occurring modification.
  
  15. The TREM of any one of embodiments 1-8, wherein [DH Domain (DHD)] comprises a nucleotide having a non-naturally occurring modification.
  
  16. The TREM of any one of embodiments 1-8, wherein [L3] is a linker comprising a nucleotide having a non-naturally occurring modification.
  
  17. The TREM of any one of embodiments 1-8, wherein [ACH Domain (ACHD)] comprises a nucleotide having a non-naturally occurring modification.
  
  18. The TREM of any one of embodiments 1-8, wherein [VL Domain (VLD)] comprises a nucleotide having a non-naturally occurring modification.
  
  19. The TREM of any one of embodiments 1-8, wherein [TH Domain (THD)] comprises a nucleotide having a non-naturally occurring modification.
  
  20. The TREM of any one of embodiments 1-8, wherein [L4] is a linker comprises a nucleotide having a non-naturally occurring modification.
  
  21. The TREM of any one of embodiments 1-8, wherein: [ASt Domain2 (AStD2)] comprises a nucleotide having a non-naturally occurring modification.
  
  22. A TREM core fragment comprising a sequence of Formula B:

[L1]_y-[ASt Domain1]_x-[L2]_y-[DH Domain]_y-[L3]_y-[ACH Domain]_x-[VL Domain]_y-[TH Domain]_y-[L4]_y-[ASt Domain2],

wherein:

x=1 and y=0 or 1;

one of [ASt Domain1], [ACH Domain], and [ASt Domain2] comprises a nucleotide having a non-naturally occurring modification; and

the TREM retains the ability to: support protein synthesis; be able to be charged by a synthetase, be bound by an elongation factor, introduce an amino acid into a peptide chain, support elongation, or support initiation.

23. The TREM core fragment of embodiment 22, wherein AStD1 and AStD2 comprise an ASt Domain (AStD).

24. The TREM core fragment of embodiment 22, wherein the [ASt Domain 1], and/or [ASt Domain 2] comprising the non-naturally occurring modification retains the ability to initiate or elongate a polypeptide chain.

25. The TREM core fragment of embodiment 22, wherein the [ACH Domain] comprising the non-naturally occurring modification retains the ability to mediate pairing with a codon.

26. The TREM core fragment of embodiment 22, wherein y=1 for any one, two, three, four, five, six, all or a combination of [L1], [L2], [DH Domain], [L3], [VL Domain], [TH Domain], [L4].

27. The TREM core fragment of embodiment 22, wherein y=0 for any one, two, three, four, five, six, all or a combination of [L1], [L2], [DH Domain], [L3], [VL Domain], [TH Domain], [L4].

28. The TREM core fragment of embodiment 22, wherein y=1 for linker [L1], and L1 comprises a nucleotide having a non-naturally occurring modification.

29. The TREM core fragment of embodiment 22, wherein y=1 for linker [L2], and L2 comprises a nucleotide having a non-naturally occurring modification.

30. The TREM core fragment of embodiment 22, wherein y=1 for [DH Domain (DHD)], and DHD comprises a nucleotide having a non-naturally occurring modification.

31. The TREM core fragment of embodiment 30, wherein the DHD comprising the non-naturally occurring modification retains the ability to mediate recognition of aminoacyl-tRNA synthetase.

32. The TREM core fragment of embodiment 22, wherein y=1 for linker [L3], and L3 comprises a nucleotide having a non-naturally occurring modification.

33. The TREM core fragment of embodiment 22, wherein y=1 for [VL Domain (VLD)], and VLD comprises a nucleotide having a non-naturally occurring modification.

34. The TREM core fragment of embodiment 22, wherein y=1 for [TH Domain (THD)], and THD comprises a nucleotide having a non-naturally occurring modification.

35. The TREM core fragment of embodiment 34, wherein the THD comprising the non-naturally occurring modification retains the ability to mediate recognition of the ribosome.

36. The TREM core fragment of embodiment 22, wherein y=1 for linker [L4], and L4 comprises a nucleotide having a non-naturally occurring modification.

37. A TREM fragment comprising a portion of a TREM, wherein the TREM comprises a sequence of Formula A:

[L1]-[ASt Domain1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain2], and wherein:

the TREM fragment comprises:

a non-naturally occurring modification; and

one, two, three or all or any combination of the following:

- (a) a TREM half (e.g., from a cleavage in the ACH Domain, e.g., in the anticodon sequence, e.g., a 5′half or a 3′ half);
- (b) a 5′ fragment (e.g., a fragment comprising the 5′ end, e.g., from a cleavage in a DH Domain or the ACH Domain);
- (c) a 3′ fragment (e.g., a fragment comprising the 3′ end, e.g., from a cleavage in the TH Domain); or
- (d) an internal fragment (e.g., from a cleavage in any one of the ACH Domain, DH Domain or TH Domain).
  
  38. The TREM of embodiment 37, wherein the TREM fragment comprise (a) a TREM half which comprises a nucleotide having a non-naturally occurring modification.
  
  39. The TREM of embodiment 37, wherein the TREM fragment comprise (b) a 5′ fragment which comprises a nucleotide having a non-naturally occurring modification.
  
  40. The TREM of embodiment 37, wherein the TREM fragment comprise (c) a 3′ fragment which comprises a nucleotide having a non-naturally occurring modification.
  
  41. The TREM of embodiment 37, wherein the TREM fragment comprise (d) an internal fragment which comprises a nucleotide having a non-naturally occurring modification.
  
  42. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM Domain comprises a plurality of nucleotides each having a non-naturally occurring modification.
  
  43. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of AStD1 have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6 or 7.
  
  44. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein no more than X of the nucleotides of AStD1 have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6 or 7.
  
  45. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of AStD2 have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6 or 7.
  
  46. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein no more than X of the nucleotides of AStD2 have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6 or 7.
  
  47. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of ACHD have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  
  48. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of ACHD have a non-naturally occurring modification, wherein X is equal to or greater than 11, 12, 13, 14, 15, 16, or 17.
  
  49. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein no more than X of the nucleotides of ACHD have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  
  50. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein no more than X of the nucleotides of ACHD have a non-naturally occurring modification, wherein X is equal to or greater than 11, 12, 13, 14, 15, or 16.
  
  51. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of THD have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  
  52. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of THD have a non-naturally occurring modification, wherein X is equal to or greater than 11, 12, 13, 14, 15, 16, or 17.
  
  53. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein no more than X of the nucleotides of THD have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  
  54. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein no more than X of the nucleotides of THD have a non-naturally occurring modification, wherein X is equal to or greater than 11, 12, 13, 14, 15, or 16.
  
  55. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of DHD have a non-naturally occurring modification, wherein X is equal to or greater than 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  
  56. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of DHD have a non-naturally occurring modification, wherein X is equal to or greater than 11, 12, 13, 14, 15, 16, 17, 18 or 19.
  
  57. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein no more than X of the nucleotides of DHD have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  
  58. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein no more than X of the nucleotides of DHD have a non-naturally occurring modification, wherein X is equal to or greater than 11, 12, 13, 14, 15, 16, 17, or 18.
  
  59. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of the VLD have a non-naturally occurring modification, wherein X is equal to or greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 50, 100, 150, 200 or 271.
  
  60. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein all of the nucleotides of the AStD1, AStD2, ACHD, DHD, and/or THD have a non-naturally occurring modification.
  
  61. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of AStD1 and/or AStD2 do not have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6 or 7.
  
  62. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of ACHD do not have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17.
  
  63. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of THD do not have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17.
  
  64. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of DHD do not have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19.
  
  65. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of VLD do not have a non-naturally occurring modification, wherein X is equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 50, 100, 150, 200 or 271.
  
  66. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM Linker L2 comprises two nucleotides each having a non-naturally occurring modification.
  
  67. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X of the nucleotides of the TREM Linker do not have a non-naturally occurring modification, wherein X is equal to 1 or 2.
  
  68. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein:

each of a plurality of TREM Domains and Linkers comprises a nucleotide having a non-naturally occurring modification.

69. The TREM, TREM core fragment or TREM fragment of embodiment 68, wherein one of the TREM Domains and Linkers of the plurality comprises a plurality of nucleotides each having a non-naturally occurring modification.

70. The TREM, TREM core fragment or TREM fragment of any of the preceding embodiments, wherein the non-naturally occurring modification is a modification in a base or a backbone of a nucleotide, e.g., a modification chosen from any one of Tables 5-9.

71. The TREM, TREM core fragment or TREM fragment of any of the preceding embodiments, wherein the non-naturally occurring modification is a base modification chosen from a modification listed in Table 10.

72. The TREM, TREM core fragment or TREM fragment of any of the preceding embodiments, wherein the non-naturally occurring modification is a base modification chosen from a modification listed in Table 11.

73. The TREM, TREM core fragment or TREM fragment of any of the preceding embodiments, wherein the non-naturally occurring modification is a base modification chosen from a modification listed in Table 12.

74. The TREM, TREM core fragment or TREM fragment of any of the preceding embodiments, wherein the non-naturally occurring modification is a backbone base modification chosen from a modification listed in Table 13.

75. The TREM, TREM core fragment or TREM fragment of any of the preceding embodiments, wherein the non-naturally occurring modification is a backbone modification chosen from a modification listed in Table 14.

76. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, comprising a nucleotide of a first type comprising a non-naturally occurring modification.

77. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, comprising a nucleotide of a first type and a nucleotide of a second type comprising a non-naturally occurring modification.

78. The TREM, TREM core fragment or TREM fragment of embodiment 77, wherein the non-naturally occurring modification on the nucleotide of the first type and the non-naturally occurring modification on the nucleotide of the second type are the same non-naturally occurring modification.

79. The TREM, TREM core fragment or TREM fragment of embodiment 77, wherein the non-naturally occurring modification on the nucleotide of the first type and the non-naturally occurring modification on the nucleotide of the second type are different non-naturally occurring modifications.

80. The TREM, TREM core fragment or TREM fragment of embodiments 76 or 77, wherein the nucleotide of the first type is chosen from: A, T, C, G or U.

81. The TREM, TREM core fragment or TREM fragment of embodiments 76 or 77, wherein the nucleotide of the second type is chosen from: A, T, C, G or U.

82. The TREM, TREM core fragment or TREM fragment of embodiments 76 or 77, wherein the nucleotide of the first type is an A.

83. The TREM, TREM core fragment or TREM fragment of embodiments 76 or 77, wherein the nucleotide of the first type is a G.

84. The TREM, TREM core fragment or TREM fragment of embodiments 76 or 77, wherein the nucleotide of the first type is a C.

85. The TREM core fragment or TREM fragment of embodiments 76 or 77, wherein the nucleotide of the first type is a T.

86. The TREM, TREM core fragment or TREM fragment of embodiments 76 or 77, wherein the nucleotide of the first type is a U.

87. The TREM, TREM core fragment or TREM fragment of embodiment 77, wherein when the nucleotide of the first type is an A, the nucleotide of the second type is chosen from: T, C, G or U.

88. The TREM, TREM core fragment or TREM fragment of embodiment 77, wherein when the nucleotide of the first type is a G, the nucleotide of the second type is chosen from: T, C, A or U.

89. The TREM, TREM core fragment or TREM fragment of embodiment 77, wherein when the nucleotide of the first type is a C, the nucleotide of the second type is chosen from: T, A, G or U.

90. The TREM, TREM core fragment or TREM fragment of embodiment 77, wherein when the nucleotide of the first type is a T, the nucleotide of the second type is chosen from: A, C, G or U.

91. The TREM, TREM core fragment or TREM fragment of embodiment 77, wherein when the nucleotide of the first type is a U, the nucleotide of the second type is chosen from: T, C, G or A.

92. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the non-naturally modification is in a purine (A or G).

93. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the non-naturally modification is not in a purine (A or G).

94. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the non-naturally modification is in a pyrimidine (U, T or C).

95. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the non-naturally modification is not in a pyrimidine (U, T or C).

96. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the DHD has a first sequence, a second sequence and a third sequence, optionally wherein the first sequence and the third sequence form a stem and the second sequence forms a loop, e.g., under physiological conditions.

97. The TREM, TREM core fragment or TREM fragment of embodiment 96, wherein the DHD comprises a non-naturally occurring modification in the first sequence or the third sequence, e.g., in the stem.

98. The TREM, TREM core fragment or TREM fragment of embodiment 96, wherein the DHD comprises a non-naturally occurring modification in the second sequence, e.g., in the loop.

100. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the ACHD has a first sequence, a second sequence and a third sequence, optionally wherein the first sequence and the third sequence form a stem and the second sequence forms a loop, e.g., under physiological conditions.

101. The TREM, TREM core fragment or TREM fragment of embodiment 100, wherein the ACHD comprises a non-naturally occurring modification in the first sequence or the third sequence, e.g., in the stem.

102. The TREM, TREM core fragment or TREM fragment of embodiment 100, wherein the ACHD comprises a non-naturally occurring modification in the second sequence, e.g., in the loop.

103. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the THD has a first sequence, a second sequence and a third sequence, optionally wherein the first sequence and the third sequence form a stem and the second sequence forms a loop, e.g., under physiological conditions.

104. The TREM, TREM core fragment or TREM fragment of embodiment 103, wherein the THD comprises a non-naturally occurring modification in the first sequence or the third sequence, e.g., in the stem.

105. The TREM, TREM core fragment or TREM fragment of embodiment 103, wherein the THD comprises a non-naturally occurring modification in the second sequence, e.g., in the loop.

106. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the VLD comprises a variable region having 1-271 nucleotides.

107. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM comprises at least X contiguous nucleotides without a non-naturally occurring modification, wherein X is greater than 10.

108. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least 3, but less than all of the nucleotides of a type (e.g., A, T, C, G or U) comprise the same non-naturally occurring modification.

109. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein at least X nucleotides of a type (e.g., A, T, C, G or U) do not comprise a non-naturally occurring modification, wherein X=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50.

110. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein no more than 5, 10, or 15 of a type (e.g., A, T, C, G or U) comprise a non-naturally occurring modification.

111. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein no more than 5, 10, or 15 of a type (e.g., A, T, C, G or U) do not comprise a non-naturally occurring modification.

112. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, which specifies X, wherein X is an amino acid selected from alanine, arginine, asparagine, aspartate, cysteine, glutamine, glutamate, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

113. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, which recognizes a codon provided in Table 7 or Table 8.

114. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM is a cognate TREM.

115. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM is a non-cognate TREM.

116. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM, TREM core fragment, or TREM fragment is encoded by a sequence provided in Table 9, e.g., any one of SEQ ID NOs 1-451.

117. The TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM, TREM core fragment, or TREM fragment is encoded by a consensus sequence chosen from any one of SEQ ID NOs: 562-621.

118. A pharmaceutical composition comprising a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37.

119. The pharmaceutical composition of embodiment 118, comprising a pharmaceutically acceptable component, e.g., an excipient.

120. A method of making a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, comprising linking a first nucleotide to a second nucleotide to form the TREM.

121. The method of embodiment 120, wherein the TREM, TREM core fragment or TREM fragment is synthetic.

122. The method of embodiment 120 or 121, wherein the synthesis is performed in vitro.

123. The method of embodiment 120, wherein the TREM, TREM core fragment or TREM fragment is made by cell-free solid phase synthesis.

124. A cell comprising a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37.

125. A cell comprising a TREM, TREM core fragment or TREM fragment made according to the method of embodiment 120.

126. A method of modulating a tRNA pool in a cell comprising an endogenous open reading frame (ORF), which ORF comprises a codon having a first sequence, comprising:

optionally, acquiring knowledge of the abundance of one or both of (i) and (ii), e.g., acquiring knowledge of the relative amounts of: (i) and (ii) in the cell, wherein (i) is a tRNA moiety having an anticodon that pairs with the codon of the ORF having a first sequence (the first tRNA moiety) and (ii) is an isoacceptor tRNA moiety having an anticodon that pairs with a codon other than the codon having the first sequence (the second tRNA moiety) in the cell;

contacting the cell with a TREM composition comprising a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with: (a) the codon having the first sequence; or (b) the codon other than the codon having the first sequence, in an amount and/or for a time sufficient to modulate the relative amounts of the first tRNA moiety and the second tRNA moiety in the cell,

thereby modulating the tRNA pool in the cell.

127. A method of modulating a tRNA pool in a subject having an endogenous open reading frame (ORF), which ORF comprises a codon having a first sequence, comprising:

optionally, acquiring knowledge of the abundance of one or both of (i) and (ii), e.g., acquiring knowledge of the relative amounts of: (i) and (ii) in the subject, wherein (i) is a tRNA moiety having an anticodon that pairs with the codon of the ORF having a first sequence (the first tRNA moiety) and (ii) is an isoacceptor tRNA moiety having an anticodon that pairs with a codon other than the codon having the first sequence (the second tRNA moiety) in the subject;

contacting the subject with a TREM composition comprising a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with: (a) the codon having the first sequence; or (b) the codon other than the codon having the first sequence, in an amount and/or for a time sufficient to modulate the relative amounts of the first tRNA moiety and the second tRNA moiety in the subject,

thereby modulating the tRNA pool in the subject.

128. The method of embodiment 126 or 127, wherein the TREM composition comprises a TREM, TREM fragment or TREM core fragment comprising an anticodon that pairs with (a).

129. The method of embodiment 126 or 127, wherein the TREM composition comprises a TREM, TREM fragment or TREM core fragment comprising an anticodon that pairs with (b).

130. The method of any one of embodiments 126-129, comprising acquiring knowledge of (i).

131. The method of any one of embodiments 126-129, comprising acquiring knowledge of (ii).

132. The method of any one of embodiments 126-129, comprising acquiring knowledge of (i) and (ii).

133. The method of any one of embodiments 126-130 or 132, wherein acquiring knowledge of (i) comprises acquiring a value for the abundance, e.g., relative amounts, of (i).

134. The method of any one of embodiments 126-129 or 131-312, wherein acquiring knowledge of (ii) comprises acquiring a value for the abundance, e.g., relative amounts, of (ii).

135. The method of embodiment 133 or 134, wherein responsive to said value, the cell or subject is contacted with the TREM composition comprising a TREM, TREM fragment or TREM core fragment having an anticodon that pairs with (a) or (b).

136. A method of evaluating a tRNA pool in a cell or subject, comprising acquiring, e.g., directly or indirectly acquiring, knowledge of the abundance of one or both of (i) and (ii), e.g., acquiring knowledge of the relative amounts of (i) and (ii) in the cell wherein (i) is a tRNA moiety having an anticodon that pairs with the codon of the ORF having a first sequence (the first tRNA moiety) and (ii) is an isoacceptor tRNA moiety having an anticodon that pairs with a codon other than the codon having the first sequence (the second tRNA moiety) in the cell, thereby evaluating the tRNA pool in the cell or subject.

137. A method of modulating a production parameter of an RNA corresponding to, or polypeptide encoded by, a nucleic acid sequence comprising an endogenous open reading frame (ORF) in a cell, which ORF comprises a codon having a first sequence, comprising:

contacting the cell with a TREM composition comprising a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37 in an amount and/or for a time sufficient to modulate the production parameter of the mRNA or polypeptide,

wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence,

thereby modulating the production parameter in the cell.

138. A method of modulating a production parameter of an RNA corresponding to, or polypeptide encoded by, a nucleic acid sequence comprising an endogenous open reading frame (ORF) in a subject, which ORF comprises a codon having a first sequence, comprising:

contacting the subject with a TREM composition comprising a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37 in an amount and/or for a time sufficient to modulate the production parameter of the mRNA or polypeptide,

wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence,

thereby modulating the production parameter in the subject.

139. The method of embodiment 137 or 138, wherein the production parameter comprises a signaling parameter, e.g., as described herein.

140. The method of embodiment 137 or 138, wherein the production parameter comprises an expression parameter, e.g., as described herein.

141. A method of modulating expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a codon having a first sequence, comprising:

wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence,

thereby modulating expression of the protein in the cell.

142. A method of modulating expression of a protein in a subject, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a codon having a first sequence, comprising:

contacting the subject with a TREM composition comprising a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, in an amount and/or for a time sufficient to modulate expression of the encoded protein,

wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence,

thereby modulating expression of the protein in the subject.

143. A method of treating a subject having an endogenous open reading frame (ORF) which comprises a codon having a first sequence, comprising:

- providing a TREM composition comprising a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM comprises a tRNA moiety having: an anticodon that pairs with the codon of the ORF having the first sequence;
- contacting the subject with the composition comprising a TREM, TREM core fragment or TREM fragment in an amount and/or for a time sufficient to treat the subject, thereby treating the subject.
  
  144. A method of treating a subject having an endogenous open reading frame (ORF) comprising a codon having a first sequence, comprising:

(i) acquiring, e.g., directly or indirectly acquiring, a value for the status of the codon having the first sequence in the subject, wherein said value comprises a measure of the presence or absence of the codon having the first sequence in a sample from the subject; and identifying the subject as having the codon having the first sequence; and

(ii) responsive to said value, administering a TREM composition comprising a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM, TREM core fragment or TREM fragment comprises a tRNA moiety having an anticodon that pairs with the codon having the first sequence, to the subject, thereby treating the subject.

145. A method of evaluating a subject having an endogenous open reading frame (ORF) comprising a codon having a first sequence, comprising:

acquiring, e.g., directly or indirectly acquiring, a value for the status of the codon having the first sequence in the subject, wherein said value comprises a measure of the presence or absence of the codon having the first sequence in a sample from the subject; and

identifying the subject as having a codon having the first sequence,

thereby evaluating the subject.

146. The method of claim 145, wherein responsive to said value the method further comprises administering a TREM composition comprising a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM, TREM core fragment or TREM fragment comprises a tRNA moiety having an anticodon that pairs with the codon having the first sequence, to the subject.

147. A method of modulating a production parameter of an RNA corresponding to, or polypeptide encoded by, a nucleic acid sequence comprising an endogenous open reading frame (ORF) in a cell, which ORF comprises a premature termination codon (PTC),

wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence,

thereby modulating the production parameter in the cell.

148. A method of modulating a production parameter of an RNA corresponding to, or polypeptide encoded by, a nucleic acid sequence comprising an endogenous open reading frame (ORF) in a subject, which ORF comprises a premature termination codon (PTC),

wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence,

thereby modulating the production parameter in the subject.

149. The method of embodiment 147 or 148, wherein the production parameter comprises a signaling parameter and/or an expression parameter, e.g., as described herein.

150. A method of treating a subject having an endogenous open reading frame (ORF) which comprises a premature termination codon (PTC), comprising:

providing a TREM composition comprising a TREM of any one of embodiments 1-8, the TREM core fragment of embodiment 22, or the TREM fragment of embodiment 37, wherein the TREM comprises a tRNA moiety having an anticodon that pairs with the PTC in the ORF;

contacting the subject with the composition comprising a TREM, TREM core fragment or TREM fragment in an amount and/or for a time sufficient to treat the subject,

thereby treating the subject.

151. The method of embodiment 150, wherein the PTC comprises UAA, UGA or UAG.

152. A method of modulating expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a premature termination codon (PTC), comprising:

wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the PTC,

thereby modulating expression of the protein in the cell.

153. The method of embodiment 152, wherein the PTC comprises UAA, UGA or UAG.

154. A method of modulating expression of a protein in a subject, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a premature termination codon (PTC), comprising:

wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the PTC,

thereby modulating expression of the protein in the subject.

155. The method of embodiment 154, wherein the PTC comprises UAA, UGA or UAG.

156. The method of any one of embodiments 126-146, wherein the codon having the first sequence comprises a mutation (e.g., a point mutation, e.g., a nonsense mutation), resulting in a premature termination codon (PTC) chosen from UAA, UGA or UAG.

157. The method of any one of embodiments 126-156, wherein the codon having the first sequence or the PTC comprises a UAA mutation.

158. The method of any one of embodiments 126-156, wherein the codon having the first sequence or the PTC comprises a UGA mutation.

159. The method of any one of embodiments 126-156, wherein the codon having the first sequence or the PTC comprises a UAG mutation.

160. The method of any one of embodiments 126-159, wherein the TREM comprises an anticodon that pairs with a stop codon, e.g., a stop codon chosen from UAA, UGA or UAG.

161. The method of any one of embodiments 126-160, wherein the codon having the first sequence or the PTC comprises a UAA mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid which preserves, e.g., maintains, a secondary and/or tertiary structure of a polypeptide encoded by the ORF into which the amino acid is incorporated.

162. The method of any one of embodiments 126-160, wherein the codon having the first sequence or the PTC comprises a UAG mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid which preserves, e.g., maintains, a secondary and/or tertiary structure of a polypeptide encoded by the ORF into which the amino acid is incorporated.

163. The method of any one of embodiments 126-160, wherein the codon having the first sequence or the PTC comprises a UGA mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid which preserves, e.g., maintains, a secondary and/or tertiary structure of a polypeptide encoded by the ORF into which the amino acid is incorporated.

164. The method of any one of embodiments 126-160, wherein the codon having the first sequence or the PTC comprises a UAA mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid which maintains a property, e.g., function, of a polypeptide encoded by the ORF into which the amino acid is incorporated.

165. The method of any one of embodiments 126-160, wherein the codon having the first sequence or the PTC comprises a UAG mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid which maintains a property, e.g., function, of a polypeptide encoded by the ORF into which the amino acid is incorporated.

166. The method of any one of embodiments 126-160, wherein the codon having the first sequence or the PTC comprises a UGA mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid which maintains a property, e.g., function, of a polypeptide encoded by the ORF into which the amino acid is incorporated.

167. The method of any one of embodiments 161-166, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of any one of the twenty amino acids listed in Table 2 or Table 8.

168. The method of any one of embodiments 161-167, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid corresponding to a non-mutated codon, e.g., a wildtype codon sequence of the codon having the first sequence or the PTC.

169. The method of any one of embodiments 161-168, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of a pre-mutation, e.g., wildtype amino acid.

170. The method of embodiment 169, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid having a similar property as the pre-mutation, e.g., wildtype amino acid, e.g., an amino acid that belongs to the same group as the pre-mutation amino acid, e.g., as provided in Table 2.

171. The method of embodiment 169 or 170, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid that belongs to the same group as the pre-mutation amino acid, e.g., as provided in Table 2.

172. The method of embodiment 171, wherein when the pre-mutation, e.g., wildtype, amino acid is a nonpolar amino acid having an aliphatic R group, the TREM mediates incorporation of any one of the following amino acids: leucine, methionine, isoleucine, glycine, alanine or valine.

173. The method of embodiment 171, wherein when the pre-mutation, e.g., wildtype, amino acid is a polar amino acid having an uncharged R group, the TREM mediates incorporation of any one of the following amino acids: serine, threonine, cysteine, proline, asparagine, or glutamine.

174. The method of embodiment 171, wherein when the pre-mutation, e.g., wildtype, amino acid has a positively charged R group, the TREM mediates incorporation of any one of the following amino acids: lysine, arginine or histidine.

175. The method of embodiment 171, wherein when the pre-mutation, e.g., wildtype, amino acid has a negatively charged R group, the TREM mediates incorporation of any one of the following amino acids: aspartate or glutamate.

176. The method of embodiment 171, wherein when the pre-mutation, e.g., wildtype, amino acid is a nonpolar amino acid having an aromatic R group, the TREM mediates incorporation of any one of the following amino acids: phenylalanine, tyrosine or tryptophan.

177. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAA mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid which does not alter, e.g., maintains, a production parameter, e.g., an expression parameter and/or a signaling parameter, of an RNA corresponding to the ORF or a polypeptide encoded by the ORF.

178. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UGA mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid which does not alter, e.g., maintains, a production parameter, e.g., an expression parameter and/or a signaling parameter, of an RNA corresponding to the ORF or a polypeptide encoded by the ORF.

179. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAG mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid which does not alter, e.g., maintains, a production parameter, e.g., an expression parameter and/or a signaling parameter, of an RNA corresponding to the ORF or a polypeptide encoded by the ORF.

180. The method of any one of embodiments 177-179, wherein the production parameter is compared to an RNA corresponding to, or a polypeptide encoded by, an otherwise similar ORF having a pre-mutation, e.g., wildtype, amino acid incorporated at the position corresponding to the first sequence codon or PTC.

181. The method of any one of embodiments 177-180, wherein the production parameter comprises an expression parameter.

182. The method of embodiment 181, wherein the expression parameter comprises:

(a) protein translation;

(b) expression level (e.g., of polypeptide or protein, or mRNA);

(d) folding (e.g., of polypeptide or protein, or mRNA),

(e) structure (e.g., of polypeptide or protein, or mRNA),

(f) transduction (e.g., of polypeptide or protein),

(g) compartmentalization (e.g., of polypeptide or protein, or mRNA),

(h) incorporation (e.g., of polypeptide or protein, or mRNA) into a supermolecular structure, e.g., incorporation into a membrane, proteasome, or ribosome,

(i) incorporation into a multimeric polypeptide, e.g., a homo or heterodimer, and/or

(j) stability.

183. The method of any one of embodiments 177-180, wherein the production parameter comprises a signaling parameter.

184. The method of embodiment 183, wherein the signaling parameter comprises:

(1) modulation of a signaling pathway, e.g., a cellular signaling pathway which is downstream or upstream of the protein encoded by the endogenous ORF having a first sequence or PTC;

(2) cell fate modulation;

(3) ribosome occupancy modulation;

(4) protein translation modulation;

(5) mRNA stability modulation;

(6) protein folding and structure modulation;

(7) protein transduction or compartmentalization modulation; and/or

(8) protein stability modulation.

185. The method of any one of embodiments 177-184, wherein the production parameter (e.g., an expression parameter and/or a signaling parameter) may be modulated (e.g., increased), e.g., by at least 5% (e.g., at least 10%, 15%, 20%, 25%, 30%, 40%. 50%. 60%. 70%, 80%, 90%, 100%, 150%, 200% or more), e.g., compared to a reference sequence.

186. The method of any one of embodiments 177-185, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of any one of the twenty amino acids listed in Table 2 or Table 8.

187. The method of any one of embodiments 177-186, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid corresponding to a non-mutated codon, e.g., a wildtype codon sequence of the codon having the first sequence or the PTC.

188. The method of any one of embodiments 177-187, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of a pre-mutation, e.g., wildtype amino acid.

189. The method of embodiment 188, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid having a similar property as the pre-mutation, e.g., wildtype amino acid, e.g., an amino acid that belongs to the same group as the pre-mutation amino acid, e.g., as provided in Table 2.

190. The method of embodiment 188 or 189, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid that belongs to the same group as the pre-mutation amino acid, e.g., as provided in Table 2.

191. The method of embodiment 190, wherein when the pre-mutation, e.g., wildtype, amino acid is a nonpolar amino acid having an aliphatic R group, the TREM mediates incorporation of any one of the following amino acids: leucine, methionine, isoleucine, glycine, alanine or valine.

192. The method of embodiment 190, wherein when the pre-mutation, e.g., wildtype, amino acid is a polar amino acid having an uncharged R group, the TREM mediates incorporation of any one of the following amino acids: serine, threonine, cysteine, proline, asparagine, or glutamine.

193. The method of embodiment 190, wherein when the pre-mutation, e.g., wildtype, amino acid has a positively charged R group, the TREM mediates incorporation of any one of the following amino acids: lysine, arginine or histidine.

194. The method of embodiment 190, wherein when the pre-mutation, e.g., wildtype, amino acid has a negatively charged R group, the TREM mediates incorporation of any one of the following amino acids: aspartate or glutamate.

195. The method of embodiment 190, wherein when the pre-mutation, e.g., wildtype, amino acid is a nonpolar amino acid having an aromatic R group, the TREM mediates incorporation of any one of the following amino acids: phenylalanine, tyrosine or tryptophan.

196. The method of any one of embodiments 126-160, wherein the codon having the first sequence or the PTC comprises a UAA mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of any one of the 20 amino acids listed in Table 8 at the UAA stop codon.

197. The method of embodiment 196, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of the amino acid corresponding to a non-mutated codon, e.g., a wildtype codon sequence of the codon having the first sequence or the PTC.

198. The method of embodiment 196 or 197, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of a pre-mutation, e.g., wildtype amino acid.

199. The method of embodiment 198, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid having similar characteristics as the pre-mutation, e.g., wildtype amino acid, e.g., an amino acid that belongs to the same group as the pre-mutation amino acid, e.g., as provided in Table 2.

200. The method of embodiment 198 or 199, wherein when the pre-mutation, e.g., wildtype, amino acid is a nonpolar amino acid having an aliphatic R group, the TREM mediates incorporation of any one of the following amino acids: leucine, methionine, isoleucine, glycine, alanine or valine.

201. The method of embodiment 198 or 199, wherein when the pre-mutation, e.g., wildtype, amino acid is a polar amino acid having an uncharged R group, the TREM mediates incorporation of any one of the following amino acids: serine, threonine, cysteine, proline, asparagine, or glutamine.

202. The method of embodiment 198 or 199, wherein when the pre-mutation, e.g., wildtype, amino acid has a positively charged R group, the TREM mediates incorporation of any one of the following amino acids: lysine, arginine or histidine.

203. The method of embodiment 198 or 199, wherein when the pre-mutation, e.g., wildtype, amino acid has a negatively charged R group, the TREM mediates incorporation of any one of the following amino acids: aspartate or glutamate.

204. The method of embodiment 198 or 199, wherein when the pre-mutation, e.g., wildtype, amino acid is a nonpolar amino acid having an aromatic R group, the TREM mediates incorporation of any one of the following amino acids: phenylalanine, tyrosine or tryptophan.

205. The method of any one of embodiments 126-160, wherein the codon having the first sequence or the PTC comprises a UGA mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of any one of the 20 amino acids listed in Table 8 at the UGA stop codon.

206. The method of embodiment 205, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of the amino acid corresponding to a non-mutated, e.g., a wildtype codon sequence of the codon having the first sequence or the PTC.

207. The method of embodiment 206, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of a pre-mutation, e.g., wildtype, amino acid.

208. The method of embodiment 206 or 207, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid having similar characteristics as the pre-mutation, e.g., wildtype, amino acid, e.g., an amino acid that belongs to the same group as the pre-mutation amino acid as provided in Table 2.

209. The method of embodiment 206 or 207, wherein when the pre-mutation, e.g., wildtype, amino acid is a nonpolar amino acid having an aliphatic R group, the TREM mediates incorporation of any one of the following amino acids: leucine, methionine, isoleucine, glycine, alanine or valine.

210. The method of embodiment 206 or 207, wherein when the pre-mutation, e.g., wildtype, amino acid is a polar amino acid having an uncharged R group, the TREM mediates incorporation of any one of the following amino acids: serine, threonine, cysteine, proline, asparagine, or glutamine.

211. The method of embodiment 206 or 207, wherein when the pre-mutation, e.g., wildtype, amino acid has a positively charged R group, the TREM mediates incorporation of any one of the following amino acids: lysine, arginine or histidine.

212. The method of embodiment 206 or 207, wherein when the pre-mutation, e.g., wildtype, amino acid has a negatively charged R group, the TREM mediates incorporation of any one of the following amino acids: aspartate or glutamate.

213. The method of embodiment 206 or 207, wherein when the pre-mutation, e.g., wildtype, amino acid is a nonpolar amino acid having an aromatic R group, the TREM mediates incorporation of any one of the following amino acids: phenylalanine, tyrosine or tryptophan.

214. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAG mutation and the TREM, TREM core fragment or TREM fragment mediates incorporation of any one of the 20 amino acids listed in Table 8 at the UAG stop codon.

215. The method of embodiment 214, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of the amino acid corresponding to a non-mutated, e.g., a wildtype codon sequence of the codon having the first sequence or the PTC.

216. The method of embodiment 215, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of a pre-mutation, e.g., wildtype, amino acid.

217. The method of embodiment 216, wherein the TREM, TREM core fragment or TREM fragment mediates incorporation of an amino acid having similar characteristics as the pre-mutation, e.g., wildtype, amino acid, e.g., an amino acid that belongs to the same group as the pre-mutation amino acid, e.g., as provided in Table 2.

218. The method of embodiment 216 or 217, wherein when the pre-mutation, e.g., wildtype, amino acid is a nonpolar amino acid having an aliphatic R group, the TREM mediates incorporation of any one of the following amino acids: leucine, methionine, isoleucine, glycine, alanine or valine.

219. The method of embodiment 216 or 217, wherein when the pre-mutation, e.g., wildtype, amino acid is a polar amino acid having an uncharged R group, the TREM mediates incorporation of any one of the following amino acids: serine, threonine, cysteine, proline, asparagine, or glutamine.

220. The method of embodiment 216 or 217, wherein when the pre-mutation, e.g., wildtype, amino acid has a positively charged R group, the TREM mediates incorporation of any one of the following amino acids: lysine, arginine or histidine.

221. The method of embodiment 216 or 217, wherein when the pre-mutation, e.g., wildtype, amino acid has a negatively charged R group, the TREM mediates incorporation of any one of the following amino acids: aspartate or glutamate.

222. The method of embodiment 216 or 217, wherein when the pre-mutation, e.g., wildtype, amino acid is a nonpolar amino acid having an aromatic R group, the TREM mediates incorporation of any one of the following amino acids: phenylalanine, tyrosine or tryptophan.

223. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UGA mutation, e.g., a UGG to UGA mutation.

224. The method of embodiment 223, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is UGA and the amino acid corresponding to the non-mutated codon is a tryptophan.

225. The method of claim 224, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of tryptophan at the position of the UGA stop codon.

226. The method of claim 224, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as tryptophan, e.g., as provided in Table 2.

227. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAA mutation, e.g., a UAU to UAA mutation.

228. The method of embodiment 227, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is UAU and the amino acid corresponding to the non-mutated codon is a tyrosine.

229. The method of claim 228, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAA stop codon and mediates incorporation of tyrosine at the position of the UAA stop codon.

230. The method of claim 228, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAA stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as tyrosine, e.g., as provided in Table 2.

231. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAG mutation, e.g., a UAC to UAG mutation.

232. The method of embodiment 231, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is UAC and the amino acid corresponding to the non-mutated codon is a tyrosine.

233. The method of claim 232, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of tyrosine at the position of the UAG stop codon.

234. The method of claim 232, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as tyrosine, e.g., as provided in Table 2.

235. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UGA mutation, e.g., a UGU to UGA mutation.

236. The method of embodiment 235, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is UGU and the amino acid corresponding to the non-mutated codon is a cysteine.

237. The method of claim 236, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of cysteine at the position of the UGA stop codon.

238. The method of claim 236, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as cysteine, e.g., as provided in Table 2.

239. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UGA mutation, e.g., a UGC to UGA mutation.

240. The method of embodiment 239, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is UGC and the amino acid corresponding to the non-mutated codon is a cysteine.

241. The method of claim 240, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of cysteine at the position of the UGA stop codon.

242. The method of claim 240, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGG stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as cysteine, e.g., as provided in Table 2.

243. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAA mutation, e.g., a GAA to UAA mutation.

244. The method of embodiment 243, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is GAA and the amino acid corresponding to the non-mutated codon is a glutamate.

245. The method of claim 244, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAA stop codon and mediates incorporation of glutamate at the position of the UAA stop codon.

246. The method of claim 244, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAA stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as glutamate, e.g., as provided in Table 2.

247. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAG mutation, e.g., a GAG to UAG mutation.

248. The method of embodiment 247, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is GAG and the amino acid corresponding to the non-mutated codon is a glutamate.

249. The method of claim 248, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of glutamate at the position of the UAG stop codon.

250. The method of claim 248, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as glutamate, e.g., as provided in Table 2.

251. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAA mutation, e.g., a AAA to UAA mutation.

252. The method of embodiment 251, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is AAA and the amino acid corresponding to the non-mutated codon is a lysine.

253. The method of claim 252, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAA stop codon and mediates incorporation of lysine at the position of the UAA stop codon.

254. The method of claim 252, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAA stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as lysine, e.g., as provided in Table 2.

255. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAG mutation, e.g., a AAG to UAG mutation.

256. The method of embodiment 255, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is AAG and the amino acid corresponding to the non-mutated codon is a lysine.

257. The method of claim 256, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of lysine at the position of the UAG stop codon.

258. The method of claim 256, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as lysine, e.g., as provided in Table 2.

259. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAA mutation, e.g., a CAA to UAA mutation.

260. The method of embodiment 259, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is CAA and the amino acid corresponding to the non-mutated codon is a glutamine.

261. The method of claim 260, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAA stop codon and mediates incorporation of glutamine at the position of the UAA stop codon.

262. The method of claim 260, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAA stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as glutamine, e.g., as provided in Table 2.

263. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAG mutation, e.g., a CAG to UAG mutation.

264. The method of embodiment 263, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is CAG and the amino acid corresponding to the non-mutated codon is a glutamine.

265. The method of claim 264, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of glutamine at the position of the UAG stop codon.

265.1. The method of claim 264, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as glutamine, e.g., as provided in Table 2.

266. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UGA mutation, e.g., a UCA to UGA mutation.

267. The method of embodiment 266, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is UCA and the amino acid corresponding to the non-mutated codon is a serine.

268. The method of claim 267, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of serine at the position of the UGA stop codon.

269. The method of claim 267, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as serine, e.g., as provided in Table 2.

270. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAG mutation, e.g., a UCG to UAG mutation.

271. The method of embodiment 270, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is UCG and the amino acid corresponding to the non-mutated codon is a serine.

272. The method of claim 271, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of serine at the position of the UAG stop codon.

273. The method of claim 271, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as serine, e.g., as provided in Table 2.

274. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAA mutation, e.g., a UUA to UAA mutation.

275. The method of embodiment 274, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is UUA and the amino acid corresponding to the non-mutated codon is a leucine.

276. The method of claim 275, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAA stop codon and mediates incorporation of leucine at the position of the UAA stop codon.

277. The method of claim 275, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAA stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as leucine, e.g., as provided in Table 2.

278. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UGA mutation, e.g., a UUA to UGA mutation.

279. The method of embodiment 278, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is UUA and the amino acid corresponding to the non-mutated codon is a leucine.

280. The method of claim 279, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of leucine at the position of the UGA stop codon.

281. The method of claim 279, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as leucine, e.g., as provided in Table 2.

282. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UAG mutation, e.g., a UUG to UAG mutation.

283. The method of embodiment 282, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is UUG and the amino acid corresponding to the non-mutated codon is a leucine.

284. The method of claim 283, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of leucine at the position of the UAG stop codon.

285. The method of claim 284, wherein the TREM, TREM core fragment or TREM fragment recognizes the UAG stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as leucine, e.g., as provided in Table 2.

286. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UGA mutation, e.g., a CGA to UGA mutation.

287. The method of embodiment 286, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is CGA and the amino acid corresponding to the non-mutated codon is an arginine.

288. The method of claim 287, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of arginine at the position of the UGA stop codon.

289. The method of claim 287, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as arginine, e.g., as provided in Table 2.

290. The method of embodiment 126-160, wherein the codon having the first sequence or the PTC comprises a UGA mutation, e.g., a GGA to UGA mutation.

291. The method of embodiment 290, wherein the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is GGA and the amino acid corresponding to the non-mutated codon is a glycine.

292. The method of claim 291, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of glycine at the position of the UGA stop codon.

293. The method of claim 291, wherein the TREM, TREM core fragment or TREM fragment recognizes the UGA stop codon and mediates incorporation of an amino acid which belongs to the same amino acid group as glycine, e.g., as provided in Table 2.

294. The method of any of embodiments 126-293, wherein incorporation of the amino acid by the TREM, TREM fragment or TREM core fragment results in modulation, e.g., increase, of a production parameter, e.g., an expression parameter and/or a signaling parameter, of an RNA corresponding to the ORF or a polypeptide encoded by the ORF.

295. The method of embodiment 294, wherein the production parameter comprises an expression parameter.

296. The method of embodiment 295, wherein the expression parameter comprises:

(a) protein translation;

(b) expression level (e.g., of polypeptide or protein, or mRNA);

(d) folding (e.g., of polypeptide or protein, or mRNA),

(e) structure (e.g., of polypeptide or protein, or mRNA),

(f) transduction (e.g., of polypeptide or protein),

(g) compartmentalization (e.g., of polypeptide or protein, or mRNA),

(h) incorporation (e.g., of polypeptide or protein, or mRNA) into a supermolecular structure, e.g., incorporation into a membrane, proteasome, or ribosome,

(i) incorporation into a multimeric polypeptide, e.g., a homo or heterodimer, and/or

(j) stability.

297. The method of embodiment 294, wherein the production parameter comprises a signaling parameter.

298. The method of embodiment 297, wherein the signaling parameter comprises:

(1) modulation of a signaling pathway, e.g., a cellular signaling pathway which is downstream or upstream of the protein encoded by the endogenous ORF having a first sequence or PTC;

(2) cell fate modulation;

(3) ribosome occupancy modulation;

(4) protein translation modulation;

(5) mRNA stability modulation;

(6) protein folding and structure modulation;

(7) protein transduction or compartmentalization modulation; and/or

(8) protein stability modulation.

299. The method of any one of embodiments 294-298, wherein the production parameter (e.g., an expression parameter and/or a signaling parameter) may be modulated (e.g., increased), e.g., by at least 5% (e.g., at least 10%, 15%, 20%, 25%, 30%, 40%. 50%. 60%. 70%, 80%, 90%, 100%, 150%, 200% or more), e.g., compared to a reference sequence.

300. The method of any one of embodiments 126-299, wherein the subject has or has been identified as having a disorder or disease listed in any one of Tables 15, 16, or 17.

301. The method of any one of embodiments 126-299, wherein the cell is associated with, e.g., obtained from a subject who has, a disorder or disease listed in any one of Tables 15, 16 or 17.

302. The method of embodiment 300 or 301, wherein the disorder or disease is chosen from the left column of Table 4.

303. The method of embodiment 300 or 301, wherein the disorder or disease is chosen from the left column of Table 4 and the codon having the first sequence or PTC is in a gene chosen from the right column of Table 4, optionally wherein the codon having the first sequence or PTC is at a position provided in Table 4.

304. The method of any one of embodiments 126-299, wherein the codon having the first sequence or PTC is in a gene chosen from the right column of Table 4, optionally wherein the codon having the first sequence or PTC is at a position provided in Table 4.

305. The method of embodiment 300 or 301, wherein the disorder or symptom is chosen from a disorder or disease provided in Table 5.

306. The method of embodiment 300 or 301, wherein the disorder or symptom is chosen from a disorder or disease provided in Table 6.

307. The method of embodiment 300 or 301, wherein the disorder or symptom is chosen from a disorder or disease provided in Table 6 and the codon having the first sequence or PTC is in any gene provided in Table 6.

308. The method of embodiment 300 or 301, wherein the disorder or symptom is chosen from a disorder or disease provided in Table 6 and the codon having the first sequence or PTC is in a corresponding gene provided in Table 6, e.g., a gene corresponding to the disease or disorder.

309. The method of embodiment 300 or 301, wherein the disorder or symptom is chosen from a disorder or disease provided in Table 6 and the codon having the first sequence or PTC is not in a gene provided in Table 6.

310. The method of any one of embodiments 126-299, wherein the codon having the first sequence or PTC is in a gene provided in Table 3.

311. The method of any one of embodiments 303, 304, 307, 308, 309 or 310, wherein the codon having the first sequence or PTC is at any position within the ORF of the gene, e.g., upstream of the naturally occurring stop codon.

Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

EXAMPLES

The following examples are provided to further illustrate some embodiments of the present invention, but are not intended to limit the scope of the invention; it will be understood by their exemplary nature that other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.

Table of Contents for Examples

Example 1
Synthesis of guanosine 2′-O-MOE phosphoramidite

Example 2
Synthesis of 5,6 dihydrouridine

Example 3
Synthesis of a TREM via 5-Silyl-2-Orthoester (2-ACE) Chemistry

Example 4
Synthesis of an arginine TREM having a 2′-O-MOE modification

Example 5
Synthesis of an arginine TREM having a pseudouridine and a 2′-O-MOE

modification

Example 6
Synthesis of a glutamine TREM having a 5,6 dihydrouridine modification

Example 7
Synthesis of a glutamine TREM having a pseudouridine modification

Example 8
Synthesis of nucleotides comprising an aminonucleobase (AN1)

Example 9
Synthesis of biotin conjugated TREM molecules

Example 10
Quality control of synthesized TREM via Mass Spectrometry Analysis

Example 11
Quality control of synthesized TREM via anion-exchange HPLC

Example 12
Quality control of synthesized TREM via PAGE Purification and Analysis

Example 13
Deprotection of synthesized TREM

Example 14
Readthrough of a premature termination codon (PTC) in a reporter protein

with administration of a synthetic arginine non-cognate TREM (1)

Example 15
Readthrough of a premature termination codon (PTC) in a reporter protein

with administration of a synthetic arginine non-cognate TREM (2)

Example 16
Readthrough of a premature termination codon (PTC) in the Coagulation

Factor IX ORF through administration of a synthetic arginine non-cognate TREM

Example 17
Correction of a missense mutation in an ORF with administration of a TREM

Example 1: Synthesis of Guanosine 2′-O-MOE Phosphoramidite

This example describes the synthesis of guanosine 2′-O-MOE phosphoramidite. Guanosine 2′-O-MOE phosphoramidite is prepared and purified according to previously published procedures (Wen K. et al. (2002) The Journal of Organic Chemistry, 67(22), 7887-7889).

Briefly, guanosine and imidazole are dried by co-evaporation with pyridine, dissolved in dry DMF, and treated with bis(diisopropylchlorosilyl) methane added dropwise at 0° C. The temperature is gradually increased to 25° C. and then held for 5 h. The reaction mixture is poured into ice water, and the precipitated white solid filtered to afford compound 1. To a solution of compound 1, BrCH2CH2OCH3, and TBAI in DMF at −20° C. is added with sodium bis (trimethylsilyl)amide, and the mixture is stirred for 4 hours under argon. After the reaction is quenched with methanol, the THF is evaporated and the residue is precipitated in ice to furnish compound 2. TBAF is added to a solution of compound 2 at 25° C. and then the mixture is stirred at 35° C. for 5 hours. The solvent is then evaporated under reduced pressure, and the residue is filtered in a short pad of silica gel using 10% methanol in dichloromethane to afford guanosine 2′-O-MOE phosphoramidite.

Example 2: Synthesis of 5,6 Dihydrouridine

This example describes the synthesis of 5,6 dihydrouridine. 5,6 dihydrouridine phosphoramidite is prepared and purified according to previously published procedures (Hanze A R et al., (1967) Journal of the American Chemical Society, 89(25), 6720-6725). Briefly, oxygen is bubbled through a solution uridine in the presence of platinum black. The reaction is followed by spotting the reaction mixture on silica gel thin layer chromatographic plates and developing in methanol-chloroform (1:1). After 1 hour, the mixture is cooled and centrifuged and the clear liquid lyophilized to yield the 5,6 dihydrouridine product.

Example 3: Synthesis of a TREM Via 5Silyl-2Orthoester (2ACE) Chemistry

This example describes the synthesis of a TREM via 50 custom-character Silyl-2Orthoester (2ACE) Chemistry summarized from (Hartsel S A et al., (2005) Oligonucleotide Synthesis, 033-050).

Protected Ribonucleoside Monomers

5 custom-character O-silyl-2O-ACE protected phosphoramidites are prepared and purified according to previously published procedures (Hartsel S A et al., (2005) Oligonucleotide Synthesis, 033-050). Briefly, monomer synthesis begins from standard base-protected ribonucleosides [rA(ibu), rC(acetyl), rG(ibu) and U]. Orthogonal, 5 custom-character silyl-2ACE protection and amidite preparation is then accomplished in five general steps:

- 1. Simultaneous transient protection of the 5 and 3hydroxyl groups with 1,1,3,3tetraispropyldisiloxane (TIPS).
- 2. Regiospecific conversion of the 2hydroxyl to the 2O-orthoester using tris(acetoxyethyl)orthoformate (ACE orthoformate).
- 3. Removal of the 53TIPS protection.
- 4. Introduction of the 5O-silyl ether protecting group using benzhydryloxybis-(trimethylsilyloxy)-chlorosilane (BzH-C1).
- 5. Phosphitylation of the 3OH with bis(N,Ndiisopropylamino)methoxyphosphine.

The fully protected, phosphitylated monomer is an oil. For ease of handling and dissolution, the phosphoramidite solution is evaporated to dryness in a tared flask to enable quantitation of yields. The phosphoramidite oil is then dissolved in anhydrous acetonitrile, distributed into synthesis vials in 1.0-mmol aliquots, and evaporated to dryness under vacuum in the presence of potassium hydroxide (KOH) and P2O5.

Synthesis of Oligoribonucleosides

TABLE 16

Delivery
Reaction

Synthesis Step
Reagent
Time
Time

Deblock
3% DCA in DCM
35

Activator
0.5M S-ethyl-tetrazole
6

Coupling
0.1M amidite 8.0
30

0.5M S-ethyl-tetrazole
8
30

Repeat Coupling

Oxidation
t-Butyl hydroperoxide
20
10

Repeat Oxidation

Delivery

Capping
1-methylimidazole and
12
10

acetic anhydride

Desilylation
TEAHF
35

5 custom-character silyl-2ACE oligoribonucleotide synthesis begins with the appropriately modified 3 terminal nucleoside attached through the 3hydroxyl to a polystyrene support. The solid support contained in an appropriate reaction cartridge is then placed on the appropriate column position on the instrument. A synthesis cycle is created using the delivery times and wait steps outlined in Table 16.

- 1. Initial detritylation: The first step in the synthesis cycle is the removal of the 5□O-DMT from the nucleoside-bound polystyrene support using 3% DCA in DCM.
- 2. Coupling: The 5-ethylthio-1H-tetrazole solution is delivered to the solid support, followed by simultaneous delivery of an equal quantity of activator and phosphoramidite solution. Depending on the desired sequence and synthesis scale, excess activator and activator plus amidite are alternately delivered repeatedly to increase coupling efficiency, which is typically in excess of 99% per coupling reaction. The 5-ethylthio-1H-tetrazole activates coupling by protonating the diisopropyl amine attached to the trivalent phosphorous. Nucleophilic attack of the 5-ethylthio-1H-tetrazole leads to the formation of the tetrazolide intermediate that reacts with the free 5OH of the support-bound nucleoside forming the internucleotide phosphite linkage.
- 3. Oxidation: In the next step of chain elongation, the phosphorous(III) linkage is oxidized for 10-20 s to the more stable and ultimately desired P(V) linkage using t-butylhydroperoxide.
- 4. Capping: Although delivery of excess activator and phosphoramidite increases coupling efficiency, a small percentage of unreacted nucleoside may remain support-bound. To prevent the introduction of mixed sequences, the unreacted 5OH are “capped” or blocked by acetylating the primary hydroxyl. This acetylation is achieved through simultaneous delivery of 1-methylimidazole and acetic anhydride.
- 5. 5Desilylation: Before the next nucleoside in the sequence can be added to the growing oligonucleotide chain, the 5silyl group is removed with fluoride ion. This requires the delivery of triethylamine trihydrogenfluoride for 45 s. The desilylation is rapid and quantitative and no wait step is required.
  
  Steps 2-5 are repeated for each subsequent nucleotide until the desired sequence is constructed.

Oligonucleotide Deprotection

A two-stage rapid deprotection strategy is employed to remove phosphate backbone protection, release the oligonucleotide from the solid support, and remove the exocyclic amine protecting groups on A, G, and C. The treatment also removes the acetyl moiety from the acetoxyethyl orthoester, resulting in the 2 bis-hydroxyethyl protected intermediate that is now 10 times more labile to final acid deprotection. In the first deprotection step, S2Na2 is used to selectively remove the methyl protection from the internucleotide phosphate, leaving the oligoribonucleotide attached to the polystyrene support. This configuration allows any residual reagent to be thoroughly washed away before proceeding. Alternatively, a multicolumn, manifold approach can also be used.

- 1. A syringe barrel is attached to one of the two luer fittings on the synthesis column. 2 mL of the S2Na2 reagent is drawn into a second syringe and attached to the opposite side of the synthesis column. The S2Na2 reagent is gently pushed through the column and into the empty syringe barrel continuing back and forth several times. The column, filled with reagent is allowed to sit at room temperature for 10 min.
- 2. S2Na2 reagent is removed from the column. Using a clean syringe, the column is washed thoroughly with water. In the second deprotection step, 40% 1-methylamine in water is used to free the oligoribonucleotide from the solid support, deprotect the exocyclic base amines, and deacylate the 2orthoester leaving the deprotected species.

N-Methylamine Deprotection

- 1. The solid support resin is transferred from the column into a 4-mL vial
- 2. 2 mL 40% methylamine is added and heated for 12 min at 60° C.
- 3. The methylamine is removed and is transferred into a fresh vial.
- 4. The oligonucleotide solution is evaporated to dryness in a SpeedVac or similar device.
  
  Oligonucleotide yields are measured using an ultraviolet (UV) spectrophotometer (absorbance at 260 nm).

Example 4: Synthesis of an Arginine TREM Having a 2′-O-MOE Modification

This example describes the synthesis of an Arg TREM having one 2′-O-MOE modification. The 2′-O-MOE modification can be placed on a nucleotide on any domain or linker of the Arg TREM, or at any position in said domain or linker.

A 2 custom-character CE RNA oligoribonucleotide synthesis is performed on a modified Applied Biosystems 394 DNA/RNA synthesizer or similar instrument. 2′-O-MOE amidites are synthesized as in Example 2. An oligonucleotide sequence: GGCUCCGUGGCGCAAUGGAUAGCGCAUUGGACUUCUAAUUCAAAGGUUCCGGGUU CG(A-MOE)GUCCCGGCGGAGUCG is synthesized following the protocol described in example 4. A similar method can be used to add a 2′-O-MOE modification on a TREM specifying any one of the other 19 amino acids.

Example 5: Synthesis of an Argnine TREM Having a Pseudouridine and a 2′-O-MOE Modification

This example describes the synthesis of an Arg TREM having a pseudouridine and 2′-O-MOE modification. The modification can be placed on a nucleotide on any domain or linker of the Arg TREM, or at any position in said domain or linker.

A 2 custom-character CE RNA oligoribonucleotide synthesis is performed on a modified Applied Biosystems 394 DNA/RNA synthesizer or similar instrument. 2′-O-MOE amidites are synthesized as in example 1. Pseudouridine (P) amidites are obtained from Glen Research or similar provider. An oligonucleotide sequence: GGCUCCGUGGCGCAAUGGAUAGCGCAPUGGACUUCUAAUUCAAAGGUUCCGGGUU CG(A-MOE)GUCCCGGCGGAGUCG is synthesized following the protocol described in example 3. A similar method can be used to add a pseudouridine and 2′-O-MOE modification on a TREM specifying any one of the other 19 amino acids.

Example 6: Synthesis of a Glutamine TREM Having a Dihydrouridine Modification

This example describes the synthesis of a Gln TREM having a dihydrouridine modification. The modification can be placed on a nucleotide on any domain or linker of the Gln TREM, or at any position in said domain or linker.

A 2 custom-character CE RNA oligoribonucleotide synthesis is performed on a modified Applied Biosystems 394 DNA/RNA synthesizer or similar instrument. Dihydrouridine (D) is synthesized as in example 2. An oligonucleotide sequence: GGUUCCAUGGUGUAAUGGDAAGCACUCUGGACUCTGAAUCCAGCGAUCCGAGUUC GAGUCUCGGUGGAACCUCCA is synthesized following the protocol described in example 3.

A similar method can be used to add a dihydrouridine modification on a TREM specifying any one of the other 19 amino acids.

Example 7: Synthesis of a Glutamine TREM Having a Pseudouridine Modification

This example describes the synthesis of a Gln TREM having a pseudouridine modification. The modification can be placed on a nucleotide on any domain or linker of the Gln TREM, or at any position in said domain or linker.

A 2 custom-character CE RNA oligoribonucleotide synthesis is performed on a modified Applied Biosystems 394 DNA/RNA synthesizer or similar instrument. Pseudouridine (P) amidites are obtained from Glen Research or similar provider. An oligonucleotide sequence: GGUUCCAUGGUGPAAUGGUAAGCACUCUGGACUCTGAAUCCAGCGAUCCGAGUUC GAGUCUCGGUGGAACCUCCA is synthesized following the protocol described in example 3.

A similar method can be used to add a pseudouridine modification on a TREM specifying any one of the other 19 amino acids.

Example 8: Synthesis of Nucleotides Comprising an Aminonucleobase (AN1)

Modified nucleotides comprising an amine handle at the nucleobase, such as AN1 (C6-U phosphoramidite (5′-Dimethoxytrityl-5-[N-(trifluoroacetylaminohexyl)-3-acrylimido]-Uridine, 2′-O-triisopropylsilyloxymethyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite)), may be purchased from Glen Research; catalog #10-3039. Briefly, Amino-Modifier C6-U phosphoramidite was purchased with the primary amine protected as trifluoroacetate and incorporated into a TREM to afford the amino nucleobase AN1.

embedded image

Example 9: Synthesis of Biotin Conjugated TREM Molecules

This example describes the synthesis of biotin conjugated TREM molecule. These molecules may be utilized as test TREMs (e.g., test chemically modified TREMs) for example, and be useful for investigation of which positions along the TREM sequence are suitable for labeling (+)-Biotin N-hydroxysuccinimide ester may be purchased from Sigma-Aldrich (catalog #H1759). The TREM molecules bearing a free amine may be synthesized as described previously, e.g., Example 8, then coupled with (+)-Biotin N-hydroxysuccinimide ester to form an amide bond, according to the method, e.g., as outlined in Bengstrom M. et al. (1990) Nucleos. Nucleot. Nucl. 9, 123-127. Briefly, a solution of TREM molecules with amino base modification and excess (+)-Biotin N-hydroxysuccinimide ester may be mixed together and vortexed for several hours at 37° C. LCMS analysis is used to determine whether the reaction is complete. The solvent is removed under vacuum, and the resulting residue is diluted with water then subjected to purification using reversed phase column chromatography to afford the final compound.

For example, the biotin moiety was installed on the arginine non-cognate TREM molecules at position 47 named TREM-Arg-TGA-Biotin-47. The arginine non-cognate TREM molecules contain the sequence of ARG-UCU-TREM body but with the anticodon sequence corresponding to UCA instead of UCU.

embedded image

Example 10: Quality Control of Synthesized TREM Via Mass Spectrometry Analysis

This example describes the quality control of a synthesized TREM via Mass Spectrometry Analysis.

Using the Perseptive Biosystems Voyager-DE BioSpectrometry Workstation, the referenced protocol for mass spectrometry analysis (4-Van Ausdall) is followed. Briefly, a 3-hydroxy picolinic acid matrix is used for sample crystallization. It is prepared by mixing (10:1:1) 3-HPA:picolinic acid:ammonium hydrogen citrate where each component is dissolved in 30% aqueous acetonitrile at a concentration of 50 mg/mL. One optical density unit (ODU) of oligonucleotide is dissolved in the matrix and heated at 55° C. for 10 min. The sample is spotted on a MALDI plate, allowed to dry, and analyzed accordingly. This method allows confirmation of oligonucleotide identity and detection of low-level impurities present in synthetic oligonucleotide samples.

Example 11: Quality Control of Synthesized TREM Via Anion-Exchange HPLC

This example describes the quality control of a synthesized TREM via anion-exchange HPLC. Using the Dionex DNA-Pac-PA-100 column, a gradient is employed using HPLC buffer A and HPLC buffer B. 0.5 ODUs of a sample that has been dissolved in H2O or Tris buffer, pH 7.5 is injected onto the gradient. The gradient employed is based on oligonucleotide length and can be applied according to Table 17. The parameters provided in Table 18 can be used to program a linear gradient on the HPLC analyzer.

TABLE 17

Oligonucleotide length and

gradient percentages

Length
Gradient

(bases)
(% B)

0-5
0-30

6-10
10-40

11-16
20-50

17-32
30-60

33-50
40-70

>50
50-80

TABLE 18

Parameters for a linear gradient on HPLC analyzer

Time
Flow
% Buffer
% Buffer

(min)
(mL/min)
A
B

0
1.5
100
0

1
1.5
100
0

3
1.5
70a
30a

15
1.5
40a
60a

15.5
2.5
0
100

17
2.5
0
100

17.25
2.5
100
0

23
2.5
100
0

s23.1
1.5
100
0

24
1.5
100
0

25
0.1
100
0

Example 12: Quality Control of Synthesized TREM Via PAGE Purification and Analysis

This example describes the quality control of a synthesized TREM via PAGE Purification and Analysis. Gel purification and analysis of 2 custom-character ACE protected RNA follows standard protocols for denaturing PAGE (Ellington and Pollard (1998) In Current Protocols in Molecular Biology, Chanda, V). Briefly, the 2CE protected oligo is resuspended in 200 mL of gel loading buffer. Invitrogen™ NuPAGE™ 4-12% Bis-Tris Gels or similar gel is prepared in gel apparatus. Samples are loaded and gel ran at 50-120 W, maintaining the apparatus at 40° C. When complete, the gel is exposed to ultraviolet (UV) light at 254 nm to visualize the purity of the RNA using UV shadowing. If necessary, the desired gel band is excised with a clean razor blade. The gel slice is crushed and 0.3M NaOAc elution buffer is added to the gel particles, and soaked overnight. The mixture is decanted and filtered through a Sephadex column such as Nap-10 or Nap-25.

Example 13: Deprotection of Synthesized TREM

This example describes the deprotection of a TREM made according to an in vitro synthesis method, e.g., as described in Example 3. The 2 custom-character protecting groups are removed using 100 mM acetic acid, pH 3.8. The formic acid and ethylene glycol byproducts are removed by incubating at 60° C. for 30 min followed by lyophilization or SpeedVac-ing to dryness. After this final deprotection step, the oligonucleotides are ready for use.

Example 14: Readthrough of a Premature Termination Codon (PTC) in a Reporter Protein with Administration of an Arginine Non-Cognate TREM (1)

This example describes an assay to test the ability of a non-cognate TREM to readthrough a PTC in a cell line expressing a reporter protein having a PTC. This Example describes an arginine non-cognate TREM. A non-cognate TREM specifying any one of the other 19 amino acids can be used.

Host Cell Modification

A cell line stably expressing a NanoLuc reporter construct containing a premature termination codon (PTC) is generated using the FlpIn system according to manufacturer's instructions. Briefly, HEK293T (293T ATCC® CRL-3216) cells are co-transfected with an expression vector containing a Nanoluc reporter with a PTC, such as pcDNA5/FRT-NanoLuc-TAA and a pOG44 Flp-Recombinase expression vector using Lipofectamine2000 according to manufacturer's instructions. After 24 hours, the media is replaced with fresh media. The next day, the cells are split 1:2 and selected with 100 ug/mL Hygromycin for 5 days. The remaining cells are expanded and tested for reporter construct expression.

Synthesis and Preparation of Non-Cognate TREM

In this example, the arginine non-cognate TREM, is produced such that it contains the sequence of the ARG-UCU-TREM body but with the anticodon sequence corresponding to UCA instead of UCU. The arginine non-cognate TREM is synthesized as described herein and quality control methods as described herein are performed. To ensure proper folding, the TREM is heated at 85° C. for 2 minutes and then snap cooled at 4° C. for 5 minutes.

Transfection of Non-Cognate TREM into Host Cells

To deliver the arginine non-cognate TREM to mammalian cells, 100 nM of TREM is transfected into HEK293T (293T ATCC® CRL-3216), U2OS (U-2OS (ATCC® HTB-96™)) H1299 (NCI-H1299 (ATCC® CRL-5803™)), or HeLa (HeLa (ATCC® CCL-2™)) cells stably expressing the PTC-containing NanoLuc reporter using lipofectamine 2000 reagents according to the manufacturer's instructions. After 6-18 hours, the transfection media is removed and replaced with fresh complete media (U2OS: McCoy custom-character 5A, 10% FBS, 1% PenStrep; H1299: RPMI1640, 10% FBS, 1% PenStrep; Hek/HeLa: EMEM, 10% FBS, 1% PenStrep).

Translation Suppression Assay

To monitor the efficacy of the arginine non-cognate TREM to readthrough the PTC in the reporter construct, 24-48 hours after transfection, cell media is replaced and allowed to equilibrate to room temperature. An equal volume to the cell media of ONE-Glo™ EX Reagent is added to the well and mixed on the orbital shaker at 500 rpm for 3 min followed by addition of an equal volume of cell media of NanoDLR™ Stop & Glo and mixing on the orbital shaker at 500 rpm for 3 min. The reaction is incubated at room temperature for 10 min and the NanoLuc activity is detected by reading the luminescence in a plate reader. As a positive control, a host cell expressing the NanoLuc reporter construct without a PTC is used. As a negative control, a host cell expressing the NanoLuc reporter construct with a PTC is used but no TREM is transfected. The TREM efficacy is measured as a ratio of the NanoLuc luminescence in the experimental sample to the NanoLuc luminescence of the positive control. It is expected that if the arginine non-cognate TREM is functional, it can read-through the stop mutation in the NanoLuc reporter and produce a luminescent reading higher than the luminescent reading measured in the negative control. If the arginine non-cognate TREM is not functional, the stop mutation is not rescued, and luminescence less or equal to the negative control is detected.

Example 15: Readthrough of a Premature Termination Codon (PTC) in a Reporter Protein with Administration of an Arginine Non-Cognate TREM (2)

Host Cell Modification

A cell line engineered to stably express a HiBiT-tagged disease reporter construct containing a premature termination codon (PTC), such as Factor IX at position 298 (FIX^R298X) Tripeptidyl-peptidase 1 at position 208 (TPP^R208X), or Protocadherin Related 15 at position 245 (PCDH15^R245X), was generated using the Jump-In system according to manufacturer's instructions. Briefly, Jump-In GripTite HEK293 (Thermo Scientific A14150) cells were co-transfected with an expression vector containing the disease reporter, such as pJTI-R4-DEST-CMV-FIX-R298X-HiBiT-pA for FIX^R298Xto make the Factor IX disease reporter expressing cell line, and a pJTI-R4-Int PhiC31 integrase expression vector using Lipofectamine2000 according to manufacturer's instructions. After 24 hours, the media was replaced with fresh media. The next day, the cells were re-seeded at 50% confluency and selected with 10 ug/mL Blasticidin and 600 ug/mL G418 for 7 days with media change every 2 days. The remaining cells were expanded and tested for reporter construct expression.

Synthesis and Preparation of Non-Cognate TREM

In this example, the modified arginine non-cognate TREMs were produced such that they contain the sequence of the ARG-UCU-TREM body but with the anticodon sequence corresponding to UCA instead of UCU and modified as described herein. The resulting TREMs may be modified, for example, to contain a biotin as in Example 8-9. To ensure proper folding, the TREM was heated at 85° C. for 2 minutes and then snap cooled at 4° C. for 5 minutes.

Transfection of Non-Cognate TREM into Host Cells

Forty-eight hours after TREM delivery into cells, conditioned media was collected, fresh media was added to the cells, and allowed to equilibrate to room temperature. To measure the efficacy of arginine non-cognate TREMs in PTC readthrough, full-length HiBiT-tagged disease reporter protein was assayed in both cells, and 48-hour conditioned media. Briefly, reconstituted Nano-Glo® HiBiT Lytic Reagent was added to both cells containing fresh media, and 48-hour conditioned media at a 1:1 v/v ratio, mixed on an orbital shaker at 500 rpm for 10 minutes, incubated at room temperature for 10 minutes, and the HiBiT-NanoLuc activity is measured by reading the luminescence in a plate reader.

Translation Suppression Assay

To monitor the efficacy of the arginine non-cognate TREM to readthrough the PTC in the reporter construct, Forty-eight hours after TREM delivery into cells, conditioned media was collected, fresh media was added to the cells, and allowed to equilibrate to room temperature. To measure the efficacy of arginine non-cognate TREMs in PTC readthrough, full-length HiBiT-tagged disease reporter protein was assayed in both cells, and 48-hour conditioned media. Briefly, reconstituted Nano-Glo® HiBiT Lytic Reagent was added to both cells containing fresh media, and 48-hour conditioned media at a 1:1 v/v ratio, mixed on an orbital shaker at 500 rpm for 10 minutes, incubated at room temperature for 10 minutes, and the HiBiT-NanoLuc activity is measured by reading the luminescence in a plate reader. The results of this experiment in the three HiBiT-tagged disease reporter constructs is shown in FIGS. 1A-1C.

Example 16: Readthrough of a Premature Termination Codon (PTC) in the Coagulation Factor IX ORF Through Administration of a Synthetic Arginine Non-Cognate TREM

This example describes an assay to test the ability of a non-cognate arginine TREM to readthrough a PTC, such as R252X or R333X, in the Coagulation Factor IX open reading frame (ORF) in a Hemophilia B patient-derived cell line. This Example describes an arginine non-cognate TREM. A non-cognate TREM specifying any one of the other 19 amino acids can be used.

Patient-Derived Cells

Fibroblast cells derived from a patient with Hemophilia B having a PTC in the Coagulation Factor IX open reading frame (ORF), such as R252X or R333X, is obtained from a center or an organization, such as the Coriell Institute. The patient-derived fibroblast cells are reprogrammed into hepatocytes as previously shown (Takahashi, K. & Yamanaka, S. (2006) Cell 126, 663-676 (2006); Park I. et al. (2008) Nature 451, 141-146); Jia, B. et al. (2014) Life Sci. 108, 22-29).

Synthesis and Preparation of TREM

In this example, the arginine non-cognate TREM, is produced such that it contains the sequence of the ARG-UCU-TREM body but with the anticodon sequence corresponding to UCA instead of UCU. The arginine TREM is synthesized as described in Examples 3-7 and quality control methods as described in Examples herein are performed. To ensure proper folding, the TREM is heated at 85° C. for 2 minutes and then snap cooled at 4° C. for 5 minutes.

Transfection of Non-Cognate TREM into Host Cells

To deliver the arginine TREM to mammalian cells, 100 nM of TREM is transfected into the reprogrammed hepatocyte cells using lipofectamine 2000 reagents according to the manufacturer's instructions. After 6-18 hours, the transfection media is removed and replaced with fresh complete media.

Translation Suppression Assay

To monitor the efficacy of the arginine non-cognate TREM to readthrough the PTC in the Coagulation Factor IX ORF, 24-48 hours after transfection, cell media is replaced, and cells are lysed. Using Western blot detection, the non-cognate TREM efficacy is measured as the level of full-length protein expression, in this example of Coagulation Factor IX protein, in the reprogrammed hepatocyte cells administered the Arg non-cognate TREM, in comparison to the Coagulation Factor IX protein expression levels found in control cells. For example, as a control, cells of a person unaffected by the disease (i.e. cells having an ORF with a WT Coagulation Factor IX transcript) can be used. It is expected that if the non-cognate TREM is functional, it can read-through the PTC and the full-length protein level will be detected at higher levels than that found in patient-derived fibroblast cells or reprogrammed hepatocyte cells which have not been administered the non-cognate TREM. If the non-cognate TREM is not functional, the full-length protein level will be detected at a similar level as detected in patient-derived fibroblast cells or reprogrammed hepatocyte cells which have not been administered the non-cognate TREM.

Example 17: Correction of a Missense Mutation in an ORF with Administration of a TREM

This example describes the administration of a TREM to correct a missense mutation. In this example, a TREM translates a reporter with a missense mutation into a wild type (WT) protein by incorporation of the WT amino acid (at the missense position) in the protein.

Host Cell Modification

A cell line stably expressing a GFP reporter construct containing a missense mutation, for example T203I or E222G, which prevent GFP excitation at the 470 nm and 390 nm wavelengths, is generated using the FlpIn system according to manufacturer's instructions. Briefly, HEK293T (293T ATCC® CRL-3216) cells are co-transfected with an expression vector containing a GFP reporter with a missense mutation, such as pcDNA5/FRT-NanoLuc-TAA and a pOG44 Flp-Recombinase expression vector using Lipofectamine2000 according to manufacturer's instructions. After 24 hours, the media is replaced with fresh media. The next day, the cells are split 1:2 and selected with 100 ug/mL Hygromycin for 5 days. The remaining cells are expanded and tested for reporter construct expression.

Synthesis and Preparation of TREM

The TREM is synthesized as described in Examples 3-7 and quality control methods as described in Examples 8-10 are performed. To ensure proper folding, the TREM is heated at 85° C. for 2 minutes and then snap cooled at 4° C. for 5 minutes.

Transfection of Non-Cognate TREM into Host Cells

To deliver the TREM to mammalian cells, 100 nM of TREM is transfected into cells expressing the ORF having a missense mutation using lipofectamine 2000 reagents according to the manufacturer's instructions. After 6-18 hours, the transfection media is removed and replaced with fresh complete media.

Missense Mutation Correction Assay

To monitor the efficacy of the TREM to correct the missense mutation in the reporter construct, 24-48 hours after TREM transfection, cell media is replaced, and cell fluorescence is measured. As a negative control, no TREM is transfected in the cells and as a positive control, cells expressing WT GFP are used for this assay. If the TREM is functional, it is expected that the GFP protein produced fluoresces when illuminated with a 390 nm excitation wavelength using a fluorimeter, as observed in the positive control. If the TREM is not functional, the GFP protein produced fluoresces only when excited with a 470 nm wavelength, as is observed in the negative control.

TREM COMPOSITIONS AND METHODS RELATING THERETO

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