FIELD OF INVENTION
The present invention relates to oligonucleotides (oligomers) that are complementary to and hybridize to SNHG14 downstream of SNORD109B, leading to induction of paternal expression of Ubiquitin-protein ligase E3A (UBE3A) in an animal or human. The present invention further relates to pharmaceutical compositions and methods for treatment of Angelman syndrome.
BACKGROUND
Angelman syndrome is neuro-genetic disorder caused by deletion or inactivation of the UBE3A genes on the maternally inherited chromosome 15q11.2. The paternal copy of the UBE3A gene is subject to genomic imprinting and silencing in neurons by an endogenous antisense transcript of UBE3A, termed SNHG14 (also known as UBE3A-ATS) (Meng et al. 2012 Hum Mol Genet. Vol. 21 pp. 3001-12). Other cell types than neurons seem to express the UBE3A gene from both the maternal and paternal allele.
Angelman syndrome is characterized by severe intellectual and developmental disability, sleep disturbance, seizures, jerky movements, EEG abnormalities, frequent laughter or smiling, and profound language impairments.
WO 2012/064806 discloses a method of inducing UBE3A expression in a cell by using a topoisomerase inhibitor. The method can be used to treat Angelman syndrome. There is no disclosure of antisense oligonucleotides.
WO 2014/004572 discloses oligonucleotides with 2′-O-methoxyethyl-RNA (MOE) modifications targeting mouse UBE3A-ATS. The oligonucleotides are only tested in mice related assays. In the region downstream of MBII-52 snoRNA (also known as SNORD115) and upstream of the UBE3A pre-mRNA there is no conservation between mouse and human. Oligonucleotides targeting mouse UBE3A-ATS can therefore not be translated into oligonucleotides that will function in a human. There is no disclosure of oligonucleotides targeting human UBE3A-ATS.
OBJECTIVE OF THE INVENTION
The present invention identifies novel oligonucleotides which induce human paternal UBE3A expression in neuronal without affection expression of the paternal SNORD115, SNORD116 and SNRPN transcripts significantly.
SUMMARY OF INVENTION
The present invention relates to oligonucleotides targeting a nucleic acid capable of suppressing the expression of UBE3A and to treat or prevent diseases related to decreased activity of UBE3A, in particular in neuronal cells.
Accordingly, in a first aspect the invention provides oligonucleotides which comprise a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 98% complementarity to the part of human SNHG14 long non-coding RNA corresponding to position 25278410 to 25419462 on human chromosome 15 version GRCh38.p2. This region is also resembled by SEQ ID NO: 1. The oligonucleotide can be an antisense oligonucleotide, preferably with a gapmer design. Preferably, the oligonucleotide is capable of inducing the expression of UBE3A, in particular paternal UBE3A expression in a neuron, by degradation, reduction or removal of the UBE3A suppressor, in particular by reduction of the SNHG14 long non-coding RNA transcript downstream of SNORD109B. The UBE3A re-expression is achieved, without significantly affecting the expression of SNORD115. The degradation of the target nucleic acid is preferably achieved via nuclease recruitment.
In a further aspect, the invention provides pharmaceutical compositions comprising the oligonucleotides of the invention and pharmaceutically acceptable diluents, carriers, salts and/or adjuvants.
In a further aspect, the invention provides methods for in vivo or in vitro induction of UBE3A expression in a target cell where expression of paternal UBE3A is suppressed, by administering an oligonucleotide or composition of the invention in an effective amount to said cell.
In a further aspect the invention provides methods for treating or preventing a disease, disorder or dysfunction associated with in vivo activity of UBE3A comprising administering a therapeutically or prophylactically effective amount of the oligonucleotide of the invention to a subject suffering from or susceptible to the disease, disorder or dysfunction.
In a further aspect the oligonucleotide or composition of the invention is used for the treatment or prevention of Angelman syndrome.
BRIEF DESCRIPTION OF FIGURES
FIG. 1: The upper strand illustrates the region of the SNHG14 transcript downstream of SNORD109B (UBE3A-ATS) where the black boxes indicate the location of the tested mouse oligonucleotides. The lower strand illustrates the UBE3A coding region, where the black boxes indicate exons. Exon 1 is located around 160 kb. The oligonucleotides are placed in the antisense region of Exon 9 (positioned at ˜97 kb), Exon 10 (positioned at ˜92 kb), Exon 13 (positioned at ˜77 kb) and the 5′ end of Exon 16 (positioned at ˜60 kb).
FIG. 2: Representation of the ability of the oligonucleotides, tested in Example 2, to induce re-expression of UBE3A in human neuronal cell cultures. Oligonucleotides complementary to the region of human SNHG14 long non-coding RNA between SNORD109B and the region upstream of the UBE3A coding region (position 1 to 55318 of SEQ ID NO: 1) are indicated with • nonoverlap. Oligonucleotides complementary to the region of human SNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA (position 55319 to 141053 of SEQ ID NO: 1) are indicated with ▴ overlap. Oligonucleotides from Table 3 with conservation to human and rhesus monkey are indicated at the bottom of each plot as ![custom character]()
. Conservation between human:rhesus:mouse is indicated by ▪. The oligonucleotide concentrations were 0.2, 1 and 5 microM as indicated in the right hand side each plot.
DEFINITIONS
Oligonucleotide
The term “oligonucleotide” as used herein is defined as it is generally understood by the skilled person as a molecule comprising two or more covalently linked nucleosides. Such covalently bound nucleosides may also be referred to as nucleic acid molecules or oligomers. Oligonucleotides are commonly made in the laboratory by solid-phase chemical synthesis followed by purification. When referring to a sequence of the oligonucleotide, reference is made to the sequence or order of nucleobase moieties, or modifications thereof, of the covalently linked nucleotides or nucleosides. The oligonucleotide of the invention is man-made, and is chemically synthesized, and is typically purified or isolated. The oligonucleotide of the invention may comprise one or more modified nucleosides or nucleotides.
Antisense Oligonucleotides
The term “Antisense oligonucleotide” as used herein is defined as oligonucleotides capable of modulating expression of a target gene by hybridizing to a target nucleic acid, in particular to a contiguous sequence on a target nucleic acid. The antisense oligonucleotides are not essentially double stranded and are therefore not siRNAs. Preferably, the antisense oligonucleotides of the present invention are single stranded.
Contiguous Nucleotide Sequence
The term “contiguous nucleotide sequence” refers to the region of the oligonucleotide which is complementary to the target nucleic acid. The term is used interchangeably herein with the term “contiguous nucleobase sequence” and the term “oligonucleotide motif sequence”. In some embodiments all the nucleotides of the oligonucleotide are present in the contiguous nucleotide sequence. In some embodiments the oligonucleotide comprises the contiguous nucleotide sequence and may, optionally comprise further nucleotide(s), for example a nucleotide linker region which may be used to attach a functional group to the contiguous nucleotide sequence. The nucleotide linker region may or may not be complementary to the target nucleic acid.
Nucleotides
Nucleotides are the building blocks of oligonucleotides and polynucleotides, and for the purposes of the present invention include both naturally occurring and non-naturally occurring nucleotides. In nature, nucleotides, such as DNA and RNA nucleotides comprise a ribose sugar moiety, a nucleobase moiety and one or more phosphate groups (which is absent in nucleosides). Nucleosides and nucleotides may also interchangeably be referred to as “units” or “monomers”.
Modified Nucleoside
The term “modified nucleoside” or “nucleoside modification” as used herein refers to nucleosides modified as compared to the equivalent DNA or RNA nucleoside by the introduction of one or more modifications of the sugar moiety or the (nucleo)base moiety. In a preferred embodiment the modified nucleoside comprises a modified sugar moiety. The term modified nucleoside may also be used herein interchangeably with the term “nucleoside analogue” or modified “units” or modified “monomers”.
Modified Internucleoside Linkage
The term “modified internucleoside linkage” is defined as generally understood by the skilled person as linkages other than phosphodiester (PO) linkages, that covalently couples two nucleosides together. Nucleotides with modified internucleoside linkage are also termed “modified nucleotides”. In some embodiments, the modified internucleoside linkage increases the nuclease resistance of the oligonucleotide compared to a phosphodiester linkage. For naturally occurring oligonucleotides, the internucleoside linkage includes phosphate groups creating a phosphodiester bond between adjacent nucleosides. Modified internucleoside linkages are particularly useful in stabilizing oligonucleotides for in vivo use, and may serve to protect against nuclease cleavage at regions of DNA or RNA nucleosides in the oligonucleotide of the invention, for example within the gap region of a gapmer oligonucleotide, as well as in regions of modified nucleosides.
In an embodiment, the oligonucleotide comprises one or more internucleoside linkages modified from the natural phosphodiester to a linkage that is for example more resistant to nuclease attack. Nuclease resistance may be determined by incubating the oligonucleotide in blood serum or by using a nuclease resistance assay (e.g. snake venom phosphodiesterase (SVPD)), both are well known in the art. Internucleoside linkages which are capable of enhancing the nuclease resistance of an oligonucleotide are referred to as nuclease resistant internucleoside linkages. In preferred embodiments at least 50% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are modified, such as at least 60%, such as at least 70%, such as at least 80 or such as at least 90% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are modified. In some embodiments all of the internucleoside linkages of the oligonucleotide, or contiguous nucleotide sequence thereof, are modified. It will be recognized that, in some embodiments the nucleosides which link the oligonucleotide of the invention to a non-nucleotide functional group, such as a conjugate, may be phosphodiester. In some embodiments all of the internucleoside linkages of the oligonucleotide, or contiguous nucleotide sequence thereof, are nuclease resistant internucleoside linkages.
Modified internucleoside linkages may be selected from the group comprising phosphorothioate, diphosphorothioate and boranophosphate. In preferred embodiments, the modified internucleoside linkages are compatible with the RNaseH recruitment of the oligonucleotide of the invention, for example phosphorothioate, diphosphorothioate or boranophosphate.
In some embodiments the internucleoside linkage comprises sulphur (S), such as a phosphorothioate internucleoside linkage.
A phosphorothioate internucleoside linkage is particularly useful due to nuclease resistance, beneficial pharmakokinetics and ease of manufacture. In preferred embodiments at least 50% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are phosphorothioate, such as at least 60%, such as at least 70%, such as at least 80 or such as at least 90% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are phosphorothioate. In some embodiments all of the internucleoside linkages of the oligonucleotide, or contiguous nucleotide sequence thereof, are phosphorothioate.
In some embodiments, the oligonucleotide comprises one or more neutral internucleoside linkage, particularly a internucleoside linkage selected from phosphotriester, methylphosphonate, MMI, amide-3, formacetal or thioformacetal.
Further internucleoside linkages are disclosed in WO2009/124238 (incorporated herein by reference). In an embodiment the internucleoside linkage is selected from linkers disclosed in WO2007/031091 (incorporated herein by reference). Particularly, the internucleoside linkage may be selected from —O—P(O)2—O—, —O—P(O,S)—O—, —O—P(S)2—O—, —S—P(O)2—O—, —S—P(O,S)—O—, —S—P(S)2—O—, —O—P(O)2—S—, —O—P(O,S)—S—, —S—P(O)2—S—, —O—PO(RH)—O—, O—PO(OCH3)—O—, —O—PO(NRH)—O—, —O—PO(OCH2CH2S—R)—O—, —O—PO(BH3)—O—, —O—PO(NHRH)—O—, —O—P(O)2—NRH—, —NRH—P(O)2—O—, —NR″—CO—O—, —NRH—CO—NRH—, and/or the internucleoside linker may be selected form the group consisting of: —O—CO—O—, —O—CO—NRH—, —NRH—CO—CH2—, —O—CH2—CO—NRH—, —O—CH2—CH2—NRH—, —CO—NRH—CH2—, —CH2—NRHCO—, —O—CH2—CH2—S—, —S—CH2—CH2—O—, —S—CH2—CH2—S—, —CH2—SO2—CH2—, —CH2—CO—NRH—, —O—CH2—CH2—NRH—CO—, —CH2—NCH3—O—CH2—, where RH is selected from hydrogen and C1-4-alkyl.
Nuclease resistant linkages, such as phosphothioate linkages, are particularly useful in oligonucleotide regions capable of recruiting nuclease when forming a duplex with the target nucleic acid, such as region G for gapmers, or the non-modified nucleoside region of headmers and tailmers. Phosphorothioate linkages may, however, also be useful in non-nuclease recruiting regions and/or affinity enhancing regions such as regions F and F′ for gapmers, or the modified nucleoside region of headmers and tailmers.
Each of the design regions may however comprise internucleoside linkages other than phosphorothioate, such as phosphodiester linkages, in particularly in regions where modified nucleosides, such as LNA, protect the linkage against nuclease degradation. Inclusion of phosphodiester linkages, such as one or two linkages, particularly between or adjacent to modified nucleoside units (typically in the non-nuclease recruiting regions) can modify the bioavailability and/or bio-distribution of an oligonucleotide—see WO2008/113832, incorporated herein by reference.
In an embodiment all the internucleoside linkages in the oligonucleotide are phosphorothioate and/or boranophosphate linkages. Preferably, all the internucleoside linkages in the oligonucleotide are phosphorothioate linkages.
Nucleobase
The term nucleobase includes the purine (e.g. adenine and guanine) and pyrimidine (e.g. uracil, thymine and cytosine) moiety present in nucleosides and nucleotides which form hydrogen bonds in nucleic acid hybridization. In the context of the present invention the term nucleobase also encompasses modified nucleobases which may differ from naturally occurring nucleobases, but are functional during nucleic acid hybridization. In this context “nucleobase” refers to both naturally occurring nucleobases such as adenine, guanine, cytosine, thymidine, uracil, xanthine and hypoxanthine, as well as non-naturally occurring variants. Such variants are for example described in Hirao et al (2012) Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1.
In a some embodiments the nucleobase moiety is modified by changing the purine or pyrimidine into a modified purine or pyrimidine, such as substituted purine or substituted pyrimidine, such as a nucleobased selected from isocytosine, pseudoisocytosine, 5-methyl cytosine, 5-thiozolo-cytosine, 5-propynyl-cytosine, 5-propynyl-uracil, 5-bromouracil 5-thiazolo-uracil, 2-thio-uracil, 2′thio-thymine, inosine, diaminopurine, 6-aminopurine, 2-aminopurine, 2,6-diaminopurine and 2-chloro-6-aminopurine.
The nucleobase moieties may be indicated by the letter code for each corresponding nucleobase, e.g. A, T, G, C or U, wherein each letter may optionally include modified nucleobases of equivalent function. For example, in the exemplified oligonucleotides, the nucleobase moieties are selected from A, T, G, C, and 5-methyl cytosine. Optionally, for LNA gapmers, 5-methyl cytosine LNA nucleosides may be used.
Modified Oligonucleotide
The term modified oligonucleotide describes an oligonucleotide comprising one or more sugar-modified nucleosides and/or modified internucleoside linkages. The term chimeric” oligonucleotide is a term that has been used in the literature to describe oligonucleotides with modified nucleosides.
Complementarity
The term complementarity describes the capacity for Watson-Crick base-pairing of nucleosides/nucleotides. Watson-Crick base pairs are guanine (G)-cytosine (C) and adenine (A)-thymine (T)/uracil (U). It will be understood that oligonucleotides may comprise nucleosides with modified nucleobases, for example 5-methyl cytosine is often used in place of cytosine, and as such the term complementarity encompasses Watson Crick base-paring between non-modified and modified nucleobases (see for example Hirao et al (2012) Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1).
The term “% complementary” as used herein, refers to the number of nucleotides in percent of a contiguous nucleotide sequence in a nucleic acid molecule (e.g. oligonucleotide) which, at a given position, are complementary to (i.e. form Watson Crick base pairs with) a contiguous nucleotide sequence, at a given position of a separate nucleic acid molecule (e.g. the target nucleic acid). The percentage is calculated by counting the number of aligned bases that form pairs between the two sequences, dividing by the total number of nucleotides in the oligonucleotide and multiplying by 100. In such a comparison a nucleobase/nucleotide which does not align (form a base pair) is termed a mismatch.
The term “fully complementary”, refers to 100% complementarity.
Hybridization
The term “hybridizing” or “hybridizes” as used herein is to be understood as two nucleic acid strands (e.g. an oligonucleotide and a target nucleic acid) forming hydrogen bonds between base pairs on opposite strands thereby forming a duplex. The affinity of the binding between two nucleic acid strands is the strength of the hybridization. It is often described in terms of the melting temperature (Tm) defined as the temperature at which half of the oligonucleotides are duplexed with the target nucleic acid. At physiological conditions Tm is not strictly proportional to the affinity (Mergny and Lacroix, 2003, Oligonucleotides 13:515-537). The standard state Gibbs free energy ΔG° is a more accurate representation of binding affinity and is related to the dissociation constant (Kd) of the reaction by ΔG°=−RT ln(Kd), where R is the gas constant and T is the absolute temperature. Therefore, a very low ΔG° of the reaction between an oligonucleotide and the target nucleic acid reflects a strong hybridization between the oligonucleotide and target nucleic acid. ΔG° is the energy associated with a reaction where aqueous concentrations are 1M, the pH is 7, and the temperature is 37° C. The hybridization of oligonucleotides to a target nucleic acid is a spontaneous reaction and for spontaneous reactions ΔG° is less than zero. ΔG° can be measured experimentally, for example, by use of the isothermal titration calorimetry (ITC) method as described in Hansen et al., 1965, Chem. Comm. 36-38 and Holdgate et al., 2005, Drug Discov Today. The skilled person will know that commercial equipment is available for ΔG° measurements. ΔG° can also be estimated numerically by using the nearest neighbor model as described by SantaLucia, 1998, Proc Natl Acad Sci USA. 95: 1460-1465 using appropriately derived thermodynamic parameters described by Sugimoto et al., 1995, Biochemistry 34:11211-11216 and McTigue et al., 2004, Biochemistry 43:5388-5405. In order to have the possibility of modulating its intended nucleic acid target by hybridization, oligonucleotides of the present invention hybridize to a target nucleic acid with estimated ΔG° values below −10 kcal for oligonucleotides that are 10-30 nucleotides in length. In some embodiments the degree or strength of hybridization is measured by the standard state Gibbs free energy ΔG°. The oligonucleotides may hybridize to a target nucleic acid with estimated ΔG° values below the range of −10 kcal, such as below −15 kcal, such as below −20 kcal and such as below −25 kcal for oligonucleotides that are 8-30 nucleotides in length. In some embodiments the oligonucleotides hybridize to a target nucleic acid with an estimated ΔG° value of −10 to −60 kcal, such as −12 to −40, such as from −15 to −30 kcal or −16 to −27 kcal such as −18 to −25 kcal.
The Target
The target refers to the protein which it is desired to modulate.
Target Nucleic Acid
A target nucleic acid is the intended target which the oligonucleotide of the invention hybridizes to, and may for example be a gene, a RNA, a non-coding RNA, a long non-coding RNA, a mRNA, and pre-mRNA, a mature mRNA or a cDNA sequence. In some embodiments the target nucleic acid is a non-coding RNA or a long non-coding RNA, or a subsequence thereof. For in vivo or in vitro application, the oligonucleotide of the invention is capable of decreasing the level of the SNHG14 transcript downstream of SNORD109B of and thereby relieving the suppression of the paternal UBE3A transcript in the intended target cell. The contiguous sequence of nucleobases of the oligonucleotide of the invention is complementary to the target nucleic acid, as measured across the length of the oligonucleotide, optionally with the exception of one or two mismatches, and optionally excluding nucleotide based linker regions which may link the oligonucleotide to an optional functional group such as a conjugate.
Target Sequence
The oligonucleotide comprises a contiguous nucleotide sequence which is complementary to or hybridizes to a sub-sequence of the target nucleic acid molecule. The term “target sequence” as used herein refers to a sequence of nucleotides present in the target nucleic acid which comprises the nucleobase sequence which is complementary to the oligonucleotide of the invention. In some embodiments, the target sequence consists of a region on the target nucleic acid which is complementary to the contiguous nucleotide sequence of the oligonucleotide of the invention. In some embodiments the target sequence is longer than the complementary sequence of a single oligonucleotide, and may, for example represent a preferred region of the target nucleic acid which may be targeted by several oligonucleotides of the invention.
The oligonucleotide of the invention comprises a contiguous nucleotide sequence which is complementary to the target nucleic acid, such as a target sequence.
The oligonucleotide comprises a contiguous nucleotide sequence of at least 8 nucleotides which is complementary to or hybridizes to a target sequence present in the target nucleic acid molecule. The contiguous nucleotide sequence (and therefore the target sequence) comprises of at least 8 contiguous nucleotides, such as 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 contiguous nucleotides, such as from 12-25, such as from 14-18 contiguous nucleotides.
Target Cell
The term a target cell as used herein refers to a cell which is expressing the target nucleic acid. In some embodiments the target cell may be in vivo or in vitro. In some embodiments the target cell is a mammalian cell such as a rodent cell, such as a mouse cell or a rat cell, or a primate cell such as a monkey cell or a human cell. In preferred embodiments the target cell is a neuronal cell.
Naturally Occurring Variant
The term “naturally occurring variant” refers to variants of SNHG14 transcript downstream of SNORD109B gene or transcripts which originate from the same genetic loci as the target nucleic acid, but may differ for example, by virtue of degeneracy of the genetic code causing a multiplicity of codons in the long non-coding RNA. The oligonucleotide of the invention may therefore be designed to target the target nucleic acid and naturally occurring variants thereof.
Modulation of Expression
The term “modulation of expression” as used herein is to be understood as an overall term for an oligonucleotide's ability to alter the amount of UBE3A protein when compared to the amount of UBE3A before administration of the oligonucleotide. Alternatively modulation of expression may be determined by reference to a control experiment where the oligonucleotide of the invention is not administered. The modulation effected by the oligonucleotide is related to it's ability to reduce, remove, prevent, lessen, lower or terminate the suppression of the paternal UBE3A transcript, e.g. by degradation or removal of the non-coding SNHG14 transcript downstream of SNORD109B or by blockage or prevention of polymerase activity associated with the SNHG14 transcript downstream of SNORD109B. The modulation can also be viewed as the oligonucleotide's ability to restore, increase or enhance expression of paternal UBE3A, e.g. by removal or blockage of inhibitory mechanisms affected by the non-coding SNHG14 transcript downstream of SNORD109B.
High Affinity Modified Nucleosides
A high affinity modified nucleoside is a modified nucleotide which, when incorporated into the oligonucleotide enhances the affinity of the oligonucleotide for its complementary target, for example as measured by the melting temperature (Tm). A high affinity modified nucleoside of the present invention preferably result in an increase in melting temperature between +0.5 to +12° C., more preferably between +1.5 to +10° C. and most preferably between +3 to +8° C. per modified nucleoside. Numerous high affinity modified nucleosides are known in the art and include for example, many 2′ substituted nucleosides as well as locked nucleic acids (LNA) (see e.g. Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213).
Sugar Modifications
The oligomer of the invention may comprise one or more nucleosides which have a modified sugar moiety, i.e. a modification of the sugar moiety when compared to the ribose sugar moiety found in DNA and RNA.
Numerous nucleosides with modification of the ribose sugar moiety have been made, primarily with the aim of improving certain properties of oligonucleotides, such as affinity and/or nuclease resistance.
Such modifications include those where the ribose ring structure is modified, e.g. by replacement with a hexose ring (HNA), or a bicyclic ring, which typically have a biradicle bridge between the C2 and C4 carbons on the ribose ring (LNA), or an unlinked ribose ring which typically lacks a bond between the C2 and C3 carbons (e.g. UNA). Other sugar modified nucleosides include, for example, bicyclohexose nucleic acids (WO2011/017521) or tricyclic nucleic acids (WO2013/154798). Modified nucleosides also include nucleosides where the sugar moiety is replaced with a non-sugar moiety, for example in the case of peptide nucleic acids (PNA), or morpholino nucleic acids.
Sugar modifications also include modifications made via altering the substituent groups on the ribose ring to groups other than hydrogen, or the 2′-OH group naturally found in DNA and RNA nucleosides. Substituents may, for example be introduced at the 2′, 3′, 4′ or 5′ positions. Nucleosides with modified sugar moieties also include 2′ modified nucleosides, such as 2′ substituted nucleosides. Indeed, much focus has been spent on developing 2′ substituted nucleosides, and numerous 2′ substituted nucleosides have been found to have beneficial properties when incorporated into oligonucleotides, such as enhanced nucleoside resistance and enhanced affinity.
2′ Modified Nucleosides.
A 2′ sugar modified nucleoside is a nucleoside which has a substituent other than H or —OH at the 2′ position (2′ substituted nucleoside) or comprises a 2′ linked biradicle, and includes 2′ substituted nucleosides and LNA (2′-4′ biradicle bridged) nucleosides. For example, the 2′ modified sugar may provide enhanced binding affinity and/or increased nuclease resistance to the oligonucleotide. Examples of 2′ substituted modified nucleosides are 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA (MOE), 2′-amino-DNA, 2′-Fluoro-RNA, and 2′-fluoro-ANA (F-ANA). For further examples, please see e.g. Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213; and Deleavey and Damha, Chemistry and Biology 2012, 19, 937. Below are illustrations of some 2′ substituted modified nucleosides.
![embedded image]()
Locked Nucleic Acid Nucleosides (LNA).
LNA nucleosides are modified nucleosides which comprise a linker group (referred to as a biradicle or a bridge) between C2′ and C4′ of the ribose sugar ring of a nucleotide. These nucleosides are also termed bridged nucleic acid or bicyclic nucleic acid (BNA) in the literature.
In some embodiments, the modified nucleoside or the LNA nucleosides of the oligomer of the invention has a general structure of the formula I or II:
![embedded image]()
wherein W is selected from —O—, —S—, —N(Ra)—, —C(RaRb)—, such as, in some embodiments —O—;
B designates a nucleobase or modified nucleobase moiety;
Z designates an internucleoside linkage to an adjacent nucleoside, or a 5′-terminal group;
Z* designates an internucleoside linkage to an adjacent nucleoside, or a 3′-terminal group;
X designates a group selected from the list consisting of —C(RaRb)—, —C(Ra)═C(Rb)—, —C(Ra)═N—, —O—, —Si(Ra)2—, —S—, —SO2—, —N(Ra)—, and >C═Z
- In some embodiments, X is selected from the group consisting of: —O—, —S—, NH—, NRaRb, —CH2—, CRaRb, —C(═CH2)—, and —C(═CRaRb)—
- In some embodiments, X is —O—
Y designates a group selected from the group consisting of —C(RaRb)—, —C(Ra)═C(Rb)—, —C(Ra)═N—, —O—, —Si(Ra)2—, —S—, —SO2—, —N(Ra)—, and >C═Z
- In some embodiments, Y is selected from the group consisting of: —CH2—, —C(RaRb)—, —CH2CH2—, —C(RaRb)—C(RaRb)—, —CH2CH2CH2—, —C(RaRb)C(RaRb)C(RaRb)—, —C(Ra)═C(Rb)—, and —C(Ra)═N—
- In some embodiments, Y is selected from the group consisting of: —CH2—, —CHRa—, —CHCH3—, CRaRb—
or —X—Y— together designate a bivalent linker group (also referred to as a radical) together designate a bivalent linker group consisting of 1, 2, 3 or 4 groups/atoms selected from the group consisting of —C(RaRb)—, —C(Ra)═C(Rb)—, —C(Ra)═N—, —O—, —Si(Ra)2—, —S—, —SO2—, —N(Ra)—, and >C═Z,
- In some embodiments, —X—Y— designates a biradicle selected from the groups consisting of: —X—CH2—, —X—CRaRb—, —X—CHRa−, —X—C(HCH3)−, —O—Y—, —O—CH2—, —S—CH2—, —NH—CH2—, —O—CHCH3—, —CH2—O—CH2, —O—CH(CH3CH3)—, —O—CH2—CH2—, OCH2—CH2—CH2—, —O—CH2OCH2—, —O—NCH2—, —C(═CH2)—CH2—, —NRa—CH2—, N—O—CH2, —S—CRaRb— and —S—CHRa—.
- In some embodiments —X—Y— designates —O—CH2— or —O—CH(CH3)—.
wherein Z is selected from —O—, —S—, and —N(Ra)—,
and Ra and, when present Rb, each is independently selected from hydrogen, optionally substituted C1-6-alkyl, optionally substituted C2-6-alkenyl, optionally substituted C2-6-alkynyl, hydroxy, optionally substituted C1-6-alkoxy, C2-6-alkoxyalkyl, C2-6-alkenyloxy, carboxy, C1-6-alkoxycarbonyl, C1-6-alkylcarbonyl, formyl, aryl, aryloxy-carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C1-6-alkyl)amino, carbamoyl, mono- and di(C1-6-alkyl)-amino-carbonyl, amino-C1-6-alkyl-aminocarbonyl, mono- and di(C1-6-alkyl)amino-C1-6-alkyl-aminocarbonyl, C1-6-alkyl-carbonylamino, carbamido, C1-6-alkanoyloxy, sulphono, C1-6-alkylsulphonyloxy, nitro, azido, sulphanyl, C1-6-alkylthio, halogen, where aryl and heteroaryl may be optionally substituted and where two geminal substituents Ra and Rb together may designate optionally substituted methylene (═CH2), wherein for all chiral centers, asymmetric groups may be found in either R or S orientation.
wherein R1, R2, R3, R5 and R5* are independently selected from the group consisting of: hydrogen, optionally substituted C1-6-alkyl, optionally substituted C2-6-alkenyl, optionally substituted C2-6-alkynyl, hydroxy, C1-6-alkoxy, C2-6-alkoxyalkyl, C2-6-alkenyloxy, carboxy, C1-6-alkoxycarbonyl, C1-6-alkylcarbonyl, formyl, aryl, aryloxy-carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C1-6-alkyl)amino, carbamoyl, mono- and di(C1-6-alkyl)-amino-carbonyl, amino-C1-6-alkyl-aminocarbonyl, mono- and di(C1-6-alkyl)amino-C1-6-alkyl-aminocarbonyl, C1-6-alkyl-carbonylamino, carbamido, C1-6-alkanoyloxy, sulphono, C1-6-alkylsulphonyloxy, nitro, azido, sulphanyl, C1-6-alkylthio, halogen, where aryl and heteroaryl may be optionally substituted, and where two geminal substituents together may designate oxo, thioxo, imino, or optionally substituted methylene.
- In some embodiments R1, R2, R3, R5 and R5* are independently selected from C1-6 alkyl, such as methyl, and hydrogen.
- In some embodiments R1, R2, R3, R5 and R5* are all hydrogen.
- In some embodiments R1, R2, R3, are all hydrogen, and either R5 and R5* is also hydrogen and the other of R5 and R5* is other than hydrogen, such as C1-6 alkyl such as methyl.
- In some embodiments, Ra is either hydrogen or methyl. In some embodiments, when present, Rb is either hydrogen or methyl.
- In some embodiments, one or both of Ra and Rb is hydrogen
- In some embodiments, one of Ra and Rb is hydrogen and the other is other than hydrogen
- In some embodiments, one of Ra and Rb is methyl and the other is hydrogen
- In some embodiments, both of Ra and Rb are methyl.
In some embodiments, the biradicle —X—Y— is —O—CH2—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such LNA nucleosides are disclosed in WO99/014226, WO00/66604, WO98/039352 and WO2004/046160 which are all hereby incorporated by reference, and include what are commonly known as beta-D-oxy LNA and alpha-L-oxy LNA nucleosides.
In some embodiments, the biradicle —X—Y— is —S—CH2—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such thio LNA nucleosides are disclosed in WO99/014226 and WO2004/046160 which are hereby incorporated by reference.
In some embodiments, the biradicle —X—Y— is —NH—CH2—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such amino LNA nucleosides are disclosed in WO99/014226 and WO2004/046160 which are hereby incorporated by reference.
In some embodiments, the biradicle —X—Y— is —O—CH2—CH2— or —O—CH2—CH2—CH2—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such LNA nucleosides are disclosed in WO00/047599 and Morita et al, Bioorganic & Med. Chem. Lett. 12 73-76, which are hereby incorporated by reference, and include what are commonly known as 2′-O-4′C-ethylene bridged nucleic acids (ENA).
In some embodiments, the biradicle —X—Y— is —O—CH2—, W is O, and all of R1, R2, R3, and one of R5 and R5* are hydrogen, and the other of R5 and R5* is other than hydrogen such as C1-6 alkyl, such as methyl. Such 5′ substituted LNA nucleosides are disclosed in WO2007/134181 which is hereby incorporated by reference.
In some embodiments, the biradicle —X—Y— is —O—CRaRb—, wherein one or both of Ra and Rb are other than hydrogen, such as methyl, W is O, and all of R1, R2, R3, and one of R5 and R5* are hydrogen, and the other of R5 and R5* is other than hydrogen such as C1-6 alkyl, such as methyl. Such bis modified LNA nucleosides are disclosed in WO2010/077578 which is hereby incorporated by reference.
In some embodiments, the biradicle —X—Y— designate the bivalent linker group —O—CH(CH2OCH3)— (2′ O-methoxyethyl bicyclic nucleic acid—Seth at al., 2010, J. Org. Chem. Vol 75(5) pp. 1569-81). In some embodiments, the biradicle —X—Y— designate the bivalent linker group —O—CH(CH2CH3)— (2′O-ethyl bicyclic nucleic acid—Seth at al., 2010, J. Org. Chem. Vol 75(5) pp. 1569-81). In some embodiments, the biradicle —X—Y— is —O—CHRa—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such 6′ substituted LNA nucleosides are disclosed in WO10036698 and WO07090071 which are both hereby incorporated by reference.
In some embodiments, the biradicle —X—Y— is —O—CH(CH2OCH3)—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such LNA nucleosides are also known as cyclic MOEs in the art (cMOE) and are disclosed in WO07090071.
In some embodiments, the biradicle —X—Y— designate the bivalent linker group —O—CH(CH3)—. —in either the R- or S-configuration. In some embodiments, the biradicle —X—Y— together designate the bivalent linker group —O—CH2—O—CH2— (Seth at al., 2010, J. Org. Chem). In some embodiments, the biradicle —X—Y— is —O—CH(CH3)—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such 6′ methyl LNA nucleosides are also known as cET nucleosides in the art, and may be either (S)cET or (R)cET stereoisomers, as disclosed in WO07090071 (beta-D) and WO2010/036698 (alpha-L) which are both hereby incorporated by reference).
In some embodiments, the biradicle —X—Y— is —O—CRaRb—, wherein in neither Ra or Rb is hydrogen, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. In some embodiments, Ra and Rb are both methyl. Such 6′ di-substituted LNA nucleosides are disclosed in WO 2009006478 which is hereby incorporated by reference.
In some embodiments, the biradicle —X—Y— is —S—CHRa—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such 6′ substituted thio LNA nucleosides are disclosed in WO11156202 which is hereby incorporated by reference. In some 6′ substituted thio LNA embodiments Ra is methyl.
In some embodiments, the biradicle —X—Y— is —C(═CH2)—C(RaRb)—, such as —C(═CH2)—CH2—, or —C(═CH2)—CH(CH3)—W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such vinyl carbo LNA nucleosides are disclosed in WO08154401 and WO09067647 which are both hereby incorporated by reference.
In some embodiments the biradicle —X—Y— is —N(—ORa)—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. In some embodiments Ra is C1-6 alkyl such as methyl. Such LNA nucleosides are also known as N substituted LNAs and are disclosed in WO2008/150729 which is hereby incorporated by reference. In some embodiments, the biradicle —X—Y— together designate the bivalent linker group —O—NRa—CH3— (Seth at al., 2010, J. Org. Chem). In some embodiments the biradicle —X—Y— is —N(Ra)—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. In some embodiments Ra is C1-6 alkyl such as methyl.
In some embodiments, one or both of R5 and R5* is hydrogen and, when substituted the other of R5 and R5* is C1-6 alkyl such as methyl. In such an embodiment, R1, R2, R3, may all be hydrogen, and the biradicle —X—Y— may be selected from —O—CH2— or —O—C(HCRa)—, such as —O—C(HCH3)-.
In some embodiments, the biradicle is —CRaRb—O—CRaRb—, such as CH2—O—CH2—, W is O and all of R1, R2, R3, R5 and R5* are all hydrogen. In some embodiments Ra is C1-6 alkyl such as methyl. Such LNA nucleosides are also known as conformationally restricted nucleotides (CRNs) and are disclosed in WO2013036868 which is hereby incorporated by reference.
In some embodiments, the biradicle is —O—CRaRb—O—CRaRb—, such as O—CH2—O—CH2—, W is O and all of R1, R2, R3, R5 and R5* are all hydrogen. In some embodiments Ra is C1-6alkyl such as methyl. Such LNA nucleosides are also known as COC nucleotides and are disclosed in Mitsuoka et al., Nucleic Acids Research 2009 37(4), 1225-1238, which is hereby incorporated by reference.
It will be recognized than, unless specified, the LNA nucleosides may be in the beta-D or alpha-L stereoisoform.
Certain examples of LNA nucleosides are presented in Scheme 1.
![embedded image]()
![embedded image]()
As illustrated in the examples, in preferred embodiments of the invention the LNA nucleosides in the oligonucleotides are beta-D-oxy-LNA nucleosides.
Nuclease Mediated Degradation
Nuclease mediated degradation refers to an oligonucleotide capable of mediating degradation of a complementary nucleotide sequence when forming a duplex with such a sequence.
In some embodiments, the oligonucleotide may function via nuclease mediated degradation of the target nucleic acid, where the oligonucleotides of the invention are capable of recruiting a nuclease, particularly and endonuclease, preferably endoribonuclease (RNase), such as RNase H. Examples of oligonucleotide designs which operate via nuclease mediated mechanisms are oligonucleotides which typically comprise a region of at least 5 or 6 DNA nucleosides and are flanked on one side or both sides by affinity enhancing nucleosides, for example gapmers, headmers and tailmers.
RNase H Activity and Recruitment
The RNase H activity of an antisense oligonucleotide refers to its ability to recruit RNase H when in a duplex with a complementary RNA molecule. WO01/23613 provides in vitro methods for determining RNaseH activity, which may be used to determine the ability to recruit RNaseH. Typically an oligonucleotide is deemed capable of recruiting RNase H if it, when provided with a complementary target nucleic acid sequence, has an initial rate, as measured in pmol/l/min, of at least 10% or more than 20% of the of the initial rate determined when using a oligonucleotide having the same base sequence as the modified oligonucleotide being tested, but containing only DNA monomers, with phosphorothioate linkages between all monomers in the oligonucleotide, and using the methodology provided by Example 91-95 of WO01/23613 (hereby incorporated by reference).
Gapmer
The term gapmer as used herein refers to an antisense oligonucleotide which comprises a region of RNase H recruiting oligonucleotides (gap) which is flanked 5′ and 3′ by one or more affinity enhancing modified nucleosides (flanks). Various gapmer designs are described herein. Headmers and tailmers are oligonucleotides capable of recruiting RNase H where one of the flanks is missing, i.e. only one of the ends of the oligonucleotide comprises affinity enhancing modified nucleosides. For headmers the 3′ flank is missing (i.e. the 5′ flank comprise affinity enhancing modified nucleosides) and for tailmers the 5′ flank is missing (i.e. the 3′ flank comprises affinity enhancing modified nucleosides).
LNA Gapmer
The term LNA gapmer is a gapmer oligonucleotide wherein at least one of the affinity enhancing modified nucleosides is an LNA nucleoside.
Mixed Wing Gapmer
The term mixed wing gapmer refers to a LNA gapmer wherein the flank regions comprise at least one LNA nucleoside and at least one non-LNA modified nucleoside, such as at least one 2′ substituted modified nucleoside, such as, for example, 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA (MOE), 2′-amino-DNA, 2′-Fluoro-RNA, and 2′-F-ANA nucleoside(s). In some embodiments the mixed wing gapmer has one flank which comprises LNA nucleosides (e.g. 5′ or 3′) and the other flank (3′ or 5′ respectfully) comprises 2′ substituted modified nucleoside(s).
Conjugate
The term conjugate as used herein refers to an oligonucleotide which is covalently linked to a non-nucleotide moiety (conjugate moiety or region C or third region).
Conjugation of the oligonucleotide of the invention to one or more non-nucleotide moieties may improve the pharmacology of the oligonucleotide, e.g. by affecting the activity, cellular distribution, cellular uptake or stability of the oligonucleotide. In some embodiments the conjugate moiety modify or enhance the pharmacokinetic properties of the oligonucleotide by improving cellular distribution, bioavailability, metabolism, excretion, permeability, and/or cellular uptake of the oligonucleotide. In particular the conjugate may target the oligonucleotide to a specific organ, tissue or cell type and thereby enhance the effectiveness of the oligonucleotide in that organ, tissue or cell type. A the same time the conjugate may serve to reduce activity of the oligonucleotide in non-target cell types, tissues or organs, e.g. off target activity or activity in non-target cell types, tissues or organs. WO 93/07883 and WO 2013/033230 provides suitable conjugate moieties, which are hereby incorporated by reference. WO 2012/143379 provides a method of delivering a drug across the blood-brain-barrier by conjugation to an antibody fragment with affinity to the transferrin receptor, which are hereby incorporated by reference.
Oligonucleotide conjugates and their synthesis has also been reported in comprehensive reviews by Manoharan in Antisense Drug Technology, Principles, Strategies, and Applications, S. T. Crooke, ed., Ch. 16, Marcel Dekker, Inc., 2001 and Manoharan, Antisense and Nucleic Acid Drug Development, 2002, 12, 103, each of which is incorporated herein by reference in its entirety.
In an embodiment, the non-nucleotide moiety (conjugate moiety) is selected from the group consisting of carbohydrates, cell surface receptor ligands, drug substances, hormones, lipophilic substances, polymers, proteins, peptides, toxins (e.g. bacterial toxins), vitamins, viral proteins (e.g. capsids) or combinations thereof. In some embodiments the non-nucleotide moiety an antibody or antibody fragment, such as an antibody or antibody fragment that facilitates delivery across the blood-brain-barrier, in particular an antibody or antibody fragment targeting the transferrin receptor.
Linkers
A linkage or linker is a connection between two atoms that links one chemical group or segment of interest to another chemical group or segment of interest via one or more covalent bonds. Conjugate moieties can be attached to the oligonucleotide directly or through a linking moiety (e.g. linker or tether). Linkers serve to covalently connect a third region, e.g. a conjugate moiety (Region C), to a first region, e.g. an oligonucleotide (region A).
In some embodiments of the invention the conjugate or oligonucleotide conjugate of the invention may optionally, comprise a linker region (second region or region B and/or region Y) which is positioned between the oligonucleotide (region A or first region) and the conjugate moiety (region C or third region).
Region B refers to biocleavable linkers comprising or consisting of a physiologically labile bond that is cleavable under conditions normally encountered or analogous to those encountered within a mammalian body. Conditions under which physiologically labile linkers undergo chemical transformation (e.g., cleavage) include chemical conditions such as pH, temperature, oxidative or reductive conditions or agents, and salt concentration found in or analogous to those encountered in mammalian cells. Mammalian intracellular conditions also include the presence of enzymatic activity normally present in a mammalian cell such as from proteolytic enzymes or hydrolytic enzymes or nucleases. In one embodiment the biocleavable linker is susceptible to S1 nuclease cleavage. In a preferred embodiment the nuclease susceptible linker comprises between 1 and 10 nucleosides, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleosides, more preferably between 2 and 6 nucleosides and most preferably between 2 and 4 linked nucleosides comprising at least two consecutive phosphodiester linkages, such as at least 3 or 4 or 5 consecutive phosphodiester linkages. Preferably the nucleosides are DNA or RNA. Phosphodiester containing biocleavable linkers are described in more detail in WO 2014/076195 (hereby incorporated by reference).
Region Y refers to linkers that are not necessarily biocleavable but primarily serve to covalently connect a conjugate moiety (region C or third region), to an oligonucleotide (region A or first region). The region Y linkers may comprise a chain structure or an oligomer of repeating units such as ethylene glycol, amino acid units or amino alkyl groups The oligonucleotide conjugates of the present invention can be constructed of the following regional elements A-C, A-B-C, A-B-Y-C, A-Y-B-C or A-Y-C. In some embodiments the linker (region Y) is an amino alkyl, such as a C2-C36 amino alkyl group, including, for example C6 to C12 amino alkyl groups. In a preferred embodiment the linker (region Y) is a C6 amino alkyl group.
Control
By the term “control” when used in relation to measurements of the effect of an oligonucleotide it is generally understood that the control is an untreated individual or target cell or a individual or target cell treated with a non-targeting oligonucleotide (mock). It may however also be an individual treated with the standard of care.
Treatment
The term ‘treatment’ as used herein refers to both treatment of an existing disease (e.g. a disease or disorder as herein referred to), or prevention of a disease, i.e. prophylaxis. It will therefore be recognized that treatment as referred to herein may, in some embodiments, be prophylactic.
DETAILED DESCRIPTION OF THE INVENTION
The Target
An aspect of the invention is to modulate the level of pig, primate or human UBE3A protein expression, in particular to increase the expression of paternal UBE3A expression in neuronal cells, in particular in human neuronal cells. The human UBE3A protein exists in several isoforms which are listed under Uniprot nr. Q05086. Several mutations in the maternal UBE3A gene can results in Angelman syndrome.
The target nucleic acid for the oligonucleotides of the invention is RNA, in particular a long non-coding RNA. The long non-coding RNA which is targeted by the oligonucleotides of the present invention is human SNHG14 (also known as UBE3A-ATS with Ensembl entry number ENSG00000224078, version GRCh38.p2). In particular the target nucleic acid is the region downstream of SNORD109B corresponding to position 25278410 to 25419462 on chromosome 15 (SEQ ID NO: 1). In Rhesus monkey (Macaca mulatta) the UBE3A supressor is defined as region downstream of SNORD109A corresponding to position 4222848 to U.S. Pat. No. 4,373,084 (forward strand) on chromosome 7 using the Ensembl assembly MMUL 1.0 (SEQ ID NO: 2).
In some embodiments, the target nucleic acid is SEQ ID NO: 1, or naturally occurring variants thereof.
In certain embodiments the target nucleic acid correspond to regions which are conserved between human (SEQ ID NO: 1) and Rhesus monkey (SEQ ID NO: 2). In certain embodiments target nucleic acid correspond to regions which are conserved between human (SEQ ID NO:1), Rhesus monkey (SEQ ID NO: 2) and mouse (SEQ ID NO: 3).
In certain embodiments the target nucleic acid is the region that is antisense to the UBE3A pre-mRNA, this region corresponds to position 55319 to 141053 of SEQ ID NO: 1.
In certain embodiments the target nucleic acid is the region that is downstream of SNORD109B and upstream of the region that is antisense to the UBE3A pre-mRNA, this region corresponds to position 1 to 55319 of SEQ ID NO: 1.
In some embodiments, the target nucleic acid is present in a cell, such as a mammalian cell in particular a human cell in vitro or in vivo (the target cell). In certain embodiments the target cell is a neuron, preferably a human neuronal cell.
The target sequence may be a sub-sequence of the target nucleic acid. In some embodiments the oligonucleotide targets sub-sequence selected from the group consisting of the antisense region of exon 9, exon10, exon13, exon14, intron 14, exon 15, intron15 and exon 16 of UBE3A. In some embodiments the oligonucleotide or contiguous nucleotide sequence hybridize or is complementary to a single stranded nucleic acid molecule selected from the group consisting of positions: 55319-76274, 77483-77573, 92157-93403 and 97056-97354 of SEQ ID NO: 1. In some embodiments the oligonucleotide or contiguous nucleotide sequence hybridize or is complementary to a single stranded nucleic acid molecule selected from the group consisting of positions: 60821-60849, 77567-77583, 92323-92339 and 97156-97172 of SEQ ID NO: 1.
In some embodiments the target nucleic acid is a region corresponding to positions 9200-9250 of SEQ ID NO: 1.
In some embodiments the target nucleic acid is a region corresponding to positions 11505-11555 of SEQ ID NO: 1.
In some embodiments the target nucleic acid is a region corresponding to positions 15100-15150 of SEQ ID NO: 1.
In some embodiments the target nucleic acid is a region corresponding to positions 30590-30740 of SEQ ID NO: 1.
In some embodiments the target nucleic acid is a region corresponding to positions 46380-46430 of SEQ ID NO: 1.
The Oligonucleotides of the Invention
The invention relates to oligonucleotides capable of modulating expression of paternal UBE3A, in particular induction or up-regulation of paternally expressed UBE3A in neuronal cells. The modulation is achieved by hybridizing to a target nucleic acid located on the long non-coding RNA SNHG14 transcript downstream of SNORD109B. In certain embodiments the oligonucleotide of the invention hybridizes to a sub-sequence of the target nucleic acid of SEQ ID NO: 1 with a ΔG° below −10 kcal, such as with a ΔG° between −10 to −60 kcal, such as −12 to −40, such as from −15 to −30 kcal or −16 to −27 kcal such as −18 to −25 kcal.
The oligonucleotide of the invention is an antisense oligonucleotide which targets the pig, rhesus monkey and/or human SNHG14 transcript downstream of SNORD109B.
In some embodiments the antisense oligonucleotide of the invention is capable of modulating the expression of the target by removing, interfering with or decreasing the suppressor of the target. Preferably, the oligonucleotides of the invention induce UBE3A expression in a cell, in particular paternal UBE3A expression in a neuron, by degradation or removal of the SNHG14 transcript downstream of SNORD109B. In some embodiments the oligonucleotides of the invention are capable of increasing the expression of UBE3A by least 20% compared to the expression level of UBE3A in a neuronal cell treated with saline or a non-targeting oligonucleotide, more preferably by at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 80%, 100%, 120%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250% compared to the expression level of UBE3A in a neuronal cell treated with saline or a non-targeting oligonucleotide. In additional embodiments the oligonucleotides of the invention are capable of decreasing the level of the SNHG14 transcript downstream of SNORD109B (in particular the part of the transcript that is antisense to the UBE3A pre-mRNA region) by at least 20% compared to the level of the SNHG14 transcript downstream of SNORD109B in a neuronal cell treated with saline or a non-targeting oligonucleotide, more preferably by at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% compared to the level of the SNHG14 transcript downstream of SNORD109B in a neuronal cell treated with saline or a non-targeting oligonucleotide, without reducing SNORD115 levels by more than 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25% or 30% compared to the level of SNORD115 in a cell treated with saline or a non-targeting oligonucleotide. SNRPN and SNORD116 transcripts are located upstream from the SNORD115 transcript consequently if the SNORD115 transcript is not reduced by the oligonucleotide it is highly likely that the SNRPN and SNORD116 transcripts are also not reduced. In a further embodiment SNRPN and SNORD116 transcripts levels are not reduced by more than 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25% or 30% compared to the level of SNRPN and SNORD116 in a cell treated with saline or a non-targeting oligonucleotide.
The target modulation is triggered by the hybridization between a contiguous nucleotide sequence of the oligonucleotide and the target nucleic acid. In some embodiments the oligonucleotide of the invention comprises mismatches between the oligonucleotide and the target nucleic acid. Despite mismatches hybridization to the target nucleic acid may still be sufficient to show a desired modulation of UBE3A expression. Reduced binding affinity resulting from mismatches may advantageously be compensated by increased number of nucleotides in the oligonucleotide and/or an increased number of modified nucleosides capable of increasing the binding affinity to the target, such as 2′ modified nucleosides, including LNA, present within the oligonucleotide sequence.
An aspect of the present invention relates to an antisense oligonucleotide which comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90%, such as 95%, such as 98% such as 100% complementarity to position 25278410 to 25419462 on human chromosome 15.
In some embodiments, the oligonucleotide comprises a contiguous sequence which is at least 90% complementary, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, or 100% complementary with a region of the target nucleic acid shown as SEQ ID NO: 1, 2 or 3.
In a preferred embodiment the oligonucleotide of the invention, or contiguous nucleotide sequence thereof is fully complementary (100% complementary) to a region of the target nucleic acid shown as SEQ ID NO: 1, or in some embodiments may comprise one or two mismatches between the oligonucleotide and the target nucleic acid.
In some embodiments the oligonucleotide sequence is 100% complementary to a corresponding target nucleic acid region present in SEQ ID NO: 1 and SEQ ID NO: 2. In some embodiments the oligonucleotide sequence is 100% complementary to a corresponding target nucleic acid region present SEQ ID NO: 1, 2 and 3.
In some embodiments, the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary, such as 100% complementarity, to a corresponding target nucleic acid region present in SEQ ID NO: 1, wherein the target nucleic acid region is selected from the group consisting of region A1 to A3649 in table 1
TABLE 1
|
|
Regions of SEQ ID NO 1 which may be targeted
|
using oligonucleotide of the invention
|
Position in
|
SEQ ID NO 1
|
Reg. A
from
to
Length
|
|
1
10
75
66
|
2
77
91
15
|
3
93
108
16
|
4
168
213
46
|
5
217
282
66
|
6
284
299
16
|
7
301
328
28
|
8
330
344
15
|
9
361
400
40
|
10
415
447
33
|
11
449
470
22
|
12
472
487
16
|
13
489
521
33
|
14
523
540
18
|
15
551
570
20
|
16
590
638
49
|
17
652
670
19
|
18
672
733
62
|
19
735
756
22
|
20
758
773
16
|
21
781
829
49
|
22
831
870
40
|
23
882
903
22
|
24
918
949
32
|
25
961
990
30
|
26
1007
1021
15
|
27
1019
1050
32
|
28
1052
1090
39
|
29
1092
1139
48
|
30
1147
1179
33
|
31
1175
1212
38
|
32
1220
1242
23
|
33
1245
1259
15
|
34
1265
1278
14
|
35
1285
1323
39
|
36
1317
1330
14
|
37
1337
1355
19
|
38
1357
1403
47
|
39
1405
1421
17
|
40
1423
1481
59
|
41
1486
1515
30
|
42
1521
1581
61
|
43
1611
1633
23
|
44
1631
1644
14
|
45
1635
1663
29
|
46
1669
1684
16
|
47
1685
1709
25
|
48
1711
1724
14
|
49
1726
1746
21
|
50
1754
1808
55
|
51
1819
1860
42
|
52
1862
1878
17
|
53
1896
1910
15
|
54
1923
1944
22
|
55
1946
1987
42
|
56
1985
2051
67
|
57
2053
2082
30
|
58
2088
2104
17
|
59
2106
2125
20
|
60
2132
2207
76
|
61
2209
2234
26
|
62
2247
2261
15
|
63
2263
2286
24
|
64
2290
2306
17
|
65
2308
2329
22
|
66
2347
2391
45
|
67
2398
2431
34
|
68
2447
2468
22
|
69
2470
2555
86
|
70
2565
2579
15
|
71
2579
2592
14
|
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40
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14
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42
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16
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35
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17
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44
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23
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15
|
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84
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59
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44
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16
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41
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28
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48
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45
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36
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81
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74
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62
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63
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52
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14
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30
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1769
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|
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32
|
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26
|
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|
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|
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14
|
1777
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|
1778
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17
|
1779
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59
|
1780
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|
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35
|
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|
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17
|
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63
|
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|
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42
|
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67
|
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16
|
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|
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|
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16
|
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34
|
1797
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14
|
1798
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23
|
1799
71910
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15
|
1800
71985
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15
|
1801
72000
72021
22
|
1802
72023
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25
|
1803
72071
72158
88
|
1804
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28
|
1805
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41
|
1806
72236
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20
|
1807
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25
|
1808
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17
|
1809
72312
72329
18
|
1810
72323
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14
|
1811
72348
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48
|
1812
72398
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14
|
1813
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43
|
1814
72470
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34
|
1815
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36
|
1816
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14
|
1817
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27
|
1818
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15
|
1819
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15
|
1820
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26
|
1821
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51
|
1822
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41
|
1823
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24
|
1824
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26
|
1825
72801
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86
|
1826
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16
|
1827
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31
|
1828
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29
|
1829
73001
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14
|
1830
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73053
37
|
1831
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24
|
1832
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14
|
1833
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34
|
1834
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30
|
1835
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26
|
1836
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40
|
1837
73218
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40
|
1838
73260
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14
|
1839
73268
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14
|
1840
73278
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14
|
1841
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73313
16
|
1842
73451
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15
|
1843
73459
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14
|
1844
73512
73567
56
|
1845
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43
|
1846
73614
73645
32
|
1847
73661
73713
53
|
1848
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16
|
1849
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16
|
1850
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14
|
1851
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20
|
1852
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19
|
1853
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19
|
1854
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35
|
1855
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14
|
1856
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20
|
1857
73906
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14
|
1858
73916
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30
|
1859
73947
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15
|
1860
73978
74018
41
|
1861
74020
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27
|
1862
74061
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22
|
1863
74092
74158
67
|
1864
74160
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18
|
1865
74179
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31
|
1866
74216
74245
30
|
1867
74270
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18
|
1868
74289
74305
17
|
1869
74307
74368
62
|
1870
74369
74411
43
|
1871
74416
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46
|
1872
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17
|
1873
74506
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36
|
1874
74543
74636
94
|
1875
74647
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58
|
1876
74745
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26
|
1877
74789
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25
|
1878
74815
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24
|
1879
74850
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28
|
1880
74891
74923
33
|
1881
74925
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16
|
1882
74952
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18
|
1883
74979
75001
23
|
1884
75037
75066
30
|
1885
75068
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21
|
1886
75097
75123
27
|
1887
75131
75149
19
|
1888
75152
75189
38
|
1889
75210
75252
43
|
1890
75254
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23
|
1891
75288
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23
|
1892
75338
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20
|
1893
75359
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14
|
1894
75376
75397
22
|
1895
75405
75432
28
|
1896
75440
75470
31
|
1897
75482
75501
20
|
1898
75503
75540
38
|
1899
75544
75560
17
|
1900
75562
75576
15
|
1901
75589
75610
22
|
1902
75633
75646
14
|
1903
75648
75679
32
|
1904
75691
75709
19
|
1905
75711
75724
14
|
1906
75740
75764
25
|
1907
75763
75776
14
|
1908
75767
75790
24
|
1909
75780
75794
15
|
1910
75792
75808
17
|
1911
75810
75829
20
|
1912
75831
75863
33
|
1913
75865
75880
16
|
1914
75882
75922
41
|
1915
75932
75998
67
|
1916
76000
76026
27
|
1917
76028
76045
18
|
1918
76046
76082
37
|
1919
76098
76413
316
|
1920
76420
76442
23
|
1921
76456
76477
22
|
1922
76484
76558
75
|
1923
76573
76592
20
|
1924
76608
76622
15
|
1925
76627
76663
37
|
1926
76665
76683
19
|
1927
76685
76698
14
|
1928
76702
76716
15
|
1929
76725
76744
20
|
1930
76745
76761
17
|
1931
76780
76796
17
|
1932
76798
76812
15
|
1933
76814
76832
19
|
1934
76834
76859
26
|
1935
76871
76934
64
|
1936
77012
77034
23
|
1937
77039
77055
17
|
1938
77081
77094
14
|
1939
77121
77184
64
|
1940
77186
77200
15
|
1941
77202
77225
24
|
1942
77227
77247
21
|
1943
77261
77317
57
|
1944
77327
77340
14
|
1945
77342
77366
25
|
1946
77377
77394
18
|
1947
77396
77439
44
|
1948
77453
77468
16
|
1949
77462
77593
132
|
1950
77586
77599
14
|
1951
77595
77641
47
|
1952
77643
77728
86
|
1953
77730
77768
39
|
1954
77778
77816
39
|
1955
77818
77835
18
|
1956
77837
77855
19
|
1957
77861
77876
16
|
1958
77882
77898
17
|
1959
77900
77924
25
|
1960
77923
77936
14
|
1961
77957
77970
14
|
1962
77962
77985
24
|
1963
77994
78022
29
|
1964
78024
78056
33
|
1965
78079
78128
50
|
1966
78132
78158
27
|
1967
78173
78213
41
|
1968
78224
78265
42
|
1969
78275
78332
58
|
1970
78334
78440
107
|
1971
78442
78489
48
|
1972
78491
78505
15
|
1973
78501
78514
14
|
1974
78507
78537
31
|
1975
78557
78570
14
|
1976
78562
78623
62
|
1977
78625
78665
41
|
1978
78668
78684
17
|
1979
78686
78759
74
|
1980
78761
78787
27
|
1981
78793
78814
22
|
1982
78816
78854
39
|
1983
78847
78860
14
|
1984
78874
78909
36
|
1985
78917
78944
28
|
1986
78956
78978
23
|
1987
78991
79008
18
|
1988
79003
79032
30
|
1989
79026
79040
15
|
1990
79044
79072
29
|
1991
79098
79158
61
|
1992
79162
79182
21
|
1993
79184
79228
45
|
1994
79221
79235
15
|
1995
79230
79262
33
|
1996
79287
79333
47
|
1997
79356
79392
37
|
1998
79441
79476
36
|
1999
79488
79522
35
|
2000
79522
79539
18
|
2001
79568
79583
16
|
2002
79574
79601
28
|
2003
79603
79618
16
|
2004
79617
79639
23
|
2005
79651
79683
33
|
2006
79685
79724
40
|
2007
79721
79736
16
|
2008
79727
79782
56
|
2009
79784
79812
29
|
2010
79809
79834
26
|
2011
79841
79861
21
|
2012
79873
79923
51
|
2013
79928
79948
21
|
2014
79950
79986
37
|
2015
79993
80019
27
|
2016
80019
80063
45
|
2017
80071
80088
18
|
2018
80114
80160
47
|
2019
80154
80183
30
|
2020
80185
80212
28
|
2021
80214
80232
19
|
2022
80240
80266
27
|
2023
80293
80312
20
|
2024
80344
80380
37
|
2025
80382
80420
39
|
2026
80410
80423
14
|
2027
80417
80438
22
|
2028
80440
80456
17
|
2029
80467
80499
33
|
2030
80501
80527
27
|
2031
80532
80561
30
|
2032
80563
80599
37
|
2033
80604
80692
89
|
2034
80702
80737
36
|
2035
80739
80795
57
|
2036
80796
80871
76
|
2037
80873
80891
19
|
2038
80925
80961
37
|
2039
80963
80992
30
|
2040
81009
81068
60
|
2041
81070
81150
81
|
2042
81156
81199
44
|
2043
81201
81225
25
|
2044
81237
81253
17
|
2045
81255
81271
17
|
2046
81292
81351
60
|
2047
81353
81371
19
|
2048
81392
81422
31
|
2049
81438
81483
46
|
2050
81485
81503
19
|
2051
81512
81526
15
|
2052
81532
81554
23
|
2053
81556
81593
38
|
2054
81606
81664
59
|
2055
81666
81698
33
|
2056
81701
81720
20
|
2057
81728
81776
49
|
2058
81781
81810
30
|
2059
81812
81847
36
|
2060
81849
81893
45
|
2061
81908
81934
27
|
2062
81943
81964
22
|
2063
81967
82034
68
|
2064
82036
82134
99
|
2065
82136
82154
19
|
2066
82176
82197
22
|
2067
82199
82250
52
|
2068
82252
82269
18
|
2069
82271
82293
23
|
2070
82300
82314
15
|
2071
82329
82343
15
|
2072
82344
82357
14
|
2073
82378
82407
30
|
2074
82406
82422
17
|
2075
82421
82443
23
|
2076
82446
82469
24
|
2077
82490
82507
18
|
2078
82502
82523
22
|
2079
82547
82576
30
|
2080
82590
82603
14
|
2081
82628
82647
20
|
2082
82650
82666
17
|
2083
82669
82683
15
|
2084
82685
82716
32
|
2085
82715
82736
22
|
2086
82760
82785
26
|
2087
82778
82791
14
|
2088
82780
82818
39
|
2089
82811
82825
15
|
2090
82821
82864
44
|
2091
82883
82915
33
|
2092
82919
82935
17
|
2093
82930
82946
17
|
2094
82937
82957
21
|
2095
82959
82972
14
|
2096
82974
83000
27
|
2097
83020
83036
17
|
2098
83038
83088
51
|
2099
83090
83115
26
|
2100
83120
83140
21
|
2101
83142
83155
14
|
2102
83160
83186
27
|
2103
83198
83215
18
|
2104
83227
83246
20
|
2105
83273
83339
67
|
2106
83341
83385
45
|
2107
83387
83400
14
|
2108
83413
83426
14
|
2109
83417
83449
33
|
2110
83486
83520
35
|
2111
83522
83565
44
|
2112
83567
83581
15
|
2113
83576
83670
95
|
2114
83681
83701
21
|
2115
83703
83716
14
|
2116
83733
83817
85
|
2117
83817
83830
14
|
2118
83832
83853
22
|
2119
83855
83871
17
|
2120
83886
83926
41
|
2121
83958
83974
17
|
2122
83976
83991
16
|
2123
83993
84031
39
|
2124
84033
84067
35
|
2125
84069
84102
34
|
2126
84104
84121
18
|
2127
84143
84233
91
|
2128
84249
84281
33
|
2129
84283
84403
121
|
2130
84404
84432
29
|
2131
84431
84444
14
|
2132
84434
84490
57
|
2133
84503
84520
18
|
2134
84522
84555
34
|
2135
84557
84572
16
|
2136
84574
84597
24
|
2137
84607
84626
20
|
2138
84650
84675
26
|
2139
84677
84700
24
|
2140
84721
84753
33
|
2141
84755
84807
53
|
2142
84809
84826
18
|
2143
84831
84849
19
|
2144
84879
84893
15
|
2145
84895
84915
21
|
2146
84917
84961
45
|
2147
85234
85247
14
|
2148
85253
85267
15
|
2149
85256
85351
96
|
2150
85359
85374
16
|
2151
85363
85376
14
|
2152
85365
85381
17
|
2153
85380
85414
35
|
2154
85416
85454
39
|
2155
85456
85484
29
|
2156
85509
85545
37
|
2157
85535
85550
16
|
2158
85566
85584
19
|
2159
85586
85610
25
|
2160
85604
85627
24
|
2161
85628
85665
38
|
2162
85698
85723
26
|
2163
85713
85728
16
|
2164
85722
85735
14
|
2165
85770
85785
16
|
2166
85800
85813
14
|
2167
85875
85888
14
|
2168
85950
85963
14
|
2169
86097
86125
29
|
2170
86127
86142
16
|
2171
86175
86198
24
|
2172
86226
86242
17
|
2173
86237
86302
66
|
2174
86308
86327
20
|
2175
86321
86334
14
|
2176
86329
86382
54
|
2177
86384
86400
17
|
2178
86403
86417
15
|
2179
86414
86437
24
|
2180
86439
86455
17
|
2181
86461
86478
18
|
2182
86473
86487
15
|
2183
86480
86517
38
|
2184
86517
86531
15
|
2185
86565
86583
19
|
2186
86600
86632
33
|
2187
86634
86651
18
|
2188
86653
86678
26
|
2189
86697
86756
60
|
2190
86782
86796
15
|
2191
86786
86809
24
|
2192
86811
86855
45
|
2193
86857
86891
35
|
2194
86894
86908
15
|
2195
86916
86933
18
|
2196
86945
86959
15
|
2197
86951
86965
15
|
2198
86969
86990
22
|
2199
87017
87057
41
|
2200
87059
87073
15
|
2201
87062
87076
15
|
2202
87066
87089
24
|
2203
87097
87121
25
|
2204
87110
87134
25
|
2205
87130
87155
26
|
2206
87160
87194
35
|
2207
87185
87198
14
|
2208
87209
87260
52
|
2209
87257
87270
14
|
2210
87274
87287
14
|
2211
87276
87294
19
|
2212
87294
87328
35
|
2213
87317
87333
17
|
2214
87336
87360
25
|
2215
87368
87418
51
|
2216
87441
87460
20
|
2217
87462
87487
26
|
2218
87489
87518
30
|
2219
87520
87539
20
|
2220
87542
87570
29
|
2221
87572
87601
30
|
2222
87603
87644
42
|
2223
87642
87750
109
|
2224
87756
87776
21
|
2225
87778
87803
26
|
2226
87803
87837
35
|
2227
87872
87888
17
|
2228
87890
87917
28
|
2229
87949
87964
16
|
2230
87963
88008
46
|
2231
88010
88027
18
|
2232
88029
88046
18
|
2233
88048
88089
42
|
2234
88091
88108
18
|
2235
88110
88177
68
|
2236
88179
88192
14
|
2237
88194
88229
36
|
2238
88234
88259
26
|
2239
88261
88291
31
|
2240
88303
88328
26
|
2241
88328
88341
14
|
2242
88340
88354
15
|
2243
88356
88372
17
|
2244
88411
88446
36
|
2245
88448
88465
18
|
2246
88469
88511
43
|
2247
88518
88533
16
|
2248
88531
88557
27
|
2249
88547
88560
14
|
2250
88573
88593
21
|
2251
88597
88618
22
|
2252
88620
88690
71
|
2253
88692
88745
54
|
2254
88954
88973
20
|
2255
88988
89047
60
|
2256
89066
89091
26
|
2257
89098
89119
22
|
2258
89135
89149
15
|
2259
89151
89181
31
|
2260
89177
89193
17
|
2261
89223
89273
51
|
2262
89285
89300
16
|
2263
89315
89383
69
|
2264
89404
89442
39
|
2265
89444
89541
98
|
2266
89579
89639
61
|
2267
89660
89692
33
|
2268
89694
89741
48
|
2269
89773
89787
15
|
2270
89789
89817
29
|
2271
89826
89888
63
|
2272
89904
89922
19
|
2273
89937
89950
14
|
2274
89945
89958
14
|
2275
89956
89974
19
|
2276
89971
89985
15
|
2277
89979
89992
14
|
2278
89984
90000
17
|
2279
89999
90014
16
|
2280
90017
90041
25
|
2281
90036
90049
14
|
2282
90077
90093
17
|
2283
90099
90128
30
|
2284
90130
90155
26
|
2285
90157
90200
44
|
2286
90225
90256
32
|
2287
90258
90293
36
|
2288
90305
90318
14
|
2289
90320
90352
33
|
2290
90356
90370
15
|
2291
90400
90421
22
|
2292
90423
90461
39
|
2293
90464
90507
44
|
2294
90509
90530
22
|
2295
90529
90542
14
|
2296
90531
90567
37
|
2297
90569
90612
44
|
2298
90614
90730
117
|
2299
90732
90758
27
|
2300
90760
90885
126
|
2301
90887
90918
32
|
2302
90920
90946
27
|
2303
90938
90955
18
|
2304
90960
90973
14
|
2305
90965
90981
17
|
2306
90973
91000
28
|
2307
90997
91011
15
|
2308
91002
91019
18
|
2309
91059
91140
82
|
2310
91142
91157
16
|
2311
91157
91194
38
|
2312
91196
91231
36
|
2313
91233
91251
19
|
2314
91253
91274
22
|
2315
91296
91310
15
|
2316
91335
91367
33
|
2317
91406
91442
37
|
2318
91447
91477
31
|
2319
91489
91509
21
|
2320
91520
91621
102
|
2321
91623
91674
52
|
2322
91680
91703
24
|
2323
91715
91731
17
|
2324
91733
91771
39
|
2325
91773
91788
16
|
2326
91790
91805
16
|
2327
91807
91823
17
|
2328
91825
91859
35
|
2329
91861
91900
40
|
2330
91907
91926
20
|
2331
91928
91943
16
|
2332
91950
91980
31
|
2333
91982
91996
15
|
2334
91998
92011
14
|
2335
92010
92027
18
|
2336
92027
92067
41
|
2337
92069
92126
58
|
2338
92128
92321
194
|
2339
92323
92540
218
|
2340
92542
92558
17
|
2341
92566
92684
119
|
2342
92686
92726
41
|
2343
92728
92837
110
|
2344
92839
93032
194
|
2345
93034
93094
61
|
2346
93100
93209
110
|
2347
93211
93254
44
|
2348
93256
93323
68
|
2349
93325
93448
124
|
2350
93459
93477
19
|
2351
93475
93497
23
|
2352
93509
93530
22
|
2353
93532
93566
35
|
2354
93568
93601
34
|
2355
93606
93646
41
|
2356
93668
93716
49
|
2357
93718
93742
25
|
2358
93744
93788
45
|
2359
93790
93808
19
|
2360
93811
93832
22
|
2361
93874
93901
28
|
2362
93904
93986
83
|
2363
94021
94036
16
|
2364
94038
94079
42
|
2365
94073
94086
14
|
2366
94097
94116
20
|
2367
94118
94141
24
|
2368
94140
94219
80
|
2369
94242
94257
16
|
2370
94264
94335
72
|
2371
94337
94356
20
|
2372
94358
94378
21
|
2373
94373
94386
14
|
2374
94384
94403
20
|
2375
94405
94422
18
|
2376
94453
94497
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43
|
3240
124662
124729
68
|
3241
124750
124767
18
|
3242
124769
124793
25
|
3243
124812
124828
17
|
3244
124853
124906
54
|
3245
124923
124948
26
|
3246
124958
124986
29
|
3247
125023
125042
20
|
3248
125032
125046
15
|
3249
125065
125083
19
|
3250
125073
125091
19
|
3251
125093
125107
15
|
3252
125132
125149
18
|
3253
125139
125154
16
|
3254
125151
125200
50
|
3255
125201
125274
74
|
3256
125314
125329
16
|
3257
125331
125370
40
|
3258
125372
125386
15
|
3259
125411
125431
21
|
3260
125433
125462
30
|
3261
125475
125562
88
|
3262
125564
125589
26
|
3263
125605
125639
35
|
3264
125641
125699
59
|
3265
125719
125732
14
|
3266
125737
125769
33
|
3267
125815
125829
15
|
3268
125834
125848
15
|
3269
125850
125884
35
|
3270
125899
125966
68
|
3271
125967
125999
33
|
3272
126026
126080
55
|
3273
126097
126115
19
|
3274
126130
126149
20
|
3275
126151
126179
29
|
3276
126186
126238
53
|
3277
126241
126279
39
|
3278
126275
126295
21
|
3279
126297
126312
16
|
3280
126320
126363
44
|
3281
126376
126395
20
|
3282
126406
126419
14
|
3283
126420
126442
23
|
3284
126467
126501
35
|
3285
126503
126538
36
|
3286
126566
126580
15
|
3287
126584
126597
14
|
3288
126620
126653
34
|
3289
126654
126694
41
|
3290
126697
126715
19
|
3291
126764
126777
14
|
3292
126792
126828
37
|
3293
126842
126862
21
|
3294
126866
126879
14
|
3295
126881
126897
17
|
3296
126906
126925
20
|
3297
126956
126987
32
|
3298
126989
127023
35
|
3299
127026
127135
110
|
3300
127142
127174
33
|
3301
127176
127191
16
|
3302
127193
127217
25
|
3303
127229
127253
25
|
3304
127255
127280
26
|
3305
127294
127394
101
|
3306
127396
127415
20
|
3307
127417
127478
62
|
3308
127491
127504
14
|
3309
127506
127530
25
|
3310
127542
127566
25
|
3311
127582
127628
47
|
3312
127654
127675
22
|
3313
127681
127706
26
|
3314
127706
127739
34
|
3315
127769
127792
24
|
3316
127808
127829
22
|
3317
127839
127888
50
|
3318
127900
127932
33
|
3319
127943
127975
33
|
3320
127988
128046
59
|
3321
128048
128069
22
|
3322
128068
128106
39
|
3323
128105
128118
14
|
3324
128121
128157
37
|
3325
128159
128188
30
|
3326
128190
128268
79
|
3327
128279
128317
39
|
3328
128321
128335
15
|
3329
128342
128368
27
|
3330
128374
128446
73
|
3331
128444
128540
97
|
3332
128546
128586
41
|
3333
128588
128640
53
|
3334
128642
128674
33
|
3335
128675
128879
205
|
3336
128881
128936
56
|
3337
128934
129000
67
|
3338
129002
129060
59
|
3339
129074
129100
27
|
3340
129107
129123
17
|
3341
129125
129163
39
|
3342
129168
129230
63
|
3343
129264
129277
14
|
3344
129284
129318
35
|
3345
129320
129346
27
|
3346
129357
129391
35
|
3347
129393
129420
28
|
3348
129447
129485
39
|
3349
129489
129504
16
|
3350
129514
129540
27
|
3351
129550
129563
14
|
3352
129559
129595
37
|
3353
129606
129627
22
|
3354
129633
129681
49
|
3355
129683
129697
15
|
3356
129699
129716
18
|
3357
129706
129738
33
|
3358
129757
129790
34
|
3359
129792
129820
29
|
3360
129812
129846
35
|
3361
129851
129867
17
|
3362
129869
129883
15
|
3363
129885
129915
31
|
3364
129917
129955
39
|
3365
129957
130046
90
|
3366
130042
130070
29
|
3367
130110
130156
47
|
3368
130158
130309
152
|
3369
130311
130373
63
|
3370
130375
130391
17
|
3371
130407
130429
23
|
3372
130439
130461
23
|
3373
130475
130507
33
|
3374
130512
130550
39
|
3375
130552
130582
31
|
3376
130584
130614
31
|
3377
130616
130764
149
|
3378
130766
130869
104
|
3379
130871
131021
151
|
3380
131033
131051
19
|
3381
131092
131105
14
|
3382
131112
131188
77
|
3383
131194
131237
44
|
3384
131233
131247
15
|
3385
131236
131287
52
|
3386
131292
131307
16
|
3387
131314
131333
20
|
3388
131373
131386
14
|
3389
131396
131417
22
|
3390
131419
131439
21
|
3391
131429
131458
30
|
3392
131481
131499
19
|
3393
131676
131689
14
|
3394
131729
131743
15
|
3395
131745
131764
20
|
3396
131785
131807
23
|
3397
131809
131875
67
|
3398
131877
131953
77
|
3399
131955
131980
26
|
3400
132020
132068
49
|
3401
132086
132108
23
|
3402
132118
132138
21
|
3403
132152
132183
32
|
3404
132185
132205
21
|
3405
132219
132232
14
|
3406
132234
132252
19
|
3407
132261
132291
31
|
3408
132319
132337
19
|
3409
132345
132363
19
|
3410
132365
132378
14
|
3411
132414
132483
70
|
3412
132504
132547
44
|
3413
132549
132582
34
|
3414
132584
132602
19
|
3415
132616
132642
27
|
3416
132643
132681
39
|
3417
132685
132714
30
|
3418
132736
132769
34
|
3419
132771
132793
23
|
3420
132809
132825
17
|
3421
132827
132841
15
|
3422
132861
132884
24
|
3423
132882
132900
19
|
3424
132899
132915
17
|
3425
132917
132951
35
|
3426
132940
132954
15
|
3427
132958
132983
26
|
3428
132985
133031
47
|
3429
133032
133051
20
|
3430
133042
133060
19
|
3431
133051
133071
21
|
3432
133073
133087
15
|
3433
133083
133104
22
|
3434
133097
133110
14
|
3435
133131
133199
69
|
3436
133198
133222
25
|
3437
133233
133249
17
|
3438
133251
133284
34
|
3439
133327
133429
103
|
3440
133431
133596
166
|
3441
133588
133602
15
|
3442
133598
133611
14
|
3443
133613
133628
16
|
3444
133628
133646
19
|
3445
133651
133670
20
|
3446
133666
133707
42
|
3447
133718
133742
25
|
3448
133743
133777
35
|
3449
133779
133794
16
|
3450
133821
133851
31
|
3451
133859
133880
22
|
3452
133890
133921
32
|
3453
133923
133974
52
|
3454
133982
133998
17
|
3455
134000
134036
37
|
3456
134065
134107
43
|
3457
134120
134173
54
|
3458
134165
134179
15
|
3459
134187
134200
14
|
3460
134207
134242
36
|
3461
134244
134258
15
|
3462
134260
134273
14
|
3463
134275
134299
25
|
3464
134314
134346
33
|
3465
134356
134371
16
|
3466
134365
134380
16
|
3467
134374
134420
47
|
3468
134445
134477
33
|
3469
134508
134523
16
|
3470
134531
134548
18
|
3471
134542
134555
14
|
3472
134568
134621
54
|
3473
134647
134667
21
|
3474
134679
134719
41
|
3475
134721
134824
104
|
3476
134826
134849
24
|
3477
134856
134869
14
|
3478
134877
134910
34
|
3479
134912
134966
55
|
3480
134960
134980
21
|
3481
134989
135012
24
|
3482
135014
135066
53
|
3483
135074
135093
20
|
3484
135108
135125
18
|
3485
135151
135260
110
|
3486
135264
135277
14
|
3487
135273
135310
38
|
3488
135321
135337
17
|
3489
135340
135365
26
|
3490
135360
135374
15
|
3491
135364
135386
23
|
3492
135388
135430
43
|
3493
135432
135447
16
|
3494
135498
135521
24
|
3495
135519
135545
27
|
3496
135559
135622
64
|
3497
135624
135647
24
|
3498
135656
135673
18
|
3499
135675
135704
30
|
3500
135721
135742
22
|
3501
135753
135796
44
|
3502
135815
135858
44
|
3503
135860
135880
21
|
3504
135883
135915
33
|
3505
135922
135965
44
|
3506
135979
135993
15
|
3507
135995
136036
42
|
3508
136051
136065
15
|
3509
136108
136165
58
|
3510
136173
136190
18
|
3511
136192
136287
96
|
3512
136289
136303
15
|
3513
136317
136346
30
|
3514
136375
136415
41
|
3515
136429
136470
42
|
3516
136472
136496
25
|
3517
136498
136532
35
|
3518
136542
136565
24
|
3519
136643
136657
15
|
3520
136674
136701
28
|
3521
136704
136719
16
|
3522
136715
136728
14
|
3523
136721
136737
17
|
3524
136737
136750
14
|
3525
136783
136810
28
|
3526
136824
136849
26
|
3527
136859
136896
38
|
3528
136898
136927
30
|
3529
136949
136983
35
|
3530
136985
137000
16
|
3531
137053
137071
19
|
3532
137077
137097
21
|
3533
137108
137164
57
|
3534
137166
137196
31
|
3535
137198
137221
24
|
3536
137223
137267
45
|
3537
137276
137359
84
|
3538
137360
137385
26
|
3539
137393
137440
48
|
3540
137438
137496
59
|
3541
137498
137518
21
|
3542
137523
137536
14
|
3543
137539
137572
34
|
3544
137584
137612
29
|
3545
137614
137628
15
|
3546
137630
137644
15
|
3547
137646
137669
24
|
3548
137702
137727
26
|
3549
137731
137745
15
|
3550
137759
137772
14
|
3551
137784
137819
36
|
3552
137832
137858
27
|
3553
137861
137876
16
|
3554
137878
137900
23
|
3555
137909
137925
17
|
3556
137924
137961
38
|
3557
137968
137981
14
|
3558
138011
138033
23
|
3559
138035
138077
43
|
3560
138079
138097
19
|
3561
138224
138238
15
|
3562
138232
138252
21
|
3563
138242
138256
15
|
3564
138255
138284
30
|
3565
138295
138326
32
|
3566
138328
138357
30
|
3567
138359
138389
31
|
3568
138403
138449
47
|
3569
138451
138492
42
|
3570
138500
138515
16
|
3571
138524
138548
25
|
3572
138555
138568
14
|
3573
138571
138589
19
|
3574
138589
138629
41
|
3575
138644
138680
37
|
3576
138697
138710
14
|
3577
138712
138729
18
|
3578
138744
138761
18
|
3579
138776
138801
26
|
3580
138860
138896
37
|
3581
138898
138923
26
|
3582
138925
138965
41
|
3583
138967
139008
42
|
3584
139010
139031
22
|
3585
139029
139043
15
|
3586
139034
139048
15
|
3587
139041
139056
16
|
3588
139055
139074
20
|
3589
139078
139094
17
|
3590
139084
139098
15
|
3591
139092
139116
25
|
3592
139133
139147
15
|
3593
139154
139173
20
|
3594
139175
139192
18
|
3595
139204
139229
26
|
3596
139231
139255
25
|
3597
139257
139270
14
|
3598
139272
139303
32
|
3599
139315
139335
21
|
3600
139337
139372
36
|
3601
139383
139397
15
|
3602
139399
139419
21
|
3603
139423
139437
15
|
3604
139435
139492
58
|
3605
139501
139518
18
|
3606
139508
139521
14
|
3607
139571
139586
16
|
3608
139588
139622
35
|
3609
139636
139655
20
|
3610
139657
139673
17
|
3611
139685
139699
15
|
3612
139724
139795
72
|
3613
139796
139811
16
|
3614
139818
139834
17
|
3615
139836
139857
22
|
3616
139856
139869
14
|
3617
139859
139882
24
|
3618
139891
139920
30
|
3619
139930
139952
23
|
3620
139965
139980
16
|
3621
139982
140011
30
|
3622
140013
140031
19
|
3623
140047
140072
26
|
3624
140074
140099
26
|
3625
140101
140119
19
|
3626
140121
140135
15
|
3627
140144
140158
15
|
3628
140157
140183
27
|
3629
140185
140210
26
|
3630
140231
140262
32
|
3631
140258
140272
15
|
3632
140264
140288
25
|
3633
140290
140325
36
|
3634
140339
140364
26
|
3635
140369
140402
34
|
3636
140428
140451
24
|
3637
140453
140510
58
|
3638
140512
140541
30
|
3639
140556
140621
66
|
3640
140626
140651
26
|
3641
140653
140724
72
|
3642
140726
140789
64
|
3643
140802
140825
24
|
3644
140837
140861
25
|
3645
140863
140896
34
|
3646
140903
140927
25
|
3647
140958
140993
36
|
3648
141001
141014
14
|
3649
141022
141053
32
|
|
In some embodiments, the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary, such as 100% complementarity, to a corresponding target nucleic acid region present in SEQ ID NO: 1, wherein the target nucleic acid region is selected from the group consisting of region B1 to B400 in table 2
TABLE 2
|
|
Regions of SEQ ID NO 1 which may be targeted
|
using oligonucleotide of the invention
|
Position in SEQ ID NO 1
|
Reg.
To
From
Length
|
|
B1
225
238
14
|
B2
1163
1178
16
|
B3
2526
2539
14
|
B4
2805
2820
16
|
B5
3027
3040
14
|
B6
3208
3222
15
|
B7
3212
3225
14
|
B8
3228
3241
14
|
B9
3243
3256
14
|
B10
3810
3854
45
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B11
4664
4680
17
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B12
5516
5529
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B13
5657
5671
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B14
5661
5676
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B15
5964
5977
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B16
6217
6234
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6224
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B18
6408
6422
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B19
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B21
7541
7564
24
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B22
7626
7640
15
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B23
7662
7694
33
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B24
7791
7806
16
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B25
7853
7868
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B26
8206
8219
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B27
8443
8456
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B28
8739
8752
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B29
9197
9212
16
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B30
10189
10203
15
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B31
10754
10768
15
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B32
10758
10771
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B33
11790
11803
14
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B34
11870
11883
14
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B35
11993
12007
15
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B36
B11996
12011
16
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B37
12017
12040
24
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B38
12095
12108
14
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B39
12345
12358
14
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B40
12721
12734
14
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B41
13372
13386
15
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B42
13489
13505
17
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B43
15576
15590
15
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B44
15617
15632
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B45
15840
15853
14
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B46
16041
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B47
16207
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16
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B48
16308
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14
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B49
16349
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14
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B50
16463
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17
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B51
16528
16542
15
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B52
16543
16556
14
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B53
20495
20508
14
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B54
20617
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14
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B55
20960
20977
18
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B56
21465
21479
15
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B57
21491
21508
18
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B58
23479
23496
18
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B59
23741
23755
15
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B60
25236
25249
14
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B61
25323
25336
14
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B62
25447
25462
16
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B63
25588
25601
14
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B64
25853
25867
15
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B65
25885
25898
14
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B66
26280
26293
14
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B67
26388
26404
17
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B68
26416
26450
35
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B69
26687
26702
16
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B70
26706
26719
14
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B71
26783
26796
14
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B72
27039
27052
14
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B73
27251
27265
15
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B74
28683
28698
16
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B75
29302
29315
14
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B76
29304
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14
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B77
29308
29321
14
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B78
29532
29545
14
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B79
29974
29987
14
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B80
30054
30068
15
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B81
30267
30281
15
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B82
30623
30638
16
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B83
30628
30641
14
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B84
30814
30827
14
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B85
30881
30894
14
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B86
32459
32478
20
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B87
37299
37315
17
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B88
39083
39096
14
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B89
39370
39383
14
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B90
39659
39672
14
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B91
40814
40831
18
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B92
40851
40864
14
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B93
41782
41795
14
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B94
41873
41886
14
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B95
42037
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14
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B96
42048
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16
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B97
42096
42116
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B98
42959
42973
15
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B99
43165
43178
14
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B100
45926
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14
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B101
48163
48176
14
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B102
52732
52745
14
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B103
52984
53015
32
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B104
54404
54420
17
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B105
55294
55320
27
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B106
55337
55350
14
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B107
55420
55434
15
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B108
55487
55501
15
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B109
55623
55638
16
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B110
56195
56214
20
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B111
56584
56597
14
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B112
57267
57282
16
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B113
58126
58139
14
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B114
58170
58183
14
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B115
58295
58309
15
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B116
58658
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B117
58906
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16
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B118
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B119
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B120
59191
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B121
59236
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B122
59298
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B123
59358
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B124
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B125
59434
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B126
59589
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B127
59620
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B128
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B129
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B130
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B131
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25
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B132
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B133
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60004
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B134
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B135
60033
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B136
60139
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B137
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B138
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B140
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B141
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B142
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B143
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B144
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72
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B145
60427
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91
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B146
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B147
60557
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B148
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B149
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B150
60675
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B151
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B152
60727
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B153
60756
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44
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B154
60801
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B155
60819
60855
37
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B156
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B157
61592
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B158
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B159
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B160
61715
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61769
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B163
61805
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B164
62101
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B165
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B167
62664
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B168
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B169
63098
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B170
63347
63367
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B171
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26
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B173
63526
63539
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B174
65032
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B175
66556
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14
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B176
67158
67183
26
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B177
67181
67194
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B178
68007
68021
15
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B179
68644
68657
14
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B180
69294
69317
24
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B181
69306
69323
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B182
69353
69366
14
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B183
70497
70511
15
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B184
71600
71613
14
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B185
71887
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19
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B186
72259
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14
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B187
72589
72602
14
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B188
72783
72796
14
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B189
73528
73541
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B190
73783
73800
18
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B191
74907
74920
14
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B192
75965
75981
17
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B193
75983
75998
16
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B194
76004
76020
17
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B195
76110
76166
57
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B196
76186
76205
20
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B197
76234
76253
20
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B198
76261
76280
20
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B199
76369
76382
14
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B200
77139
77152
14
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B201
77409
77422
14
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B202
77478
77524
47
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B203
77526
77590
65
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B204
77628
77641
14
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B205
77688
77701
14
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B206
78275
78308
34
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B207
78310
78332
23
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B208
78340
78356
17
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B209
78358
78371
14
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B210
78373
78395
23
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B211
78397
78440
44
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B212
78442
78455
14
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B213
78475
78489
15
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B214
78696
78709
14
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B215
78847
78860
14
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B216
79493
79516
24
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B217
79705
79718
14
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B218
81009
81054
46
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B219
81353
81367
15
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B220
81970
81986
17
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B221
81991
82006
16
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B222
82042
82106
65
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B223
82278
82291
14
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B224
82716
82735
20
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B225
84314
84328
15
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B226
85628
85665
38
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B227
86226
86239
14
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B228
86237
86253
17
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B229
86566
86579
14
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B230
86945
86959
15
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B231
87337
87358
22
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B232
87662
87675
14
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B233
89424
89439
16
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B234
89972
89985
14
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B235
90782
90795
14
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B236
90939
90953
15
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B237
90942
90955
14
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B238
90965
90981
17
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B239
91101
91115
15
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B240
92083
92096
14
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B241
92164
92177
14
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B242
92179
92192
14
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B243
92194
92210
17
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B244
92212
92236
25
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B245
92245
92260
16
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B246
92262
92302
41
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B247
92304
92321
18
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B248
92323
92366
44
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B249
92375
92389
15
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B250
92392
92405
14
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B251
92407
92426
20
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B252
92442
92459
18
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B253
92497
92516
20
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B254
92578
92591
14
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B255
92599
92612
14
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B256
92614
92651
38
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B257
92659
92684
26
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B258
92686
92699
14
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B259
92704
92726
23
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B260
92731
92750
20
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B261
92752
92774
23
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B262
92780
92795
16
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B263
92800
92813
14
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B264
92839
92858
20
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B265
92860
92891
32
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B266
92893
92906
14
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B267
92908
92921
14
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B268
92923
92941
19
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B269
92965
92986
22
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B270
92988
93002
15
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B271
93044
93059
16
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B272
93061
93076
16
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B273
93105
93122
18
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B274
93142
93209
68
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B275
93227
93241
15
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B276
93288
93305
18
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B277
93325
93344
20
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B278
93398
93412
15
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B279
93572
93586
15
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B280
94509
94522
14
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B281
95720
95738
19
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B282
97050
97065
16
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B283
97079
97098
20
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B284
97127
97194
68
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B285
97208
97230
23
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B286
97232
97284
53
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B287
97286
97311
26
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B288
97313
97362
50
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B289
97368
97383
16
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B290
97426
97439
14
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B291
98077
98090
14
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B292
98227
98240
14
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B293
98232
98255
24
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B294
99151
99164
14
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B295
99405
99418
14
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B296
99570
99583
14
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B297
99733
99748
16
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B298
101829
101842
14
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B299
101882
101895
14
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B300
101955
101968
14
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B301
102202
102215
14
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B302
103310
103325
16
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B303
103653
103666
14
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B304
103908
103923
16
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B305
103912
103928
17
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B306
103917
103933
17
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B307
104971
104984
14
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B308
105217
105230
14
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B309
105233
105250
18
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B310
105443
105457
15
|
B311
105544
105559
16
|
B312
106047
106071
25
|
B313
106061
106074
14
|
B314
106093
106107
15
|
B315
106114
106130
17
|
B316
106243
106256
14
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B317
106251
106264
14
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B318
106840
106855
16
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B319
108113
108130
18
|
B320
108325
108338
14
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B321
108856
108869
14
|
B322
109109
109122
14
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B323
109113
109127
15
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B324
109116
109132
17
|
B325
110301
110314
14
|
B326
110315
110328
14
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B327
110317
110330
14
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B328
112528
112546
19
|
B329
112607
112620
14
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B330
114775
114788
14
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B331
116322
116335
14
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B332
116968
116981
14
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B333
117788
117801
14
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B334
118034
118057
24
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B335
118230
118246
17
|
B336
118235
118248
14
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B337
118870
118883
14
|
B338
119755
119784
30
|
B339
119786
119800
15
|
B340
120363
120406
44
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B341
120504
120517
14
|
B342
121161
121174
14
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B343
121330
121347
18
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B344
121338
121351
14
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B345
123417
123430
14
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B346
123464
123481
18
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B347
125026
125042
17
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B348
127046
127071
26
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B349
127090
127103
14
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B350
127311
127324
14
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B351
127354
127367
14
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B352
127363
127379
17
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B353
127399
127412
14
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B354
127863
127876
14
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B355
128134
128148
15
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B356
128280
128310
31
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B357
128343
128368
26
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B358
128444
128457
14
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B359
128446
128469
24
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B360
128498
128511
14
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B361
128511
128524
14
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B362
129892
129905
14
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B363
130261
130283
23
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B364
130375
130388
14
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B365
130415
130428
14
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B366
130634
130650
17
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B367
130667
130717
51
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B368
130719
130764
46
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B369
130783
130796
14
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B370
130798
130820
23
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B371
130840
130861
22
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B372
130975
130994
20
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B373
131112
131132
21
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B374
131142
131161
20
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B375
131233
131246
14
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B376
131729
131743
15
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B377
132754
132767
14
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B378
132924
132937
14
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B379
133174
133190
17
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B380
133198
133212
15
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B381
133207
133222
16
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B382
133476
133489
14
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B383
133479
133492
14
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B384
133491
133531
41
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B385
133533
133550
18
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B386
133555
133594
40
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B387
134160
134173
14
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B388
134165
134178
14
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B389
134533
134546
14
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B390
136724
136737
14
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B391
137438
137463
26
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B392
137878
137891
14
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B393
138082
138097
16
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B394
138233
138252
20
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B395
138930
138943
14
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B396
138947
138960
14
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B397
138950
138963
14
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B398
139502
139518
17
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B399
139508
139521
14
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B400
140978
140991
14
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|
In certain embodiments the oligonucleotide or contiguous nucleotide sequence is complementary to a region (or sub-sequence)(or sub-sequence) of the target nucleic acid, wherein the target nucleic acid region is selected from the group consisting of position 1589-10889, 46089-53989 and 60789-62489 of SEQ ID NO: 1.
In one embodiment the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90%, such as 100% complementary to a target nucleic acid sequence of position 55319 to 141053 of SEQ ID NO: 1.
In one embodiment the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90%, such as 100% complementary to a target nucleic acid sequence of position 1 to 55318 of SEQ ID NO: 1.
In some embodiments, the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid selected from the group corresponding to positions: 55319-76274, 77483-77573, 92157-93403 and 97056-97354 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid selected from the group corresponding to positions: 60821-60849, 77567-77583, 92323-92339 and 97156-97172 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 5218-5240 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 5782-5803 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 8113-8139 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 9200-9250 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 11505-11555 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 13223-13242 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 15100-15150 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 15113-15180 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 29635-29705 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 30590-30740 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 39800-39855 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 44435-44460 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 45245-45270 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 46380-46430 of SEQ ID NO: 1.
In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 68915-68940 of SEQ ID NO: 1.
In some embodiments, the oligonucleotide comprises or consists of 8 to 35 nucleotides in length, such as from 10 to 30, such as 11 to 22, such as from 12 to 18, such as from 13 to 17 or 14 to 16 contiguous nucleotides in length. In a preferred embodiment, the oligonucleotide comprises or consists of 15 to 20 nucleotides in length.
In some embodiments, the oligonucleotide or contiguous nucleotide sequence thereof comprises or consists of 22 or less nucleotides, such as 20 or less nucleotides, such as 18 or less nucleotides, such as 14, 15, 16 or 17 nucleotides. It is to be understood that any range given herein includes the range endpoints. Accordingly, if an oligonucleotide is said to include from 10 to 30 nucleotides, both 10 and 30 nucleotides are included.
In some embodiments, the contiguous nucleotide sequence comprises or consists of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 contiguous nucleotides in length. In a preferred embodiment, the oligonucleotide comprises or consists of 16, 17, 18 or 19 nucleotides in length.
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 4 to 150 (see motif sequences listed in table 3 in the Examples section).
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 4 to 818 (see motif sequences listed in table 3 in the Examples section).
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 4 to 678 (see motif sequences listed in table 3 in the Examples section).
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 166, 167, 167 or 169 (see motif sequences listed in table 3 in the Examples section).
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 570, 571, 572, 679, 680, 681, 682 and 683 (see motif sequences listed in table 3 in the Examples section).
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 34, 186, 187, 188, 573, 574, 575, 576, 572, 684, 685, 686, 687, 688, 689, 690, 691, 692, 963, 964, 965 and 696 (see motif sequences listed in table 3 in the Examples section).
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 35, 199, 200, 201, 202, 203, 204, 205, 206, 207, 209 and 210 or SEQ ID NO: 582, 583 and 584 (see motif sequences listed in table 3 in the Examples section).
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 221, 222, 223, 224, 225, 585, 586, 587, 588, 589, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717 and 718 (see motif sequences listed in table 3 in the Examples section).
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 236, 237, 238, 239, 240 and 590.
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 241, 591 and 719 (see motif sequences listed in table 3 in the Examples section).
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 46, 47, 48, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 800, 800, 800, 800, 801, 801, 802, 803, 804, 805, 806 and 807 (see motif sequences listed in table 3 in the Examples section).
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 331, 332, 638, 639, 640, 808, 809, 810, 811, 812, 813, 814 and 815 (see motif sequences listed in table 3 in the Examples section).
In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 409, 410, 411, 642, 643, 644, 645, 646, 816, 818 and 818 (see motif sequences listed in table 3 in the Examples section).
It is understood that the contiguous nucleobase sequences (motif sequence) can be modified to for example increase nuclease resistance and/or binding affinity to the target nucleic acid. Modifications are described in the definitions and in the “Oligonucleotide design” section. Table 3 lists preferred designs of each motif sequence.
Oligonucleotide Design
Oligonucleotide design refers to the pattern of nucleoside sugar modifications in the oligonucleotide sequence. The oligonucleotides of the invention comprise sugar-modified nucleosides and may also comprise DNA or RNA nucleosides. In some embodiments, the oligonucleotide comprises sugar-modified nucleosides and DNA nucleosides. Incorporation of modified nucleosides into the oligonucleotide of the invention may enhance the affinity of the oligonucleotide for the target nucleic acid. In that case, the modified nucleosides can be referred to as affinity enhancing modified nucleotides.
In an embodiment, the oligonucleotide comprises at least 1 modified nucleoside, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or at least 16 modified nucleosides. In an embodiment the oligonucleotide comprises from 1 to 10 modified nucleosides, such as from 2 to 9 modified nucleosides, such as from 3 to 8 modified nucleosides, such as from 4 to 7 modified nucleosides, such as 6 or 7 modified nucleosides.
In some embodiments, at least 1 of the modified nucleosides is a locked nucleic acid (LNA), such as at least 2, such as at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 of the modified nucleosides are LNA. In a still further embodiment all the modified nucleosides are LNA.
In an embodiment, the oligonucleotide of the invention may comprise modifications, which are independently selected from these three types of modifications (modified sugar, modified nucleobase and modified internucleoside linkage) or a combination thereof. Preferably the oligonucleotide comprises one or more sugar modified nucleosides, such as 2′ sugar modified nucleosides. Preferably the oligonucleotide of the invention comprise the one or more 2′ sugar modified nucleoside independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic acid (ANA), 2′-fluoro-ANA and LNA nucleosides. Even more preferably the one or more modified nucleoside is LNA.
In a further embodiment the oligonucleotide comprises at least one modified internucleoside linkage. In a preferred embodiment the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate or boranophosphate internucleoside linkages.
In some embodiments, the oligonucleotide of the invention comprise at least one modified nucleoside which is a 2′-MOE-RNA, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 2′-MOE-RNA nucleoside units. In some embodiments, at least one of said modified nucleoside is 2′-fluoro DNA, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 2′-fluoro-DNA nucleoside units.
In some embodiments, the oligonucleotide of the invention comprises at least one LNA unit, such as 1, 2, 3, 4, 5, 6, 7, or 8 LNA units, such as from 2 to 6 LNA units, such as from 3 to 7 LNA units, 4 to 8 LNA units or 3, 4, 5, 6 or 7 LNA units. In some embodiments, all the modified nucleosides are LNA nucleosides. In a further embodiment, the oligonucleotide may comprise both beta-D-oxy-LNA, and one or more of the following LNA units: thio-LNA, amino-LNA, oxy-LNA, and/or ENA in either the beta-D or alpha-L configurations or combinations thereof. In a further embodiment, all LNA cytosine units are 5-methyl-cytosine. In a preferred embodiment the oligonucleotide or contiguous nucleotide sequence has at least 1 LNA unit at the 5′ end and at least 2 LNA units at the 3′ end of the nucleotide sequence.
In some embodiments, the oligonucleotide of the invention comprises at least one LNA unit and at least one 2′ substituted modified nucleoside.
In some embodiments of the invention, the oligonucleotide comprise both 2′ sugar modified nucleosides and DNA units. Preferably the oligonucleotide comprise both LNA and DNA units. Preferably, the combined total of LNA and DNA units is 8-30, such as 10-25, preferably 12-22, such as 12-18, even more preferably 11-16. In some embodiments of the invention, the nucleotide sequence of the oligonucleotide, such as the contiguous nucleotide sequence consists of at least one or two LNA units and the remaining nucleotide units are DNA units. In some embodiments the oligonucleotide comprises only LNA nucleosides and naturally occurring nucleosides (such as RNA or DNA, most preferably
DNA nucleosides), optionally with modified internucleoside linkages such as phosphorothioate.
In an embodiment of the invention the oligonucleotide of the invention is capable of recruiting RNase H.
Gapmer Design
In a preferred embodiment the oligonucleotide of the invention has a gapmer design or structure also referred herein merely as “Gapmer”. In a gapmer structure the oligonucleotide comprises at least three distinct structural regions a 5′-flank, a gap and a 3′-flank, F-G-F′ in ′5→3′ orientation. In this design, flanking regions F and F′ (also termed wing regions) comprise a contiguous stretch of modified nucleosides, which are complementary to the UBE3A target nucleic acid, while the gap region, G, comprises a contiguous stretch of nucleotides which are capable of recruiting a nuclease, preferably an endonuclease such as RNase, for example RNase H, when the oligonucleotide is in duplex with the target nucleic acid. Nucleosides which are capable of recruiting a nuclease, in particular RNase H, can be selected from the group consisting of DNA, alpha-L-oxy-LNA, 2′-Flouro-ANA and UNA. Regions F and F′, flanking the 5′ and 3′ ends of region G, preferably comprise non-nuclease recruiting nucleosides (nucleosides with a 3′ endo structure), more preferably one or more affinity enhancing modified nucleosides. In some embodiments, the 3′ flank comprises at least one LNA nucleoside, preferably at least 2 LNA nucleosides. In some embodiments, the 5′ flank comprises at least one LNA nucleoside. In some embodiments both the 5′ and 3′ flanking regions comprise a LNA nucleoside. In some embodiments all the nucleosides in the flanking regions are LNA nucleosides. In other embodiments, the flanking regions may comprise both LNA nucleosides and other nucleosides (mixed flanks), such as DNA nucleosides and/or non-LNA modified nucleosides, such as 2′ substituted nucleosides. In this case the gap is defined as a contiguous sequence of at least 5 RNase H recruiting nucleosides (nucleosides with a 2′ endo structure, preferably DNA) flanked at the 5′ and 3′ end by an affinity enhancing modified nucleoside, preferably LNA, such as beta-D-oxy-LNA. Consequently, the nucleosides of the 5′ flanking region and the 3′ flanking region which are adjacent to the gap region are modified nucleosides, preferably non-nuclease recruiting nucleosides. In oligonucleotides with mixed flanks where the flanks comprise DNA the 5′ and 3′ nucleosides are modified nucleosides.
Region F
Region F (5′ flank or 5′ wing) attached to the ′5 end of region G comprises, contains or consists of at least one modified nucleoside such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 modified nucleosides. In an embodiment region F comprises or consists of from 1 to 7 modified nucleosides, such as from 2 to 6 modified nucleosides, such as from 2 to 5 modified nucleosides, such as from 2 to 4 modified nucleosides, such as from 1 to 3 modified nucleosides, such as 1, 2, 3 or 4 modified nucleosides. In a further embodiment further additional nucleosides may be attached to the ′5 end of region F, representing a region D preferably comprising 1, 2 or 3 nucleoside units, such as DNA nucleosides. Region D can take the function of a biocleavable (B) linker described in the definition of “Linkers”.
In some embodiments, the modified nucleosides in region F have a 3′ endo structure.
In an embodiment, one or more of the modified nucleosides in region F are 2′ modified nucleosides.
In a further embodiment one or more of the 2′ modified nucleosides in region F are selected from 2′-O-alkyl-RNA units, 2′-O-methyl-RNA, 2′-amino-DNA units, 2′-fluoro-DNA units, 2′-alkoxy-RNA, MOE units, LNA units, arabino nucleic acid (ANA) units and 2′-fluoro-ANA units.
In one embodiment of the invention all the modified nucleosides in region F are LNA nucleosides. In a further embodiment the LNA nucleosides in region F are independently selected from the group consisting of oxy-LNA, thio-LNA, amino-LNA, cET, and/or ENA, in either the beta-D or alpha-L configurations or combinations thereof. In a preferred embodiment region F has at least 1 beta-D-oxy LNA unit, at the 5′ end of the contiguous sequence.
Region G
Region G (gap region) preferably comprise, contain or consist of at least 4, such as at least 5, such as at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or at least 16 consecutive nucleosides capable of recruiting the aforementioned nuclease, in particular RNaseH. In a further embodiment region G comprise, contain or consist of from 5 to 12, or from 6 to 10 or from 7 to 9, such as 8 consecutive nucleotide units capable of recruiting aforementioned nuclease.
The nucleoside units in region G, which are capable of recruiting nuclease are in an embodiment selected from the group consisting of DNA, alpha-L-LNA, C4′ alkylated DNA (as described in PCT/EP2009/050349 and Vester et al., Bioorg. Med. Chem. Lett. 18 (2008) 2296-2300, both incorporated herein by reference), arabinose derived nucleosides like ANA and 2′F-ANA (Mangos et al. 2003 J. AM. CHEM. SOC. 125, 654-661), UNA (unlocked nucleic acid) (as described in Fluiter et al., Mol. Biosyst., 2009, 10, 1039 incorporated herein by reference). UNA is unlocked nucleic acid, typically where the bond between C2 and C3 of the ribose has been removed, forming an unlocked “sugar” residue.
In a still further embodiment at least one nucleoside unit in region G is a DNA nucleoside unit, such as from 1 to 16 DNA units, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 DNA units, preferably from 2 to 13 DNA units, such as from 4 to 12 DNA units, more preferably from 5 to 11, or from 10 to 16, 11 to 15 or 12 to 14 DNA units. In some embodiments, region G consists of 100% DNA units. In a preferred embodiment G consists of, most preferably 10, 11, 12, 13, 14 or 15 DNA units.
In further embodiments the region G may consist of a mixture of DNA and other nucleosides capable of mediating RNase H cleavage. Region G may consist of at least 50% DNA, more preferably 60%, 70% or 80% DNA, and even more preferred 90% or 95% DNA.
In a still further embodiment at least one nucleoside unit in region G is an alpha-L-LNA nucleoside unit, such as at least one alpha-L-LNA unit, such as 2, 3, 4, 5, 6, 7, 8 or 9 alpha-L-LNA units. In a further embodiment, region G comprises the least one alpha-L-LNA is alpha-L-oxy-LNA unit. In a further embodiment region G comprises a combination of DNA and alpha-L-LNA nucleoside units.
In some embodiments the size of the contiguous sequence in region G may be longer, such as 15, 16, 17, 18, 19 or 20 nucleoside units.
In some embodiments, nucleosides in region G have a 2′ endo structure.
Region F′
Region F′ (3′ flank or 3′ wing) attached to the ′3 end of region G comprises, contains or consists of at least one modified nucleoside such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 modified nucleosides. In an embodiment region F′ comprise or consist of from 1 to 7 modified nucleosides, such as from 2 to 6 modified nucleoside, such as from 2 to 4 modified nucleosides, such as from 1 to 3 modified nucleosides, such as 1, 2, 3 or 4 modified nucleosides. In a further embodiment further additional nucleosides attached to the ′3 end of region F′, representing a region D′, preferably comprising 1, 2 or 3 nucleoside units, such as DNA nucleosides. Region D′ can take the function of a biocleavable (B) linker described, in the section “Linkers”.
In some embodiments, the modified nucleosides in region F′ have a 3′ endo structure.
In a preferred embodiment, modified nucleosides in region F′ is LNA.
In a further embodiment modified nucleosides in region F′ are selected from 2′-O-alkyl-RNA units, 2′-O-methyl-RNA, 2′-amino-DNA units, 2′-fluoro-DNA units, 2′-alkoxy-RNA, MOE units, LNA units, arabino nucleic acid (ANA) units and 2′-fluoro-ANA units.
In one embodiment of the invention all the modified nucleosides in region F′ are LNA nucleosides. In a further embodiment the LNA nucleosides in region F′ are independently selected from the group consisting of oxy-LNA, thio-LNA, amino-LNA, cET and/or ENA, in either the beta-D or alpha-L configurations or combinations thereof. In a preferred embodiment region F′ has at least 2 beta-D-oxy LNA unit, at the 3′ end of the contiguous sequence.
Region D and D′
Region D and D′ can be attached to the 5′ end of region F or the 3′ end of region F′, respectively.
Region D or D′ may independently comprise 1, 2, 3, 4 or 5 additional nucleotides, which may be complementary or non-complementary to the target nucleic acid. In this respect the oligonucleotide of the invention, may in some embodiments comprise a contiguous nucleotide sequence capable of modulating the target which is flanked at the 5′ and/or 3′ end by additional nucleotides. Such additional nucleotides may serve as a nuclease susceptible biocleavable linker (see definition of linkers). In some embodiments the additional 5′ and/or 3′ end nucleotides are linked with phosphodiester linkages, and may be DNA or RNA. In another embodiment, the additional 5′ and/or 3′ end nucleotides are modified nucleotides which may for example be included to enhance nuclease stability or for ease of synthesis. In an embodiment of the oligonucleotide of the invention, comprises a region D and/or D′ in addition to the contiguous nucleotide sequence.
The gapmer oligonucleotide of the present invention can be represented by the following formulae:
F-G-F′; in particular F1-7-G4-12-F1-7
D-F-G-F′, in particular D1-3-F1-7-G4-12-F1-7
F-G-F′-D′, in particular F1-7-G4-12-F′1-7-D′1-3
D-F-G-F′-D′, in particular D1-3-F1-7-G4-12-F′1-7-D′1-3
The preferred number and types of nucleosides in regions F, G and F′, D and D′ have been described above. The design of the individual oligonucleotide may also have profound impact on the properties of the oligonucleotide in its use for modulating expression of UBE3A.
In some embodiments the oligonucleotide is a gapmer consisting of 14, 15, 16, 17, 18, 19 or 20 nucleotides in length, wherein each of regions F and F′ independently consists of 2, 3 or 4 modified nucleoside units complementary to a part of the human SNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA (the target nucleic acid) and region G consists of 10, 11, 12, 13, 14 or 15 nucleoside units, capable of recruiting nuclease when in duplex with the target nucleic acid.
In a further embodiments, the oligonucleotide is a gapmer wherein each of regions F and F′ independently consists of 2, 3, 4 or 5 modified nucleoside units, such as nucleoside units containing a 2′-O-methoxyethyl-ribose sugar (2′-MOE) or nucleoside units containing a 2′-fluoro-deoxyribose sugar and/or LNA units, and region G consists of 9, 10, 11, 12, 13, 14 or 15 nucleoside units, such as DNA units or other nuclease recruiting nucleosides such as alpha-L-LNA or a mixture of DNA and nuclease recruiting nucleosides.
In a further specific embodiment, the oligonucleotide is a gapmer wherein each of regions F and F′ region consists of two LNA units each, and region G consists of 10, 11, 12, 13, 14 or 15 nucleoside units, preferably DNA units. Specific gapmer designs of this nature include 2-10-2, 2-11-2, 2-12-2, 2-13-2, 2-14-2 and 2-15-2.
In a further specific embodiment, the oligonucleotide is a gapmer wherein each of regions F and F′ independently consists of three LNA units, and region G consists of 10, 11, 12, 13, 14 or 15 nucleoside units, preferably DNA units. Specific gapmer designs of this nature include 3-10-3, 3-11-3, 3-12-3, 3-13-3, 3-14-3 and 3-15-3.
In a further specific embodiment, the oligonucleotide is a gapmer wherein each of regions F and F′ consists of four LNA units each, and region G consists of 10, 11, 12, 13, 14 or 15 nucleoside units, preferably DNA units. Specific gapmer designs of this nature include 4-10-4, 4-11-4, 4-12-4, 4-13-4, 4-14-4 and 4-15-4.
Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 10 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-10-1, 2-10-1, 1-10-2, 1-10-3, 3-10-1, 1-10-4, 4-10-1, 2-10-2, 2-10-3, 3-10-2, 2-10-4, 4-10-2, 3-10-3, 3-10-4, 4-10-3 and 4-10-4 gapmers.
Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 11 nucleosides and independently 1 to 4 modified nucleosides in the wings including, 1-11-1, 2-11-1, 1-11-2, 1-11-3, 3-11-1, 1-11-4, 4-11-1, 2-11-2, 2-11-3, 3-11-2, 2-11-4, 4-11-2, 3-11-3, 3-11-4, 4-11-3 and 4-11-4 gapmers.
Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 12 nucleosides including, 1-12-1, 2-12-1, 1-12-2, 1-12-3, 3-12-1, 1-12-4, 4-12-1, 2-12-2, 2-12-3, 3-12-2, 2-12-4, 4-12-2, 3-12-3, 3-12-4, 4-12-3 and 4-12-4 gapmers.
Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 13 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-13-1, 1-13-2, 1-13-3, 3-13-1, 1-13-4, 4-13-1, 2-13-1, 2-13-2, 2-13-3, 3-13-2, 2-13-4, 4-13-2, 3-13-3, 3-13-4, 4-13-3, and 4-13-4 gapmers.
Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 14 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-14-1, 1-14-2, 2-14-1, 1-14-3, 3-14-1, 1-14-4, 4-14-1, 2-14-2, 2-14-3, 3-14-2 2-14-4, 4-14-2, 3-14-3, 3-14-4 and 4-14-3 gapmers.
Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 15 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-15-1, 1-15-2, 2-15-1, 1-15-3, 3-15-1, 1-15-4, 4-15-1, 2-15-2, 2-15-3, 3-15-2 2-15-4, 4-15-2, 3-15-3, 3-15-4 and 4-15-3 gapmers.
Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 16 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-16-1, 1-16-2, 2-16-1, 1-15-3, 3-16-1, 1-16-4, 4-16-1, 2-16-2, 2-16-3, 3-16-2 2-16-4, 4-16-2, 3-16-3, 3-16-4 and 4-16-3 gapmers.
In some embodiments the F-G-F′ design is selected from 2-10-4, 3-10-3 and 4-10-2.
In some embodiments the F-G-F′ design is selected from 2-11-4, 3-11-2, 3-11-3 and 4-11-2.
In some embodiments the F-G-F′ design is selected from 2-12-2, 2-12-3, 2-12-4, 3-12-2, 3-12-3, and 4-12-2.
In some embodiments the F-G-F′ design is selected from 2-13-2, 2-13-3, 2-13-4, 3-13-3 and 4-13-2.
In some embodiments the F-G-F′ design is selected from 2-14-2, 2-14-4, 3-14-3 and 4-14-2.
In some embodiments the F-G-F′ design is selected from 2-15-2 and 2-16-2.
In some embodiments the F-G-F′ design is selected from the designs indicated in table 3.
In all instances the F-G-F′ design may further include region D and/or D′, which may have 1, 2 or 3 nucleoside units, such as DNA units. Preferably, the nucleosides in region F and F′ are modified nucleosides, while nucleotides in region G are preferably unmodified nucleosides.
In each design, the preferred modified nucleoside is LNA.
In another embodiment all the internucleoside linkages in the gap in a gapmer are phosphorothioate and/or boranophosphate linkages. In another embodiment all the internucleoside linkages in the flanks (F and F′ region) in a gapmer are phosphorothioate and/or boranophosphate linkages. In another preferred embodiment all the internucleoside linkages in the D and D′ region in a gapmer are phosphodiester linkages.
For specific gapmers as disclosed herein, when the cytosine (C) residues are annotated as 5-methyl-cytosine, in various embodiments, one or more of the C's present in the oligonucleotide may be unmodified C residues.
Further gapmer designs are disclosed in WO2004/046160, WO2007/146511 and incorporated by reference.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds in table 3.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1 to 150_2.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1 to 678_1.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1 to 818_1 (see oligonucleotide sequences listed in table 3 in the Examples section).
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 155_1 or 165_1.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 169_52, 169_50 or 169_56.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 172_1, 272_1, 572_7, 572_6 or 572_5.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 175_1.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 178_1.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 573_8, 186_1 or 187_1.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 186_1.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 200_1, 204_1, 206_1, 35_2 or 209_1.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 585_1, 585_8, 586_9, 586_5, 586_8, 586_4 or 586_6.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 233_1.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 237_8 or 590_13.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 220_1.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 591_1, 592_2, 592_4 or 241_9.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 597_4, 598_4, 39_1 or 602_1.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 39_1.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 611_7.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 271_1 or 278_1.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 616_4, 621_2, 621_1, 622_3, 622_5, 622_4, 624_3, 624_5, 287_1, 625_6, 626_7, 626_8, 626_9, 48_1, 631_6, 631_1, 303_1, 304_6 or 304_10.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 636_8.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 638_8, 639_5, 331_1 or 640_4.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 359_1, 361_1, 361_5, 362_1 or 641_5.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 378_1, 379_1, 399_1.
For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 403_1, 405_1, 642_12, 642_13, 644_3 or 646_16.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 85_1 or 425_5.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 116_1.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 123_1 or 124_1.
For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 126_2.
Method of Manufacture
In a further aspect, the invention provides methods for manufacturing the oligonucleotides of the invention comprising reacting nucleotide units and thereby forming covalently linked contiguous nucleotide units comprised in the oligonucleotide. Preferably, the method uses phophoramidite chemistry (see for example Caruthers et al, 1987, Methods in Enzymology vol. 154, pages 287-313). In a further embodiment the method further comprises reacting the contiguous nucleotide sequence with a conjugating moiety (ligand). In a further aspect a method is provided for manufacturing the composition of the invention, comprising mixing the oligonucleotide or conjugated oligonucleotide of the invention with a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.
Pharmaceutical Composition
In a further aspect, the invention provides pharmaceutical compositions comprising any of the aforementioned oligonucleotides and/or oligonucleotide conjugates and a pharmaceutically acceptable diluent, carrier, salt and/or adjuvant. A pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS) and pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.
WO 2007/031091 provides suitable and preferred examples of pharmaceutically acceptable diluents, carriers and adjuvants (hereby incorporated by reference). Suitable dosages, formulations, administration routes, compositions, dosage forms, combinations with other therapeutic agents, pro-drug formulations are also provided in WO2007/031091.
Oligonucleotides or oligonucleotide conjugates of the invention may be mixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.
In some embodiments, the oligonucleotide or oligonucleotide conjugate of the invention is a prodrug. In particular with respect to oligonucleotide conjugates the conjugate moiety is cleaved of the oligonucleotide once the prodrug is delivered to the site of action, e.g. the target cell.
Applications
The oligonucleotides of the invention may be utilized as research reagents for, for example, therapeutics and prophylaxis.
In research, such oligonucleotides may be used to specifically modulate the synthesis of UBE3A protein in cells (e.g. in vitro cell cultures) and experimental animals thereby facilitating functional analysis of the target or an appraisal of its usefulness as a target for therapeutic intervention. The target modulation is achieved by degrading or inhibiting a modulator of the gene or mRNA producing the protein.
For therapeutics, an animal or a human, suspected of having a disease or disorder, which can be treated by modulating the expression of UBE3A.
The invention provides methods for treating or preventing a disease, comprising administering a therapeutically or prophylactically effective amount of an oligonucleotide, an oligonucleotide conjugate or a pharmaceutical composition of the invention to a subject suffering from or susceptible to the disease.
The invention also relates to an oligonucleotide, a composition or a conjugate as defined herein for use as a medicament.
The oligonucleotide, oligonucleotide conjugate or a pharmaceutical composition according to the invention is typically administered in an effective amount.
The invention also provides for the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament for the treatment of a disorder as referred to herein, or for a method of the treatment of as a disorder as referred to herein.
The disease or disorder, as referred to herein, is associated with expression of UBE3A. In some embodiments the disease or disorder may be associated with a mutation in the maternal UBE3A gene. In some embodiments, the target nucleic acid is a regulator of the paternal UBE3A gene.
The methods of the invention are preferably employed for treatment or prophylaxis against diseases caused by abnormal levels and/or activity of UBE3A. The disease may in particular be caused by reduced levels and/or activity of UBE3A protein.
The invention further relates to use of an oligonucleotide, oligonucleotide conjugate or a pharmaceutical composition as defined herein for the manufacture of a medicament for the treatment of abnormal levels and/or activity of UBE3A, in particular low levels and/or activity of UBE3A.
In one embodiment, the invention relates to oligonucleotides, oligonucleotide conjugates or pharmaceutical compositions for use in the treatment of Angelman syndrome.
Administration
The oligonucleotides or pharmaceutical compositions of the present invention may be administered topical (such as, to the skin, inhalation, ophthalmic or otic) or enteral (such as, orally or through the gastrointestinal tract) or parenteral (such as, intravenous, subcutaneous, intra-muscular, intracerebral, intracerebroventricular or intrathecal).
In a preferred embodiment the oligonucleotide or pharmaceutical compositions of the present invention are administered by a parenteral route including intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion, intrathecal or intracranial, e.g., intracerebral or intraventricular, administration. In one embodiment the active oligonucleotide or oligonucleotide conjugate is administered intracerebral or intracerebroventricular. In another embodiment the active oligonucleotide or oligonucleotide conjugate is administered intrathecal.
The invention also provides for the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament wherein the medicament is in a dosage form for intrathecal administration.
The invention also provides for the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament wherein the medicament is in a dosage form for intracerebral or intraventricular administration.
The invention also provides for the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament wherein the medicament is in a dosage form for intracerebroventricular administration.
Combination Therapies
In some embodiments the oligonucleotide, oligonucleotide conjugate or pharmaceutical composition of the invention is for use in a combination treatment with another therapeutic agent. The therapeutic agent can for example be anticonvulsant medication.
EMBODIMENTS
The following embodiments of the present invention may be used in combination with any other embodiments described herein.
1. An antisense oligonucleotide which comprises or consists of a contiguous nucleotide sequence of 10 to 30 nucleotides in length capable of inducing human paternal UBE3A expression, in particular in a neuronal cell.
2. The oligonucleotide of embodiment 1, wherein the contiguous nucleotide sequence is at least 95% complementarity to the part of human SNHG14 long non-coding RNA which is downstream of SNORD109B corresponding to position 25278410 to 25419462 on chromosome 15.
3. The oligonucleotide of embodiment 1 or 2, wherein the oligonucleotide is capable of hybridizing to a target nucleic acid of SEQ ID NO: 1 with a ΔG° below −10 kcal.
4. The oligonucleotide of embodiment 1-3, wherein the contiguous nucleotide sequence is at least 95%, such as 98%, such as 100% complementarity to region of the target nucleic acid of SEQ ID NO: 1 and/or 2.
5. The oligonucleotide of embodiment 1-3, wherein the contiguous nucleotide sequence is 100% complementary to a region of the target nucleic acid of position 1 to 55318 of SEQ ID NO: 1.
6. The oligonucleotide of embodiment 1-4, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid, wherein the subsequence is selected from the group consisting of the regions indicated in table 1 or 2.
7. The oligonucleotide of embodiment 1-4, wherein the contiguous nucleotide sequence is at least 98% complementarity to the part of human SNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA.
8. The oligonucleotide of embodiments 1-4 or 7, wherein the oligonucleotide is capable of hybridizing to a target nucleic acid corresponding to position 55319 to 141053 of SEQ ID NO: 1, with a ΔG° below −10 kcal.
9. The oligonucleotide of embodiments 1-4 or 7-8, wherein the contiguous nucleotide sequence is 100% complementary to a target nucleic acid of position 55319 to 141053 of SEQ ID NO: 1.
10. The oligonucleotide of embodiment 1-8, wherein the target nucleic acid is RNA.
11. The oligonucleotide of embodiment 10, wherein the RNA is a long non-coding RNA.
12. The oligonucleotide of embodiment 1-11, wherein the contiguous nucleotide sequence comprises or consists of at least 10 contiguous nucleotides, particularly 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 contiguous nucleotides.
13. The oligonucleotide of embodiment 1-12, wherein the contiguous nucleotide sequence comprises or consists of from 12 to 22 nucleotides.
14. The oligonucleotide of embodiment 13, wherein the contiguous nucleotide sequence comprises or consists of from 15-20 nucleotides.
15. The oligonucleotide of embodiment 1-14, wherein the oligonucleotide comprises or consists of 10 to 35 nucleotides in length.
16. The oligonucleotide of embodiment 15, wherein the oligonucleotide comprises or consists of 15 to 24 nucleotides in length.
17. The oligonucleotide of embodiment 15 or 17, wherein the oligonucleotide comprises or consists of 17 to 22 nucleotides in length.
18. The oligonucleotide of embodiment 1-17, wherein the oligonucleotide or contiguous nucleotide sequence is single stranded.
19. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid, selected from the group consisting of the regions indicated in table 1 or 2.
20. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid selected from the group consisting of position 1589-10889, 46089-53989 and 60789-62489 of SEQ ID NO: 1.
21. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 5218-5240 of SEQ ID NO: 1.
22. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 5782-5803 of SEQ ID NO: 1.
23. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 8113-8139 of SEQ ID NO: 1.
24. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions: 9200-9250 of SEQ ID NO: 1.
25. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions: 11505-11555 of SEQ ID NO: 1.
26. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 13223-13242 of SEQ ID NO: 1.
27. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 15100-15150 of SEQ ID NO: 1.
28. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 15113-15180 of SEQ ID NO: 1.
29. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 29635-29705 of SEQ ID NO: 1.
30. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 30590-30740 of SEQ ID NO: 1.
31. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 39800-39855 of SEQ ID NO: 1.
32. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 44435-44460 of SEQ ID NO: 1.
33. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 45245-45270 of SEQ ID NO: 1
34. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid to positions 46380-46430 of SEQ ID NO: 1.
35. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 68915-68940 of SEQ ID NO: 1.
36. The oligonucleotide of embodiment 1-35, wherein the oligonucleotide is neither siRNA nor self-complementary.
37. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1819, 20, 21, 22, 23, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 44, 45, 45, 46, 47, 48, 49, 50, 51, 52, 53, 53, 54, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 79, 80, 81, 8283, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 95, 96, 96, 96, 97, 98, 99, 100, 101, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817 and 818.
38. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 166, 167, 167 or 169 (see motif sequences listed in table 3 in the Examples section).
39. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 570, 571, 572, 679, 680, 681, 682 and 683 (see motif sequences listed in table 3 in the Examples section).
40. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 570, 571, 572, 679, 680, 681, 682 and 683 (see motif sequences listed in table 3 in the Examples section).
41. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 35, 199 to 210 or SEQ ID NO: 582 to 584 (see motif sequences listed in table 3 in the Examples section).
42. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 236, 237, 238, 239, 240 and 590 (see motif sequences listed in table 3 in the Examples section).
43. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 221 to 225 or SEQ ID NO: 585 to 589 (see motif sequences listed in table 3 in the Examples section).
44. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 241 or 591 (see motif sequences listed in table 3 in the Examples section).
45. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 46-48, 285 to 305 or SEQ ID NO: 613 to 632 or SEQ ID NO: 721 to 807 (see motif sequences listed in table 3 in the Examples section).
46. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 331, 332, 638, 639, 640, 808, 809, 810, 811, 812, 813, 814 and 815 (see motif sequences listed in table 3 in the Examples section).
47. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 409 to 411 or SEQ ID NO: 642 to 646 or SEQ ID NO: 816 to 818 (see motif sequences listed in table 3 in the Examples section).
48. The oligonucleotide of embodiment 1-47, wherein the contiguous nucleotide sequence has zero to three mismatches compared to the target nucleic acid it is complementary to.
49. The oligonucleotide of embodiment 48, wherein the contiguous nucleotide sequence has one mismatch compared to the target nucleic acid.
50. The oligonucleotide of embodiment 48, wherein the contiguous nucleotide sequence has two mismatches compared to the target nucleic acid.
51. The oligonucleotide of embodiment 48, wherein the contiguous nucleotide sequence is fully complementary to the target nucleic acid sequence.
52. The oligonucleotide of embodiment 1-51, comprising one or more modified nucleosides.
53. The oligonucleotide of embodiment 52, wherein the one or more modified nucleoside is a high-affinity modified nucleosides.
54. The oligonucleotide of embodiment 52 or 53, wherein the one or more modified nucleoside is a 2′ sugar modified nucleoside.
55. The oligonucleotide of embodiment 54, wherein the one or more 2′ sugar modified nucleoside is independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, 2′-fluoro-ANA and LNA nucleosides.
56. The oligonucleotide of embodiment 54, wherein the one or more modified nucleoside is a LNA nucleoside.
57. The oligonucleotide of embodiment 56, wherein the modified LNA nucleoside is oxy-LNA.
58. The oligonucleotide of embodiment 57, wherein the modified nucleoside is beta-D-oxy-LNA.
59. The oligonucleotide of embodiment 57, wherein the modified nucleoside is alpha-L-oxy-LNA
60. The oligonucleotide of embodiment 56, wherein the modified nucleoside is thio-LNA.
61. The oligonucleotide of embodiment 56, wherein the modified nucleoside is amino-LNA.
62. The oligonucleotide of embodiment 56, wherein the modified nucleoside is cET.
63. The oligonucleotide of embodiment 56, wherein the modified nucleoside is ENA.
64. The oligonucleotide of embodiment 56, wherein the modified LNA nucleoside is selected from beta-D-oxy-LNA, alpha-L-oxy-LNA, beta-D-amino-LNA, alpha-L-amino-LNA, beta-D-thio-LNA, alpha-L-thio-LNA, (S)cET, (R)cET beta-D-ENA and alpha-L-ENA.
65. The oligonucleotide of any one of embodiments 1-64, wherein the oligonucleotide comprises at least one modified internucleoside linkage.
66. The oligonucleotide of embodiment 65, wherein the modified internucleoside linkage is nuclease resistant.
67. The oligonucleotide of embodiment 65 or 66, wherein at least 50% of the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate internucleoside linkages or boranophosphate internucleoside linkages.
68. The oligonucleotide of embodiment 65 or 66, wherein all the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate internucleoside linkages.
69. The oligonucleotide of embodiment 1-68, wherein the oligonucleotide is capable of recruiting RNase H.
70. The oligonucleotide of embodiment 69, wherein the oligonucleotide is a gapmer.
71. The oligonucleotide of embodiment 69 or 70, wherein the oligonucleotide is a gapmer of formula 5′-F-G-F′-3′, where region F and F′ independently comprise or consist of 1-7 modified nucleosides and G is a region between 6 and 16 nucleosides which are capable of recruiting RNaseH.
72. The oligonucleotide of embodiment 71, wherein the modified nucleoside is a 2′ sugar modified nucleoside independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic acid (ANA), 2′-fluoro-ANA and LNA nucleosides.
73. The oligonucleotide of embodiment 71 or 72, wherein one or more of the modified nucleosides in region F and F′ is a LNA nucleoside.
74. The oligonucleotide of embodiment 73, wherein all the modified nucleosides in region F and F′ are LNA nucleosides.
75. The oligonucleotide of embodiment 74, wherein region F and F′ consist of LNA nucleosides.
76. The oligonucleotide of embodiment 73-75, wherein all the modified nucleosides in region F and F′ are oxy-LNA nucleosides.
77. The oligonucleotide of embodiment 73, wherein at least one of region F or F′ further comprises at least one 2′ substituted modified nucleoside independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA and 2′-fluoro-DNA.
78. The oligonucleotide of embodiment 73-77, wherein the RNaseH recruiting nucleosides in region G are independently selected from DNA, alpha-L-LNA, C4′ alkylated DNA, ANA and 2′F-ANA and UNA.
79. The oligonucleotide of embodiment 78, wherein the nucleosides in region G is DNA and/or alpha-L-LNA nucleosides.
80. The oligonucleotide of embodiment 78 or 79, wherein region G consists of at least 75% DNA nucleosides.
81. The oligonucleotide of embodiment 1-80, wherein the oligonucleotide is capable of increasing the expression of UBE3A by at least 30% compared to a control.
82. The oligonucleotide of embodiment 1-81, wherein the level of the SNHG14 transcript downstream of SNORD109B is reduced by at least 20% compared to a control.
83. The oligonucleotide of embodiment 1-82, wherein the expression of SNORD115 is not significantly affected compared to a control.
84. The oligonucleotide of embodiment 1-83, wherein the oligonucleotide is selected from CMP ID NO: 4_1 to 678_1.
85. The oligonucleotide of embodiment 1-83, wherein the oligonucleotide is selected from the group consisting of CMP ID NO: 4_1, 4_2, 5_1, 5_2, 6_1, 6_2, 7_1, 7_2, 8_1, 9_1, 10_1, 11_1, 11_2, 12_1, 12_2, 13_1, 13_2, 14_1, 15_1, 16_1, 17_1, 17_2, 18_1, 18_2, 19_1, 19_2, 20_1, 21_1, 22_1, 23_1, 23_2, 24_1, 25_1, 26_1, 26_2, 27_1, 28_1, 28_2, 29_1, 29_2, 30_1, 31_1, 31_2, 32_1, 33_1, 34_1, 34_2, 34_3, 34_4, 34_5, 34_6, 34_7, 35_1, 35_2, 36_1, 37_1, 38_1, 38_2, 38_3, 38_4, 38_5, 38_6, 39_1, 39_2, 39_3, 39_4, 39_5, 40_1, 40_2, 40_3, 40_4, 40_5, 40_6, 40_7, 40_8, 41_1, 42_1, 43_1, 44_1, 44_2, 45_1, 45_2, 46_1, 47_1, 48_1, 48_2, 48_3, 48_4, 48_5, 48_6, 48_7, 49_1, 50_1, 51_1, 52_1, 53_1, 53_2, 54_1, 54_2, 54_3, 55_1, 55_2, 56_1, 57_1, 58_1, 58_2, 58_3, 59_1, 59_2, 60_1, 60_2, 60_3, 61_1, 62_1, 63_1, 64_1, 64_2, 65_1, 66_1, 67_1, 68_1, 69_1, 69_2, 69_3, 70_1, 70_2, 70_3, 71_1, 72_1, 72_2, 73_1, 73_2, 73_3, 74_1, 74_2, 75_1, 75_2, 76_1, 77_1, 77_2, 77_3, 78_1, 79_1, 79_2, 79_3, 80_1, 80_2, 80_3, 81_1, 82_1, 82_2, 83_1, 83_2, 84_1, 84_2, 85_1, 85_2, 86_1, 87_1, 88_1, 88_2, 89_1, 90_1, 91_1, 92_1, 93_1, 94_1, 95_1, 95_2, 96_1, 96_2, 96_3, 97_1, 97_2, 97_3, 97_4, 98_1, 98_2, 98_3, 99_1, 99_2, 99_3, 99_4, 100_1, 100_2, 100_3, 101_1, 101_2, 101_3, 101_4, 102_1, 102_2, 102_3, 102_4, 103_1, 103_2, 103_3, 103_4, 104_1, 104_2, 104_3, 105_1, 105_2, 105_3, 105_4, 106_1, 106_2, 106_3, 106_4, 107_1, 107_2, 107_3, 107_4, 108_1, 108_2, 108_3, 108_4, 109_1, 109_2, 109_3, 109_4, 110_1, 110_2, 111_1, 111_2, 111_3, 112_1, 112_2, 113_1, 114_1, 115_1, 116_1, 117_1, 118_1, 119_1, 120_1, 120_2, 121_1, 122_1, 123_1, 124_1, 125_1, 126_1, 126_2, 127_1, 128_1, 128_2, 128_3, 128_4, 129_1, 129_2, 130_1, 131_1, 132_1, 132_2, 132_3, 133_1, 133_2, 133_3, 133_4, 134_1, 134_2, 135_1, 135_2, 136_1, 137_1, 138_1, 139_1, 140_1, 141_1, 142_1, 143_1, 144_1, 145_1, 145_2, 146_1, 146_2, 147_1, 148_1, 149_1, 150_1, 150_2, 151_1, 152_1, 153_1, 154_1, 155_1, 156_1, 157_1, 158_1, 159_1, 160_1, 161_1, 162_1, 163_1, 164_1, 165_1, 166_1, 167_1, 168_1, 169_1, 169_10, 169_11, 169_12, 169_13, 169_14, 169_15, 169_16, 169_17, 169_18, 169_19, 169_2, 169_20, 169_21, 169_22, 169_23, 169_24, 169_25, 169_26, 169_27, 169_28, 169_29, 169_3, 169_30, 169_31, 169_32, 169_33, 169_34, 169_35, 169_36, 169_37, 169_38, 169_39, 169_4, 169_40, 169_41, 169_42, 169_43, 169_44, 169_45, 169_46, 169_47, 169_48, 169_49, 169_5, 169_50, 169_51, 169_52, 169_53, 169_54, 169_55, 169_56, 169_57, 169_6, 169_7, 169_8, 169_9, 169_58, 169_59, 169_60, 169_61, 169_62, 170_1, 171_1, 172_1, 173_1, 174_1, 175_1, 176_1, 177_1, 178_1, 179_1, 180_1, 181_1, 182_1, 183_1, 184_1, 185_1, 186_1, 187_1, 188_1, 189_1, 190_1, 191_1, 192_1, 193_1, 194_1, 195_1, 196_1, 197_1, 198_1, 199_1, 200_1, 201_1, 202_1, 203_1, 204_1, 205_1, 206_1, 207_1, 208_1, 208_2, 208_3, 208_4, 208_5, 208_6, 208_7, 209_1, 209_10, 209_2, 209_3, 209_4, 209_5, 209_6, 209_7, 209_8, 209_9, 210_1, 211_1, 212_1, 213_1, 214_1, 215_1, 216_1, 217_1, 218_1, 219_1, 220_1, 221_1, 222_1, 223_1, 224_1, 225_1, 226_1, 227_1, 228_1, 229_1, 230_1, 231_1, 232_1, 233_1, 234_1, 235_1, 236_1, 236_10, 236_11, 236_12, 236_13, 236_14, 236_15, 236_16, 236_2, 236_3, 236_4, 236_5, 236_6, 236_7, 236_8, 236_9, 236_17, 236_18, 236_19, 236_20, 236_21, 237_1, 237_10, 237_11, 237_12, 237_13, 237_14, 237_15, 237_16, 237_2, 237_3, 237_4, 237_5, 237_6, 237_7, 237_8, 237_9, 237_17, 237_18, 237_19, 237_20, 237_21, 238_1, 239_1, 239_10, 239_11, 239_12, 239_13, 239_14, 239_15, 239_16, 239_2, 239_3, 239_4, 239_5, 239_6, 239_7, 239_8, 239_9, 239_17, 239_18, 239_19, 239_20, 239_21, 240_1, 241_1, 241_10, 241_2, 241_3, 241_4, 241_5, 241_6, 241_7, 241_8, 241_9, 241_11, 241_12, 241_13, 241_14, 241_15, 242_1, 243_1, 244_1, 244_2, 244_3, 244_4, 244_5, 245_1, 246_1, 247_1, 248_1, 249_1, 250_1, 251_1, 252_1, 253_1, 254_1, 255_1, 256_1, 257_1, 258_1, 259_1, 260_1, 261_1, 262_1, 263_1, 264_1, 265_1, 266_1, 267_1, 268_1, 269_1, 270_1, 271_1, 272_1, 273_1, 274_1, 275_1, 276_1, 277_1, 278_1, 279_1, 280_1, 281_1, 282_1, 283_1, 284_1, 285_1, 285_2, 285_3, 285_4, 285_5, 285_6, 285_7, 285_8, 285_9, 285_10, 285_11, 286_1, 287_1, 288_1, 289_1, 290_1, 291_1, 292_1, 293_1, 294_1, 295_1, 296_1, 297_1, 298_1, 299_1, 300_1, 301_1, 302_1, 303_1, 304_1, 304_10, 304_2, 304_3, 304_4, 304_5, 304_6, 304_7, 304_8, 304_9, 304_11, 304_12, 304_13, 304_14, 304_15, 305_1, 306_1, 307_1, 308_1, 309_1, 310_1, 311_1, 312_1, 313_1, 314_1, 315_1, 316_1, 317_1, 318_1, 319_1, 320_1, 321_1, 322_1, 323_1, 324_1, 325_1, 326_1, 327_1, 328_1, 329_1, 330_1, 331_1, 332_1, 333_1, 334_1, 335_1, 336_1, 337_1, 338_1, 339_1, 340_1, 341_1, 342_1, 343_1, 344_1, 345_1, 346_1, 347_1, 348_1, 349_1, 350_1, 351_1, 352_1, 353_1, 354_1, 355_1, 356_1, 357_1, 358_1, 359_1, 360_1, 361_1, 361_10, 361_2, 361_3, 361_4, 361_5, 361_6, 361_7, 361_8, 361_9, 362_1, 362_10, 362_2, 362_3, 362_4, 362_5, 362_6, 362_7, 362_8, 362_9, 363_1, 364_1, 365_1, 366_1, 367_1, 368_1, 369_1, 370_1, 371_1, 372_1, 373_1, 374_1, 375_1, 376_1, 377_1, 378_1, 379_1, 380_1, 381_1, 382_1, 383_1, 384_1, 385_1, 386_1, 387_1, 388_1, 389_1, 390_1, 391_1, 392_1, 393_1, 394_1, 395_1, 396_1, 397_1, 398_1, 399_1, 400_1, 401_1, 402_1, 403_1, 404_1, 405_1, 406_1, 407_1, 408_1, 409_1, 410_1, 411_1, 412_1, 413_1, 414_1, 415_1, 416_1, 417_1, 418_1, 419_1, 420_1, 421_1, 422_1, 423_1, 424_1, 425_1, 425_10, 425_2, 425_3, 425_4, 425_5, 425_6, 425_7, 425_8, 425_9, 426_1, 427_1, 428_1, 429_1, 430_1, 431_1, 432_1, 433_1, 434_1, 435_1, 436_1, 437_1, 438_1, 439_1, 440_1, 441_1, 442_1, 443_1, 444_1, 445_1, 446_1, 447_1, 448_1, 449_1, 450_1, 451_1, 452_1, 453_1, 454_1, 455_1, 456_1, 457_1, 458_1, 459_1, 460_1, 461_1, 462_1, 463_1, 464_1, 465_1, 466_1, 467_1, 468_1, 469_1, 470_1, 471_1, 472_1, 473_1, 474_1, 475_1, 476_1, 477_1, 478_1, 479_1, 480_1, 481_1, 482_1, 483_1, 484_1, 485_1, 486_1, 487_1, 488_1, 489_1, 490_1, 491_1, 492_1, 493_1, 494_1, 495_1, 496_1, 497_1, 498_1, 499_1, 500_1, 501_1, 502_1, 503_1, 504_1, 505_1, 506_1, 507_1, 508_1, 509_1, 510_1, 511_1, 512_1, 513_1, 514_1, 515_1, 516_1, 517_1, 518_1, 519_1, 520_1, 521_1, 522_1, 523_1, 524_1, 525_1, 526_1, 527_1, 528_1, 529_1, 530_1, 531_1, 532_1, 533_1, 534_1, 535_1, 536_1, 537_1, 538_1, 539_1, 540_1, 541_1, 542_1, 543_1, 544_1, 545_1, 546_1, 547_1, 548_1, 549_1, 550_1, 551_1, 552_1, 553_1, 554_1, 555_1, 556_1, 557_1, 558_1, 559_1, 560_1, 561_1, 562_1, 563_1, 564_1, 565_1, 566_1, 567_1, 568_1, 569_1, 570_1, 570_2, 570_3, 570_4, 570_5, 570_6, 570_7, 570_8, 570_9, 570_10, 570_11, 570_12, 570_13, 570_14, 571_1, 571_2, 571_3, 571_4, 571_5, 571_6, 571_7, 571_8, 571_9, 571_10, 571_11, 571_12, 571_13, 571_14, 572_1, 572_2, 572_3, 572_4, 575_5, 575_6, 575_7, 575_8, 575_9, 572_10, 572_11, 572_12, 572_13, 572_14, 573_1, 573_2, 573_3, 573_4, 573_5, 573_6, 573_7, 573_8, 573_9, 573_10, 573_11, 573_12, 573_13, 573_14, 574_1, 574_2, 574_3, 574_4, 574_5, 574_6, 574_7, 574_8, 574_9, 574_10, 574_11, 574_12, 574_13, 574_14, 575_1, 575_2, 575_3, 575_4, 575_5, 575_6, 575_7, 575_8, 575_9, 575_10, 575_11, 575_12, 575_13, 575_14, 576_1, 576_2, 576_3, 576_4, 576_5, 576_6, 576_7, 576_8, 576_9, 576_10, 576_11, 576_12, 576_13, 576_14, 577_1, 577_2, 577_3, 577_4, 577_5, 577_6, 577_7, 577_8, 577_9, 577_10, 577_11, 577_12, 577_13, 577_14, 578_1, 578_2, 578_3, 578_4, 578_5, 578_6, 578_7, 578_8, 578_9, 579_1, 579_2, 579_3, 579_4, 579_5, 579_6, 579_7, 579_8, 579_9, 580_1, 580_2, 580_3, 580_4, 580_5, 580_6, 580_7, 580_8, 580_9, 581_1, 581_2, 581_3, 581_4, 581_5, 581_6, 581_7, 581_8, 581_9, 582_1, 582_2, 582_3, 582_4, 585_5, 585_6, 585_7, 585_8, 585_9, 583_1, 583_2, 583_3, 583_4, 583_5, 583_6, 583_7, 583_8, 583_9, 584_1, 584_2, 584_3, 584_4, 584_5, 584_6, 584_7, 584_8, 585_1, 585_2, 585_3, 585_4, 585_5, 585_6, 585_7, 585_8, 585_9, 585_10, 585_11, 585_12, 585_13, 585_14, 586_1, 586_2, 586_3, 586_4, 586_5, 586_6, 586_7, 586_8, 586_9, 586_10, 586_11, 586_12, 586_13, 586_14, 587_1, 587_2, 587_3, 587_4, 587_5, 587_6, 587_7, 587_8, 587_9, 587_10, 587_11, 587_12, 587_13, 587_14, 588_1, 588_2, 588_3, 588_4, 588_5, 588_6, 588_7, 588_8, 588_9, 588_10, 588_11, 588_12, 588_13, 588_14, 589_1, 589_2, 589_3, 589_4, 589_5, 589_6, 589_7, 589_8, 589_9, 589_10, 589_11, 589_12, 589_13, 589_14, 590_1, 590_10, 590_11, 590_12, 590_13, 590_14, 590_15, 590_2, 590_3, 590_4, 590_5, 590_6, 590_7, 590_8, 590_9, 590_16, 590_17, 590_18, 590_19, 590_20, 591_1, 591_2, 592_1, 592_2, 592_3, 592_4, 595_5, 595_6, 595_7, 595_8, 595_9, 592_10, 592_11, 592_12, 592_13, 592_14, 593_1, 593_2, 593_3, 593_4, 594_1, 594_2, 594_3, 594_4, 595_1, 595_2, 595_3, 595_4, 596_1, 596_2, 596_3, 596_4, 597_1, 597_2, 597_3, 597_4, 598_1, 598_2, 598_3, 598_4, 599_1, 599_2, 599_3, 599_4, 600_1, 600_2, 600_3, 600_4, 601_1, 601_2, 601_3, 601_4, 602_1, 602_2, 602_3, 602_4, 603_1, 603_2, 603_3, 603_4, 604_1, 604_2, 604_3, 604_4, 605_1, 605_2, 605_3, 605_4, 606_1, 606_2, 606_3, 606_4, 607_1, 607_2, 607_3, 607_4, 608_1, 608_2, 608_3, 608_4, 608_5, 608_6, 608_7, 608_8, 608_9, 609_1, 609_2, 609_3, 609_4, 609_5, 609_6, 609_7, 609_8, 609_9, 610_1, 610_2, 610_3, 610_4, 610_5, 610_6, 610_7, 610_8, 610_9, 611_1, 611_2, 611_3, 611_4, 611_5, 611_6, 611_7, 611_8, 611_9, 612_1, 612_2, 612_3, 612_4, 615_5, 615_6, 615_7, 615_8, 615_9, 613_1, 613_2, 613_3, 613_4, 613_5, 613_6, 613_7, 613_8, 613_9, 613_10, 614_1, 614_2, 614_3, 614_4, 614_5, 614_6, 614_7, 614_8, 614_9, 614_10, 615_1, 615_2, 615_3, 615_4, 615_5, 615_6, 615_7, 615_8, 615_9, 615_10, 616_1, 616_2, 616_3, 616_4, 616_5, 616_6, 616_7, 616_8, 616_9, 616_10, 617_1, 617_2, 617_3, 617_4, 617_5, 617_6, 617_7, 617_8, 617_9, 617_10, 618_1, 618_2, 618_3, 618_4, 618_5, 618_6, 618_7, 618_8, 618_9, 618_10, 619_1, 619_2, 619_3, 619_4, 619_5, 619_6, 619_7, 619_8, 619_9, 619_10, 620_1, 620_2, 620_3, 620_4, 620_5, 620_6, 620_7, 620_8, 620_9, 620_10, 621_1, 621_2, 621_3, 621_4, 621_5, 621_6, 621_7, 621_8, 621_9, 621_10, 621_11, 622_1, 622_2, 622_3, 622_4, 625_5, 625_6, 625_7, 625_8, 625_9, 622_10, 623_1, 623_2, 623_3, 623_4, 623_5, 623_6, 623_7, 623_8, 623_9, 623_10, 624_1, 624_2, 624_3, 624_4, 624_5, 624_6, 624_7, 624_8, 624_9, 624_10, 625_1, 625_2, 625_3, 625_4, 625_5, 625_6, 625_7, 625_8, 625_9, 625_10, 625_11, 625_12, 625_13, 625_14, 626_1, 626_2, 626_3, 626_4, 626_5, 626_6, 626_7, 626_8, 626_9, 626_10, 626_11, 626_12, 626_13, 626_14, 627_1, 627_2, 627_3, 627_4, 627_5, 627_6, 627_7, 627_8, 627_9, 627_10, 627_11, 627_12, 627_13, 627_14, 628_1, 628_2, 628_3, 628_4, 628_5, 628_6, 628_7, 628_8, 628_9, 628_10, 628_11, 628_12, 628_13, 628_14, 629_1, 629_10, 629_11, 629_2, 629_3, 629_4, 629_5, 629_6, 629_7, 629_8, 629_9, 629_12, 629_13, 629_14, 629_15, 629_16, 630_1, 630_2, 630_3, 631_1, 631_10, 631_2, 631_3, 631_4, 631_5, 631_6, 631_7, 631_8, 631_9, 631_11, 631_12, 631_13, 631_14, 631_15, 632_1, 632_2, 632_3, 632_4, 635_5, 635_6, 635_7, 635_8, 635_9, 632_10, 632_11, 632_12, 632_13, 632_14, 633_1, 633_2, 633_3, 633_4, 633_5, 633_6, 633_7, 633_8, 633_9, 634_1, 634_2, 634_3, 634_4, 634_5, 634_6, 634_7, 634_8, 634_9, 635_1, 635_2, 635_3, 635_4, 635_5, 635_6, 635_7, 635_8, 635_9, 636_1, 636_2, 636_3, 636_4, 636_5, 636_6, 636_7, 636_8, 636_9, 637_1, 637_2, 637_3, 637_4, 637_5, 637_6, 637_7, 637_8, 637_9, 638_1, 638_2, 638_3, 638_4, 638_5, 638_6, 638_7, 638_8, 638_9, 638_10, 638_11, 638_12, 638_13, 638_14, 639_1, 639_2, 639_3, 639_4, 639_5, 639_6, 639_7, 639_8, 639_9, 639_10, 639_11, 639_12, 639_13, 639_14, 640_1, 640_2, 640_3, 640_4, 640_5, 640_6, 640_7, 640_8, 640_9, 640_10, 640_11, 640_12, 640_13, 640_14, 641_1, 641_2, 641_3, 641_4, 641_5, 641_6, 641_7, 641_8, 641_9, 642_1, 642_10, 642_11, 642_12, 642_13, 642_14, 642_15, 642_16, 642_17, 642_2, 642_3, 642_4, 645_5, 645_6, 645_7, 645_8, 645_9, 642_18, 642_19, 642_20, 642_21, 642_22, 643_1, 644_1, 644_2, 644_3, 644_4, 644_5, 644_6, 645_1, 645_2, 645_3, 645_4, 645_5, 645_6, 645_7, 645_8, 645_9, 645_10, 646_1, 646_10, 646_11, 646_12, 646_13, 646_14, 646_15, 646_16, 646_17, 646_18, 646_19, 646_2, 646_3, 646_4, 646_5, 646_6, 646_7, 646_8, 646_9, 646_20, 646_21, 646_22, 646_23, 646_24, 647_1, 648_1, 649_1, 650_1, 651_1, 652_1, 653_1, 654_1, 655_1, 656_1, 657_1, 658_1, 659_1, 660_1, 661_1, 662_1, 663_1, 664_1, 665_1, 666_1, 667_1, 668_1, 669_1, 670_1, 671_1, 672_1, 673_1, 674_1, 675_1, 676_1, 677_1, 678_1, 679_1, 679_2, 679_3, 679_4, 679_5, 680_1, 680_2, 680_3, 680_4, 680_5, 681_1, 681_2, 681_3, 681_4, 681_5, 682_1, 682_2, 682_3, 682_4, 685_5, 683_1, 683_2, 683_3, 683_4, 683_5, 684_1, 684_2, 684_3, 684_4, 684_5, 685_1, 685_2, 685_3, 685_4, 685_5, 686_1, 686_2, 686_3, 686_4, 686_5, 687_1, 687_2, 687_3, 687_4, 687_5, 688_1, 688_2, 688_3, 688_4, 688_5, 689_1, 689_2, 689_3, 689_4, 689_5, 690_1, 690_2, 690_3, 690_4, 690_5, 691_1, 691_2, 692_1, 692_2, 692_3, 692_4, 695_5, 693_1, 693_2, 693_3, 693_4, 693_5, 694_1, 694_2, 694_3, 694_4, 694_5, 695_1, 695_2, 695_3, 695_4, 695_5, 696_1, 696_2, 696_3, 696_4, 696_5, 697_1, 697_2, 697_3, 697_4, 697_5, 698_1, 698_2, 698_3, 698_4, 698_5, 699_1, 699_2, 699_3, 699_4, 699_5, 700_1, 700_2, 700_3, 700_4, 700_5, 701_1, 701_2, 701_3, 701_4, 701_5, 702_1, 702_2, 702_3, 702_4, 705_5, 703_1, 703_2, 703_3, 703_4, 703_5, 704_1, 704_2, 704_3, 704_4, 704_5, 705_1, 705_2, 705_3, 705_4, 705_5, 706_1, 706_2, 706_3, 706_4, 706_5, 707_1, 707_2, 707_3, 707_4, 707_5, 708_1, 708_2, 708_3, 708_4, 708_5, 709_1, 709_2, 709_3, 709_4, 709_5, 710_1, 710_2, 710_3, 710_4, 710_5, 711_1, 711_2, 711_3, 711_4, 711_5, 712_1, 712_2, 712_3, 712_4, 715_5, 713_1, 713_2, 713_3, 713_4, 713_5, 714_1, 714_2, 714_3, 714_4, 714_5, 715_1, 715_2, 715_3, 715_4, 715_5, 716_1, 716_2, 716_3, 716_4, 716_5, 717_1, 717_2, 717_3, 717_4, 717_5, 718_1, 718_2, 719_1, 719_2, 719_3, 719_4, 719_5, 720_1, 720_2, 720_3, 720_4, 720_5, 721_1, 721_2, 721_3, 721_4, 721_5, 722_1, 722_2, 722_3, 722_4, 725_5, 723_1, 723_2, 723_3, 723_4, 723_5, 724_1, 724_2, 724_3, 724_4, 724_5, 725_1, 725_2, 725_3, 725_4, 725_5, 726_1, 726_2, 726_3, 726_4, 726_5, 727_1, 727_2, 727_3, 727_4, 727_5, 728_1, 728_2, 728_3, 728_4, 728_5, 729_1, 729_2, 729_3, 729_4, 729_5, 730_1, 730_2, 730_3, 730_4, 730_5, 731_1, 731_2, 731_3, 731_4, 731_5, 732_1, 732_2, 732_3, 732_4, 735_5, 733_1, 733_2, 733_3, 733_4, 733_5, 734_1, 734_2, 734_3, 734_4, 734_5, 735_1, 735_2, 735_3, 735_4, 735_5, 736_1, 736_2, 736_3, 736_4, 736_5, 737_1, 737_2, 737_3, 737_4, 737_5, 738_1, 738_2, 738_3, 738_4, 738_5, 738_6, 739_1, 739_2, 739_3, 739_4, 739_5, 740_1, 740_2, 740_3, 740_4, 740_5, 741_1, 741_2, 741_3, 741_4, 741_5, 742_1, 742_2, 742_3, 743_1, 743_2, 743_3, 743_4, 743_5, 744_1, 744_2, 744_3, 744_4, 744_5, 745_1, 745_2, 745_3, 745_4, 745_5, 746_1, 746_2, 746_3, 747_1, 747_2, 747_3, 747_4, 747_5, 748_1, 748_2, 748_3, 748_4, 748_5, 749_1, 749_2, 749_3, 749_4, 749_5, 750_1, 750_2, 750_3, 750_4, 751_1, 751_2, 751_3, 751_4, 751_5, 752_1, 752_2, 752_3, 752_4, 755_5, 753_1, 753_2, 753_3, 753_4, 753_5, 754_1, 754_2, 754_3, 754_4, 754_5, 755_1, 755_2, 755_3, 755_4, 755_5, 756_1, 756_2, 756_3, 756_4, 756_5, 757_1, 757_2, 757_3, 757_4, 757_5, 758_1, 758_2, 758_3, 758_4, 758_5, 759_1, 759_2, 759_3, 759_4, 759_5, 760_1, 760_2, 760_3, 760_4, 760_5, 761_1, 761_2, 761_3, 761_4, 761_5, 762_1, 762_2, 762_3, 762_4, 765_5, 763_1, 763_2, 763_3, 763_4, 763_5, 764_1, 764_2, 764_3, 764_4, 764_5, 765_1, 765_2, 765_3, 765_4, 765_5, 766_1, 766_2, 766_3, 766_4, 766_5, 767_1, 767_2, 767_3, 767_4, 767_5, 768_1, 768_2, 768_3, 768_4, 768_5, 769_1, 769_2, 769_3, 769_4, 769_5, 770_1, 770_2, 770_3, 770_4, 770_5, 771_1, 771_2, 771_3, 771_4, 771_5, 772_1, 772_2, 772_3, 772_4, 775_5, 773_1, 773_2, 773_3, 773_4, 773_5, 774_1, 774_2, 774_3, 774_4, 774_5, 775_1, 775_2, 775_3, 775_4, 775_5, 776_1, 776_2, 776_3, 776_4, 776_5, 777_1, 777_2, 777_3, 777_4, 777_5, 778_1, 778_2, 778_3, 778_4, 778_5, 779_1, 779_2, 779_3, 779_4, 779_5, 780_1, 780_2, 780_3, 780_4, 780_5, 781_1, 782_1, 782_2, 782_3, 782_4, 785_5, 783_1, 783_2, 783_3, 783_4, 783_5, 784_1, 784_2, 784_3, 784_4, 784_5, 785_1, 786_1, 786_2, 786_3, 786_4, 786_5, 787_1, 787_2, 787_3, 787_4, 787_5, 788_1, 788_2, 788_3, 788_4, 788_5, 789_1, 789_2, 789_3, 789_4, 789_5, 790_1, 790_2, 790_3, 790_4, 790_5, 791_1, 791_2, 791_3, 791_4, 791_5, 792_1, 792_2, 792_3, 792_4, 795_5, 793_1, 793_2, 793_3, 793_4, 793_5, 794_1, 794_2, 794_3, 794_4, 794_5, 795_1, 795_2, 795_3, 795_4, 795_5, 796_1, 796_2, 796_3, 796_4, 796_5, 797_1, 797_2, 797_3, 797_4, 797_5, 798_1, 798_2, 798_3, 798_4, 798_5, 799_1, 799_2, 799_3, 799_4, 799_5, 800_1, 800_2, 800_3, 800_4, 800_5, 801_1, 801_2, 801_3, 801_4, 801_5, 802_1, 802_2, 802_3, 802_4, 805_5, 803_1, 803_2, 803_3, 803_4, 803_5, 804_1, 804_2, 804_3, 804_4, 804_5, 805_1, 805_2, 805_3, 805_4, 805_5, 806_1, 806_2, 806_3, 806_4, 806_5, 807_1, 807_2, 807_3, 807_4, 807_5, 808_1, 808_2, 808_3, 808_4, 808_5, 809_1, 809_2, 809_3, 809_4, 809_5, 810_1, 810_2, 810_3, 810_4, 810_5, 811_1, 811_2, 811_3, 811_4, 811_5, 812_1, 812_2, 812_3, 812_4, 815_5, 813_1, 813_2, 813_3, 813_4, 813_5, 814_1, 814_2, 814_3, 814_4, 814_5, 815_1, 815_2, 815_3, 815_4, 815_5, 816_1, 816_2, 816_3, 816_4, 816_5, 816_6, 817_1 and 818_1.
86. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 155_1 or 165_1.
87. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO 169_52, 169_50 or 169_56.
88. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 172_1, 272_1, 572_7, 572_6 or 572_5.
89. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 175_1.
90. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 178_1.
91. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 573_8, 186_1 or 187_1.
92. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 186_1.
93. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 200_1, 204_1, 206_1, 35_2 or 209_1.
94. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 585_1, 585_8, 586_9, 586_5, 586_8, 586_4 or 586_6.
95. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 233_1.
96. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 237_8 or 590_13.
97. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 220_1.
98. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 591_1, 592_2, 592_4 or 241_9.
99. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 597_4, 598_4, 39_1 or 602_1.
100. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 39_1.
101. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 611_7.
102. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 271_1 or 278_1.
103. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 616_4, 621_2, 621_1, 622_3, 622_5, 622_4, 624_3, 624_5, 287_1, 625_6, 626_7, 626_8, 626_9, 48_1, 631_6, 631_1, 303_1, 304_6 or 304_10.
104. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 636_8.
105. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 638_8, 639_5, 331_1 or 640_4.
106. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 359_1, 361_1, 361_5, 362_1 or 641_5.
107. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 378_1, 379_1 or 399_1.
108. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 403_1, 405_1, 642_12, 642_13, 644_3 or 646_16.
109. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 85_1 or 425_5.
110. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 116_1.
111. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 123_1 or 124_1.
112. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 126_2.
113. A conjugate comprising the oligonucleotide according to any one of claims 1-112, and at least one conjugate moiety covalently attached to said oligonucleotide.
114. The oligonucleotide conjugate of embodiment 113, wherein the conjugate moiety is selected from carbohydrates, cell surface receptor ligands, drug substances, hormones, lipophilic substances, polymers, proteins, peptides, toxins, vitamins, viral proteins or combinations thereof.
115. The oligonucleotide conjugate of embodiment 113 or 114, wherein the conjugate moiety is an antibody or antibody fragment.
116. The oligonucleotide conjugate of embodiment 115, wherein the antibody or antibody fragment has affinity to the transferrin receptor.
117. The oligonucleotide conjugate of embodiment 113-115, comprising a linker which is positioned between the oligonucleotide and the conjugate moiety.
118. The oligonucleotide conjugate of embodiment 117, wherein the linker is a physiologically labile linker.
119. The oligonucleotide conjugate of embodiment 118, wherein the physiologically labile linker is nuclease susceptible linker.
120. The oligonucleotide conjugate of embodiment 118 or 119, wherein the oligonucleotide has the formula D-F-G-F′ or F-G-F′-D′, wherein F, F′ and G are as defined in embodiments 73-80 and D or D′ comprises 1, 2 or 3 DNA nucleosides with phosphorothioate internucleoside linkages.
121. The oligonucleotide conjugate of embodiment 113-120, which display improved uptake into the brain of the conjugate oligonucleotide as compared to an unconjugated oligonucleotide.
122. A pharmaceutical composition comprising the oligonucleotide of embodiment 1-112 or a conjugate of embodiment 113-121 and a pharmaceutically acceptable diluent, carrier, salt and/or adjuvant.
123. A method for manufacturing the oligonucleotide of embodiment 1-112, comprising reacting nucleotide units thereby forming covalently linked contiguous nucleotide units comprised in the oligonucleotide.
124. The method of embodiment 123, further comprising reacting the contiguous nucleotide sequence with a non-nucleotide conjugation moiety.
125. A method for manufacturing the composition of embodiment 122, comprising mixing the oligonucleotide with a pharmaceutically acceptable diluent, carrier, salt and/or adjuvant.
126. An in vivo or in vitro method for inducing UBE3A expression in a target cell where expression of paternal UBE3A is suppressed, said method comprising administering an oligonucleotide of any one of embodiments 1-112 or a conjugate of embodiment 113-121 or the pharmaceutical composition of embodiment 122 in an effective amount to said cell.
127. The method of embodiment 126, wherein the expression of UBE3A is increased by at least 40% compared to a control.
128. The method of embodiment 126 or 127, wherein the level of the SNHG14 transcript downstream of SNORD109B is reduced by at least 30% compared to a control.
129. The method of embodiment 126-128, wherein the target cell is a neuronal cell.
130. The method of embodiment 126-129, wherein the expression of SNORD115 is not significantly affected compared to a control.
131. A method for treating or preventing a disease comprising administering a therapeutically or prophylactically effective amount of an oligonucleotide of embodiment 1-112 or a conjugate of embodiment 113-121 or the pharmaceutical composition of embodiment 122 to a subject suffering from or susceptible to the disease.
132. The oligonucleotide of embodiment 1-112 or a conjugate of embodiment 113-121 or the pharmaceutical composition of embodiment 122, for use as a medicament for treatment or prevention of a disease in a subject.
133. Use of the oligonucleotide of oligonucleotide of embodiment 1-112 or a conjugate of embodiment 113-121 for the preparation of a medicament for treatment or prevention of a disease in a subject.
134. The method, the oligonucleotide or the use of embodiments 131-133, wherein the disease is associated with in vivo activity of UBE3A.
135. The method, the oligonucleotide or the use of embodiments 131-134, wherein the disease is associated with reduced expression of UBE3A and/or reduced activity of UBE3A in neuronal cells.
136. The method, the oligonucleotide or the use of embodiment 135, wherein the reduced expression of UBE3A and/or reduced activity of UBE3A is due to mutations in the maternal allele of the UBE3A gene.
137. The method, the oligonucleotide or the use of embodiments 134-136, wherein the UBE3A expression is increased by at least 30%, or at least 50%, or at least 70%, or at least 90%, or at least 100%, or at least 150% or at least 200%, compared to the expression without the oligonucleotide of embodiment 1-112 or a conjugate of embodiment 113-121 or the pharmaceutical composition of embodiment 122.
138. The method, the oligonucleotide or the use of embodiments 131-137, wherein the disease is Angelman syndrome.
139. The method, the oligonucleotide or the use of embodiments 131-138, wherein the subject is a mammal.
140. The method, the oligonucleotide or the use of embodiment 139, wherein the mammal is human.
141. The method, the oligonucleotide or the use of embodiment 139 or 140, wherein the subject is an infant or a juvenile.
EXAMPLES
Materials and Methods
|
List of oligonucleotides or contiguous nucleobase sequences complementary to
|
SEQ ID NO: 1 (motif sequences indicated by SEQ ID NO), oligonucleotide designs made
|
from these, as well as specific oligonucleotide compounds (indicated by CMP ID NO)
|
designed based on the motif sequence.
|
Seq
Start
|
ID
CMP
SEQ ID
|
NO
Motif
Design
Compound
ID NO
ΔG°
NO 1
|
|
4
AACTTCATCAATATTTCCC
3-13-3
AACttcatcaatatttCCC
4_1
-23.36
1677
|
|
4
AACTTCATCAATATTTCCC
2-15-2
AActtcatcaatatttcCC
4_2
-19.60
1677
|
|
5
ACTTCATCAATATTTCCC
3-12-3
ACTtcatcaatatttCCC
5_1
-23.80
1677
|
|
5
ACTTCATCAATATTTCCC
2-14-2
ACttcatcaatatttcCC
5_2
-20.24
1677
|
|
6
CAACTTCATCAATATTTCCC
2-14-4
CAacttcatcaatattTCCC
6_1
-25.64
1677
|
|
6
CAACTTCATCAATATTTCCC
2-16-2
CAacttcatcaatatttcCC
6_2
-22.28
1677
|
|
7
CAACTTCATCAATATTTCC
4-13-2
CAACttcatcaatatttCC
7_1
-21.47
1678
|
|
7
CAACTTCATCAATATTTCC
2-15-2
CAacttcatcaatatttCC
7_2
-19.46
1678
|
|
8
CCAACTTCATCAATATTTCC
3-14-3
CCAacttcatcaatattTCC
8_1
-25.64
1678
|
|
9
CCCAACTTCATCAATATTTC
4-14-2
CCCAacttcatcaatattTC
9_1
-25.64
1679
|
|
10
ACCCAACTTCATCAATATTT
2-16-2
ACccaacttcatcaatatTT
10_1
-20.05
1680
|
|
11
CCCAACTTCATCAATATTT
4-13-2
CCCAacttcatcaatatTT
11_1
-23.96
1680
|
|
11
CCCAACTTCATCAATATTT
2-15-2
CCcaacttcatcaatatTT
11_2
-20.28
1680
|
|
12
ACCCAACTTCATCAATATT
4-13-2
ACCCaacttcatcaataTT
12_1
-23.64
1681
|
|
12
ACCCAACTTCATCAATATT
2-15-2
ACccaacttcatcaataTT
12_2
-19.18
1681
|
|
13
CCCAACTTCATCAATATT
4-12-2
CCCAacttcatcaataTT
13_1
-23.09
1681
|
|
13
CCCAACTTCATCAATATT
2-14-2
CCcaacttcatcaataTT
13_2
-19.41
1681
|
|
14
TACCCAACTTCATCAATAT
2-15-2
TAcccaacttcatcaatAT
14_1
-19.31
1682
|
|
15
TACCCAACTTCATCAATA
2-14-2
TAcccaacttcatcaaTA
15_1
-19.14
1683
|
|
16
TTACCCAACTTCATCAATA
2-15-2
TTacccaacttcatcaaTA
16_1
-19.74
1683
|
|
17
TTTACCCAACTTCATCAAT
4-13-2
TTTAcccaacttcatcaAT
17_1
-21.68
1684
|
|
17
TTTACCCAACTTCATCAAT
2-15-2
TTtacccaacttcatcaAT
17_2
-19.22
1684
|
|
18
ATACTTTACCCAACTTCAT
3-13-3
ATActttacccaacttCAT
18_1
-23.44
1688
|
|
18
ATACTTTACCCAACTTCAT
2-15-2
ATactttacccaacttcAT
18_2
-20.13
1688
|
|
19
TACTTTACCCAACTTCAT
3-12-3
TACtttacccaacttCAT
19_1
-22.78
1688
|
|
19
TACTTTACCCAACTTCAT
2-14-2
TActttacccaacttcAT
19_2
-19.30
1688
|
|
20
TTATACTTTACCCAACTTCA
2-16-2
TTatactttacccaacttCA
20_1
-21.40
1689
|
|
21
TCACTGTTCTGACTTT
3-10-3
TCActgttctgacTTT
21_1
-19.11
1712
|
|
22
TTCAATCTCTATCTCATCAT
2-16-2
TTcaatctctatctcatcAT
22_1
-19.42
4169
|
|
23
CTTCAATCTCTATCTCATCA
4-14-2
CTTCaatctctatctcatCA
23_1
-24.21
4170
|
|
23
CTTCAATCTCTATCTCATCA
2-16-2
CTtcaatctctatctcatCA
23_2
-22.04
4170
|
|
24
TTCAATCTCTATCTCATCA
2-15-2
TTcaatctctatctcatCA
24_1
-19.44
4170
|
|
25
CTTCAATCTCTATCTCATC
2-15-2
CTtcaatctctatctcaTC
25_1
-19.87
4171
|
|
26
ACTTCAATCTCTATCTCAT
3-13-3
ACTtcaatctctatctCAT
26_1
-22.36
4172
|
|
26
ACTTCAATCTCTATCTCAT
2-15-2
ACttcaatctctatctcAT
26_2
-19.08
4172
|
|
27
CACTTCAATCTCTATCTCAT
2-16-2
CActtcaatctctatctcAT
27_1
-20.98
4172
|
|
28
ACTTCAATCTCTATCTCA
2-12-4
ACttcaatctctatCTCA
28_1
-21.96
4173
|
|
28
ACTTCAATCTCTATCTCA
2-14-2
ACttcaatctctatctCA
28_2
-19.10
4173
|
|
29
CACTTCAATCTCTATCTCA
2-13-4
CActtcaatctctatCTCA
29_1
-23.86
4173
|
|
29
CACTTCAATCTCTATCTCA
2-15-2
CActtcaatctctatctCA
29_2
-21.00
4173
|
|
30
ACACTTCAATCTCTATCTC
2-15-2
ACacttcaatctctatcTC
30_1
-19.38
4174
|
|
31
TACACTTCAATCTCTATCTC
2-14-4
TAcacttcaatctctaTCTC
31_1
-23.31
4174
|
|
31
TACACTTCAATCTCTATCTC
2-16-2
TAcacttcaatctctatcTC
31_2
-20.53
4174
|
|
32
TACACTTCAATCTCTATCT
4-13-2
TACActtcaatctctatCT
32_1
-22.34
4175
|
|
33
CTTTGTCTCTCTTTACT
2-13-2
CTttgtctctctttaCT
33_1
-19.36
4374
|
|
34
TATACCTTTCTTTAACCC
3-12-3
TATacctttctttaaCCC
34_1
-24.89
8118
|
|
34
TATACCTTTCTTTAACCC
2-14-2
TAtacctttctttaacCC
34_2
-20.83
8118
|
|
34
TATACCTTTCTTTAACCC
1-3-1-
TataCctttcttTaAcCC
34_3
-21.63
8116
|
7-1-1-
|
1-1-2
|
|
34
TATACCTTTCTTTAACCC
1-4-1-
TatacCtttcttTaacCC
34_4
-21.31
8116
|
6-1-3-2
|
|
34
TATACCTTTCTTTAACCC
1-2-1-
TatAcCtttctttAAcCC
34_5
-21.51
8116
|
1-1-7-
|
2-1-2
|
|
34
TATACCTTTCTTTAACCC
2-3-1-
TAtacCtttctttAacCC
34_6
-21.84
8116
|
7-1-2-2
|
|
34
TATACCTTTCTTTAACCC
2-13-3
TAtacctttctttaaCCC
34_7
-23.21
8116
|
|
35
TGTTTATACCCTTTCC
2-12-2
TGtttataccctttCC
35_1
-20.33
9212
|
|
35
TGTTTATACCCTTTCC
4-10-2
TGTTtataccctttCC
35_2
-22.69
9212
|
|
36
TCTCCTTTATGACTCC
2-10-4
TCtcctttatgaCTCC
36_1
-23.29
10839
|
|
37
CTTCTCCTTTATGACTC
2-13-2
CTtctcctttatgacTC
37_1
-19.26
10840
|
|
38
CCATTTATTTCCATTTATT
4-13-2
CCATttatttccatttaTT
38_1
-22.32
15567
|
|
38
CCATTTATTTCCATTTATT
2-15-2
CCatttatttccatttaTT
38_2
-19.61
15567
|
|
38
CCATTTATTTCCATTTATT
1-2-1-
CcaTttatttccaTTtATT
38_3
-20.02
15567
|
9-2-1-3
|
|
38
CCATTTATTTCCATTTATT
1-1-1-
CcAtTtatttccaTtTaTT
38_4
-18.95
15567
|
1-1-8-
|
1-1-1-
|
1-2
|
|
38
CCATTTATTTCCATTTATT
2-2-1-
CCatTtatttccaTttaTT
38_5
-20.35
15567
|
8-1-3-2
|
|
38
CCATTTATTTCCATTTATT
1-2-3-
CcaTTTatttccAtttATT
38_6
-20.87
15567
|
6-1-3-3
|
|
39
CTTTCCATTTATTTCCATTT
2-14-4
CTttccatttatttccATTT
39_1
-23.14
15570
|
|
39
CTTTCCATTTATTTCCATTT
1-13-
CtttccatttatttCcAtTT
39_2
-20.96
15570
|
1-1-1-
|
1-2
|
|
39
CTTTCCATTTATTTCCATTT
1-13-
CtttccatttatttCcatTT
39_3
-20.91
15570
|
1-3-2
|
|
39
CTTTCCATTTATTTCCATTT
1-3-1-
CtttCcAtttatttccatTT
39_4
-20.96
15570
|
1-1-11-
|
2
|
|
39
CTTTCCATTTATTTCCATTT
1-1-1-
CtTtccAtttatttccAtTT
39_5
-20.54
15570
|
3-1-9-
|
1-1-2
|
|
40
TCTTTCCATTTATTTCCATT
2-14-4
TCtttccatttatttcCATT
40_1
-24.62
15571
|
|
40
TCTTTCCATTTATTTCCATT
2-13-
TCtttccatttatttCcATT
40_2
-23.39
15571
|
1-1-3
|
|
40
TCTTTCCATTTATTTCCATT
2-13-
TCtttccatttatttCcaTT
40_3
-22.53
15571
|
1-2-2
|
|
40
TCTTTCCATTTATTTCCATT
2-14-
TCtttccatttatttcCaTT
40_4
-22.34
15571
|
1-1-2
|
|
40
TCTTTCCATTTATTTCCATT
2-3-1-
TCtttCcatttatttccATT
40_5
-23.39
15571
|
11-3
|
|
40
TCTTTCCATTTATTTCCATT
2-4-1-
TCtttcCatttatttccATT
40_6
-23.20
15571
|
10-3
|
|
40
TCTTTCCATTTATTTCCATT
2-3-1-
TCtttCcatttatttccaTT
40_7
-22.53
15571
|
12-2
|
|
40
TCTTTCCATTTATTTCCATT
2-4-1-
TCtttcCatttatttccaTT
40_8
-22.34
15571
|
11-2
|
|
41
ATTACCCATCCGTTCT
2-12-2
ATtacccatccgttCT
41_1
-21.15
21965
|
|
42
GCATTAGGCACATTACAT
3-12-3
GCAttaggcacattaCAT
42_1
-23.96
22211
|
|
43
ATTATTATTTAACCTTCCTA
2-16-2
ATtattatttaaccttccTA
43_1
-19.28
30451
|
|
44
ACATTATTATTTAACCTTCC
4-14-2
ACATtattatttaaccttCC
44_1
-22.84
30453
|
|
44
ACATTATTATTTAACCTTCC
2-16-2
ACattattatttaaccttCC
44_2
-20.13
30453
|
|
45
CATTATTATTTAACCTTCC
4-13-2
CATTattatttaaccttCC
45_1
-22.04
30453
|
|
45
CATTATTATTTAACCTTCC
2-15-2
CAttattatttaaccttCC
45_2
-19.55
30453
|
|
46
CCTCTGCTTATAACTTT
2-13-2
CCtctgcttataactTT
46_1
-19.15
30699
|
|
47
CTACTATACTTTCCTCT
2-11-4
CTactatactttcCTCT
47_1
-22.32
30711
|
|
48
GTTCTACTATACTTTCC
4-11-2
GTTCtactatactttCC
48_1
-21.69
30714
|
|
48
GTTCTACTATACTTTCC
2-13-2
GTtctactatactttCC
48_2
-19.21
30714
|
|
48
GTTCTACTATACTTTCC
1-2-1-
GttCtactataCTttCC
48_3
-20.83
30712
|
7-2-2-2
|
|
48
GTTCTACTATACTTTCC
2-9-1-
GTtctactataCtttCC
48_4
-20.20
30712
|
3-2
|
|
48
GTTCTACTATACTTTCC
1-2-1-
GttCtactatactTtCC
48_5
-18.95
30712
|
9-1-1-2
|
|
48
GTTCTACTATACTTTCC
2-1-1-
GTtCtactatacttTCC
48_6
-21.18
30712
|
10-3
|
|
48
GTTCTACTATACTTTCC
1-3-1-
GttcTactatactttCC
48_7
-18.61
30712
|
10-2
|
|
49
CACCTGATAACAGACCCT
3-12-3
CACctgataacagacCCT
49_1
-26.38
36068
|
|
50
CACCTGATAACAGACC
3-10-3
CACctgataacagACC
50_1
-21.10
36070
|
|
51
CCCACCAAAGGATATATT
3-12-3
CCCaccaaaggatatATT
51_1
-23.47
37208
|
|
52
ACCAGCTACAGGAACCTC
3-12-3
ACCagctacaggaacCTC
52_1
-26.57
46132
|
|
53
CTATATCTCACTCCTATTT
4-13-2
CTATatctcactcctatTT
53_1
-23.07
48143
|
|
53
CTATATCTCACTCCTATTT
2-13-4
CTatatctcactcctATTT
53_2
-22.12
48143
|
|
54
CTATATCTCACTCCTATT
2-14-2
CTatatctcactcctaTT
54_1
-19.40
48144
|
|
54
CTATATCTCACTCCTATT
2-12-4
CTatatctcactccTATT
54_2
-22.28
48144
|
|
54
CTATATCTCACTCCTATT
3-12-3
CTAtatctcactcctATT
54_3
-21.44
48144
|
|
55
CTACTATATCTCACTCCTAT
2-16-2
CTactatatctcactcctAT
55_1
-22.00
48145
|
|
55
CTACTATATCTCACTCCTAT
2-14-4
CTactatatctcactcCTAT
55_2
-25.54
48145
|
|
56
TACTATATCTCACTCCTAT
2-13-4
TActatatctcactcCTAT
56_1
-23.29
48145
|
|
57
CTACTATATCTCACTCCTA
2-15-2
CTactatatctcactccTA
57_1
-21.91
48146
|
|
58
TACTATATCTCACTCCTA
2-14-2
TActatatctcactccTA
58_1
-19.66
48146
|
|
58
TACTATATCTCACTCCTA
2-12-4
TActatatctcactCCTA
58_2
-23.59
48146
|
|
58
TACTATATCTCACTCCTA
3-12-3
TACtatatctcactcCTA
58_3
-22.62
48146
|
|
59
CTACTATATCTCACTCCT
2-14-2
CTactatatctcactcCT
59_1
-21.25
48147
|
|
59
CTACTATATCTCACTCCT
4-12-2
CTACtatatctcactcCT
59_2
-23.87
48147
|
|
60
CTACTATATCTCACTCC
2-13-2
CTactatatctcactCC
60_1
-20.13
48148
|
|
60
CTACTATATCTCACTCC
2-11-4
CTactatatctcaCTCC
60_2
-23.00
48148
|
|
60
CTACTATATCTCACTCC
3-11-3
CTActatatctcacTCC
60_3
-22.56
48148
|
|
61
CCTACTATATCTCACTC
2-11-4
CCtactatatctcACTC
61_1
-21.93
48149
|
|
62
CTCCTACTATATCTCACTC
4-13-2
CTCCtactatatctcacTC
62_1
-25.69
48149
|
|
63
TCCTACTATATCTCACTC
3-12-3
TCCtactatatctcaCTC
63_1
-23.88
48149
|
|
64
CTCCTACTATATCTCACT
4-12-2
CTCCtactatatctcaCT
64_1
-24.87
48150
|
|
64
CTCCTACTATATCTCACT
3-12-3
CTCctactatatctcACT
64_2
-22.93
48150
|
|
65
TTTCCTCTCCTACTATATC
2-15-2
TTtcctctcctactataTC
65_1
-21.23
48155
|
|
66
ATCCATATCCTTTCCT
3-10-3
ATCcatatcctttCCT
66_1
-24.02
48168
|
|
67
CATCCATATCCTTTCCT
4-11-2
CATCcatatcctttcCT
67_1
-24.94
48168
|
|
68
ATCATCCATATCCTTTCC
4-12-2
ATCAtccatatcctttCC
68_1
-25.69
48169
|
|
69
CATCATCCATATCCTTTC
4-12-2
CATCatccatatccttTC
69_1
-23.32
48170
|
|
69
CATCATCCATATCCTTTC
2-14-2
CAtcatccatatccttTC
69_2
-20.72
48170
|
|
69
CATCATCCATATCCTTTC
2-12-4
CAtcatccatatccTTTC
69_3
-22.56
48170
|
|
70
TACATCATCCATATCCTTTC
2-16-2
TAcatcatccatatccttTC
70_1
-22.45
48170
|
|
70
TACATCATCCATATCCTTTC
4-14-2
TACAtcatccatatccttTC
70_2
-25.00
48170
|
|
70
TACATCATCCATATCCTTTC
2-14-4
TAcatcatccatatccTTTC
70_3
-24.29
48170
|
|
71
ACATCATCCATATCCTTT
3-12-3
ACAtcatccatatccTTT
71_1
-22.11
48171
|
|
72
CATCATCCATATCCTTT
2-13-2
CAtcatccatatcctTT
72_1
-19.04
48171
|
|
72
CATCATCCATATCCTTT
4-11-2
CATCatccatatcctTT
72_2
-21.64
48171
|
|
73
TACATCATCCATATCCTTT
2-15-2
TAcatcatccatatcctTT
73_1
-20.76
48171
|
|
73
TACATCATCCATATCCTTT
2-13-4
TAcatcatccatatcCTTT
73_2
-23.36
48171
|
|
73
TACATCATCCATATCCTTT
3-13-3
TACatcatccatatccTTT
73_3
-22.88
48171
|
|
74
ATACATCATCCATATCCTT
2-15-2
ATacatcatccatatccTT
74_1
-20.80
48172
|
|
74
ATACATCATCCATATCCTT
4-13-2
ATACatcatccatatccTT
74_2
-23.12
48172
|
|
75
TACATCATCCATATCCTT
2-14-2
TAcatcatccatatccTT
75_1
-19.97
48172
|
|
75
TACATCATCCATATCCTT
4-12-2
TACAtcatccatatccTT
75_2
-22.52
48172
|
|
78
TATACATCATCCATATCCTT
2-16-2
TAtacatcatccatatccTT
76_1
-21.36
48172
|
|
77
ATACATCATCCATATCCT
3-12-3
ATAcatcatccatatCCT
77_1
-24.15
48173
|
|
77
ATACATCATCCATATCCT
2-14-2
ATacatcatccatatcCT
77_2
-20.55
48173
|
|
77
ATACATCATCCATATCCT
2-13-3
ATacatcatccatatCCT
77_3
-22.92
48173
|
|
78
ATATACATCATCCATATCCT
2-16-2
ATatacatcatccatatcCT
78_1
-22.04
48173
|
|
79
TACATCATCCATATCCT
2-11-4
TAcatcatccataTCCT
79_1
-23.21
48173
|
|
79
TACATCATCCATATCCT
2-13-2
TAcatcatccatatcCT
79_2
-19.71
48173
|
|
79
TACATCATCCATATCCT
4-11-2
TACAtcatccatatcCT
79_3
-22.27
48173
|
|
80
TATACATCATCCATATCCT
2-15-2
TAtacatcatccatatcCT
80_1
-21.11
48173
|
|
80
TATACATCATCCATATCCT
3-13-3
TATacatcatccatatCCT
80_2
-25.15
48173
|
|
80
TATACATCATCCATATCCT
4-13-2
TATAcatcatccatatcCT
80_3
-24.01
48173
|
|
81
ATACATCATCCATATCC
3-11-3
ATAcatcatccataTCC
81_1
-21.79
48174
|
|
82
ATATACATCATCCATATCC
4-13-2
ATATacatcatccatatCC
82_1
-23.73
48174
|
|
82
ATATACATCATCCATATCC
2-15-2
ATatacatcatccatatCC
82_2
-20.93
48174
|
|
83
TATACATCATCCATATCC
2-14-2
TAtacatcatccatatCC
83_1
-20.00
48174
|
|
83
TATACATCATCCATATCC
4-12-2
TATAcatcatccatatCC
83_2
-22.90
48174
|
|
84
TATATACATCATCCATATCC
2-16-2
TAtatacatcatccatatCC
84_1
-21.49
48174
|
|
84
TATATACATCATCCATATCC
4-14-2
TATAtacatcatccatatCC
84_2
-24.29
48174
|
|
85
GCTTCATATTTCTCCA
2-12-2
GCttcatatttctcCA
85_1
-20.44
49345
|
|
85
GCTTCATATTTCTCCA
2-11-3
GCttcatatttctCCA
85_2
-22.81
49345
|
|
86
CATCTTGTTCTTTACCT
2-13-2
CAtcttgttctttacCT
86_1
-19.67
49581
|
|
87
TATATTCACCATTGCC
2-10-4
TAtattcaccatTGCC
87_1
-22.70
49724
|
|
88
CCTTATATTCACCATTG
2-13-2
CCttatattcaccatTG
88_1
-19.44
49726
|
|
88
CCTTATATTCACCATTG
2-11-4
CCttatattcaccATTG
88_2
-21.25
49726
|
|
89
CCTCCTTATATTCACC
4-10-2
CCTCcttatattcaCC
89_1
-24.64
49730
|
|
90
CCCTTCCTTTATTCAA
3-10-3
CCCttcctttattCAA
90_1
-23.86
50189
|
|
91
CCTTACTGTTAAATCCT
2-13-2
CCttactgttaaatcCT
91_1
-19.81
50475
|
|
92
CAGGCAGATAACCTCCAA
3-12-3
CAGgcagataacctcCAA
92_1
-25.31
52419
|
|
93
CAGCAGGCAGATAACCTC
3-12-3
CAGcaggcagataacCTC
93_1
-25.88
52422
|
|
94
CGAATCTTGACATACAGG
3-12-3
CGAatcttgacatacAGG
94_1
-21.47
53955
|
|
95
CTCATACTTGCTTTAAT
4-11-2
CTCAtacttgctttaAT
95_1
-19.10
60821
|
|
95
CTCATACTTGCTTTAAT
2-13-2
CTcatacttgctttaAT
95_2
-16.35
60821
|
|
96
ACATCTCATACTTGCTT
2-11-4
ACatctcatacttGCTT
96_1
-21.31
60825
|
|
96
ACATCTCATACTTGCTT
2-13-2
ACatctcatacttgcTT
96_2
-17.66
60825
|
|
96
ACATCTCATACTTGCTT
2-12-3
ACatctcatacttgCTT
96_3
-19.52
60825
|
|
97
ACATCTCATACTTGCT
2-10-4
ACatctcatactTGCT
97_1
-21.18
60826
|
|
97
ACATCTCATACTTGCT
2-12-2
ACatctcatacttgCT
97_2
-17.70
60826
|
|
97
ACATCTCATACTTGCT
2-11-3
ACatctcatacttGCT
97_3
-19.49
60826
|
|
97
ACATCTCATACTTGCT
4-10-2
ACATctcatacttgCT
97_4
-20.48
60826
|
|
98
TACATCTCATACTTGCT
2-11-4
TAcatctcatactTGCT
98_1
-22.33
60826
|
|
98
TACATCTCATACTTGCT
2-13-2
TAcatctcatacttgCT
98_2
-18.85
60826
|
|
98
TACATCTCATACTTGCT
4-11-2
TACAtctcatacttgCT
98_3
-21.40
60826
|
|
99
CCTACATCTCATACTTGC
3-12-3
CCTacatctcatactTGC
99_1
-26.29
60827
|
|
99
CCTACATCTCATACTTGC
2-14-2
CCtacatctcatacttGC
99_2
-22.98
60827
|
|
99
CCTACATCTCATACTTGC
2-13-3
CCtacatctcatactTGC
99_3
-24.67
60827
|
|
99
CCTACATCTCATACTTGC
2-12-4
CCtacatctcatacTTGC
99_4
-25.70
60827
|
|
100
CTACATCTCATACTTGC
3-11-3
CTAcatctcatactTGC
100_1
-22.33
60827
|
|
100
CTACATCTCATACTTGC
2-13-2
CTacatctcatacttGC
100_2
-19.41
60827
|
|
100
CTACATCTCATACTTGC
2-12-3
CTacatctcatactTGC
100_3
-21.10
60827
|
|
101
TACATCTCATACTTGC
3-10-3
TACatctcatactTGC
101_1
-19.94
60827
|
|
101
TACATCTCATACTTGC
2-12-2
TAcatctcatacttGC
101_2
-17.15
60827
|
|
101
TACATCTCATACTTGC
2-11-3
TAcatctcatactTGC
101_3
-18.85
60827
|
|
101
TACATCTCATACTTGC
4-10-2
TACAtctcatacttGC
101_4
-19.71
60827
|
|
102
CCTACATCTCATACTTG
4-11-2
CCTAcatctcatactTG
102_1
-22.52
60828
|
|
102
CCTACATCTCATACTTG
2-13-2
CCtacatctcatactTG
102_2
-19.67
60828
|
|
102
CCTACATCTCATACTTG
3-12-2
CCTacatctcatactTG
102_3
-21.29
60828
|
|
102
CCTACATCTCATACTTG
3-11-3
CCTacatctcatacTTG
102_4
-22.31
60828
|
|
103
ACCTACATCTCATACTT
3-11-3
ACCtacatctcataCTT
103_1
-21.93
60829
|
|
103
ACCTACATCTCATACTT
2-13-2
ACctacatctcatacTT
103_2
-17.76
60829
|
|
103
ACCTACATCTCATACTT
2-11-4
ACctacatctcatACTT
103_3
-20.03
60829
|
|
103
ACCTACATCTCATACTT
3-12-2
ACCtacatctcatacTT
103_4
-20.26
60829
|
|
104
CCTACATCTCATACTT
3-10-3
CCTacatctcataCTT
104_1
-21.50
60829
|
|
104
CCTACATCTCATACTT
2-12-2
CCtacatctcatacTT
104_2
-18.21
60829
|
|
104
CCTACATCTCATACTT
2-10-4
CCtacatctcatACTT
104_3
-20.48
60829
|
|
105
TACCTACATCTCATACTT
4-12-2
TACCtacatctcatacTT
105_1
-22.49
60829
|
|
105
TACCTACATCTCATACTT
2-14-2
TAcctacatctcatacTT
105_2
-18.81
60829
|
|
105
TACCTACATCTCATACTT
2-13-3
TAcctacatctcataCTT
105_3
-20.48
60829
|
|
105
TACCTACATCTCATACTT
2-12-4
TAcctacatctcatACTT
105_4
-21.08
60829
|
|
106
TTACCTACATCTCATACTT
3-13-3
TTAcctacatctcataCTT
106_1
-22.30
60829
|
|
106
TTACCTACATCTCATACTT
2-15-2
TTacctacatctcatacTT
106_2
-19.40
60829
|
|
106
TTACCTACATCTCATACTT
2-14-3
TTacctacatctcataCTT
106_3
-21.08
60829
|
|
106
TTACCTACATCTCATACTT
2-13-4
TTacctacatctcatACTT
106_4
-21.67
60829
|
|
107
ACCTACATCTCATACT
4-10-2
ACCTacatctcataCT
107_1
-21.72
60830
|
|
107
ACCTACATCTCATACT
2-12-2
ACctacatctcataCT
107_2
-17.61
60830
|
|
107
ACCTACATCTCATACT
3-11-2
ACCtacatctcataCT
107_3
-20.10
60830
|
|
107
ACCTACATCTCATACT
2-10-4
ACctacatctcaTACT
107_4
-20.11
60830
|
|
108
TACCTACATCTCATACT
4-11-2
TACCtacatctcataCT
108_1
-22.34
60830
|
|
108
TACCTACATCTCATACT
2-13-2
TAcctacatctcataCT
108_2
-18.66
60830
|
|
108
TACCTACATCTCATACT
3-12-2
TACctacatctcataCT
108_3
-19.85
60830
|
|
108
TACCTACATCTCATACT
3-11-3
TACctacatctcatACT
108_4
-20.44
60830
|
|
109
TTACCTACATCTCATACT
2-12-4
TTacctacatctcaTACT
109_1
-21.75
60830
|
|
109
TTACCTACATCTCATACT
2-14-2
TTacctacatctcataCT
109_2
-19.25
60830
|
|
109
TTACCTACATCTCATACT
3-13-2
TTAcctacatctcataCT
109_3
-20.48
60830
|
|
109
TTACCTACATCTCATACT
3-12-3
TTAcctacatctcatACT
109_4
-21.08
60830
|
|
110
TTACCTACATCTCATAC
3-11-3
TTAcctacatctcaTAC
110_1
-19.50
60831
|
|
110
TTACCTACATCTCATAC
2-13-2
TTacctacatctcatAC
110_2
-16.37
60831
|
|
111
GTTACCTACATCTCATA
2-11-4
GTtacctacatctCATA
111_1
-21.69
60832
|
|
111
GTTACCTACATCTCATA
2-13-2
GTtacctacatctcaTA
111_2
-18.74
60832
|
|
111
GTTACCTACATCTCATA
3-12-2
GTTacctacatctcaTA
111_3
-19.98
60832
|
|
112
GTTACCTACATCTCAT
3-10-3
GTTacctacatctCAT
112_1
-20.69
60833
|
|
112
GTTACCTACATCTCAT
2-12-2
GTtacctacatctcAT
112_2
-17.37
60833
|
|
113
ATATACCCAAAGGCACCT
3-12-3
ATAtacccaaaggcaCCT
113_1
-25.99
62200
|
|
114
TCTACTCATCCTTTAACTCA
2-14-4
TCtactcatcctttaaCTCA
114_1
-25.63
62251
|
|
115
CCTTAATCTGTATCACT
2-13-2
CCttaatctgtatcaCT
115_1
-19.58
62286
|
|
116
CCATACACAGCACATA
2-12-2
CCatacacagcacaTA
116_1
-19.04
62424
|
|
117
CTCCATACACAGCACAT
2-13-2
CTccatacacagcacAT
117_1
-20.08
62425
|
|
118
CAGAATAATTCTCCTCC
2-13-2
CAgaataattctcctCC
118_1
-19.86
62441
|
|
119
GTCCTACATATATACC
4-10-2
GTCCtacatatataCC
119_1
-22.09
66380
|
|
120
TGCTTCCTTACTAACC
4-10-2
TGCTtccttactaaCC
120_1
-23.93
66701
|
|
120
TGCTTCCTTACTAACC
2-12-2
TGcttccttactaaCC
120_2
-20.10
66701
|
|
121
CCCTTTGTAATCATCT
4-10-2
CCCTttgtaatcatCT
121_1
-23.44
66838
|
|
122
TCCCTTTGTAATCATCT
2-13-2
TCcctttgtaatcatCT
122_1
-19.97
66838
|
|
123
CTGCCATCAATACCAT
2-12-2
CTgccatcaataccAT
123_1
-19.14
68918
|
|
124
TCACTGCCATCAATACC
2-13-2
TCactgccatcaataCC
124_1
-21.35
68920
|
|
125
ATTCTTACTTTATTCCTCA
2-15-2
ATtcttactttattcctCA
125_1
-20.16
70033
|
|
126
TCACTTTCCAGATATCA
4-11-2
TCACtttccagatatCA
126_1
-21.61
77567
|
|
126
TCACTTTCCAGATATCA
2-13-2
TCactttccagatatCA
126_2
-18.65
77567
|
|
127
TCCTTCAAATTCCACATAC
3-13-3
TCCttcaaattccacaTAC
127_1
-24.09
82053
|
|
128
ACATGTCCCTTTATATT
4-11-2
ACATgtccctttataTT
128_1
-20.87
92323
|
|
128
ACATGTCCCTTTATATT
2-13-2
ACatgtccctttataTT
128_2
-17.66
92323
|
|
128
ACATGTCCCTTTATATT
3-12-2
ACAtgtccctttataTT
128_3
-19.13
92323
|
|
128
ACATGTCCCTTTATATT
3-11-3
ACAtgtccctttatATT
128_4
-20.03
92323
|
|
129
ACATGTCCCTTTATAT
3-10-3
ACAtgtccctttaTAT
129_1
-20.11
92324
|
|
129
ACATGTCCCTTTATAT
2-12-2
ACatgtccctttatAT
129_2
-16.74
92324
|
|
130
CCAAGAAAGGAGCAAGCT
3-12-3
CCAagaaaggagcaaGCT
130_1
-25.26
97146
|
|
131
TCCAAGAAAGGAGCAAGC
3-12-3
TCCaagaaaggagcaAGC
131_1
-24.12
97147
|
|
132
CTCATCCCTCCAAGAAA
4-11-2
CTCAtccctccaagaAA
132_1
-22.58
97156
|
|
132
CTCATCCCTCCAAGAAA
2-13-2
CTcatccctccaagaAA
132_2
-19.83
97156
|
|
132
CTCATCCCTCCAAGAAA
3-12-2
CTCatccctccaagaAA
132_3
-21.11
97156
|
|
133
TCATCCCTCCAAGAAA
4-10-2
TCATccctccaagaAA
133_1
-20.41
97156
|
|
133
TCATCCCTCCAAGAAA
2-12-2
TCatccctccaagaAA
133_2
-17.63
97156
|
|
133
TCATCCCTCCAAGAAA
3-11-2
TCAtccctccaagaAA
133_3
-19.09
97156
|
|
133
TCATCCCTCCAAGAAA
3-10-3
TCAtccctccaagAAA
133_4
-19.81
97156
|
|
134
CACCTCCCTATTACATAAA
4-13-2
CACCtccctattacataAA
134_1
-24.18
100018
|
|
134
CACCTCCCTATTACATAAA
2-15-2
CAcctccctattacataAA
134_2
-20.51
100018
|
|
135
CACCTCCCTATTACATAA
4-12-2
CACCtccctattacatAA
135_1
-23.75
100019
|
|
135
CACCTCCCTATTACATAA
2-14-2
CAcctccctattacatAA
135_2
-20.07
100019
|
|
136
CCTCCCTATTACATAA
2-12-2
CCtccctattacatAA
136_1
-18.40
100019
|
|
137
CTAAATCTTCCAATTCATA
2-15-2
CTaaatcttccaattcaTA
137_1
-18.12
106139
|
|
138
TATCCCTTGATTATCCT
2-13-2
TAtcccttgattatcCT
138_1
-20.68
109406
|
|
139
CCTCTTTGTCAAATACT
2-13-2
CCtctttgtcaaataCT
139_1
-19.30
110768
|
|
140
CAGCTTATTTACCTCTT
2-13-2
CAgcttatttacctcTT
140_1
-19.30
114828
|
|
141
ACTCTTTACCTCTAACACT
4-13-2
ACTCtttacctctaacaCT
141_1
-24.26
117468
|
|
142
TTACTCTTTACCTCTAACAC
3-14-3
TTActctttacctctaaCAC
142_1
-23.23
117469
|
|
143
CCAACCTAATACCTTAATA
2-15-2
CCaacctaataccttaaTA
143_1
-20.27
118639
|
|
144
TACCAACCTAATACCTTAA
2-15-2
TAccaacctaataccttAA
144_1
-18.32
118641
|
|
145
CCAATACCCACAAACC
3-10-3
CCAatacccacaaACC
145_1
-23.17
124162
|
|
145
CCAATACCCACAAACC
2-12-2
CCaatacccacaaaCC
145_2
-20.85
124162
|
|
146
CCATTATTCTACTTTGT
3-11-3
CCAttattctacttTGT
146_1
-21.79
125501
|
|
146
CCATTATTCTACTTTGT
2-13-2
CCattattctactttGT
146_2
-18.63
125501
|
|
147
CATTTCCTTATCTTCACA
2-14-2
CAtttccttatcttcaCA
147_1
-20.39
125529
|
|
148
TCATTTCCTTATCTTCACA
4-13-2
TCATttccttatcttcaCA
148_1
-24.13
125529
|
|
149
AATAATTCCTCATTTCCT
2-14-2
AAtaattcctcatttcCT
149_1
-18.01
125539
|
|
150
ACAATAATTCCTCATTTCC
3-13-3
ACAataattcctcattTCC
150_1
-22.71
125540
|
|
150
ACAATAATTCCTCATTTCC
2-15-2
ACaataattcctcatttCC
150_2
-20.23
125540
|
|
151
TATTGAACCAATTCTA
3-10-3
TATtgaaccaattCTA
151_1
-16.93
4806
|
|
152
CATATTGAACCAATTC
4-10-2
CATAttgaaccaatTC
152_1
-16.32
4808
|
|
153
TCATATTGAACCAATT
4-10-2
TCATattgaaccaaTT
153_1
-16.14
4809
|
|
154
CATCATATTGAACCAA
2-10-4
CAtcatattgaaCCAA
154_1
-17.65
4811
|
|
155
TCATCATATTGAACCA
3-10-3
TCAtcatattgaaCCA
155_1
-19.40
4812
|
|
156
CACAATCAACAACAAATA
4-12-2
CACAatcaacaacaaaTA
156_1
-16.16
4972
|
|
157
TACACAATCAACAACAAAT
4-13-2
TACAcaatcaacaacaaAT
157_1
-16.76
4973
|
|
158
CTGTACACAATCAACA
4-10-2
CTGTacacaatcaaCA
158_1
-19.05
4979
|
|
159
CACTAATAATTCACTTT
4-11-2
CACTaataattcactTT
159_1
-16.39
5058
|
|
160
CAACATTATTGACACT
2-10-4
CAacattattgaCACT
160_1
-17.17
5071
|
|
161
AAACTTTCCCAACATTAT
2-12-4
AAactttcccaacaTTAT
161_1
-18.69
5078
|
|
162
TCCTATATTCTCTTAAA
4-11-2
TCCTatattctcttaAA
162_1
-18.58
5094
|
|
163
TTTCCTATATTCTCTTA
4-11-2
TTTCctatattctctTA
163_1
-18.69
5096
|
|
164
CAAGTTTCCTATATTCT
4-11-2
CAAGtttcctatattCT
164_1
-19.97
5100
|
|
165
CAAGTTTCCTATATTC
4-10-2
CAAGtttcctatatTC
165_1
-17.47
5101
|
|
166
CATTCTATCTGCCAAA
2-10-4
CAttctatctgcCAAA
166_1
-18.36
5218
|
|
167
CCATTCTATCTGCCAAA
2-11-4
CCattctatctgcCAAA
167_1
-22.08
5218
|
|
168
TATAGCCATTCTATCT
4-10-2
TATAgccattctatCT
168_1
-20.63
5224
|
|
169
TTATAGCCATTCTATCT
4-11-2
TTATagccattctatCT
169_1
-20.82
5224
|
|
169
TTATAGCCATTCTATCT
1-10-3-
TtatagccattCTAtCT
169_2
-20.51
5224
|
1-2
|
|
169
TTATAGCCATTCTATCT
2-9-1-
TTatagccattCtaTCT
169_3
-20.12
5224
|
2-3
|
|
169
TTATAGCCATTCTATCT
1-1-1-
TtAtagccattCTaTCT
169_4
-20.59
5224
|
8-2-1-3
|
|
169
TTATAGCCATTCTATCT
1-3-1-
TtatAgccattCTatCT
169_5
-19.97
5224
|
6-2-2-2
|
|
169
TTATAGCCATTCTATCT
3-8-1-
TTAtagccattCtatCT
169_6
-20.13
5224
|
3-2
|
|
169
TTATAGCCATTCTATCT
1-10-2-
TtatagccattCTatCT
169_7
-19.37
5224
|
2-2
|
|
169
TTATAGCCATTCTATCT
2-9-1-
TTatagccattCtATCT
169_8
-21.02
5224
|
1-4
|
|
169
TTATAGCCATTCTATCT
1-1-1-
TtAtagccattCtATCT
169_9
-19.88
5224
|
8-1-1-4
|
|
169
TTATAGCCATTCTATCT
1-2-1-
TtaTagccattCtATCT
169_10
-20.65
5224
|
7-1-1-4
|
|
169
TTATAGCCATTCTATCT
1-3-1-
TtatAgccattCtATCT
169_11
-20.38
5224
|
6-1-1-4
|
|
169
TTATAGCCATTCTATCT
1-10-
TtatagccattCtATCT
169_12
-19.78
5224
|
1-1-4
|
|
169
TTATAGCCATTCTATCT
3-8-1-
TTAtagccattCtAtCT
169_13
-20.22
5224
|
1-1-1-2
|
|
169
TTATAGCCATTCTATCT
2-1-1-
TTaTagccattCtAtCT
169_14
-19.96
5224
|
7-1-1-
|
1-1-2
|
|
169
TTATAGCCATTCTATCT
2-2-1-
TTatAgccattCtAtCT
169_15
-19.69
5224
|
6-1-1-
|
1-1-2
|
|
169
TTATAGCCATTCTATCT
2-9-1-
TTatagccattCtAtCT
169_16
-19.09
5224
|
1-1-1-2
|
|
169
TTATAGCCATTCTATCT
1-2-2-
TtaTAgccattCtAtCT
169_17
-20.35
5224
|
6-1-1-
|
1-1-2
|
|
169
TTATAGCCATTCTATCT
1-2-1-
TtaTagccattCtAtCT
169_18
-18.72
5224
|
7-1-1-
|
1-1-2
|
|
169
TTATAGCCATTCTATCT
1-3-1-
TtatAgccattCtAtCT
169_19
-18.45
5224
|
6-1-1-
|
1-1-2
|
|
169
TTATAGCCATTCTATCT
2-2-1-
TTatAgccattCtaTCT
169_20
-20.71
5224
|
6-1-2-3
|
|
169
TTATAGCCATTCTATCT
1-1-2-
TtATagccattCtaTCT
169_21
-20.65
5224
|
7-1-2-3
|
|
169
TTATAGCCATTCTATCT
1-1-1-
TtAtAgccattCtaTCT
169_22
-19.57
5224
|
1-1-6-
|
1-2-3
|
|
169
TTATAGCCATTCTATCT
1-1-1-
TtAtagccattCtaTCT
169_23
-18.98
5224
|
8-1-2-3
|
|
169
TTATAGCCATTCTATCT
4-7-1-
TTATagccattCtatCT
169_24
-21.80
5224
|
3-2
|
|
169
TTATAGCCATTCTATCT
3-1-1-
TTAtAgccattCtatCT
169_25
-20.72
5224
|
6-1-3-2
|
|
169
TTATAGCCATTCTATCT
2-1-1-
TTaTagccattCtatCT
169_26
-19.86
5224
|
7-1-3-2
|
|
169
TTATAGCCATTCTATCT
2-2-1-
TTatAgccattCtatCT
169_27
-19.59
5224
|
6-1-3-2
|
|
169
TTATAGCCATTCTATCT
2-9-1-
TTatagccattCtatCT
169_28
-18.99
5224
|
3-2
|
|
169
TTATAGCCATTCTATCT
1-1-3-
TtATAgccattCtatCT
169_29
-21.16
5224
|
6-1-3-2
|
|
169
TTATAGCCATTCTATCT
1-1-2-
TtATagccattCtatCT
169_30
-19.53
5224
|
7-1-3-2
|
|
169
TTATAGCCATTCTATCT
1-1-1-
TtAtAgccattCtatCT
169_31
-18.45
5224
|
1-1-6-
|
1-3-2
|
|
169
TTATAGCCATTCTATCT
1-2-2-
TtaTAgccattCtatCT
169_32
-20.25
5224
|
6-1-3-2
|
|
169
TTATAGCCATTCTATCT
1-2-1-
TtaTagccattCtatCT
169_33
-18.62
5224
|
7-1-3-2
|
|
169
TTATAGCCATTCTATCT
1-3-1-
TtatAgccattCtatCT
169_34
-18.35
5224
|
6-1-3-2
|
|
169
TTATAGCCATTCTATCT
1-1-1-
TtAtagccattcTATCT
169_35
-20.88
5224
|
9-5
|
|
169
TTATAGCCATTCTATCT
2-10-
TTatagccattcTAtCT
169_36
-20.09
5224
|
2-1-2
|
|
169
TTATAGCCATTCTATCT
1-1-1-
TtAtagccattcTAtCT
169_37
-18.95
5224
|
9-2-1-2
|
|
169
TTATAGCCATTCTATCT
1-2-1-
TtaTagccattcTAtCT
169_38
-19.72
5224
|
8-2-1-2
|
|
169
TTATAGCCATTCTATCT
1-3-1-
TtatAgccattcTAtCT
169_39
-19.44
5224
|
7-2-1-2
|
|
169
TTATAGCCATTCTATCT
1-11-
TtatagccattcTAtCT
169_40
-18.85
5224
|
2-1-2
|
|
169
TTATAGCCATTCTATCT
3-9-1-
TTAtagccattcTaTCT
169_41
-21.21
5224
|
1-3
|
|
169
TTATAGCCATTCTATCT
1-1-1-
TtAtagccattcTaTCT
169_42
-18.94
5224
|
9-1-1-3
|
|
169
TTATAGCCATTCTATCT
3-9-1-
TTAtagccattcTatCT
169_43
-20.09
5224
|
2-2
|
|
169
TTATAGCCATTCTATCT
1-2-1-
TtaTagccattcTatCT
169_44
-18.58
5224
|
8-1-2-2
|
|
169
TTATAGCCATTCTATCT
1-3-1-
TtatAgccattcTatCT
169_45
-18.31
5224
|
7-1-2-2
|
|
169
TTATAGCCATTCTATCT
1-1-1-
TtAtagccattctATCT
169_46
-18.90
5224
|
10-4
|
|
169
TTATAGCCATTCTATCT
3-10-
TTAtagccattctAtCT
169_47
-19.24
5224
|
1-1-2
|
|
169
TTATAGCCATTCTATCT
2-11-
TTatagccattctAtCT
169_48
-18.11
5224
|
1-1-2
|
|
169
TTATAGCCATTCTATCT
1-2-2-
TtaTAgccattctAtCT
169_49
-19.37
5224
|
8-1-1-2
|
|
169
TTATAGCCATTCTATCT
3-1-1-
TTAtAgccattctatCT
169_50
-19.74
5224
|
10-2
|
|
169
TTATAGCCATTCTATCT
3-12-2
TTAtagccattctatCT
169_51
-19.15
5224
|
|
169
TTATAGCCATTCTATCT
2-1-2-
TTaTAgccattctatCT
169_52
-20.51
5224
|
10-2
|
|
169
TTATAGCCATTCTATCT
2-1-1-
TTaTagccattctatCT
169_53
-18.88
5224
|
11-2
|
|
169
TTATAGCCATTCTATCT
2-2-1-
TTatAgccattctatCT
169_54
-18.61
5224
|
10-2
|
|
169
TTATAGCCATTCTATCT
2-13-2
TTatagccattctatCT
169_55
-18.02
5224
|
|
169
TTATAGCCATTCTATCT
1-1-3-
TtATAgccattctatCT
169_56
-20.18
5224
|
10-2
|
|
169
TTATAGCCATTCTATCT
1-1-2-
TtATagccattctatCT
169_57
-18.55
5224
|
11-2
|
|
169
TTATAGCCATTCTATCT
2-9-3-
TTatagccattCTAtCT
169_58
-21.75
5224
|
1-2
|
|
169
TTATAGCCATTCTATCT
1-1-1-
TtAtagccattCTatCT
169_59
-19.47
5224
|
8-2-2-2
|
|
169
TTATAGCCATTCTATCT
1-2-2-
TtaTAgccattCTatCT
169_60
-21.87
5224
|
6-2-2-2
|
|
169
TTATAGCCATTCTATCT
1-1-3-
TtATAgccattCtAtCT
169_61
-21.25
5224
|
6-1-1-
|
1-1-2
|
|
169
TTATAGCCATTCTATCT
3-8-1-
TTAtagccattCtaTCT
169_62
-21.25
5224
|
2-3
|
|
170
ATTTAAATTTCCAAACATT
2-13-4
ATttaaatttccaaaCATT
170_1
-16.82
5427
|
|
171
GCTAATTTAAATTTCC
4-10-2
GCTAatttaaatttCC
171_1
-18.50
5434
|
|
172
ATCAATATCTTCTCAC
3-10-3
ATCaatatcttctCAC
172_1
-17.10
5785
|
|
173
TATCAATATCTTCTCA
2-10-4
TAtcaatatcttCTCA
173_1
-17.55
5786
|
|
174
CTACAAATTCAATTTACT
2-12-4
CTacaaattcaattTACT
174_1
-17.38
6341
|
|
175
TCTTACTCTGACTTTCCA
2-14-2
TCttactctgactttcCA
175_1
-21.47
6694
|
|
176
TCTTACTCTGACTTTCC
2-12-3
TCttactctgacttTCC
176_1
-21.53
6695
|
|
177
AAATTTCCAAACCTTTC
2-11-4
AAatttccaaaccTTTC
177_1
-16.30
6958
|
|
178
CTTCTTGTTTATCCCAA
2-11-4
CTtcttgtttatcCCAA
178_1
-22.77
7159
|
|
179
TTCTTGTTTATCCCAA
2-10-4
TTcttgtttatcCCAA
179_1
-20.17
7159
|
|
180
ATGCTTCTAACTAACA
4-10-2
ATGCttctaactaaCA
180_1
-19.21
7720
|
|
181
CTTTAATGCTTCTAACT
4-11-2
CTTTaatgcttctaaCT
181_1
-18.49
7724
|
|
182
CCTTTAATGCTTCTAAC
2-11-4
CCtttaatgcttcTAAC
182_1
-20.06
7725
|
|
183
CTTTAATGCTTCTAAC
2-10-4
CTttaatgcttcTAAC
183_1
-16.07
7725
|
|
184
TTCCTTTAATGCTTCTA
4-11-2
TTCCtttaatgcttcTA
184_1
-21.59
7727
|
|
185
TATACCTTTCTTTAACCCT
2-15-2
TAtacctttctttaaccCT
185_1
-22.03
8117
|
|
186
ATACCTTTCTTTAACCC
4-11-2
ATACctttctttaacCC
186_1
-22.68
8118
|
|
187
TTATACCTTTCTTTAACC
4-12-2
TTATacctttctttaaCC
187_1
-21.52
8119
|
|
188
TTTATACCTTTCTTTAAC
2-12-4
TTtatacctttcttTAAC
188_1
-17.01
8120
|
|
189
TCAAGAATTCTCTCCTT
2-11-4
TCaagaattctctCCTT
189_1
-21.29
8571
|
|
190
TTCAAGAATTCTCTCC
2-10-4
TTcaagaattctCTCC
190_1
-19.38
8573
|
|
191
CTTCAAGAATTCTCTC
2-10-4
CTtcaagaattcTCTC
191_1
-18.00
8574
|
|
192
TCTTCAAGAATTCTCT
2-10-4
TCttcaagaattCTCT
192_1
-18.46
8575
|
|
193
ATCTTCAAGAATTCTC
3-10-3
ATCttcaagaattCTC
193_1
-17.04
8576
|
|
194
TTTCTTACTATCTTCA
4-10-2
TTTCttactatcttCA
194_1
-17.47
8585
|
|
195
CCTTTAGCATTTCTATT
2-11-4
CCtttagcatttcTATT
195_1
-21.72
8819
|
|
196
TCCTTTAGCATTTCTAT
3-11-3
TCCtttagcatttcTAT
196_1
-22.39
8820
|
|
197
GTTCTCTTTATTTCTTCT
2-12-4
GTtctctttatttcTTCT
197_1
-21.76
8887
|
|
198
TTTACTGTCAACTCCT
2-10-4
TTtactgtcaacTCCT
198_1
-20.83
9150
|
|
199
TTTCCAATGAATCTAT
2-10-4
TTtccaatgaatCTAT
199_1
-16.61
9201
|
|
200
CCTTTCCAATGAATCTA
2-11-4
CCtttccaatgaaTCTA
200_1
-22.34
9202
|
|
201
CTTTCCAATGAATCTA
2-10-4
CTttccaatgaaTCTA
201_1
-18.34
9202
|
|
202
CCTTTCCAATGAATCT
3-10-3
CCTttccaatgaaTCT
202_1
-21.30
9203
|
|
203
TTATACCCTTTCCAAT
2-10-4
TTataccctttcCAAT
203_1
-19.61
9209
|
|
204
GTTTATACCCTTTCCAA
3-11-3
GTTtataccctttcCAA
204_1
-21.88
9210
|
|
205
TTTATACCCTTTCCAA
2-10-4
TTtataccctttCCAA
205_1
-20.50
9210
|
|
206
GTTTATACCCTTTCCA
2-11-3
GTttataccctttCCA
206_1
-22.69
9211
|
|
207
TGTTTATACCCTTTCCA
3-12-2
TGTttataccctttcCA
207_1
-22.80
9211
|
|
208
ACTGTTTATACCCTTTCC
2-14-2
ACtgtttataccctttCC
208_1
-22.96
9212
|
|
208
ACTGTTTATACCCTTTCC
1-11-
ActgtttataccCtttCC
208_2
-22.45
9212
|
1-3-2
|
|
208
ACTGTTTATACCCTTTCC
1-2-1-
ActGtttataccctTtCC
208_3
-22.17
9212
|
10-1-1-
|
2
|
|
208
ACTGTTTATACCCTTTCC
1-2-1-
ActGtTtataccctttCC
208_4
-22.17
9212
|
1-1-10-
|
2
|
|
208
ACTGTTTATACCCTTTCC
1-2-1-
ActGtttataccctttCC
208_5
-21.87
9212
|
12-2
|
|
208
ACTGTTTATACCCTTTCC
1-3-1-
ActgTttataccctttCC
208_6
-22.22
9212
|
11-2
|
|
208
ACTGTTTATACCCTTTCC
1-15-2
ActgtttataccctttCC
208_7
-21.56
9212
|
|
209
ACTGTTTATACCCTTTC
4-11-2
ACTGtttatacccttTC
209_1
-21.65
9213
|
|
209
ACTGTTTATACCCTTTC
1-11-
ActgtttataccCttTC
209_2
-18.25
9213
|
1-2-2
|
|
209
ACTGTTTATACCCTTTC
1-1-1-
AcTgtttatacCcTtTC
209_3
-19.56
9213
|
8-1-1-
|
1-1-2
|
|
209
ACTGTTTATACCCTTTC
1-2-1-
ActGtttatacccTTTC
209_4
-19.51
9213
|
9-4
|
|
209
ACTGTTTATACCCTTTC
1-3-1-
ActgTttatacCctTTC
209_5
-19.51
9213
|
6-1-2-3
|
|
209
ACTGTTTATACCCTTTC
2-9-1-
ACtgtttatacCcttTC
209_6
-19.43
9213
|
3-2
|
|
209
ACTGTTTATACCCTTTC
1-2-1-
ActGtttatacCcttTC
209_7
-18.35
9213
|
7-1-3-2
|
|
209
ACTGTTTATACCCTTTC
1-3-1-
ActgTttatacccTtTC
209_8
-18.53
9213
|
8-1-1-2
|
|
209
ACTGTTTATACCCTTTC
1-11-
ActgtttataccCtTTC
209_9
-19.06
9213
|
1-1-3
|
|
209
ACTGTTTATACCCTTTC
2-10-
ACtgtttataccCttTC
209_10
-19.64
9213
|
1-2-2
|
|
210
AACTGTTTATACCCTTT
4-11-2
AACTgtttataccctTT
210_1
-19.51
9214
|
|
211
TATGACTCCAATAATC
3-10-3
TATgactccaataATC
211_1
-16.57
10832
|
|
212
CTCCTTTATGACTCCAA
4-11-2
CTCCtttatgactccAA
212_1
-22.74
10837
|
|
213
CTCCTTTATGACTCCA
3-11-2
CTCctttatgactcCA
213_1
-21.50
10838
|
|
214
CCATTATTTCTTAAATA
4-11-2
CCATtatttcttaaaTA
214_1
-17.56
10877
|
|
215
ATTTCATATTACTAACTA
2-12-4
ATttcatattactaACTA
215_1
-16.64
11434
|
|
216
CATTTCATATTACTAACT
3-12-3
CATttcatattactaACT
216_1
-17.70
11435
|
|
217
TCATTTCATATTACTAAC
4-12-2
TCATttcatattactaAC
217_1
-16.72
11436
|
|
218
ATCATTTCATATTACTA
3-11-3
ATCatttcatattaCTA
218_1
-17.23
11438
|
|
219
TTATCATTTCATATTACT
4-12-2
TTATcatttcatattaCT
219_1
-17.77
11439
|
|
220
TGTACTTTCCTTTACCA
2-13-2
TGtactttcctttacCA
220_1
-20.37
11464
|
|
221
TATACACCATCATTATA
4-11-2
TATAcaccatcattaTA
221_1
-18.48
11507
|
|
222
TTATACACCATCATTAT
3-11-3
TTAtacaccatcatTAT
222_1
-17.83
11508
|
|
223
TATTTATACACCATCAT
3-11-3
TATttatacaccatCAT
223_1
-18.54
11511
|
|
224
TTATTTATACACCATC
2-10-4
TTatttatacacCATC
224_1
-16.60
11513
|
|
225
AATTATTTATACACCAT
2-11-4
AAttatttatacaCCAT
225_1
-16.82
11514
|
|
226
CATGACACTTACATAA
3-10-3
CATgacacttacaTAA
226_1
-16.26
11736
|
|
227
AGTTCACTACTATTAC
3-10-3
AGTtcactactatTAC
227_1
-17.55
12361
|
|
228
ATAAGCTTACCTCATA
2-10-4
ATaagcttacctCATA
228_1
-19.32
12794
|
|
229
TATAAGCTTACCTCAT
3-10-3
TATaagcttacctCAT
229_1
-19.32
12795
|
|
230
ATATAAGCTTACCTCA
4-10-2
ATATaagcttacctCA
230_1
-19.32
12796
|
|
231
CTTCCCTTTGATAACAT
3-11-3
CTTccctttgataaCAT
231_1
-21.19
12894
|
|
232
TTCCCTTTGATAACAT
4-10-2
TTCCctttgataacAT
232_1
-19.27
12894
|
|
233
CCTTCCCTTTGATAACA
2-12-3
CCttccctttgataACA
233_1
-23.06
12895
|
|
234
CTTCCCTTTGATAACA
4-10-2
CTTCcctttgataaCA
234_1
-20.51
12895
|
|
235
CCTTCCCTTTGATAAC
3-11-2
CCTtccctttgataAC
235_1
-20.96
12896
|
|
236
TTGATTCAATTCCCTTA
2-11-4
TTgattcaattccCTTA
236_1
-20.48
13223
|
|
236
TTGATTCAATTCCCTTA
2-9-1-
TTgattcaattCcCtTA
236_2
-19.54
13223
|
1-1-1-2
|
|
236
TTGATTCAATTCCCTTA
2-10-
TTgattcaattcCcTTA
236_3
-19.59
13223
|
1-1-3
|
|
236
TTGATTCAATTCCCTTA
2-1-1-
TTgAttcaattcCctTA
236_4
-19.06
13223
|
8-1-2-2
|
|
236
TTGATTCAATTCCCTTA
2-2-1-
TTgaTtcaattcCctTA
236_5
-19.00
13223
|
7-1-2-2
|
|
236
TTGATTCAATTCCCTTA
2-9-1-
TTgattcaattCcctTA
236_6
-18.65
13223
|
3-2
|
|
236
TTGATTCAATTCCCTTA
1-2-2-
TtgATtcaattCCctTA
236_7
-21.37
13223
|
6-2-2-2
|
|
236
TTGATTCAATTCCCTTA
2-1-1-
TTgAttcaattCcCtTA
236_8
-20.04
13223
|
7-1-1-
|
1-1-2
|
|
236
TTGATTCAATTCCCTTA
1-1-2-
TtGAttcaattCcCtTA
236_9
-20.10
13223
|
7-1-1-
|
1-1-2
|
|
236
TTGATTCAATTCCCTTA
1-2-1-
TtgAttcaattccCTTA
236_10
-19.67
13223
|
9-4
|
|
236
TTGATTCAATTCCCTTA
1-3-1-
TtgaTtcaattCcCtTA
236_11
-18.67
13223
|
6-1-1-
|
1-1-2
|
|
236
TTGATTCAATTCCCTTA
2-10-
TTgattcaattcCctTA
236_12
-18.56
13223
|
1-2-2
|
|
236
TTGATTCAATTCCCTTA
1-2-2-
TtgATtcaattcCCtTA
236_13
-21.49
13223
|
7-2-1-2
|
|
236
TTGATTCAATTCCCTTA
1-1-2-
TtGAttcaattcCctTA
236_14
-19.13
13223
|
8-1-2-2
|
|
236
TTGATTCAATTCCCTTA
2-11-
TTgattcaattccCtTA
236_15
-18.77
13223
|
1-1-2
|
|
236
TTGATTCAATTCCCTTA
1-1-1-
TtGaTtcaattccCtTA
236_16
-18.07
13223
|
1-1-8-
|
1-1-2
|
|
236
TTGATTCAATTCCCTTA
1-1-2-
TtGAttcaattCCctTA
236_17
-21.50
13223
|
7-2-2-2
|
|
236
TTGATTCAATTCCCTTA
1-2-1-
TtgAttcaattCcCTTA
236_18
-20.44
13223
|
7-1-1-4
|
|
236
TTGATTCAATTCCCTTA
3-8-1-
TTGattcaattCcCtTA
236_19
-20.60
13223
|
1-1-1-2
|
|
236
TTGATTCAATTCCCTTA
2-2-1-
TTgaTtcaattCcctTA
236_20
-19.09
13223
|
6-1-3-2
|
|
236
TTGATTCAATTCCCTTA
2-2-1-
TTgaTtcaattcCCtTA
236_21
-21.49
13223
|
7-2-1-2
|
|
237
ATTGATTCAATTCCCTT
2-11-4
ATtgattcaattcCCTT
237_1
-21.28
13224
|
|
237
ATTGATTCAATTCCCTT
3-8-3-
ATTgattcaatTCCcTT
237_2
-22.78
13224
|
1-2
|
|
237
ATTGATTCAATTCCCTT
1-1-1-
AtTgattcaatTCCcTT
237_3
-21.02
13224
|
8-3-1-2
|
|
237
ATTGATTCAATTCCCTT
1-2-1-
AttGattcaattCCcTT
237_4
-19.40
13224
|
8-2-1-2
|
|
237
ATTGATTCAATTCCCTT
1-3-1-
AttgAttcaattCCcTT
237_5
-19.74
13224
|
7-2-1-2
|
|
237
ATTGATTCAATTCCCTT
1-2-1-
AttGattcaatTCcCTT
237_6
-19.67
13224
|
7-2-1-3
|
|
237
ATTGATTCAATTCCCTT
2-2-1-
ATtgAttcaattCcCTT
237_7
-20.27
13224
|
7-1-1-3
|
|
237
ATTGATTCAATTCCCTT
1-1-1-
AtTgattcaattCcCTT
237_8
-19.32
13224
|
9-1-1-3
|
|
237
ATTGATTCAATTCCCTT
1-3-1-
AttgAttcaattCcCTT
237_9
-19.02
13224
|
7-1-1-3
|
|
237
ATTGATTCAATTCCCTT
1-1-1-
AtTgAttcaattCCcTT
237_10
-20.53
13224
|
1-1-7-
|
2-1-2
|
|
237
ATTGATTCAATTCCCTT
1-2-2-
AttGAttcaattCCcTT
237_11
-21.11
13224
|
7-2-1-2
|
|
237
ATTGATTCAATTCCCTT
1-2-1-
AttGattcaattCcCTT
237_12
-18.68
13224
|
8-1-1-3
|
|
237
ATTGATTCAATTCCCTT
1-1-2-
AtTGattcaattCccTT
237_13
-18.81
13224
|
8-1-2-2
|
|
237
ATTGATTCAATTCCCTT
3-10-
ATTgattcaattcCcTT
237_14
-19.42
13224
|
1-1-2
|
|
237
ATTGATTCAATTCCCTT
1-1-2-
AtTGattcaattcCCTT
237_15
-21.89
13224
|
9-4
|
|
237
ATTGATTCAATTCCCTT
2-2-1-
ATtgAttcaattcCcTT
237_16
-18.61
13224
|
8-1-1-2
|
|
237
ATTGATTCAATTCCCTT
1-2-2-
AttGAttcaatTCCcTT
237_17
-22.09
13224
|
6-3-1-2
|
|
237
ATTGATTCAATTCCCTT
1-1-1-
AtTgattcaatTCcCTT
237_18
-20.30
13224
|
8-2-1-3
|
|
237
ATTGATTCAATTCCCTT
1-1-1-
AtTgattcaattCCcTT
237_19
-20.03
13224
|
9-2-1-2
|
|
237
ATTGATTCAATTCCCTT
1-1-1-
AtTgAttcaattCcCTT
237_20
-19.82
13224
|
1-1-7-
|
1-1-3
|
|
237
ATTGATTCAATTCCCTT
3-1-1-
ATTgAttcaattcCcTT
237_21
-19.92
13224
|
8-1-1-2
|
|
238
TTGATTCAATTCCCTT
2-10-4
TTgattcaattcCCTT
238_1
-20.52
13224
|
|
239
TATTGATTCAATTCCCT
2-11-4
TAttgattcaattCCCT
239_1
-22.82
13225
|
|
239
TATTGATTCAATTCCCT
3-9-2-
TATtgattcaatTCcCT
239_2
-21.17
13225
|
1-2
|
|
239
TATTGATTCAATTCCCT
2-9-1-
TAttgattcaaTtCcCT
239_3
-19.37
13225
|
1-1-1-2
|
|
239
TATTGATTCAATTCCCT
1-1-2-
TaTTgattcaaTTCcCT
239_4
-21.49
13225
|
7-3-1-2
|
|
239
TATTGATTCAATTCCCT
1-3-1-
TattGattcaaTTCcCT
239_5
-19.90
13225
|
6-3-1-2
|
|
239
TATTGATTCAATTCCCT
2-9-1-
TAttattcaaTtcCCT
239_6
-20.89
13225
|
2-3
|
|
239
TATTGATTCAATTCCCT
1-10-
TattgattcaaTtcCCT
239_7
-19.76
13225
|
1-2-3
|
|
239
TATTGATTCAATTCCCT
1-1-1-
TaTtGattcaattCcCT
239_8
-18.41
13225
|
1-1-8-
|
1-1-2
|
|
239
TATTGATTCAATTCCCT
1-2-2-
TatTGattcaattCcCT
239_9
-19.66
13225
|
8-1-1-2
|
|
239
TATTGATTCAATTCCCT
1-2-1-
TatTgattcaattCcCT
239_10
-18.60
13225
|
9-1-1-2
|
|
239
TATTGATTCAATTCCCT
2-2-1-
TAttGattcaattccCT
239_11
-18.33
13225
|
10-2
|
|
239
TATTGATTCAATTCCCT
1-12-4
TattgattcaattCCCT
239_12
-21.69
13225
|
|
239
TATTGATTCAATTCCCT
2-1-1-
TAtTgattcaattCcCT
239_13
-19.73
13225
|
9-1-1-2
|
|
239
TATTGATTCAATTCCCT
2-12-3
TAttgattcaattcCCT
239_14
-20.45
13225
|
|
239
TATTGATTCAATTCCCT
1-2-1-
TatTgattcaattcCCT
239_15
-20.11
13225
|
10-3
|
|
239
TATTGATTCAATTCCCT
1-1-3-
TaTTGattcaattccCT
239_16
-19.84
13225
|
10-2
|
|
239
TATTGATTCAATTCCCT
1-1-1-
TaTtGattcaaTTCcCT
239_17
-20.34
13225
|
1-1-6-
|
3-1-2
|
|
239
TATTGATTCAATTCCCT
2-2-1-
TAttGattcaaTtCcCT
239_18
-19.54
13225
|
6-1-1-
|
1-1-2
|
|
239
TATTGATTCAATTCCCT
2-1-1-
TAtTgattcaatTCcCT
239_19
-20.72
13225
|
8-2-1-2
|
|
239
TATTGATTCAATTCCCT
1-1-2-
TaTTgattcaattCcCT
239_20
-19.55
13225
|
9-1-1-2
|
|
239
TATTGATTCAATTCCCT
2-1-1-
TAtTgattcaattcCCT
239_21
-21.24
13225
|
10-3
|
|
240
TATTGATTCAATTCCC
3-10-3
TATtgattcaattCCC
240_1
-20.58
13226
|
|
241
GCACATTCTTTCTATAC
3-11-3
GCAcattctttctaTAC
241_1
-21.17
15115
|
|
241
GCACATTCTTTCTATAC
1-1-3-
GcACAttctttCTatAC
241_2
-20.68
15115
|
6-2-2-2
|
|
241
GCACATTCTTTCTATAC
1-1-1-
GcAcAttctttCtaTAC
241_3
-18.46
15115
|
1-1-6-
|
1-2-3
|
|
241
GCACATTCTTTCTATAC
1-1-2-
GcACattctttCtaTAC
241_4
-19.49
15115
|
7-1-2-3
|
|
241
GCACATTCTTTCTATAC
2-9-1-
GCacattctttCtatAC
241_5
-18.68
15115
|
3-2
|
|
241
GCACATTCTTTCTATAC
1-1-3-
GcACAttctttctATAC
241_6
-20.89
15115
|
8-4
|
|
241
GCACATTCTTTCTATAC
2-2-1-
GCacAttctttctaTAC
241_7
-19.66
15115
|
9-3
|
|
241
GCACATTCTTTCTATAC
2-1-1-
GCaCattctttctatAC
241_8
-18.39
15115
|
11-2
|
|
241
GCACATTCTTTCTATAC
1-1-3-
GcACAttctttctaTAC
241_9
-19.98
15115
|
9-3
|
|
241
GCACATTCTTTCTATAC
3-12-2
GCAcattctttctatAC
241_10
-19.27
15115
|
|
241
GCACATTCTTTCTATAC
1-1-1-
GcAcAttctttCtATAC
241_11
-19.36
15115
|
1-1-6-
|
1-1-4
|
|
241
GCACATTCTTTCTATAC
3-8-1-
GCAcattctttCtAtAC
241_12
-20.34
15115
|
1-1-1-2
|
|
241
GCACATTCTTTCTATAC
2-1-1-
GCaCattctttCtaTAC
241_13
-21.27
15115
|
7-1-2-3
|
|
241
GCACATTCTTTCTATAC
1-2-2-
GcaCAttctttctATAC
241_14
-20.33
15115
|
8-4
|
|
241
GCACATTCTTTCTATAC
1-1-3-
GcACAttctttctatAC
241_15
-18.08
15115
|
10-2
|
|
242
GAATTTCAACTACTAT
2-10-4
GAatttcaactaCTAT
242_1
-16.13
15258
|
|
243
CCATTTATTTCCATTTAT
3-12-3
CCAtttatttccattTAT
243_1
-21.92
15568
|
|
244
TTTCCATTTATTTCCATTT
4-13-2
TTTCcatttatttccatTT
244_1
-20.93
15570
|
|
244
TTTCCATTTATTTCCATTT
1-4-1-
TttccAtttatttCcATTT
244_2
-20.48
15570
|
7-1-1-4
|
|
244
TTTCCATTTATTTCCATTT
2-1-1-
TTtCcatttatttcCAtTT
244_3
-21.47
15570
|
10-2-1-
|
2
|
|
244
TTTCCATTTATTTCCATTT
1-2-1-
TttCcAtttatttCcatTT
244_4
-19.43
15570
|
1-1-7-
|
1-3-2
|
|
244
TTTCCATTTATTTCCATTT
2-2-2-
TTtcCAtttatttccatTT
244_5
-20.70
15570
|
11-2
|
|
245
CTTTCCATTTATTTCCAT
3-12-3
CTTtccatttatttcCAT
245_1
-22.31
15572
|
|
246
TCTTTCCATTTATTTCCA
4-12-2
TCTTtccatttatttcCA
246_1
-22.74
15573
|
|
247
ATCTTTCCATTTATTTCC
3-12-3
ATCtttccatttattTCC
247_1
-22.85
15574
|
|
248
TTCCATGCAAACTTTA
4-10-2
TTCCatgcaaacttTA
248_1
-19.01
15722
|
|
249
CAGTTTAAATTCACAC
3-10-3
CAGtttaaattcaCAC
249_1
-16.68
16597
|
|
250
CTATTCCAGTTTAAAT
4-10-2
CTATtccagtttaaAT
250_1
-16.86
16603
|
|
251
TGCAAATACCTCTTCA
4-10-2
TGCAaatacctcttCA
251_1
-21.49
16730
|
|
252
CTAAATAGATTCCACT
2-10-4
CTaaatagattcCACT
252_1
-17.95
16849
|
|
253
TATTGATATTTACTCT
2-10-4
TAttgatatttaCTCT
253_1
-16.32
17089
|
|
254
CCTTAGTATTACAATT
4-10-2
CCTTagtattacaaTT
254_1
-17.43
17401
|
|
255
CTATTCAATAAACTAAACA
4-13-2
CTATtcaataaactaaaCA
255_1
-16.45
24290
|
|
256
CAGCTATTCAATAAAC
4-10-2
CAGCtattcaataaAC
256_1
-16.94
24296
|
|
257
TATAGACCCAAACTAT
3-10-3
TATagacccaaacTAT
257_1
-18.15
24811
|
|
258
TAATCCCATACATCTAT
2-11-4
TAatcccatacatCTAT
258_1
-20.45
25032
|
|
259
ATAATCCCATACATCTA
3-11-3
ATAatcccatacatCTA
259_1
-20.45
25033
|
|
260
ATCTCAACTACCATTT
4-10-2
ATCTcaactaccatTT
260_1
-18.14
25250
|
|
261
AATCTCAACTACCATT
4-10-2
AATCtcaactaccaTT
261_1
-16.76
25251
|
|
262
ACAACTTCTATCATAC
3-10-3
ACAacttctatcaTAC
262_1
-16.33
25718
|
|
263
GAACAACTTCTATCAT
2-10-4
GAacaacttctaTCAT
263_1
-16.94
25720
|
|
264
TGAACAACTTCTATCA
3-10-3
TGAacaacttctaTCA
264_1
-17.36
25721
|
|
265
TACACAAATACTTAAATCA
4-13-2
TACAcaaatacttaaatCA
265_1
-16.93
26331
|
|
266
TTAAGCTTTCACCTAT
2-10-4
TTaagctttcacCTAT
266_1
-19.36
27165
|
|
267
AAACTCTTGCATCTACT
2-13-2
AAactcttgcatctaCT
267_1
-16.65
27248
|
|
268
AAATTTCTCAACCTAAATTT
2-14-4
AAatttctcaacctaaATTT
268_1
-16.78
29330
|
|
269
CCAACATAGATCCTCT
2-10-4
CCaacatagatcCTCT
269_1
-22.49
29635
|
|
270
TCCAACATAGATCCTCT
2-11-4
TCcaacatagatcCTCT
270_1
-22.81
29635
|
|
271
CTCCAACATAGATCCTC
3-11-3
CTCcaacatagatcCTC
271_1
-22.81
29636
|
|
272
TCCAACATAGATCCTC
2-10-4
TCcaacatagatCCTC
272_1
-21.69
29636
|
|
273
CTCCAACATAGATCCT
3-10-3
CTCcaacatagatCCT
273_1
-22.68
29637
|
|
274
TCTCCAACATAGATCCT
4-11-2
TCTCcaacatagatcCT
274_1
-22.81
29637
|
|
275
ATTCTCAATTGCACTT
4-10-2
ATTCtcaattgcacTT
275_1
-17.90
29661
|
|
276
TATTCTCAATTGCACTT
4-11-2
TATTctcaattgcacTT
276_1
-18.54
29661
|
|
277
TCACCTAATAGCACCA
2-10-4
TCacctaatagcACCA
277_1
-21.99
29684
|
|
278
TTCACCTAATAGCACCA
2-11-4
TTcacctaatagcACCA
278_1
-22.53
29684
|
|
279
CATTATTATTTAACCTT
2-11-4
CAttattatttaaCCTT
279_1
-17.83
30455
|
|
280
ACATTATTATTTAACCT
3-11-3
ACAttattatttaaCCT
280_1
-18.05
30456
|
|
281
TACATTATTATTTAACC
4-11-2
TACAttattatttaaCC
281_1
-16.80
30457
|
|
282
CATTTACATTATTATTTAAC
2-14-4
CAtttacattattattTAAC
282_1
-16.44
30458
|
|
283
CTCATTTACATTATTATT
4-12-2
CTCAtttacattattaTT
283_1
-17.33
30462
|
|
284
TATCTCATTTACATTATT
4-12-2
TATCtcatttacattaTT
284_1
-17.62
30465
|
|
285
ATCATTCTCAACAATTA
4-11-2
ATCAttctcaacaatTA
285_1
-17.04
30601
|
|
285
ATCATTCTCAACAATTA
4-7-6
ATCAttctcaaCAATTA
285_2
-21.48
30601
|
|
285
ATCATTCTCAACAATTA
1-1-3-
AtCATtctcaaCAATTA
285_3
-20.80
30601
|
6-6
|
|
285
ATCATTCTCAACAATTA
5-6-2-
ATCATtctcaaCAatTA
285_4
-20.46
30601
|
2-2
|
|
285
ATCATTCTCAACAATTA
4-7-1-
ATCAttctcaaCaATTA
285_5
-19.80
30601
|
1-4
|
|
285
ATCATTCTCAACAATTA
5-7-1-
ATCATtctcaacAaTTA
285_6
-19.31
30601
|
1-3
|
|
285
ATCATTCTCAACAATTA
5-6-3-
ATCATtctcaaCAAtTA
285_7
-20.97
30601
|
1-2
|
|
285
ATCATTCTCAACAATTA
4-7-2-
ATCAttctcaaCAaTTA
285_8
-20.16
30601
|
1-3
|
|
285
ATCATTCTCAACAATTA
5-6-1-
ATCATtctcaaCaATTA
285_9
-21.05
30601
|
1-4
|
|
285
ATCATTCTCAACAATTA
5-6-1-
ATCATtctcaaCaAtTA
285_10
-19.29
30601
|
1-1-1-2
|
|
285
ATCATTCTCAACAATTA
1-1-3-
AtCATtctcaacAATTA
285_11
-18.70
30601
|
7-5
|
|
286
AAGATCATTCTCAACA
4-10-2
AAGAtcattctcaaCA
286_1
-17.15
30605
|
|
287
TCTCAAAGATCATTCTC
3-11-3
TCTcaaagatcattCTC
287_1
-19.02
30609
|
|
288
TCTCAAAGATCATTCT
4-10-2
TCTCaaagatcattCT
288_1
-17.81
30610
|
|
289
ACTTAATTATACTTCC
4-10-2
ACTTaattatacttCC
289_1
-17.28
30667
|
|
290
TACACTTAATTATACTTC
2-12-4
TAcacttaattataCTTC
290_1
-16.87
30668
|
|
291
TTACACTTAATTATACTT
3-12-3
TTAcacttaattataCTT
291_1
-16.20
30669
|
|
292
TTTACACTTAATTATACT
2-12-4
TTtacacttaattaTACT
292_1
-16.23
30670
|
|
293
CTATTTAATTTACACTT
3-11-3
CTAtttaatttacaCTT
293_1
-16.26
30679
|
|
294
TATCTATTTAATTTACAC
3-12-3
TATctatttaatttaCAC
294_1
-16.06
30681
|
|
295
TTTATCTATTTAATTTACA
4-13-2
TTTAtctatttaatttaCA
295_1
-16.34
30682
|
|
296
CTCTGCTTATAACTTT
4-10-2
CTCTgcttataactTT
296_1
-18.51
30699
|
|
297
CCTCTGCTTATAACTT
3-10-3
CCTctgcttataaCTT
297_1
-21.29
30700
|
|
298
TCCTCTGCTTATAACTT
3-12-2
TCCtctgcttataacTT
298_1
-20.86
30700
|
|
299
TCCTCTGCTTATAACT
3-11-2
TCCtctgcttataaCT
299_1
-20.70
30701
|
|
300
TTCCTCTGCTTATAACT
3-12-2
TTCctctgcttataaCT
300_1
-20.03
30701
|
|
301
TTTCCTCTGCTTATAAC
4-11-2
TTTCctctgcttataAC
301_1
-19.20
30702
|
|
302
TACTATACTTTCCTCT
2-10-4
TActatactttcCTCT
302_1
-20.07
30711
|
|
303
TTCTACTATACTTTCC
4-10-2
TTCTactatactttCC
303_1
-19.55
30714
|
|
304
AGTTCTACTATACTTTC
4-11-2
AGTTctactatacttTC
304_1
-18.49
30715
|
|
304
AGTTCTACTATACTTTC
1-10-6
AgttctactatACTTTC
304_2
-18.76
30715
|
|
304
AGTTCTACTATACTTTC
1-1-2-
AgTTctactatAcTTTC
304_3
-18.23
30715
|
7-1-1-4
|
|
304
AGTTCTACTATACTTTC
3-8-2-
AGTtctactatACTTTC
304_4
-19.19
30715
|
2-2
|
|
304
AGTTCTACTATACTTTC
2-2-1-
AGttCtactatAcTTTC
304_5
-19.07
30715
|
6-1-1-4
|
|
304
AGTTCTACTATACTTTC
1-2-2-
AgtTCtactatacTTTC
304_6
-18.46
30715
|
8-4
|
|
304
AGTTCTACTATACTTTC
3-10-
AGTtctactatacTtTC
304_7
-18.12
30715
|
1-1-2
|
|
304
AGTTCTACTATACTTTC
3-11-3
AGTtctactatactTTC
304_8
-18.42
30715
|
|
304
AGTTCTACTATACTTTC
3-1-1-
AGTtCtactatacttTC
304_9
-18.58
30715
|
10-2
|
|
304
AGTTCTACTATACTTTC
2-1-2-
AGtTCtactatacttTC
304_10
-18.02
30715
|
10-2
|
|
304
AGTTCTACTATACTTTC
1-2-2-
AgtTCtactatACtTTC
304_11
-19.02
30715
|
6-2-1-3
|
|
304
AGTTCTACTATACTTTC
2-1-2-
AGtTCtactatActtTC
304_12
-18.22
30715
|
6-1-3-2
|
|
304
AGTTCTACTATACTTTC
2-2-1-
AGttCtactataCTtTC
304_13
-19.22
30715
|
7-2-1-2
|
|
304
AGTTCTACTATACTTTC
3-1-1-
AGTtCtactataCtTTC
304_14
-20.39
30715
|
7-1-1-3
|
|
304
AGTTCTACTATACTTTC
1-1-1-
AgTtCtactatacTTTC
304_15
-18.13
30715
|
1-1-8-4
|
|
305
GTTCTACTATACTTTC
4-10-2
GTTCtactatacttTC
305_1
-17.48
30715
|
|
306
CATTATATTTAAACTATCA
4-13-2
CATTatatttaaactatCA
306_1
-16.93
31630
|
|
307
CACATTATATTTAAACTAT
2-13-4
CAcattatatttaaaCTAT
307_1
-17.11
31632
|
|
308
ACACATTATATTTAAACTA
3-13-3
ACAcattatatttaaaCTA
308_1
-17.09
31633
|
|
309
ACCACCTAAGACCTCAA
2-11-4
ACcacctaagaccTCAA
309_1
-22.49
32755
|
|
310
CCACCTAAGACCTCAA
2-10-4
CCacctaagaccTCAA
310_1
-22.63
32755
|
|
311
ACCACCTAAGACCTCA
2-11-3
ACcacctaagaccTCA
311_1
-21.74
32756
|
|
312
ACCTTAAGTAACATTT
4-10-2
ACCTtaagtaacatTT
312_1
-16.82
33366
|
|
313
CACCTTAAGTAACATT
4-10-2
CACCttaagtaacaTT
313_1
-18.05
33367
|
|
314
CCACCTTAAGTAACAT
3-10-3
CCAccttaagtaaCAT
314_1
-20.70
33368
|
|
315
ACCACCTTAAGTAACA
4-10-2
ACCAccttaagtaaCA
315_1
-20.68
33369
|
|
316
TTATTAACCACCTTAA
3-10-3
TTAttaaccacctTAA
316_1
-16.19
33375
|
|
317
CATTATTAACCACCTT
2-10-4
CAttattaaccaCCTT
317_1
-19.92
33377
|
|
318
ACATTATTAACCACCT
3-10-3
ACAttattaaccaCCT
318_1
-20.14
33378
|
|
319
ACCAATTATACTTACAA
3-11-3
ACCaattatacttaCAA
319_1
-17.16
36606
|
|
320
AACCAATTATACTTACA
4-11-2
AACCaattatacttaCA
320_1
-17.16
36607
|
|
321
CAAATACAGATTATCC
2-10-4
CAaatacagattATCC
321_1
-16.44
38092
|
|
322
TTTACATTCCCATCATC
2-11-4
TTtacattcccatCATC
322_1
-21.08
38297
|
|
323
CACACCTATTATATAAT
4-11-2
CACAcctattatataAT
323_1
-17.02
39173
|
|
324
TCACACCTATTATATAA
3-11-3
TCAcacctattataTAA
324_1
-17.02
39174
|
|
325
CTTCACACCTATTATATA
2-12-4
CTtcacacctattaTATA
325_1
-20.65
39175
|
|
326
ACTTCACACCTATTATAT
3-12-3
ACTtcacacctattaTAT
326_1
-20.46
39176
|
|
327
GCTCACACTAATTATT
2-10-4
GCtcacactaatTATT
327_1
-18.72
39228
|
|
328
ATGCTCACACTAATTA
4-10-2
ATGCtcacactaatTA
328_1
-19.38
39230
|
|
329
AATGCTCACACTAATT
4-10-2
AATGctcacactaaTT
329_1
-16.21
39231
|
|
330
AAACTGTACACCTACT
2-10-4
AAactgtacaccTACT
330_1
-17.99
39563
|
|
331
GTTTCCATCTACTATTA
2-11-4
GTttccatctactATTA
331_1
-19.78
39808
|
|
332
TTTCCATCTACTATTA
4-10-2
TTTCcatctactatTA
332_1
-17.25
39808
|
|
333
TGACATAACCATATAC
3-10-3
TGAcataaccataTAC
333_1
-16.63
39931
|
|
334
GCTCCCAAACAACTAA
2-12-2
GCtcccaaacaactAA
334_1
-17.55
41114
|
|
335
CCTCAATACTCTACTT
4-10-2
CCTCaatactctacTT
335_1
-20.30
41444
|
|
336
GACCTCAATACTCTACT
3-11-3
GACctcaatactctACT
336_1
-21.01
41445
|
|
337
GACCTCAATACTCTAC
4-10-2
GACCtcaatactctAC
337_1
-20.02
41446
|
|
338
TACTAAACATACACATA
4-11-2
TACTaaacatacacaTA
338_1
-16.12
41725
|
|
339
CTACTAAACATACACAT
3-11-3
CTActaaacatacaCAT
339_1
-17.31
41726
|
|
340
TTCTACTAAACATACAC
3-11-3
TTCtactaaacataCAC
340_1
-16.07
41728
|
|
341
TACCAATAGTTACCTT
2-10-4
TAccaatagttaCCTT
341_1
-20.03
42167
|
|
342
CTTACCAATAGTTACCT
3-11-3
CTTaccaatagttaCCT
342_1
-22.29
42168
|
|
343
TTACCAATAGTTACCT
3-10-3
TTAccaatagttaCCT
343_1
-20.03
42168
|
|
344
CTTACCAATAGTTACC
4-10-2
CTTAccaatagttaCC
344_1
-20.03
42169
|
|
345
TCTTACCAATAGTTACC
4-11-2
TCTTaccaatagttaCC
345_1
-21.30
42169
|
|
346
TCAAAGCACACCACCAC
2-12-3
TCaaagcacaccacCAC
346_1
-21.69
42287
|
|
347
ATTCAAAGCACACCACC
2-12-3
ATtcaaagcacaccACC
347_1
-21.00
42289
|
|
348
AGACTAATCCTCTTAA
3-10-3
AGActaatcctctTAA
348_1
-17.72
43452
|
|
349
TAGACTAATCCTCTTA
4-10-2
TAGActaatcctctTA
349_1
-19.20
43453
|
|
350
CCCATTTCTAACATTTAC
3-12-3
CCCatttctaacattTAC
350_1
-22.93
43562
|
|
351
ACCCATTTCTAACATT
4-10-2
ACCCatttctaacaTT
351_1
-20.64
43565
|
|
352
AACCCATTTCTAACAT
4-10-2
AACCcatttctaacAT
352_1
-18.25
43566
|
|
353
CCTCAACTTCACCAAT
2-10-4
CCtcaacttcacCAAT
353_1
-21.73
43634
|
|
354
ACTGATTTCCTTAAAC
4-10-2
ACTGatttccttaaAC
354_1
-16.67
44180
|
|
355
CACTGATTTCCTTAAAC
4-11-2
CACTgatttccttaaAC
355_1
-18.91
44180
|
|
356
CCACTGATTTCCTTAAA
4-11-2
CCACtgatttccttaAA
356_1
-20.91
44181
|
|
357
ACCACTGATTTCCTTA
2-10-4
ACcactgatttcCTTA
357_1
-20.98
44183
|
|
358
CACCACTGATTTCCTT
3-10-3
CACcactgatttcCTT
358_1
-22.04
44184
|
|
359
CTCTGCAATACACCAA
2-10-4
CTctgcaatacaCCAA
359_1
-20.90
44439
|
|
360
ACTCTGCAATACACCA
3-10-3
ACTctgcaatacaCCA
360_1
-22.19
44440
|
|
361
TACTCTGCAATACACCA
2-11-4
TActctgcaatacACCA
361_1
-22.32
44440
|
|
361
TACTCTGCAATACACCA
1-1-1-
TaCtctgcaatacAcCA
361_2
-19.29
44440
|
10-1-1-
|
2
|
|
361
TACTCTGCAATACACCA
1-3-1-
TactCtgcaatacAcCA
361_3
-19.28
44440
|
8-1-1-2
|
|
361
TACTCTGCAATACACCA
1-10-
TactctgcaatAcacCA
361_4
-18.35
44440
|
1-3-2
|
|
361
TACTCTGCAATACACCA
2-10-
TActctgcaataCAcCA
361_5
-21.63
44440
|
2-1-2
|
|
361
TACTCTGCAATACACCA
1-13-3
TactctgcaatacaCCA
361_6
-20.54
44440
|
|
361
TACTCTGCAATACACCA
2-10-
TActctgcaataCacCA
361_7
-20.06
44440
|
1-2-2
|
|
361
TACTCTGCAATACACCA
1-1-1-
TaCtctgcaatacacCA
361_8
-19.14
44440
|
12-2
|
|
361
TACTCTGCAATACACCA
1-2-2-
TacTCtgcaatacacCA
361_9
-20.33
44440
|
10-2
|
|
361
TACTCTGCAATACACCA
1-3-1-
TactCtgcaatacacCA
361_10
-19.13
44440
|
10-2
|
|
362
TACTCTGCAATACACC
2-10-4
TActctgcaataCACC
362_1
-21.12
44441
|
|
362
TACTCTGCAATACACC
1-1-1-
TaCtctgcaatacaCC
362_2
-18.23
44441
|
11-2
|
|
362
TACTCTGCAATACACC
1-1-1-
TaCtctgcaatacACC
362_3
-18.78
44441
|
10-3
|
|
362
TACTCTGCAATACACC
1-3-1-
TactCtgcaataCACC
362_4
-20.87
44441
|
7-4
|
|
362
TACTCTGCAATACACC
3-11-2
TACtctgcaatacaCC
362_5
-19.86
44441
|
|
362
TACTCTGCAATACACC
2-2-1-
TActCtgcaatacaCC
362_6
-19.44
44441
|
9-2
|
|
362
TACTCTGCAATACACC
2-12-2
TActctgcaatacaCC
362_7
-18.47
44441
|
|
362
TACTCTGCAATACACC
1-2-2-
TacTCtgcaatacaCC
362_8
-19.42
44441
|
9-2
|
|
362
TACTCTGCAATACACC
2-1-2-
TAcTCtgcaatacaCC
362_9
-20.64
44441
|
9-2
|
|
362
TACTCTGCAATACACC
1-3-1-
TactCtgcaatacaCC
362_10
-18.22
44441
|
9-2
|
|
383
TTACTCTGCAATACACC
2-11-4
TTactctgcaataCACC
363_1
-21.71
44441
|
|
364
TTACTCTGCAATACAC
3-10-3
TTActctgcaataCAC
364_1
-17.75
44442
|
|
385
TTTACTCTGCAATACAC
3-11-3
TTTactctgcaataCAC
365_1
-18.34
44442
|
|
366
CTTTACTCTGCAATACA
2-11-4
CTttactctgcaaTACA
366_1
-20.23
44443
|
|
387
TTTACTCTGCAATACA
2-10-4
TTtactctgcaaTACA
367_1
-17.56
44443
|
|
368
GACCACACTTTCTACCA
2-13-2
GAccacactttctacCA
368_1
-21.72
44477
|
|
389
GACCACACTTTCTACC
2-12-2
GAccacactttctaCC
369_1
-20.81
44478
|
|
370
AAGAAACACCCTTCCA
2-10-4
AAgaaacaccctTCCA
370_1
-21.48
44776
|
|
371
ATCTGCTACATATTCTT
4-11-2
ATCTgctacatattcTT
371_1
-19.88
45216
|
|
372
ATCTGCTACATATTCT
4-10-2
ATCTgctacatattCT
372_1
-19.71
45217
|
|
373
CATCTGCTACATATTCT
4-11-2
CATCtgctacatattCT
373_1
-21.32
45217
|
|
374
CATCTGCTACATATTC
4-10-2
CATCtgctacatatTC
374_1
-18.82
45218
|
|
375
TTCAACCCTAATCACT
4-10-2
TTCAaccctaatcaCT
375_1
-19.99
45246
|
|
378
ATTCAACCCTAATCAC
2-10-4
ATtcaaccctaaTCAC
376_1
-18.67
45247
|
|
377
CATTCAACCCTAATCA
3-10-3
CATtcaaccctaaTCA
377_1
-19.93
45248
|
|
378
GCATTCAACCCTAATCA
3-12-2
GCAttcaaccctaatCA
378_1
-22.56
45248
|
|
379
AGCATTCAACCCTAATC
4-11-2
AGCAttcaaccctaaTC
379_1
-22.98
45249
|
|
380
GCATTCAACCCTAATC
4-10-2
GCATtcaaccctaaTC
380_1
-21.63
45249
|
|
381
AGCATTCAACCCTAAT
4-10-2
AGCAttcaaccctaAT
381_1
-21.62
45250
|
|
382
CAGCATTCAACCCTAAT
3-12-2
CAGcattcaaccctaAT
382_1
-21.12
45250
|
|
383
TTAAATCCAGCATTCA
3-10-3
TTAaatccagcatTCA
383_1
-18.08
45258
|
|
384
CTCCATATTTAAATCC
4-10-2
CTCCatatttaaatCC
384_1
-20.02
45266
|
|
385
GCTCCATATTTAAATCC
4-11-2
GCTCcatatttaaatCC
385_1
-22.84
45266
|
|
386
GCTCCATATTTAAATC
4-10-2
GCTCcatatttaaaTC
386_1
-18.78
45267
|
|
387
AGCTCCATATTTAAAT
4-10-2
AGCTccatatttaaAT
387_1
-18.62
45268
|
|
388
TAAGCTCCATATTTAA
3-10-3
TAAgctccatattTAA
388_1
-16.08
45270
|
|
389
CCTAAGCTCCATATTTA
3-11-3
CCTaagctccatatTTA
389_1
-22.65
45271
|
|
390
CTAAGCTCCATATTTA
4-10-2
CTAAgctccatattTA
390_1
-18.81
45271
|
|
391
CCTAAGCTCCATATTT
4-10-2
CCTAagctccatatTT
391_1
-21.57
45272
|
|
392
TCTACCCTAAATTCCC
2-11-3
TCtaccctaaattCCC
392_1
-23.00
45560
|
|
393
CACATCTTGTATACAA
3-10-3
CACatcttgtataCAA
393_1
-16.65
45627
|
|
394
ACACATCTTGTATACA
4-10-2
ACACatcttgtataCA
394_1
-17.95
45628
|
|
395
CTACACATCTTGTATAC
3-11-3
CTAcacatcttgtaTAC
395_1
-19.13
45629
|
|
396
TACACATCTTGTATAC
3-10-3
TACacatcttgtaTAC
396_1
-16.73
45629
|
|
397
CTTGACTACACATCTT
3-10-3
CTTgactacacatCTT
397_1
-18.89
45635
|
|
398
CTCTACAACAGTCCCA
3-11-2
CTCtacaacagtccCA
398_1
-22.06
45709
|
|
399
TCTCTACAACAGTCCCA
2-13-2
TCtctacaacagtccCA
399_1
-21.70
45709
|
|
400
ATAACATTACTCTTAACA
3-12-3
ATAacattactcttaACA
400_1
-17.03
46215
|
|
401
TTTGACATTCCATCTCC
2-12-3
TTtgacattccatcTCC
401_1
-21.62
46256
|
|
402
CTTTGACATTCCATCTC
2-11-4
CTttgacattccaTCTC
402_1
-21.88
46257
|
|
403
TCTTTGACATTCCATCTC
4-12-2
TCTTtgacattccatcTC
403_1
-22.41
46257
|
|
404
TTTGACATTCCATCTC
3-10-3
TTTgacattccatCTC
404_1
-19.40
46257
|
|
405
ATCTTTGACATTCCATC
2-11-4
ATctttgacattcCATC
405_1
-20.53
46259
|
|
406
TATCTTTGACATTCCAT
2-11-4
TAtctttgacattCCAT
406_1
-21.32
46260
|
|
407
TACTATCTTTGACATTC
4-11-2
TACTatctttgacatTC
407_1
-18.39
46263
|
|
408
TACTATCTTTGACATT
4-10-2
TACTatctttgacaTT
408_1
-16.84
46264
|
|
409
CTGTATACACCATCCC
2-12-2
CTgtatacaccatcCC
409_1
-21.84
46392
|
|
410
TCTGTATACACCATCC
4-10-2
TCTGtatacaccatCC
410_1
-22.73
46393
|
|
411
TTTCTGACTCCCTATCC
2-13-2
TTtctgactccctatCC
411_1
-22.48
46420
|
|
412
CCTATGTTAATACTTTC
4-11-2
CCTAtgttaatacttTC
412_1
-19.53
46505
|
|
413
CTATGTTAATACTTTC
4-10-2
CTATgttaatacttTC
413_1
-16.09
46505
|
|
414
CCTATGTTAATACTTT
4-10-2
CCTAtgttaatactTT
414_1
-17.85
46506
|
|
415
TCCTATGTTAATACTT
3-10-3
TCCtatgttaataCTT
415_1
-18.47
46507
|
|
416
ATCCTATGTTAATACT
4-10-2
ATCCtatgttaataCT
416_1
-18.71
46508
|
|
417
ATTTCATTAAGTCACCC
3-11-3
ATTtcattaagtcaCCC
417_1
-22.16
47364
|
|
418
ATTTCATTAAGTCACC
2-10-4
ATttcattaagtCACC
418_1
-18.79
47365
|
|
419
CTCTCCTCAAGATCAAC
3-11-3
CTCtcctcaagatcAAC
419_1
-20.29
48110
|
|
420
CTCTCCTCAAGATCAA
3-10-3
CTCtcctcaagatCAA
420_1
-20.33
48111
|
|
421
CCATACAGTATATACA
4-10-2
CCATacagtatataCA
421_1
-19.53
48186
|
|
422
CAACTATTATCTTCTT
2-10-4
CAactattatctTCTT
422_1
-16.38
48221
|
|
423
ACAACTATTATCTTCT
3-10-3
ACAactattatctTCT
423_1
-16.60
48222
|
|
424
TTGCTTCCAATTTATTT
4-11-2
TTGCttccaatttatTT
424_1
-19.93
50282
|
|
425
ATCTCATGACCACCTAA
3-11-3
ATCtcatgaccaccTAA
425_1
-21.74
51241
|
|
425
ATCTCATGACCACCTAA
1-1-1-
AtCtcatgaccaCCtAA
425_2
-21.11
51241
|
9-2-1-2
|
|
425
ATCTCATGACCACCTAA
1-1-1-
AtCtcatgaccAccTAA
425_3
-19.96
51241
|
8-1-2-3
|
|
425
ATCTCATGACCACCTAA
1-12-4
AtctcatgaccacCTAA
425_4
-20.40
51241
|
|
425
ATCTCATGACCACCTAA
3-10-
ATCtcatgaccacCtAA
425_5
-20.66
51241
|
1-1-2
|
|
425
ATCTCATGACCACCTAA
1-1-1-
AtCtcatgaccacCtAA
425_6
-18.72
51241
|
10-1-1-
|
2
|
|
425
ATCTCATGACCACCTAA
1-1-1-
AtCtcatgaccaCcTAA
425_7
-20.59
51241
|
9-1-1-3
|
|
425
ATCTCATGACCACCTAA
1-2-2-
AtcTCatgaccaCcTAA
425_8
-21.48
51241
|
7-1-1-3
|
|
425
ATCTCATGACCACCTAA
1-3-1-
AtctCatgaccacCTAA
425_9
-21.07
51241
|
8-4
|
|
425
ATCTCATGACCACCTAA
1-1-3-
AtCTCatgaccacCtAA
425_10
-21.27
51241
|
8-1-1-2
|
|
426
TCTCATGACCACCTAA
2-10-4
TCtcatgaccacCTAA
426_1
-21.25
51241
|
|
427
ATCTCATGACCACCTA
3-10-3
ATCtcatgaccacCTA
427_1
-22.56
51242
|
|
428
TATCTCATGACCACCTA
2-12-3
TAtctcatgaccacCTA
428_1
-21.88
51242
|
|
429
TTTATCTCATGACCACC
2-11-4
TTtatctcatgacCACC
429_1
-22.37
51244
|
|
430
TTTATCTCATGACCAC
2-10-4
TTtatctcatgaCCAC
430_1
-19.56
51245
|
|
431
ATTCTTACCGTCTTTA
4-10-2
ATTCttaccgtcttTA
431_1
-19.52
51358
|
|
432
TATTCTTACCGTCTTTA
3-11-3
TATtcttaccgtctTTA
432_1
-20.10
51358
|
|
433
TATTCTTACCGTCTTT
2-10-4
TAttcttaccgtCTTT
433_1
-19.30
51359
|
|
434
TTATTCTTACCGTCTTT
2-11-4
TTattcttaccgtCTTT
434_1
-19.99
51359
|
|
435
ATCTGATCTCACACAT
3-10-3
ATCtgatctcacaCAT
435_1
-19.62
51438
|
|
436
CATCTGATCTCACACAT
4-11-2
CATCtgatctcacacAT
436_1
-20.82
51438
|
|
437
ACTTCCAGATTTCTACA
2-11-4
ACttccagatttcTACA
437_1
-21.44
51953
|
|
438
TTTATGTTTACTTCAT
3-10-3
TTTatgtttacttCAT
438_1
-16.05
52150
|
|
439
TAAAGATCCCATCACTC
3-11-3
TAAagatcccatcaCTC
439_1
-20.31
52549
|
|
440
TAAAGATCCCATCACT
4-10-2
TAAAgatcccatcaCT
440_1
-18.82
52550
|
|
441
CCTAAAGATCCCATCAC
2-12-3
CCtaaagatcccatCAC
441_1
-22.32
52551
|
|
442
ATCATCAGTTACATCA
4-10-2
ATCAtcagttacatCA
442_1
-18.64
52579
|
|
443
ACTCTCACTGTAACTTT
4-11-2
ACTCtcactgtaactTT
443_1
-19.76
53012
|
|
444
AACTCTCACTGTAACTT
3-11-3
AACtctcactgtaaCTT
444_1
-18.53
53013
|
|
445
ACTCTCACTGTAACTT
3-10-3
ACTctcactgtaaCTT
445_1
-19.04
53013
|
|
446
AACTCTCACTGTAACT
4-10-2
AACTctcactgtaaCT
446_1
-17.97
53014
|
|
447
CAACTCTCACTGTAACT
4-11-2
CAACtctcactgtaaCT
447_1
-20.01
53014
|
|
448
CCTTTCATTAACATTTA
3-11-3
CCTttcattaacatTTA
448_1
-19.03
54198
|
|
449
TTCCTTTCATTAACATTT
4-12-2
TTCCtttcattaacatTT
449_1
-19.92
54199
|
|
450
TAATCCTATTCCAACT
3-10-3
TAAtcctattccaACT
450_1
-18.05
54232
|
|
451
CTAATCCTATTCCAAC
2-10-4
CTaatcctattcCAAC
451_1
-18.65
54233
|
|
452
CTCTAATCCTATTCCA
3-10-3
CTCtaatcctattCCA
452_1
-22.58
54235
|
|
453
TCTCTAATCCTATTCC
4-10-2
TCTCtaatcctattCC
453_1
-21.78
54236
|
|
454
TTGTCTCTAATCCTATT
2-11-4
TTgtctctaatccTATT
454_1
-19.70
54238
|
|
455
TTGTCTCTAATCCTAT
2-10-4
TTgtctctaatcCTAT
455_1
-19.45
54239
|
|
456
TCTTTAAGCTTCCCAC
2-10-4
TCtttaagcttcCCAC
456_1
-22.96
54609
|
|
457
AAACTACCCTGCACAA
3-10-3
AAActaccctgcaCAA
457_1
-18.41
54924
|
|
458
CCATGCTACATAAACC
4-10-2
CCATgctacataaaCC
458_1
-22.25
55337
|
|
459
TCCATGCTACATAAAC
4-10-2
TCCAtgctacataaAC
459_1
-18.64
55338
|
|
460
ACTCCTAAGAATTACA
4-10-2
ACTCctaagaattaCA
460_1
-17.62
59565
|
|
461
GAAACTATTACTCCTA
2-10-4
GAaactattactCCTA
461_1
-19.06
59574
|
|
462
TGAAACTATTACTCCT
3-10-3
TGAaactattactCCT
462_1
-19.30
59575
|
|
463
ATGAAACTATTACTCC
2-10-4
ATgaaactattaCTCC
463_1
-17.96
59576
|
|
464
AACAACTCATGCCACA
2-10-4
AAcaactcatgcCACA
464_1
-19.72
60012
|
|
465
AAATATTGCCACCATT
2-10-4
AAatattgccacCATT
465_1
-17.78
60298
|
|
466
GTTACATATTCTTTCAC
3-11-3
GTTacatattctttCAC
466_1
-18.76
60448
|
|
467
TCATACTTGCTTTAAT
4-10-2
TCATacttgctttaAT
467_1
-17.29
60821
|
|
468
ATCCTGATAATTAACT
4-10-2
ATCCtgataattaaCT
468_1
-17.73
61925
|
|
469
CCTTAATCTGTATCAC
3-10-3
CCTtaatctgtatCAC
469_1
-19.92
62287
|
|
470
ATACACAGCACATATT
2-10-4
ATacacagcacaTATT
470_1
-17.58
62422
|
|
471
TCAGAATAATTCTCCT
3-10-3
TCAgaataattctCCT
471_1
-19.81
62443
|
|
472
TCTTCAGCTTTCTAAAT
4-11-2
TCTTcagctttctaaAT
472_1
-18.58
64113
|
|
473
AGTCCTTCCTTTAACCA
2-13-2
AGtccttcctttaacCA
473_1
-22.20
64461
|
|
474
TAGTCCTTCCTTTAACC
2-13-2
TAgtccttcctttaaCC
474_1
-22.12
64462
|
|
475
TTTAACCTTGCTTATA
2-10-4
TTtaaccttgctTATA
475_1
-17.50
65272
|
|
476
ATCCCTTTGTAATCAT
4-10-2
ATCCctttgtaatcAT
476_1
-20.31
66840
|
|
477
CTTGCATTTCTAATTAC
3-11-3
CTTgcatttctaatTAC
477_1
-18.09
67426
|
|
478
CTTGTCAAATCATTTCT
4-11-2
CTTGtcaaatcatttCT
478_1
-19.10
68194
|
|
479
CCATCTAATGATTATT
4-10-2
CCATctaatgattaTT
479_1
-17.28
68328
|
|
480
TATCAGTTATCCAATA
4-10-2
TATCagttatccaaTA
480_1
-17.39
68805
|
|
481
TCACTGCCATCAATAC
4-10-2
TCACtgccatcaatAC
481_1
-19.71
68921
|
|
482
TGTCATCTACAAATCA
4-10-2
TGTCatctacaaatCA
482_1
-18.01
70133
|
|
483
CTCTTTAGATTCATCC
4-10-2
CTCTttagattcatCC
483_1
-20.94
72377
|
|
484
ACTCTTTAGATTCATC
2-10-4
ACtctttagattCATC
484_1
-17.81
72378
|
|
485
CAACTCTATGACTACC
2-10-4
CAactctatgacTACC
485_1
-20.07
72826
|
|
486
ACCTGTAATACTTCTT
4-10-2
ACCTgtaatacttcTT
486_1
-19.67
72861
|
|
487
GAATTCTTTATTCCTCC
2-11-4
GAattctttattcCTCC
487_1
-22.53
72887
|
|
488
ATCTGAATCAAACCTT
2-10-4
ATctgaatcaaaCCTT
488_1
-17.97
73474
|
|
489
ACTTTACTGCCATAATC
3-11-3
ACTttactgccataATC
489_1
-19.60
73992
|
|
490
TTACTCTTAGCAACCT
4-10-2
TTACtcttagcaacCT
490_1
-20.19
74791
|
|
491
CACCAGTATTTCTTCTT
4-11-2
CACCagtatttcttcTT
491_1
-22.15
74851
|
|
492
TTCACCAGTATTTCTTC
4-11-2
TTCAccagtatttctTC
492_1
-20.43
74853
|
|
493
CCAAATAAGCAAACTC
3-10-3
CCAaataagcaaaCTC
493_1
-17.54
75840
|
|
494
CCCAAATAAGCAAACT
4-10-2
CCCAaataagcaaaCT
494_1
-20.23
75841
|
|
495
GACTACATTCTCAATA
3-10-3
GACtacattctcaATA
495_1
-17.49
76238
|
|
496
TTGTCAATCTTTATTCT
4-11-2
TTGTcaatctttattCT
496_1
-18.85
76254
|
|
497
AGCTTACCAAATATTC
4-10-2
AGCTtaccaaatatTC
497_1
-18.68
76811
|
|
498
TTACACATGTATATCC
3-10-3
TTAcacatgtataTCC
498_1
-18.23
77114
|
|
499
ATCCTGTTAATACCAT
2-10-4
ATcctgttaataCCAT
499_1
-20.41
80468
|
|
500
TTCTTAGTCACACACA
4-10-2
TTCTtagtcacacaCA
500_1
-19.37
81047
|
|
501
TTCTGTTTCCATTTACA
4-11-2
TTCTgtttccatttaCA
501_1
-21.31
82233
|
|
502
TCTATATCAAGTTCCTT
2-11-4
TCtatatcaagttCCTT
502_1
-20.95
84166
|
|
503
ATTCAGTTACCAACTA
3-10-3
ATTcagttaccaaCTA
503_1
-18.37
85392
|
|
504
GCTTCTACTTAAATAT
3-10-3
GCTtctacttaaaTAT
504_1
-17.58
86974
|
|
505
CCCTCAAAGTAATTTC
4-10-2
CCCTcaaagtaattTC
505_1
-20.53
87728
|
|
506
AACATGTAATTTCCAT
2-10-4
AAcatgtaatttCCAT
506_1
-17.21
87810
|
|
507
CCAGACTCCAATATTT
4-10-2
CCAGactccaatatTT
507_1
-20.78
88417
|
|
508
CTTAGACTTCACCTTTC
2-11-4
CTtagacttcaccTTTC
508_1
-20.56
88991
|
|
509
CTGCTTAATTATATCA
4-10-2
CTGCttaattatatCA
509_1
-18.85
90228
|
|
510
AAATTGTCTACCTTCCT
2-12-3
AAattgtctaccttCCT
510_1
-20.62
90474
|
|
511
CACTTAGAATATCCCT
2-10-4
CActtagaatatCCCT
511_1
-22.28
91625
|
|
512
ATCCAAAGTTTCTTTC
4-10-2
ATCCaaagtttcttTC
512_1
-18.64
91885
|
|
513
ATATTTGTCACCTAAC
4-10-2
ATATttgtcacctaAC
513_1
-17.12
92976
|
|
514
CTATTCTCAGTATTAT
3-10-3
CTAttctcagtatTAT
514_1
-17.42
94304
|
|
515
CCATTCAATGATCACT
2-10-4
CCattcaatgatCACT
515_1
-20.55
94528
|
|
516
CACTAGTACTCTTATT
4-10-2
CACTagtactcttaTT
516_1
-18.01
95653
|
|
517
GCCACAACATCTATTT
4-10-2
GCCAcaacatctatTT
517_1
-21.53
96751
|
|
518
AGCACATATACCATCA
4-10-2
AGCAcatataccatCA
518_1
-21.98
97636
|
|
519
GTCATCTAACTTCTTAC
3-11-3
GTCatctaacttctTAC
519_1
-19.25
98480
|
|
520
TGTCATCTAACTTCTTA
4-11-2
TGTCatctaacttctTA
520_1
-19.69
98481
|
|
521
CCCTTATAGTTATTAA
3-10-3
CCCttatagttatTAA
521_1
-19.32
99646
|
|
522
TCCATAGAATTCTTCA
4-10-2
TCCAtagaattcttCA
522_1
-19.92
100334
|
|
523
TTGATTCCACCATTAA
3-10-3
TTGattccaccatTAA
523_1
-18.05
101110
|
|
524
CAGCCATAAACTATAT
4-10-2
CAGCcataaactatAT
524_1
-18.60
101898
|
|
525
TATGACTTATTCCATA
2-10-4
TAtgacttattcCATA
525_1
-17.88
102558
|
|
526
GTTAACCTATATTTCA
4-10-2
GTTAacctatatttCA
526_1
-17.69
103589
|
|
527
TGTCTATTCTCTTCATT
4-11-2
TGTCtattctcttcaTT
527_1
-20.62
104309
|
|
528
TTACTCTTTGATTTCAT
3-11-3
TTActctttgatttCAT
528_1
-18.39
105686
|
|
529
GATAATTCCAAATCCC
2-10-4
GAtaattccaaaTCCC
529_1
-20.99
107972
|
|
530
TCTTATCCTTGAATTTC
4-11-2
TCTTatccttgaattTC
530_1
-18.85
108257
|
|
531
ATATCCCTTGATTATCC
3-11-3
ATAtcccttgattaTCC
531_1
-22.75
109407
|
|
532
TTAGTATACCCTTTAT
3-10-3
TTAgtatacccttTAT
532_1
-18.67
110210
|
|
533
CTCTTTGTCAAATACT
4-10-2
CTCTttgtcaaataCT
533_1
-18.16
110768
|
|
534
CCAAACTGTCTTCTAAT
2-11-4
CCaaactgtcttcTAAT
534_1
-19.87
111811
|
|
535
TCCAAACTGTCTTCTAA
3-12-2
TCCaaactgtcttctAA
535_1
-18.33
111812
|
|
536
CCAGCATATTATATAC
3-10-3
CCAgcatattataTAC
536_1
-18.96
112149
|
|
537
TCCAGCATATTATATA
4-10-2
TCCAgcatattataTA
537_1
-19.41
112150
|
|
538
TCATTGAACAACTCTTC
4-11-2
TCATtgaacaactctTC
538_1
-18.01
112945
|
|
539
CTGCCATCTTTATTTAT
4-11-2
CTGCcatctttatttAT
539_1
-21.89
113533
|
|
540
TGAAACATTCTTCCCAC
2-12-3
TGaaacattcttccCAC
540_1
-19.76
114274
|
|
541
TTTATTAGATTACTCC
2-10-4
TTtattagattaCTCC
541_1
-17.38
114495
|
|
542
TTCCAGCTTATTTACCT
3-12-2
TTCcagcttatttacCT
542_1
-21.28
114831
|
|
543
AGCATCATATAAACCT
3-10-3
AGCatcatataaaCCT
543_1
-20.62
115355
|
|
544
GTACTTACACATCTAT
2-10-4
GTacttacacatCTAT
544_1
-18.96
116105
|
|
545
TGTACTTACACATCTA
3-10-3
TGTacttacacatCTA
545_1
-19.38
116106
|
|
546
ATTTCTCTATGTCACAT
3-11-3
ATTtctctatgtcaCAT
546_1
-19.28
117096
|
|
547
CAAACCTACGTCTCTC
2-10-4
CAaacctacgtcTCTC
547_1
-20.87
117189
|
|
548
GTATTTACTCTTTACCT
3-11-3
GTAtttactctttaCCT
548_1
-22.15
117476
|
|
549
CTAATGCAATAACCCA
2-10-4
CTaatgcaataaCCCA
549_1
-21.79
118293
|
|
550
ACTAATGCAATAACCC
3-10-3
ACTaatgcaataaCCC
550_1
-20.53
118294
|
|
551
AGCTCTAAACCTTCAA
3-10-3
AGCtctaaaccttCAA
551_1
-20.51
118756
|
|
552
TATTTGTCACCAAACC
3-10-3
TATttgtcaccaaACC
552_1
-19.63
119621
|
|
553
CTCAGACATCTCAATA
4-10-2
CTCAgacatctcaaTA
553_1
-19.25
120655
|
|
554
TCTCAGCTTCTTCAAAT
2-12-3
TCtcagcttcttcaAAT
554_1
-18.33
123733
|
|
555
GCCAATACCCACAAAC
3-10-3
GCCaatacccacaAAC
555_1
-22.03
124163
|
|
556
CCTCTGACAACCATTA
4-10-2
CCTCtgacaaccatTA
556_1
-22.57
125512
|
|
557
CAGATAACTCTAAACC
4-10-2
CAGAtaactctaaaCC
557_1
-18.43
126882
|
|
558
CTAACTGTTTCTCAATT
3-11-3
CTAactgtttctcaATT
558_1
-18.10
127105
|
|
559
CCAAGATAATCATCAT
3-10-3
CCAagataatcatCAT
559_1
-18.37
127809
|
|
560
TACATATTGTACTTCT
4-10-2
TACAtattgtacttCT
560_1
-17.48
129020
|
|
561
TAGCCTACTTTAATAT
4-10-2
TAGCctactttaatAT
561_1
-18.67
129205
|
|
562
CATTTACAAGCACATA
2-10-4
CAtttacaagcaCATA
562_1
-17.81
129928
|
|
563
TTATTCTGACACACTT
3-10-3
TTAttctgacacaCTT
563_1
-17.49
130020
|
|
564
TACATTGACACCTAAT
4-10-2
TACAttgacacctaAT
564_1
-17.37
130884
|
|
565
TTTACATTGACACCTA
2-10-4
TTtacattgacaCCTA
565_1
-19.42
130886
|
|
566
TGTATATAACTATTCC
4-10-2
TGTAtataactattCC
566_1
-17.79
131404
|
|
567
GAATCTTCTAATTCCAC
2-11-4
GAatcttctaattCCAC
567_1
-20.40
132514
|
|
568
TGCTCACTAACTACAC
3-10-3
TGCtcactaactaCAC
568_1
-20.66
133367
|
|
569
TGCTACCATCATTACCT
2-13-2
TGctaccatcattacCT
569_1
-21.32
136198
|
|
570
TTTATCAATATCTTCTCACT
1-13-
TttatcaatatcttCtCaCT
570_1
-19.69
5784
|
1-1-1-
|
1-2
|
|
570
TTTATCAATATCTTCTCACT
1-2-1-
TttAtcaatatcttCtcACT
570_2
-19.67
5784
|
10-1-2-
|
3
|
|
570
TTTATCAATATCTTCTCACT
1-5-1-
TttatcAatatcttCtcACT
570_3
-19.65
5784
|
7-1-2-3
|
|
570
TTTATCAATATCTTCTCACT
1-1-1-
TtTatcaatatcttCtcaCT
570_4
-19.75
5784
|
11-1-3-
|
2
|
|
570
TTTATCAATATCTTCTCACT
1-2-1-
TttAtcAatatcttctcaCT
570_5
-18.21
5784
|
2-1-11-
|
2
|
|
570
TTTATCAATATCTTCTCACT
1-4-1-
TttatCaatatcttCtcaCT
570_6
-19.69
5784
|
8-1-3-2
|
|
570
TTTATCAATATCTTCTCACT
1-2-1-
TttAtcAatatcttctCaCT
570_7
-18.88
5784
|
2-1-9-
|
1-1-2
|
|
570
TTTATCAATATCTTCTCACT
1-2-1-
TttAtCaatatcttctcACT
570_8
-19.36
5784
|
1-1-11-
|
3
|
|
570
TTTATCAATATCTTCTCACT
1-4-1-
TttatCaatatcttctCaCT
570_9
-19.38
5784
|
10-1-1-
|
2
|
|
570
TTTATCAATATCTTCTCACT
2-1-1-
TTtAtcaatatcttCtCaCT
570_10
-20.60
5784
|
10-1-1-
|
1-1-2
|
|
570
TTTATCAATATCTTCTCACT
1-4-1-
TttatCaatatcttCtCaCT
570_11
-20.36
5784
|
8-1-1-
|
1-1-2
|
|
570
TTTATCAATATCTTCTCACT
1-2-1-
TttAtCaatatcttCtcACT
570_12
-20.34
5784
|
1-1-8-
|
1-2-3
|
|
570
TTTATCAATATCTTCTCACT
1-2-1-
TttAtcAatatcttCtcaCT
570_13
-19.19
5784
|
2-1-7-
|
1-3-2
|
|
570
TTTATCAATATCTTCTCACT
1-1-2-
TtTAtCaatatcttctCaCT
570_14
-21.24
5784
|
1-1-10-
|
1-1-2
|
|
571
TTTATCAATATCTTCTCAC
1-12-
TttatcaatatctTCtCAC
571_1
-19.16
5785
|
2-1-3
|
|
571
TTTATCAATATCTTCTCAC
2-1-1-
TTtAtCaatatcTTctCAC
571_2
-20.17
5785
|
1-1-6-
|
2-2-3
|
|
571
TTTATCAATATCTTCTCAC
3-2-1-
TTTatCaatatctTCtcAC
571_3
-19.79
5785
|
7-2-2-2
|
|
571
TTTATCAATATCTTCTCAC
1-2-3-
TttATCaatatcttCtcAC
571_4
-18.78
5785
|
8-1-2-2
|
|
571
TTTATCAATATCTTCTCAC
1-4-1-
TttatCaatatcttcTCAC
571_5
-19.06
5785
|
9-4
|
|
571
TTTATCAATATCTTCTCAC
2-1-1-
TTtAtCaatatcttCtCAC
571_6
-19.75
5785
|
1-1-8-
|
1-1-3
|
|
571
TTTATCAATATCTTCTCAC
1-1-1-
TtTatCaatatcTtctCAC
571_7
-19.11
5785
|
2-1-6-
|
1-3-3
|
|
571
TTTATCAATATCTTCTCAC
2-1-3-
TTTATCaatatcTtctcAC
571_8
-19.13
5785
|
6-1-4-2
|
|
571
TTTATCAATATCTTCTCAC
4-12-3
TTTAtcaatatcttctCAC
571_9
-20.38
5785
|
|
571
TTTATCAATATCTTCTCAC
1-1-2-
TtTAtCaatatcTtctCAC
571_10
-20.24
5785
|
1-1-6-
|
1-3-3
|
|
571
TTTATCAATATCTTCTCAC
2-1-1-
TTtAtCaatatctTCtcAC
571_11
-18.65
5785
|
1-1-7-
|
2-2-2
|
|
571
TTTATCAATATCTTCTCAC
3-2-1-
TTTatCaatatcttCtCAC
571_12
-20.89
5785
|
8-1-1-3
|
|
571
TTTATCAATATCTTCTCAC
1-3-2-
TttaTCaatatcttCtCAC
571_13
-19.96
5785
|
8-1-1-3
|
|
571
TTTATCAATATCTTCTCAC
1-2-1-
TttAtCaatatcttcTCAC
571_14
-19.16
5785
|
1-1-9-4
|
|
572
TTTATCAATATCTTCTCA
2-1-1-
TTtAtCaatatctTCtCA
572_1
-18.69
5786
|
1-1-7-
|
2-1-2
|
|
572
TTTATCAATATCTTCTCA
3-2-1-
TTTatCaatatcTtCtCA
572_2
-19.36
5786
|
6-1-1-
|
1-1-2
|
|
572
TTTATCAATATCTTCTCA
1-4-1-
TttatCaatatcTtCTCA
572_3
-19.19
5786
|
6-1-1-4
|
|
572
TTTATCAATATCTTCTCA
1-2-3-
TttATCaatatcTtcTCA
572_4
-19.56
5786
|
6-1-2-3
|
|
572
TTTATCAATATCTTCTCA
4-1-1-
TTTAtCaatatctTctCA
572_5
-19.37
5786
|
7-1-2-2
|
|
572
TTTATCAATATCTTCTCA
1-2-3-
TttATCaatatcttCtCA
572_6
-18.83
5786
|
8-1-1-2
|
|
572
TTTATCAATATCTTCTCA
3-2-1-
TTTatCaatatcttcTCA
572_7
-19.07
5786
|
9-3
|
|
572
TTTATCAATATCTTCTCA
1-2-1-
TttAtcaatatcttCTCA
572_8
-18.10
5786
|
10-4
|
|
572
TTTATCAATATCTTCTCA
4-10-
TTTAtcaatatcttCtCA
572_9
-19.31
5786
|
1-1-2
|
|
572
TTTATCAATATCTTCTCA
2-1-3-
TTtATCaatatcTtCtCA
572_10
-20.15
5786
|
6-1-1-
|
1-1-2
|
|
572
TTTATCAATATCTTCTCA
3-2-1-
TTTatCaatatcTtcTCA
572_11
-19.59
5786
|
6-1-2-3
|
|
572
TTTATCAATATCTTCTCA
1-1-2-
TtTAtCaatatctTCtCA
572_12
-19.64
5786
|
1-1-7-
|
2-1-2
|
|
572
TTTATCAATATCTTCTCA
4-9-1-
TTTAtcaatatctTcTCA
572_13
-19.90
5786
|
1-3
|
|
572
TTTATCAATATCTTCTCA
1-3-2-
TttaTCaatatcttCTCA
572_14
-19.80
5786
|
8-4
|
|
573
TATACCTTTCTTTAACCCTT
1-4-1-
TatacCtttctttaacCcTT
573_1
-22.72
8116
|
10-1-1-
|
2
|
|
573
TATACCTTTCTTTAACCCTT
2-4-1-
TAtaccTttctttaacccTT
573_2
-22.80
8116
|
11-2
|
|
573
TATACCTTTCTTTAACCCTT
1-3-1-
TataCctttctttaaCccTT
573_3
-22.72
8116
|
10-1-2-
|
2
|
|
573
TATACCTTTCTTTAACCCTT
1-4-1-
TatacCtttctttaaCccTT
573_4
-22.82
8116
|
9-1-2-2
|
|
573
TATACCTTTCTTTAACCCTT
1-5-1-
TataccTttctttaacCcTT
573_5
-22.35
8116
|
9-1-1-2
|
|
573
TATACCTTTCTTTAACCCTT
1-15-
TatacctttctttaacCcTT
573_6
-21.83
8116
|
1-1-2
|
|
573
TATACCTTTCTTTAACCCTT
1-2-1-
TatAcCtttctttaacCcTT
573_7
-22.91
8116
|
1-1-10-
|
1-1-2
|
|
573
TATACCTTTCTTTAACCCTT
2-2-1-
TAtaCcTttctttaacccTT
573_8
-23.58
8116
|
1-1-11-
|
2
|
|
573
TATACCTTTCTTTAACCCTT
2-3-1-
TAtacCtttctttaacccTT
573_9
-23.17
8116
|
12-2
|
|
573
TATACCTTTCTTTAACCCTT
1-3-1-
TataCctttctttAAcCcTT
573_10
-23.35
8116
|
8-2-1-
|
1-1-2
|
|
573
TATACCTTTCTTTAACCCTT
2-2-1-
TAtaCcTttctttaAcCcTT
573_11
-24.68
8116
|
1-1-7-
|
1-1-1-
|
1-2
|
|
573
TATACCTTTCTTTAACCCTT
2-4-1-
TAtaccTttctttaaCCcTT
573_12
-25.86
8116
|
8-2-1-2
|
|
573
TATACCTTTCTTTAACCCTT
2-3-1-
TAtacCtttctttaaCccTT
573_13
-23.96
8116
|
9-1-2-2
|
|
573
TATACCTTTCTTTAACCCTT
2-3-1-
TAtacCtttctttaacCcTT
573_14
-23.85
8116
|
10-1-1-
|
2
|
|
574
TTATACCTTTCTTTAACCCT
1-1-1-
TtAtacctttcttTaaccCT
574_1
-22.31
8117
|
10-1-4-
|
2
|
|
574
TTATACCTTTCTTTAACCCT
1-13-
TtatacctttctttAaCcCT
574_2
-22.38
8117
|
1-1-1-
|
1-2
|
|
574
TTATACCTTTCTTTAACCCT
1-1-1-
TtAtacCtttctttaaccCT
574_3
-22.47
8117
|
3-1-11-
|
2
|
|
574
TTATACCTTTCTTTAACCCT
1-3-1-
TtatAcCtttctttAaccCT
574_4
-22.68
8117
|
1-1-7-
|
1-3-2
|
|
574
TTATACCTTTCTTTAACCCT
1-4-1-
TtataCctttctttAaccCT
574_5
-22.38
8117
|
8-1-3-2
|
|
574
TTATACCTTTCTTTAACCCT
1-1-1-
TtAtacctttctttaaCcCT
574_6
-22.36
8117
|
13-1-1-
|
2
|
|
574
TTATACCTTTCTTTAACCCT
1-3-1-
TtatAcctttctttaaCcCT
574_7
-22.46
8117
|
11-1-1-
|
2
|
|
574
TTATACCTTTCTTTAACCCT
1-1-1-
TtAtaCctttctttaaccCT
574_8
-22.36
8117
|
2-1-12-
|
2
|
|
574
TTATACCTTTCTTTAACCCT
1-5-1-
TtatacCtttctttaaccCT
574_9
-22.37
8117
|
11-2
|
|
574
TTATACCTTTCTTTAACCCT
1-1-1-
TtAtaCctttctttaaCcCT
574_10
-23.14
8117
|
2-1-10-
|
1-1-2
|
|
574
TTATACCTTTCTTTAACCCT
1-1-1-
TtAtacCtttctttaaCcCT
574_11
-23.25
8117
|
3-1-9-
|
1-1-2
|
|
574
TTATACCTTTCTTTAACCCT
1-1-1-
TtAtacCtttctttaacCCT
574_12
-24.75
8117
|
3-1-10-
|
3
|
|
574
TTATACCTTTCTTTAACCCT
1-1-1-
TtAtaCCtttctttaaccCT
574_13
-24.85
8117
|
2-2-11-
|
2
|
|
574
TTATACCTTTCTTTAACCCT
1-3-1-
TtatAcCtttctttaaccCT
574_14
-22.56
8117
|
1-1-11-
|
2
|
|
575
TTTATACCTTTCTTTAACCC
1-2-1-
TttAtacctttctTtaacCC
575_1
-21.69
8118
|
9-1-4-2
|
|
575
TTTATACCTTTCTTTAACCC
1-12-
TttatacctttctTtaacCC
575_2
-21.59
8118
|
1-4-2
|
|
575
TTTATACCTTTCTTTAACCC
1-12-
TttatacctttctTtAacCC
575_3
-21.71
8118
|
1-1-1-
|
2-2
|
|
575
TTTATACCTTTCTTTAACCC
1-4-1-
TttatAcctttctttaAcCC
575_4
-21.90
8118
|
10-1-1-
|
2
|
|
575
TTTATACCTTTCTTTAACCC
1-13-
TttatacctttcttTaacCC
575_5
-22.01
8118
|
1-3-2
|
|
575
TTTATACCTTTCTTTAACCC
2-1-1-
TTtAtacctttctttaacCC
575_6
-22.20
8118
|
14-2
|
|
575
TTTATACCTTTCTTTAACCC
1-14-
TttatacctttctttAAcCC
575_7
-22.02
8118
|
2-1-2
|
|
575
TTTATACCTTTCTTTAACCC
1-14-
TttatacctttctttAacCC
575_8
-21.41
8118
|
1-2-2
|
|
575
TTTATACCTTTCTTTAACCC
1-15-
TttatacctttctttaAcCC
575_9
-21.71
8118
|
1-1-2
|
|
575
TTTATACCTTTCTTTAACCC
2-1-1-
TTtAtacctttctTtaacCC
575_10
-22.50
8118
|
9-1-4-2
|
|
575
TTTATACCTTTCTTTAACCC
1-2-1-
TttAtacctttcttTaacCC
575_11
-22.11
8118
|
10-1-3-
|
2
|
|
575
TTTATACCTTTCTTTAACCC
1-4-2-
TttatACctttctttAAcCC
575_12
-23.40
8118
|
8-2-1-2
|
|
575
TTTATACCTTTCTTTAACCC
1-2-1-
TttAtaCctttctttaAcCC
575_13
-22.59
8118
|
2-1-9-
|
1-1-2
|
|
575
TTTATACCTTTCTTTAACCC
1-1-2-
TtTAtacctttctttaacCC
575_14
-23.15
8118
|
14-2
|
|
576
TTTTATACCTTTCTTTAACC
1-1-1-
TtTtatacctttcTTtaaCC
576_1
-21.12
8119
|
10-2-3-
|
2
|
|
576
TTTTATACCTTTCTTTAACC
1-3-1-
TtttAtacctttcTttaaCC
576_2
-20.10
8119
|
8-1-4-2
|
|
576
TTTTATACCTTTCTTTAACC
1-1-1-
TtTtatacctttcTttAACC
576_3
-21.45
8119
|
10-1-2-
|
4
|
|
576
TTTTATACCTTTCTTTAACC
3-11-
TTTtatacctttctTtAaCC
576_4
-21.54
8119
|
1-1-1-
|
1-2
|
|
576
TTTTATACCTTTCTTTAACC
2-4-1-
TTttatAcctttctTtaaCC
576_5
-20.80
8119
|
7-1-3-2
|
|
576
TTTTATACCTTTCTTTAACC
1-14-
TtttatacctttcttTaaCC
576_6
-20.22
8119
|
1-2-2
|
|
576
TTTTATACCTTTCTTTAACC
1-15-
TtttatacctttctttAaCC
576_7
-19.61
8119
|
1-1-2
|
|
576
TTTTATACCTTTCTTTAACC
1-5-1-
TtttatAcctttctttaACC
576_8
-20.51
8119
|
10-3
|
|
576
TTTTATACCTTTCTTTAACC
1-1-2-
TtTTatacctttctttaaCC
576_9
-21.03
8119
|
14-2
|
|
576
TTTTATACCTTTCTTTAACC
1-1-2-
TtTTatacctttctTtAaCC
576_10
-21.46
8119
|
10-1-1-
|
1-1-2
|
|
576
TTTTATACCTTTCTTTAACC
2-2-1-
TTttAtacctttctTtaaCC
576_11
-20.70
8119
|
9-1-3-2
|
|
576
TTTTATACCTTTCTTTAACC
1-5-1-
TtttatAcctttctTtaaCC
576_12
-19.99
8119
|
7-1-3-2
|
|
576
TTTTATACCTTTCTTTAACC
1-1-1-
TtTtatacctttcttTAaCC
576_13
-21.68
8119
|
12-2-1-
|
2
|
|
576
TTTTATACCTTTCTTTAACC
1-1-1-
TtTtAtacctttctttaaCC
576_14
-19.89
8119
|
1-1-13-
|
2
|
|
577
TTTTTATACCTTTCTTTAAC
1-12-
TttttatacctttCttTAAC
577_1
-19.19
8120
|
1-2-4
|
|
577
TTTTTATACCTTTCTTTAAC
1-2-1-
TttTtatacctttCtTTaAC
577_2
-18.96
8120
|
9-1-1-
|
2-1-2
|
|
577
TTTTTATACCTTTCTTTAAC
2-12-
TTtttatacctttcTTTaAC
577_3
-19.52
8120
|
3-1-2
|
|
577
TTTTTATACCTTTCTTTAAC
1-1-1-
TtTttAtacctttCTttaAC
577_4
-18.71
8120
|
2-1-7-
|
2-3-2
|
|
577
TTTTTATACCTTTCTTTAAC
4-9-1-
TTTTtatacctttCtTtaAC
577_5
-19.85
8120
|
1-1-2-2
|
|
577
TTTTTATACCTTTCTTTAAC
3-1-1-
TTTtTatacctttCtTtAAC
577_6
-20.08
8120
|
8-1-1-
|
1-1-3
|
|
577
TTTTTATACCTTTCTTTAAC
2-1-2-
TTtTTatacctttCTttAAC
577_7
-20.97
8120
|
8-2-2-3
|
|
577
TTTTTATACCTTTCTTTAAC
1-1-2-
TtTTtatacctttcTTTAAC
577_8
-18.89
8120
|
10-2-1-
|
3
|
|
577
TTTTTATACCTTTCTTTAAC
1-3-2-
TtttTAtacctttCtttaAC
577_9
-18.97
8120
|
7-14-2
|
|
577
TTTTTATACCTTTCTTTAAC
1-2-1-
TttTtatacctttCTtTaAC
577_10
-19.34
8120
|
9-2-1-
|
1-1-2
|
|
577
TTTTTATACCTTTCTTTAAC
2-3-1-
TTtttAtacctttCTttAAC
577_11
-19.53
8120
|
7-2-2-3
|
|
577
TTTTTATACCTTTCTTTAAC
1-1-2-
TtTTtatacctttCtTtAAC
577_12
-18.84
8120
|
9-1-1-
|
1-1-3
|
|
577
TTTTTATACCTTTCTTTAAC
1-3-2-
TtttTAtacctttCtTtaAC
577_13
-19.27
8120
|
7-1-1-
|
1-2-2
|
|
577
TTTTTATACCTTTCTTTAAC
3-1-1-
TTTtTatacctttCttTaAC
577_14
-20.20
8120
|
8-1-2-
|
1-1-2
|
|
578
TTTTTTCTTACTATCTTCAA
1-5-1-
TtttttCttactatCTtcAA
578_1
-19.02
8584
|
7-2-2-2
|
|
578
TTTTTTCTTACTATCTTCAA
2-2-1-
TTttTtCttactatCtTcAA
578_2
-19.31
8584
|
1-1-7-
|
1-1-1-
|
1-2
|
|
578
TTTTTTCTTACTATCTTCAA
1-2-2-
TtttTtcttactatCttCAA
578_3
-20.05
8584
|
9-1-2-3
|
|
578
TTTTTTCTTACTATCTTCAA
1-1-1-
TtTtTtCttactatCttcAA
578_4
-18.43
8584
|
1-1-1-
|
1-7-1-
|
3-2
|
|
578
TTTTTTCTTACTATCTTCAA
3-3-1-
TTTtttCttactatcTtcAA
578_5
-18.99
8584
|
8-1-2-2
|
|
578
TTTTTTCTTACTATCTTCAA
2-1-2-
TTtTTtCttactatcttcAA
578_6
-19.29
8584
|
1-1-8-
|
1-2-2
|
|
578
TTTTTTCTTACTATCTTCAA
1-1-3-
TtTTTtCttactatctTcAA
578_7
-19.15
8584
|
1-1-9-
|
1-1-2
|
|
578
TTTTTTCTTACTATCTTCAA
2-1-1-
TTtTttcttactatcTtCAA
578_8
-19.58
8584
|
11-1-1-
|
3
|
|
578
TTTTTTCTTACTATCTTCAA
1-4-1-
TttttTcttactatctTCAA
578_9
-19.31
8584
|
10-4
|
|
579
TTTTTTTCTTACTATCTTCA
1-12-
TttttttcttactAtCttCA
579_1
-19.29
8585
|
1-1-1-
|
2-2
|
|
579
TTTTTTTCTTACTATCTTCA
2-1-1-
TTtTtttcttactAtcttCA
579_2
-19.42
8585
|
9-1-4-2
|
|
579
TTTTTTTCTTACTATCTTCA
1-1-1-
TtTttttcttactAtcttCA
579_3
-18.91
8585
|
2-1-7-
|
1-4-2
|
|
579
TTTTTTTCTTACTATCTTCA
1-1-2-
TtTTtttcttactAtcTtCA
579_4
-19.94
8585
|
9-1-2-
|
1-1-2
|
|
579
TTTTTTTCTTACTATCTTCA
1-3-2-
TttttTtcttactatcTtCA
579_5
-19.84
8585
|
10-1-1-
|
2
|
|
579
TTTTTTTCTTACTATCTTCA
2-3-1-
TTtttTtcttactatcttCA
579_6
-19.33
8585
|
12-2
|
|
579
TTTTTTTCTTACTATCTTCA
3-15-2
TTTttttcttactatcttCA
579_7
-19.84
8585
|
|
579
TTTTTTTCTTACTATCTTCA
1-2-2-
TtttTttcttactatcttCA
579_8
-19.33
8585
|
13-2
|
|
579
TTTTTTTCTTACTATCTTCA
1-14-
TttttttcttactatCttCA
579_9
-19.19
8585
|
1-2-2
|
|
580
ATTTTTTTCTTACTATCTTC
1-4-1-
AttttTttcttactAtCtTC
580_1
-18.09
8586
|
8-1-1-
|
1-1-2
|
|
580
ATTTTTTTCTTACTATCTTC
2-1-1-
ATtTttttcttactAtcTTC
580_2
-19.39
8586
|
10-1-2-
|
3
|
|
580
ATTTTTTTCTTACTATCTTC
1-3-2-
AttttTttcttactAtcTTC
580_3
-18.95
8586
|
8-1-2-3
|
|
580
ATTTTTTTCTTACTATCTTC
1-5-1-
AtttttTtcttacTatcTTC
580_4
-18.98
8586
|
6-1-3-3
|
|
580
ATTTTTTTCTTACTATCTTC
2-2-1-
ATttTtTtcttactAtctTC
580_5
-18.66
8586
|
1-1-7-
|
1-3-2
|
|
580
ATTTTTTTCTTACTATCTTC
1-1-3-
AtTTTtttcttacTatctTC
580_6
-19.58
8586
|
8-1-4-2
|
|
580
ATTTTTTTCTTACTATCTTC
2-1-1-
ATtTttttcttactatCtTC
580_7
-19.24
8586
|
12-1-1-
|
2
|
|
580
ATTTTTTTCTTACTATCTTC
1-1-1-
AtTtttttcttactatcTTC
580_8
-18.34
8586
|
2-1-11-
|
3
|
|
580
ATTTTTTTCTTACTATCTTC
1-1-2-
AtTTtTTtcttactatctTC
580_9
-18.94
8586
|
1-2-11-
|
2
|
|
581
AATTTTTTTCTTACTATCTT
1-4-1-
AatttTtttcttaCtAtCTT
581_1
-18.53
8587
|
7-1-1-
|
1-1-3
|
|
581
AATTTTTTTCTTACTATCTT
1-3-1-
AattTtTttcttaCTatcTT
581_2
-18.69
8587
|
1-1-6-
|
2-3-2
|
|
581
AATTTTTTTCTTACTATCTT
1-1-2-
AaTTtttttcttacTAtcTT
581_3
-18.80
8587
|
10-2-2-
|
2
|
|
581
AATTTTTTTCTTACTATCTT
2-1-1-
AAtTtTtttcttacTatCTT
581_4
-19.20
8587
|
1-1-8-
|
1-2-3
|
|
581
AATTTTTTTCTTACTATCTT
4-2-1-
AATTttTttcttacTatcTT
581_5
-19.30
8587
|
7-1-3-2
|
|
581
AATTTTTTTCTTACTATCTT
2-2-2-
AAttTTtttcttaCtATcTT
581_6
-19.52
8587
|
7-1-1-
|
2-1-2
|
|
581
AATTTTTTTCTTACTATCTT
1-12-
AatttttttcttaCtaTCTT
581_7
-19.25
8587
|
1-2-4
|
|
581
AATTTTTTTCTTACTATCTT
1-1-4-
AaTTTTtttcttaCtatcTT
581_8
-19.35
8587
|
7-14-2
|
|
581
AATTTTTTTCTTACTATCTT
2-1-3-
AAtTTTtttcttactAtCTT
581_9
-19.68
8587
|
9-1-1-3
|
|
582
GTTTATACCCTTTCCAAT
1-1-1-
GtTtAtacccttTCcaAT
582_1
-21.48
9209
|
1-1-7-
|
2-2-2
|
|
582
GTTTATACCCTTTCCAAT
1-12-
GtttataccctttCCaAT
582_2
-22.28
9209
|
2-1-2
|
|
582
GTTTATACCCTTTCCAAT
1-3-1-
GtttAtaccctttCcAAT
582_3
-20.46
9209
|
8-1-1-3
|
|
582
GTTTATACCCTTTCCAAT
1-1-1-
GtTtAtaccctttcCaAT
582_4
-20.30
9209
|
1-1-9-
|
1-1-2
|
|
582
GTTTATACCCTTTCCAAT
2-11-
GTttataccctttCcaAT
582_5
-21.64
9209
|
1-2-2
|
|
582
GTTTATACCCTTTCCAAT
1-1-2-
GtTTataccctttCcAAT
582_6
-21.90
9209
|
9-1-1-3
|
|
582
GTTTATACCCTTTCCAAT
1-1-1-
GtTtataccctttccaAT
582_7
-19.63
9209
|
13-2
|
|
582
GTTTATACCCTTTCCAAT
1-2-1-
GttTataccctttccaAT
582_8
-20.05
9209
|
12-2
|
|
582
GTTTATACCCTTTCCAAT
1-13-4
GtttataccctttcCAAT
582_9
-21.59
9209
|
|
583
TGTTTATACCCTTTCCAA
2-1-1-
TGtTtataccctttCcAA
583_1
-21.08
9210
|
10-1-1-
|
2
|
|
583
TGTTTATACCCTTTCCAA
1-4-1-
TgtttAtaccctTtCcAA
583_2
-19.97
9210
|
6-1-1-
|
1-1-2
|
|
583
TGTTTATACCCTTTCCAA
1-3-1-
TgttTataccctttCcAA
583_3
-20.30
9210
|
9-1-1-2
|
|
583
TGTTTATACCCTTTCCAA
2-1-1-
TGtTtAtaccctTtccAA
583_4
-20.71
9210
|
1-1-6-
|
1-3-2
|
|
583
TGTTTATACCCTTTCCAA
1-2-1-
TgtTtataccctTtcCAA
583_5
-21.40
9210
|
8-1-2-3
|
|
583
TGTTTATACCCTTTCCAA
1-4-1-
TgtttAtaccctttcCAA
583_6
-20.89
9210
|
9-3
|
|
583
TGTTTATACCCTTTCCAA
1-1-2-
TgTTtataccctttccAA
583_7
-20.27
9210
|
12-2
|
|
583
TGTTTATACCCTTTCCAA
1-12-
TgtttatacccttTCcAA
583_8
-20.56
9210
|
2-1-2
|
|
583
TGTTTATACCCTTTCCAA
2-2-1-
TGttTataccctttccAA
583_9
-20.74
9210
|
11-2
|
|
584
CTGTTTATACCCTTTCCA
1-1-1-
CtGtttataccctTtcCA
584_1
-22.45
9211
|
10-1-2-
|
2
|
|
584
CTGTTTATACCCTTTCCA
1-12-
CtgtttataccctTtcCA
584_2
-22.14
9211
|
1-2-2
|
|
584
CTGTTTATACCCTTTCCA
1-1-1-
CtGtTtataccctttcCA
584_3
-22.45
9211
|
1-1-11-
|
2
|
|
584
CTGTTTATACCCTTTCCA
1-1-1-
CtGtttataccctttcCA
584_4
-22.15
9211
|
13-2
|
|
584
CTGTTTATACCCTTTCCA
1-2-1-
CtgTttataccctttcCA
584_5
-22.50
9211
|
12-2
|
|
584
CTGTTTATACCCTTTCCA
1-3-1-
CtgtTtataccctttcCA
584_6
-22.14
9211
|
11-2
|
|
584
CTGTTTATACCCTTTCCA
1-4-1-
CtgttTataccctttcCA
584_7
-22.57
9211
|
10-2
|
|
584
CTGTTTATACCCTTTCCA
1-15-2
CtgtttataccctttcCA
584_8
-21.84
9211
|
|
585
AATTATTTATACACCATCAT
2-1-1-
AAtTaTttatacacCATcAT
585_1
-20.76
11511
|
1-1-8-
|
3-1-2
|
|
585
AATTATTTATACACCATCAT
3-2-2-
AATtaTTtatacaCcATcAT
585_2
-20.88
11511
|
6-1-1-
|
2-1-2
|
|
585
AATTATTTATACACCATCAT
1-4-1-
AattaTttatacaCCaTcAT
585_3
-19.62
11511
|
7-2-1-
|
1-1-2
|
|
585
AATTATTTATACACCATCAT
1-3-1-
AattAtTtatacaCcatCAT
585_4
-18.98
11511
|
1-1-6-
|
1-3-3
|
|
585
AATTATTTATACACCATCAT
1-2-3-
AatTATttatacaCcAtcAT
585_5
-19.65
11511
|
7-1-1-
|
1-2-2
|
|
585
AATTATTTATACACCATCAT
1-1-2-
AaTTatttatacaccAtCAT
585_6
-19.53
11511
|
11-1-1-
|
3
|
|
585
AATTATTTATACACCATCAT
2-2-1-
AAttAtttatacacCaTCAT
585_7
-20.11
11511
|
9-1-1-4
|
|
585
AATTATTTATACACCATCAT
3-1-2-
AATtATttatacacCatCAT
585_8
-21.48
11511
|
8-1-2-3
|
|
585
AATTATTTATACACCATCAT
4-2-1-
AATTatTtatacacCatcAT
585_9
-19.60
11511
|
7-1-3-2
|
|
585
AATTATTTATACACCATCAT
2-1-1-
AAtTatTtatacaCCAtcAT
585_10
-21.69
11511
|
2-1-6-
|
3-2-2
|
|
585
AATTATTTATACACCATCAT
1-3-2-
AattATttatacaCcAtCAT
585_11
-19.97
11511
|
7-1-1-
|
1-1-3
|
|
585
AATTATTTATACACCATCAT
2-1-3-
AAtTATttatacacCaTcAT
585_12
-20.42
11511
|
8-1-1-
|
1-1-2
|
|
585
AATTATTTATACACCATCAT
1-1-2-
AaTTaTttatacacCatCAT
585_13
-20.49
11511
|
1-1-8-
|
1-2-3
|
|
585
AATTATTTATACACCATCAT
2-1-1-
AAtTatTtatacaccaTCAT
585_14
-20.47
11511
|
2-1-9-4
|
|
586
AAATTATTTATACACCATCA
1-12-
AaattatttatacACCaTCA
586_1
-20.58
11512
|
3-1-3
|
|
586
AAATTATTTATACACCATCA
1-1-1-
AaAttAtttatacAcCAtCA
586_2
-18.56
11512
|
2-1-7-
|
1-1-2-
|
1-2
|
|
586
AAATTATTTATACACCATCA
3-2-2-
AAAttATttatacACcatCA
586_3
-19.68
11512
|
6-2-3-2
|
|
586
AAATTATTTATACACCATCA
4-10-
AAATtatttatacaCcaTCA
586_4
-20.15
11512
|
1-2-3
|
|
586
AAATTATTTATACACCATCA
1-1-4-
AaATTAtttatacaCcAtCA
586_5
-20.72
11512
|
8-1-1-
|
1-1-2
|
|
586
AAATTATTTATACACCATCA
2-1-2-
AAaTTaTttatacaCcatCA
586_6
-19.39
11512
|
1-1-7-
|
1-3-2
|
|
586
AAATTATTTATACACCATCA
1-3-2-
AaatTAtttatacAcCaTCA
586_7
-19.65
11512
|
7-1-1-
|
1-1-3
|
|
586
AAATTATTTATACACCATCA
1-1-3-
AaATTatttatacAccATCA
586_8
-20.88
11512
|
8-1-2-4
|
|
586
AAATTATTTATACACCATCA
2-2-1-
AAatTaTttatacaccATCA
586_9
-19.63
11512
|
1-1-9-4
|
|
586
AAATTATTTATACACCATCA
1-1-1-
AaAtTaTttatacACCatCA
586_10
-20.95
11512
|
1-1-1-
|
1-6-3-
|
2-2
|
|
586
AAATTATTTATACACCATCA
1-3-2-
AaatTAtttatacAcCAtCA
586_11
-20.00
11512
|
7-1-1-
|
2-1-2
|
|
586
AAATTATTTATACACCATCA
2-1-2-
AAaTTaTttatacaCcAtCA
586_12
-19.44
11512
|
1-1-7-
|
1-1-1-
|
1-2
|
|
586
AAATTATTTATACACCATCA
3-2-1-
AAAttAtttatacaCcaTCA
586_13
-19.00
11512
|
8-1-2-3
|
|
586
AAATTATTTATACACCATCA
1-1-4-
AaATTAtttatacacCaTCA
586_14
-21.59
11512
|
9-1-1-3
|
|
587
AAAATTATTTATACACCATC
2-3-1-
AAaatTatttataCaCCATC
587_1
-21.17
11513
|
7-1-1-5
|
|
587
AAAATTATTTATACACCATC
1-2-2-
AaaATtatttatacACCATC
587_2
-21.34
11513
|
9-6
|
|
587
AAAATTATTTATACACCATC
2-3-2-
AAaatTAtttataCACcATC
587_3
-20.67
11513
|
6-3-1-3
|
|
587
AAAATTATTTATACACCATC
3-1-1-
AAAaTtAtttatacACCaTC
587_4
-19.11
11513
|
1-1-7-
|
3-1-2
|
|
587
AAAATTATTTATACACCATC
7-6-1-
AAAATTAtttataCaCcaTC
587_5
-20.66
11513
|
1-1-2-2
|
|
587
AAAATTATTTATACACCATC
1-1-1-
AaAaTTatttatacACcATC
587_6
-18.20
11513
|
1-2-8-
|
2-1-3
|
|
587
AAAATTATTTATACACCATC
1-1-5-
AaAATTAtttataCAccaTC
587_7
-20.71
11513
|
6-2-3-2
|
|
587
AAAATTATTTATACACCATC
2-1-3-
AAaATTatttataCacCATC
587_8
-20.87
11513
|
7-1-2-4
|
|
587
AAAATTATTTATACACCATC
4-1-1-
AAAAtTatttatacAcCATC
587_9
-19.30
11513
|
8-1-1-4
|
|
587
AAAATTATTTATACACCATC
1-1-2-
AaAAtTAtttataCACcaTC
587_10
-20.13
11513
|
1-2-6-
|
3-2-2
|
|
587
AAAATTATTTATACACCATC
1-2-3-
AaaATTatttataCaCCaTC
587_11
-20.44
11513
|
7-1-1-
|
2-1-2
|
|
587
AAAATTATTTATACACCATC
3-1-2-
AAAaTTatttataCacCATC
587_12
-20.27
11513
|
7-1-2-4
|
|
587
AAAATTATTTATACACCATC
3-2-1-
AAAatTatttatacACCaTC
587_13
-19.30
11513
|
8-3-1-2
|
|
587
AAAATTATTTATACACCATC
2-1-3-
AAaATTatttatacACcATC
587_14
-19.52
11513
|
8-2-1-3
|
|
588
TAAAATTATTTATACACCAT
2-3-1-
TAaaaTtatttatAcACCAT
588_1
-20.14
11514
|
7-1-1-5
|
|
588
TAAAATTATTTATACACCAT
1-2-1-
TaaAatTatttatACaCCAT
588_2
-20.15
11514
|
2-1-6-
|
2-1-4
|
|
588
TAAAATTATTTATACACCAT
1-1-1-
TaAaATtatttataCaCCAT
588_3
-20.40
11514
|
1-2-8-
|
1-1-4
|
|
588
TAAAATTATTTATACACCAT
4-1-2-
TAAAaTTatttatACACcAT
588_4
-21.36
11514
|
6-4-1-2
|
|
588
TAAAATTATTTATACACCAT
1-3-3-
TaaaATTatttatACAcCAT
588_5
-21.07
11514
|
6-3-1-3
|
|
588
TAAAATTATTTATACACCAT
2-1-4-
TAaAATTatttataCACcAT
588_6
-21.36
11514
|
7-3-1-2
|
|
588
TAAAATTATTTATACACCAT
3-1-1-
TAAaAtTatttataCAcCAT
588_7
-20.41
11514
|
1-1-7-
|
2-1-3
|
|
588
TAAAATTATTTATACACCAT
7-6-1-
TAAAATTatttatAcacCAT
588_8
-20.85
11514
|
3-3
|
|
588
TAAAATTATTTATACACCAT
2-1-2-
TAaAAttatttatacaCCAT
588_9
-19.82
11514
|
11-4
|
|
588
TAAAATTATTTATACACCAT
2-2-3-
TAaaATTatttatACACcAT
588_10
-21.41
11514
|
6-4-1-2
|
|
588
TAAAATTATTTATACACCAT
1-1-1-
TaAaATTatttatAcaCCAT
588_11
-21.15
11514
|
1-3-6-
|
1-2-4
|
|
588
TAAAATTATTTATACACCAT
2-1-2-
TAaAAtTatttataCAcCAT
588_12
-20.41
11514
|
1-1-7-
|
2-1-3
|
|
588
TAAAATTATTTATACACCAT
3-2-2-
TAAaaTTatttataCaCCAT
588_13
-21.86
11514
|
7-1-1-4
|
|
588
TAAAATTATTTATACACCAT
1-1-2-
TaAAaTtatttatacACCAT
588_14
-19.68
11514
|
1-1-9-5
|
|
589
TAAAATTATTTATACACCA
1-1-2-
TaAAaTtatttatACACCA
589_1
-20.31
11515
|
1-1-7-6
|
|
589
TAAAATTATTTATACACCA
1-2-3-
TaaAATtatttaTaCACCA
589_2
-21.36
11515
|
6-1-1-5
|
|
589
TAAAATTATTTATACACCA
2-3-1-
TAaaaTtatttatACACCA
589_3
-20.58
11515
|
7-6
|
|
589
TAAAATTATTTATACACCA
3-1-2-
TAAaATtatttaTACAcCA
589_4
-21.36
11515
|
6-4-1-2
|
|
589
TAAAATTATTTATACACCA
4-1-1-
TAAAaTtatttaTAcaCCA
589_5
-20.51
11515
|
6-2-2-3
|
|
589
TAAAATTATTTATACACCA
2-1-2-
TAaAAttatttaTaCaCCA
589_6
-19.30
11515
|
7-1-1-
|
1-1-3
|
|
589
TAAAATTATTTATACACCA
1-3-2-
TaaaATtatttaTAcaCCA
589_7
-19.40
11515
|
6-2-2-3
|
|
589
TAAAATTATTTATACACCA
5-8-2-
TAAAAttatttatACaCCA
589_8
-19.77
11515
|
1-3
|
|
589
TAAAATTATTTATACACCA
3-1-2-
TAAaATtatttatacACCA
589_9
-19.55
11515
|
9-4
|
|
589
TAAAATTATTTATACACCA
2-1-3-
TAaAATtatttaTACAcCA
589_10
-21.36
11515
|
6-4-1-2
|
|
589
TAAAATTATTTATACACCA
3-1-2-
TAAaATtatttaTACaCCA
589_11
-22.18
11515
|
6-3-1-3
|
|
589
TAAAATTATTTATACACCA
1-1-3-
TaAAAttatttaTAcACCA
589_12
-19.78
11515
|
7-2-1-4
|
|
589
TAAAATTATTTATACACCA
2-2-1-
TAaaAttatttaTaCaCCA
589_13
-18.76
11515
|
7-1-1-
|
1-1-3
|
|
589
TAAAATTATTTATACACCA
4-1-1-
TAAAaTtatttataCACCA
589_14
-21.06
11515
|
8-5
|
|
590
ATATTGATTCAATTCCC
2-9-2-
ATattgattcaATtCCC
590_1
-21.84
13226
|
1-3
|
|
590
ATATTGATTCAATTCCC
1-2-1-
AtaTtgattcaATTCCC
590_2
-22.10
13226
|
7-6
|
|
590
ATATTGATTCAATTCCC
2-9-1-
ATattgattcaAtTcCC
590_3
-18.59
13226
|
1-1-1-2
|
|
590
ATATTGATTCAATTCCC
1-1-2-
AtATtgattcaaTTCCC
590_4
-21.87
13226
|
8-5
|
|
590
ATATTGATTCAATTCCC
1-2-2-
AtaTTgattcaaTTcCC
590_5
-19.29
13226
|
7-2-1-2
|
|
590
ATATTGATTCAATTCCC
1-3-1-
AtatTgattcaATtcCC
590_6
-18.59
13226
|
6-2-2-2
|
|
590
ATATTGATTCAATTCCC
1-2-2-
AtaTTgattcaAttCCC
590_7
-20.66
13226
|
6-1-2-3
|
|
590
ATATTGATTCAATTCCC
1-1-1-
AtAtTgattcaaTtCCC
590_8
-19.92
13226
|
1-1-7-
|
1-1-3
|
|
590
ATATTGATTCAATTCCC
1-1-1-
AtAttgattcaAttCCC
590_9
-19.01
13226
|
8-1-2-3
|
|
590
ATATTGATTCAATTCCC
4-7-1-
ATATtgattcaAttcCC
590_10
-20.60
13226
|
3-2
|
|
590
ATATTGATTCAATTCCC
3-1-1-
ATAtTgattcaaTtcCC
590_11
-20.26
13226
|
7-1-2-2
|
|
590
ATATTGATTCAATTCCC
1-3-1-
AtatTgattcaatTCCC
590_12
-20.37
13226
|
8-4
|
|
590
ATATTGATTCAATTCCC
2-1-1-
ATaTtgattcaattCCC
590_13
-20.71
13226
|
10-3
|
|
590
ATATTGATTCAATTCCC
2-2-1-
ATatTgattcaattCCC
590_14
-21.06
13226
|
9-3
|
|
590
ATATTGATTCAATTCCC
1-1-3-
AtATTgattcaattcCC
590_15
-18.87
13226
|
10-2
|
|
590
ATATTGATTCAATTCCC
2-2-1-
ATatTgattcaATtcCC
590_16
-20.26
13226
|
6-2-2-2
|
|
590
ATATTGATTCAATTCCC
3-8-1-
ATAttgattcaAtTCCC
590_17
-22.71
13226
|
1-4
|
|
590
ATATTGATTCAATTCCC
1-1-3-
AtATTgattcaAttCCC
590_18
-21.57
13226
|
6-1-2-3
|
|
590
ATATTGATTCAATTCCC
1-1-1-
AtAtTgattcaaTTCCC
590_19
-21.42
13226
|
1-1-7-5
|
|
590
ATATTGATTCAATTCCC
2-1-1-
ATaTtgattcaaTtCCC
590_20
-21.15
13226
|
8-1-1-3
|
|
591
GCACATTCTTTCTATACCT
1-1-1-
GcAcAttctttctatacCT
591_1
-21.27
15113
|
1-1-12-
|
2
|
|
591
GCACATTCTTTCTATACCT
1-3-1-
GcacAttctttctatacCT
591_2
-21.12
15113
|
12-2
|
|
592
GCACATTCTTTCTATACC
1-12-
GcacattctttctAtaCC
592_1
-20.07
15114
|
1-2-2
|
|
592
GCACATTCTTTCTATACC
1-1-1-
GcAcAttctttctataCC
592_2
-20.17
15114
|
1-1-11-
|
2
|
|
592
GCACATTCTTTCTATACC
1-3-1-
GcacAttctttctataCC
592_3
-20.02
15114
|
11-2
|
|
592
GCACATTCTTTCTATACC
1-1-2-
GcACattctttctatACC
592_4
-21.80
15114
|
11-3
|
|
592
GCACATTCTTTCTATACC
1-1-1-
GcAcATtctttctAtACC
592_5
-22.11
15114
|
1-2-7-
|
1-1-3
|
|
592
GCACATTCTTTCTATACC
1-1-1-
GcAcATtctttctAtaCC
592_6
-21.51
15114
|
1-2-7-
|
1-2-2
|
|
592
GCACATTCTTTCTATACC
1-15-2
GcacattctttctataCC
592_7
-19.97
15114
|
|
592
GCACATTCTTTCTATACC
1-4-1-
GcacaTtctttctatACC
592_8
-21.01
15114
|
9-3
|
|
592
GCACATTCTTTCTATACC
1-4-1-
GcacaTtctttctataCC
592_9
-20.41
15114
|
10-2
|
|
592
GCACATTCTTTCTATACC
2-11-1-
GCacattctttctAtaCC
592_10
-22.39
15114
|
2-2
|
|
592
GCACATTCTTTCTATACC
1-1-1-
GcAcAttctttctAtaCC
592_11
-20.27
15114
|
1-1-8-
|
1-2-2
|
|
592
GCACATTCTTTCTATACC
1-3-1-
GcacAttctttctaTaCC
592_12
-20.89
15114
|
9-1-1-2
|
|
592
GCACATTCTTTCTATACC
1-1-1-
GcAcAttctttctatACC
592_13
-20.77
15114
|
1-1-10-
|
3
|
|
592
GCACATTCTTTCTATACC
1-1-1-
GcAcaTtctttctataCC
592_14
-20.56
15114
|
2-1-10-
|
2
|
|
593
TTATTTCCATTTATTTTCA
1-1-1-
TtAtTtccatttaTTTtCA
593_1
-19.10
15563
|
1-1-8-
|
3-1-2
|
|
593
TTATTTCCATTTATTTTCA
1-2-2-
TtaTTtccatttAtTtTCA
593_2
-19.27
15563
|
7-1-1-
|
1-1-3
|
|
593
TTATTTCCATTTATTTTCA
2-2-1-
TTatTtccatttaTtTtCA
593_3
-18.92
15563
|
8-1-1-
|
1-1-2
|
|
593
TTATTTCCATTTATTTTCA
1-1-2-
TtATttccatttaTttTCA
593_4
-19.41
15563
|
9-1-2-3
|
|
594
TTTATTTCCATTTATTTTCA
1-1-1-
TtTatttccatttaTttTCA
594_1
-19.80
15563
|
11-1-2-
|
3
|
|
594
TTTATTTCCATTTATTTTCA
1-4-1-
TttatTtccatttAtTttCA
594_2
-18.34
15563
|
7-1-1-
|
1-2-2
|
|
594
TTTATTTCCATTTATTTTCA
1-3-2-
TttaTTtccatttatTTtCA
594_3
-20.01
15563
|
9-2-1-2
|
|
594
TTTATTTCCATTTATTTTCA
2-1-1-
TTtAtTtccatttaTtTtCA
594_4
-19.60
15563
|
1-1-8-
|
1-1-1-
|
1-2
|
|
595
ATTTATTTCCATTTATTTTC
1-1-1-
AtTtaTttccatttATTtTC
595_1
-19.05
15564
|
2-1-8-
|
3-1-2
|
|
595
ATTTATTTCCATTTATTTTC
1-3-2-
AtttATttccattTattTTC
595_2
-19.03
15564
|
7-1-3-3
|
|
595
ATTTATTTCCATTTATTTTC
1-1-2-
AtTTatttccatttAttTTC
595_3
-18.60
15564
|
10-1-2-
|
3
|
|
595
ATTTATTTCCATTTATTTTC
2-1-1-
ATtTaTttccatttAtTtTC
595_4
-18.96
15564
|
1-1-8-
|
1-1-1-
|
1-2
|
|
596
TTTATTTCCATTTATTTTC
1-1-1-
TtTaTttccatttATtTTC
596_1
-18.66
15564
|
1-1-8-
|
2-1-3
|
|
596
TTTATTTCCATTTATTTTC
3-2-1-
TTTatTtccatttATTtTC
596_2
-19.84
15564
|
7-3-1-2
|
|
596
TTTATTTCCATTTATTTTC
2-2-2-
TTtaTTtccatttAtTTTC
596_3
-19.12
15564
|
7-1-1-4
|
|
596
TTTATTTCCATTTATTTTC
5-7-1-
TTTATttccattTattTTC
596_4
-21.30
15564
|
3-3
|
|
597
CCATTTATTTCCATTTATTT
1-1-1-
CcAtttatttccatTTatTT
597_1
-19.89
15566
|
11-2-2-
|
2
|
|
597
CCATTTATTTCCATTTATTT
1-3-1-
CcatTtatttccatTtAtTT
597_2
-19.00
15566
|
9-1-1-
|
1-1-2
|
|
597
CCATTTATTTCCATTTATTT
1-1-1-
CcAttTatttccatTtaTTT
597_3
-20.33
15566
|
2-1-8-
|
1-2-3
|
|
597
CCATTTATTTCCATTTATTT
1-2-2-
CcaTTtAtttccatttatTT
597_4
-19.64
15566
|
1-1-11-
|
2
|
|
598
TCCATTTATTTCCATTTATT
2-11-
TCcatttatttccATttaTT
598_1
-21.22
15567
|
2-3-2
|
|
598
TCCATTTATTTCCATTTATT
2-2-1-
TCcaTttatttccAtTtaTT
598_2
-20.71
15567
|
8-1-1-
|
1-2-2
|
|
598
TCCATTTATTTCCATTTATT
1-1-2-
TcCAtttatttccAtttaTT
598_3
-20.63
15567
|
9-14-2
|
|
598
TCCATTTATTTCCATTTATT
2-1-1-
TCcAtTtatttccatttATT
598_4
-21.18
15567
|
1-1-11-
|
3
|
|
599
TCCATTTATTTCCATTTAT
2-11-
TCcatttatttccATttAT
599_1
-20.30
15568
|
2-2-2
|
|
599
TCCATTTATTTCCATTTAT
2-2-1-
TCcaTttatttccAtTtAT
599_2
-19.80
15568
|
8-1-1-
|
1-1-2
|
|
599
TCCATTTATTTCCATTTAT
1-1-2-
TcCAtttatttccAtttAT
599_3
-19.72
15568
|
9-1-3-2
|
|
599
TCCATTTATTTCCATTTAT
1-1-1-
TcCaTTtatttccAtttAT
599_4
-19.50
15568
|
1-2-7-
|
1-3-2
|
|
600
TTCCATTTATTTCCATTTAT
1-1-1-
TtCcaTttatttccAtTtAT
600_1
-20.12
15568
|
2-1-8-
|
1-1-1-
|
1-2
|
|
600
TTCCATTTATTTCCATTTAT
1-3-1-
TtccAtttatttccaTTtAT
600_2
-19.86
15568
|
10-2-1-
|
2
|
|
600
TTCCATTTATTTCCATTTAT
1-1-1-
TtCcatTtatttccAtttAT
600_3
-19.68
15568
|
3-1-7-
|
1-3-2
|
|
600
TTCCATTTATTTCCATTTAT
1-1-1-
TtCcATttatttccAtttAT
600_4
-20.68
15568
|
1-2-8-
|
1-3-2
|
|
601
TTTCCATTTATTTCCATTTA
1-4-1-
TttccAtttatttCcaTtTA
601_1
-20.53
15569
|
7-1-2-
|
1-1-2
|
|
601
TTTCCATTTATTTCCATTTA
2-2-1-
TTtcCatttatttccatTTA
601_2
-21.47
15569
|
12-3
|
|
601
TTTCCATTTATTTCCATTTA
1-2-1-
TttCcaTttatttccAttTA
601_3
-20.53
15569
|
2-1-8-
|
1-2-2
|
|
601
TTTCCATTTATTTCCATTTA
1-4-1-
TttccAtttatttccAttTA
601_4
-19.37
15569
|
9-1-2-2
|
|
602
CTTTCCATTTATTTCCATT
1-11-
CtttccatttatTtCcATT
602_1
-21.20
15571
|
1-1-1-
|
1-3
|
|
602
CTTTCCATTTATTTCCATT
2-2-1-
CTttCcatttatttCcaTT
602_2
-22.00
15571
|
9-1-2-2
|
|
602
CTTTCCATTTATTTCCATT
1-4-1-
CtttcCatttatttcCaTT
602_3
-20.42
15571
|
9-1-1-2
|
|
602
CTTTCCATTTATTTCCATT
1-3-1-
CtttCcatttatttccATT
602_4
-20.89
15571
|
11-3
|
|
603
ATCTTTCCATTTATTTCCAT
1-2-1-
AtcTttccatttatttCcAT
603_1
-21.24
15572
|
12-1-1-
|
2
|
|
603
ATCTTTCCATTTATTTCCAT
1-3-1-
AtctTtCcatttatTtccAT
603_2
-21.33
15572
|
1-1-7-
|
1-3-2
|
|
603
ATCTTTCCATTTATTTCCAT
1-5-1-
AtctttCcatttaTttccAT
603_3
-21.16
15572
|
6-1-4-2
|
|
603
ATCTTTCCATTTATTTCCAT
1-16-3
AtctttccatttatttcCAT
603_4
-21.95
15572
|
|
604
TCTTTCCATTTATTTCCAT
2-13-
TCtttccatttatttCcAT
604_1
-21.57
15572
|
1-1-2
|
|
604
TCTTTCCATTTATTTCCAT
1-2-1-
TctTtCcatttatTtCcAT
604_2
-21.35
15572
|
1-1-7-
|
1-1-1-
|
1-2
|
|
604
TCTTTCCATTTATTTCCAT
2-14-3
TCtttccatttatttcCAT
604_3
-22.80
15572
|
|
604
TCTTTCCATTTATTTCCAT
2-3-1-
TCtttCcatttatttccAT
604_4
-21.57
15572
|
11-2
|
|
605
ATCTTTCCATTTATTTCCA
1-2-1-
AtcTttccatttatTtcCA
605_1
-20.70
15573
|
10-1-2-
|
2
|
|
605
ATCTTTCCATTTATTTCCA
1-3-1-
AtctTtccatttaTttcCA
605_2
-20.63
15573
|
8-1-3-2
|
|
605
ATCTTTCCATTTATTTCCA
1-1-1-
AtCtttccatttatttcCA
605_3
-20.86
15573
|
14-2
|
|
605
ATCTTTCCATTTATTTCCA
1-4-1-
AtcttTccatttattTcCA
605_4
-20.63
15573
|
9-1-1-2
|
|
606
TATCTTTCCATTTATTTCCA
1-4-1-
TatctTtccatttaTTtcCA
606_1
-22.54
15573
|
8-2-2-2
|
|
606
TATCTTTCCATTTATTTCCA
2-16-2
TAtctttccatttatttcCA
606_2
-22.12
15573
|
|
606
TATCTTTCCATTTATTTCCA
1-2-1-
TatCtttccatttatttcCA
606_3
-21.97
15573
|
14-2
|
|
606
TATCTTTCCATTTATTTCCA
1-17-2
TatctttccatttatttcCA
606_4
-20.99
15573
|
|
607
TATCTTTCCATTTATTTCC
2-12-
TAtctttccatttaTttCC
607_1
-21.63
15574
|
1-2-2
|
|
607
TATCTTTCCATTTATTTCC
1-2-1-
TatCtttccatttatttCC
607_2
-21.04
15574
|
13-2
|
|
607
TATCTTTCCATTTATTTCC
1-2-2-
TatCTttccatttatttCC
607_3
-22.23
15574
|
12-2
|
|
607
TATCTTTCCATTTATTTCC
1-4-1-
TatctTtccatttatTtCC
607_4
-20.66
15574
|
9-1-1-2
|
|
608
AAATCTCAACTACCATTTTT
1-1-1-
AaAtctCaactaccATTtTT
608_1
-19.53
25248
|
3-1-7-
|
3-1-2
|
|
608
AAATCTCAACTACCATTTTT
3-1-1-
AAAtCtcaactaccATtTTT
608_2
-20.58
25248
|
9-2-1-3
|
|
608
AAATCTCAACTACCATTTTT
1-3-1-
AaatCtcaactacCaTTTTT
608_3
-20.56
25248
|
8-1-1-5
|
|
608
AAATCTCAACTACCATTTTT
1-1-1-
AaAtcTcaactacCAttTTT
608_4
-20.20
25248
|
2-1-7-
|
2-2-3
|
|
608
AAATCTCAACTACCATTTTT
1-3-1-
AaatCtCaactacCaTttTT
608_5
-19.10
25248
|
1-1-6-
|
1-1-1-
|
2-2
|
|
608
AAATCTCAACTACCATTTTT
2-3-2-
AAatcTCaactacCatTTTT
608_6
-21.04
25248
|
6-1-2-4
|
|
608
AAATCTCAACTACCATTTTT
2-1-2-
AAaTCtCaactaccAtttTT
608_7
-19.79
25248
|
1-1-7-
|
1-3-2
|
|
608
AAATCTCAACTACCATTTTT
1-1-3-
AaATCtcaactaccatTtTT
608_8
-19.97
25248
|
11-1-1-
|
2
|
|
608
AAATCTCAACTACCATTTTT
3-1-1-
AAAtCtCaactaccattTTT
608_9
-19.95
25248
|
1-1-10-
|
3
|
|
609
AAAATCTCAACTACCATTTT
1-12-
AaaatctcaactaCCATtTT
609_1
-21.31
25249
|
4-1-2
|
|
609
AAAATCTCAACTACCATTTT
3-11-
AAAatctcaactacCAtTTT
609_2
-19.57
25249
|
2-1-3
|
|
609
AAAATCTCAACTACCATTTT
2-1-1-
AAaAtCtcaactacCAtTTT
609_3
-20.33
25249
|
1-1-8-
|
2-1-3
|
|
609
AAAATCTCAACTACCATTTT
1-1-4-
AaAATCtcaactaccAttTT
609_4
-19.46
25249
|
9-1-2-2
|
|
609
AAAATCTCAACTACCATTTT
1-1-2-
AaAAtcTcaactacCAttTT
609_5
-19.13
25249
|
2-1-7-
|
2-2-2
|
|
609
AAAATCTCAACTACCATTTT
4-1-1-
AAAAtCtcaactaCcaTTTT
609_6
-20.75
25249
|
7-1-2-4
|
|
609
AAAATCTCAACTACCATTTT
1-1-1-
AaAatCtcaactacCaTTTT
609_7
-19.30
25249
|
2-1-8-
|
1-1-4
|
|
609
AAAATCTCAACTACCATTTT
1-2-3-
AaaATCtcaactaCcAtTTT
609_8
-20.51
25249
|
7-1-1-
|
1-1-3
|
|
609
AAAATCTCAACTACCATTTT
2-2-2-
AAaaTCtcaactaccaTtTT
609_9
-18.72
25249
|
10-1-1-
|
2
|
|
610
AAAATCTCAACTACCATTT
1-4-1-
AaaatCtcaactACCAtTT
610_1
-20.63
25250
|
6-4-1-2
|
|
610
AAAATCTCAACTACCATTT
3-10-6
AAAatctcaactaCCATTT
610_2
-21.90
25250
|
|
610
AAAATCTCAACTACCATTT
6-6-2-
AAAATCtcaactACcaTTT
610_3
-21.46
25250
|
2-3
|
|
610
AAAATCTCAACTACCATTT
2-2-2-
AAaaTCtcaactaCCaTTT
610_4
-21.18
25250
|
7-2-1-3
|
|
610
AAAATCTCAACTACCATTT
6-7-2-
AAAATCtcaactaCCatTT
610_5
-22.10
25250
|
2-2
|
|
610
AAAATCTCAACTACCATTT
2-1-1-
AAaAtCtcaactacCATTT
610_6
-20.27
25250
|
1-1-8-5
|
|
610
AAAATCTCAACTACCATTT
1-1-1-
AaAaTCtcaactacCATTT
610_7
-20.88
25250
|
1-2-8-5
|
|
610
AAAATCTCAACTACCATTT
1-1-2-
AaAAtCtcaactacCAtTT
610_8
-18.51
25250
|
1-1-8-
|
2-1-2
|
|
610
AAAATCTCAACTACCATTT
6-9-4
AAAATCtcaactaccATTT
610_9
-20.94
25250
|
|
611
GAAAATCTCAACTACCATT
1-1-3-
GaAAAtctcaacTacCATT
611_1
-20.48
25251
|
7-1-2-4
|
|
611
GAAAATCTCAACTACCATT
1-1-2-
GaAAatctcaacTaCcATT
611_2
-18.75
25251
|
8-1-1-
|
1-1-3
|
|
611
GAAAATCTCAACTACCATT
3-1-1-
GAAaAtctcaactacCATT
611_3
-20.73
25251
|
10-4
|
|
611
GAAAATCTCAACTACCATT
2-1-2-
GAaAAtctcaactacCATT
611_4
-20.73
25251
|
10-4
|
|
611
GAAAATCTCAACTACCATT
2-2-1-
GAaaAtctcaacTaccaTT
611_5
-18.28
25251
|
7-14-2
|
|
611
GAAAATCTCAACTACCATT
2-12-5
GAaaatctcaactaCCATT
611_6
-22.25
25251
|
|
611
GAAAATCTCAACTACCATT
4-10-
GAAAatctcaactaCCaTT
611_7
-21.06
25251
|
2-1-2
|
|
611
GAAAATCTCAACTACCATT
4-10-
GAAAatctcaactaCcATT
611_8
-19.73
25251
|
1-1-3
|
|
611
GAAAATCTCAACTACCATT
5-12-2
GAAAAtctcaactaccaTT
611_9
-18.61
25251
|
|
612
TGAAAATCTCAACTACCAT
1-4-1-
TgaaaAtctcaaCtACcAT
612_1
-18.43
25252
|
6-1-1-
|
2-1-2
|
|
612
TGAAAATCTCAACTACCAT
2-1-2-
TGaAAatctcaaCtaCcAT
612_2
-19.46
25252
|
7-1-2-
|
1-1-2
|
|
612
TGAAAATCTCAACTACCAT
1-1-2-
TgAAaatctcaaCtaCcAT
612_3
-18.58
25252
|
8-1-2-
|
1-1-2
|
|
612
TGAAAATCTCAACTACCAT
1-2-1-
TgaAaAtctcaaCtacCAT
612_4
-19.40
25252
|
1-1-6-
|
1-3-3
|
|
612
TGAAAATCTCAACTACCAT
1-3-2-
TgaaAAtctcaactacCAT
612_5
-18.60
25252
|
10-3
|
|
612
TGAAAATCTCAACTACCAT
1-11-
TgaaaatctcaaCtaCCAT
612_6
-21.11
25252
|
1-2-4
|
|
612
TGAAAATCTCAACTACCAT
3-1-2-
TGAaAAtctcaaCtaccAT
612_7
-20.39
25252
|
6-1-4-2
|
|
612
TGAAAATCTCAACTACCAT
1-1-1-
TgAaAatctcaaCtacCAT
612_8
-19.60
25252
|
1-1-7-
|
1-3-3
|
|
612
TGAAAATCTCAACTACCAT
4-12-3
TGAAaatctcaactacCAT
612_9
-21.07
25252
|
|
613
ATCATTCTCAACAATTAAA
4-8-7
ATCAttctcaacAATTAAA
613_1
-20.89
30599
|
|
613
ATCATTCTCAACAATTAAA
1-1-4-
AtCATTctcaacAATTAAA
613_2
-21.09
30599
|
6-7
|
|
613
ATCATTCTCAACAATTAAA
5-7-2-
ATCATtctcaacAAtTaAA
613_3
-19.03
30599
|
1-1-1-2
|
|
613
ATCATTCTCAACAATTAAA
5-8-2-
ATCATtctcaacaATtaAA
613_4
-19.28
30599
|
2-2
|
|
613
ATCATTCTCAACAATTAAA
4-1-1-
ATCAtTctcaacaaTTAAA
613_5
-19.86
30599
|
8-5
|
|
613
ATCATTCTCAACAATTAAA
5-7-4-
ATCATtctcaacAATTaAA
613_6
-20.79
30599
|
1-2
|
|
613
ATCATTCTCAACAATTAAA
4-8-1-
ATCAttctcaacAaTTAAA
613_7
-19.56
30599
|
1-5
|
|
613
ATCATTCTCAACAATTAAA
1-1-4-
AtCATTctcaacAaTTAAA
613_8
-19.76
30599
|
6-1-1-5
|
|
613
ATCATTCTCAACAATTAAA
4-1-1-
ATCAtTctcaacaATTaAA
613_9
-19.64
30599
|
7-3-1-2
|
|
613
ATCATTCTCAACAATTAAA
5-8-1-
ATCATtctcaacaAtTAAA
613_10
-20.11
30599
|
1-4
|
|
614
ATCATTCTCAACAATTAA
4-8-6
ATCAttctcaacAATTAA
614_1
-20.14
30600
|
|
614
ATCATTCTCAACAATTAA
1-1-4-
AtCATTctcaacAATTAA
614_2
-20.34
30600
|
6-6
|
|
614
ATCATTCTCAACAATTAA
5-8-1-
ATCATtctcaacaAtTAA
614_3
-19.36
30600
|
1-3
|
|
614
ATCATTCTCAACAATTAA
4-8-1-
ATCAttctcaacAaTTAA
614_4
-18.81
30600
|
1-4
|
|
614
ATCATTCTCAACAATTAA
5-8-5
ATCATtctcaacaATTAA
614_5
-21.12
30600
|
|
614
ATCATTCTCAACAATTAA
5-7-1-
ATCATtctcaacAatTAA
614_6
-19.11
30600
|
2-3
|
|
614
ATCATTCTCAACAATTAA
3-10-5
ATCattctcaacaATTAA
614_7
-18.40
30600
|
|
614
ATCATTCTCAACAATTAA
4-9-1-
ATCAttctcaacaAtTAA
614_8
-18.11
30600
|
1-3
|
|
614
ATCATTCTCAACAATTAA
4-1-1-
ATCAtTctcaacaaTTAA
614_9
-19.11
30600
|
8-4
|
|
614
ATCATTCTCAACAATTAA
1-1-3-
AtCATtctcaacaaTTAA
614_10
-18.05
30600
|
9-4
|
|
615
GATCATTCTCAACAATTAA
2-3-1-
GAtcaTtctcaaCAaTTAA
615_1
-20.54
30600
|
6-2-1-4
|
|
615
GATCATTCTCAACAATTAA
1-2-2-
GatCAttctcaaCaaTTAA
615_2
-19.04
30600
|
7-1-2-4
|
|
615
GATCATTCTCAACAATTAA
2-1-3-
GAtCATtctcaaCAAttAA
615_3
-21.29
30600
|
6-3-2-2
|
|
615
GATCATTCTCAACAATTAA
2-1-2-
GAtCAttctcaacAAtTAA
615_4
-19.70
30600
|
8-2-1-3
|
|
615
GATCATTCTCAACAATTAA
5-8-1-
GATCAttctcaacAaTtAA
615_5
-19.79
30600
|
1-1-1-2
|
|
615
GATCATTCTCAACAATTAA
4-8-3-
GATCattctcaaCAAttAA
615_6
-20.50
30600
|
2-2
|
|
615
GATCATTCTCAACAATTAA
1-2-3-
GatCATtctcaaCAatTAA
615_7
-20.82
30600
|
6-2-2-3
|
|
615
GATCATTCTCAACAATTAA
2-2-2-
GAtcATtctcaaCaATTAA
615_8
-21.04
30600
|
6-1-1-5
|
|
615
GATCATTCTCAACAATTAA
2-1-1-
GAtCattctcaaCaaTTAA
615_9
-19.28
30600
|
8-1-2-4
|
|
615
GATCATTCTCAACAATTAA
1-1-3-
GaTCAttctcaacaAtTAA
615_10
-18.85
30600
|
9-1-1-3
|
|
616
AGATCATTCTCAACAATTA
1-1-1-
AgAtcAttctcaaCAAtTA
616_1
-19.10
30601
|
2-1-7-
|
3-1-2
|
|
616
AGATCATTCTCAACAATTA
1-3-1-
AgatCattctcaaCAaTTA
616_2
-19.65
30601
|
8-2-1-3
|
|
616
AGATCATTCTCAACAATTA
1-3-2-
AgatCAttctcaAcAatTA
616_3
-18.49
30601
|
6-1-1-
|
1-2-2
|
|
616
AGATCATTCTCAACAATTA
1-1-1-
AgAtCAttctcaacaatTA
616_4
-18.49
30601
|
1-2-11-
|
2
|
|
616
AGATCATTCTCAACAATTA
1-1-1-
AgAtcAttctcaacaATTA
616_5
-18.49
30601
|
2-1-9-4
|
|
616
AGATCATTCTCAACAATTA
1-3-2-
AgatCAttctcaAcAATTA
616_6
-20.76
30601
|
6-1-1-5
|
|
616
AGATCATTCTCAACAATTA
2-2-1-
AGatCattctcaaCAAtTA
616_7
-20.47
30601
|
8-3-1-2
|
|
616
AGATCATTCTCAACAATTA
3-2-1-
AGAtcAttctcaaCaaTTA
616_8
-20.51
30601
|
7-1-2-3
|
|
616
AGATCATTCTCAACAATTA
1-2-3-
AgaTCAttctcaaCaatTA
616_9
-19.80
30601
|
7-1-3-2
|
|
616
AGATCATTCTCAACAATTA
1-1-1-
AgAtCAttctcaacAAtTA
616_10
-19.08
30601
|
1-2-8-
|
2-1-2
|
|
617
GATCATTCTCAACAATTA
2-3-1-
GAtcaTtctcaaCAATTA
617_1
-21.11
30601
|
6-6
|
|
617
GATCATTCTCAACAATTA
2-1-2-
GAtCAttctcaacAATTA
617_2
-20.71
30601
|
8-5
|
|
617
GATCATTCTCAACAATTA
2-2-2-
GAtcATtctcaaCAatTA
617_3
-19.70
30601
|
6-2-2-2
|
|
617
GATCATTCTCAACAATTA
1-1-3-
GaTCAttctcaaCaAtTA
617_4
-18.78
30601
|
7-1-1-
|
1-1-2
|
|
617
GATCATTCTCAACAATTA
2-1-2-
GAtCAttctcaacaaTTA
617_5
-19.31
30601
|
10-3
|
|
617
GATCATTCTCAACAATTA
2-1-1-
GAtCaTtctcaaCAAtTA
617_6
-20.02
30601
|
1-1-6-
|
3-1-2
|
|
617
GATCATTCTCAACAATTA
2-1-2-
GAtCAttctcaaCAatTA
617_7
-20.53
30601
|
7-2-2-2
|
|
617
GATCATTCTCAACAATTA
2-1-3-
GAtCATtctcaaCaaTTA
617_8
-21.24
30601
|
6-1-2-3
|
|
617
GATCATTCTCAACAATTA
2-2-1-
GAtcAttctcaacAATTA
617_9
-18.63
30601
|
8-5
|
|
617
GATCATTCTCAACAATTA
1-1-3-
GaTCAttctcaacaAtTA
617_10
-18.10
30601
|
9-1-1-2
|
|
618
AGATCATTCTCAACAATT
1-3-2-
AgatCAttctcaACAATT
618_1
-21.03
30602
|
6-6
|
|
618
AGATCATTCTCAACAATT
1-1-1-
AgAtCAttctcaaCAATT
618_2
-20.70
30602
|
1-2-7-5
|
|
618
AGATCATTCTCAACAATT
1-1-4-
AgATCAttctcaAcaaTT
618_3
-19.56
30602
|
6-1-3-2
|
|
618
AGATCATTCTCAACAATT
3-1-1-
AGAtCattctcaacAATT
618_4
-19.61
30602
|
9-4
|
|
618
AGATCATTCTCAACAATT
2-1-3-
AGaTCAttctcaacaaTT
618_5
-19.09
30602
|
10-2
|
|
618
AGATCATTCTCAACAATT
1-2-3-
AgaTCAttctcaAcaaTT
618_6
-18.25
30602
|
6-1-3-2
|
|
618
AGATCATTCTCAACAATT
2-2-2-
AGatCAttctcaaCAaTT
618_7
-20.14
30602
|
7-2-1-2
|
|
618
AGATCATTCTCAACAATT
1-1-1-
AgAtCAttctcaaCaATT
618_8
-19.02
30602
|
1-2-7-
|
1-1-3
|
|
618
AGATCATTCTCAACAATT
1-2-3-
AgaTCAttctcaacAATT
618_9
-19.23
30602
|
8-4
|
|
618
AGATCATTCTCAACAATT
3-1-1-
AGAtCattctcaacaATT
618_10
-19.34
30602
|
10-3
|
|
619
GATCATTCTCAACAATT
2-1-2-
GAtCAttctcaACAATT
619_1
-21.40
30602
|
6-6
|
|
619
GATCATTCTCAACAATT
1-1-3-
GaTCAttctcaaCAATT
619_2
-19.99
30602
|
7-5
|
|
619
GATCATTCTCAACAATT
5-7-1-
GATCAttctcaaCaaTT
619_3
-19.69
30602
|
2-2
|
|
619
GATCATTCTCAACAATT
5-6-1-
GATCAttctcaAcAATT
619_4
-20.83
30602
|
1-4
|
|
619
GATCATTCTCAACAATT
2-1-2-
GAtCAttctcaaCAATT
619_5
-20.57
30602
|
7-5
|
|
619
GATCATTCTCAACAATT
5-6-1-
GATCAttctcaAcaaTT
619_6
-19.43
30602
|
3-2
|
|
619
GATCATTCTCAACAATT
4-8-5
GATCattctcaaCAATT
619_7
-21.04
30602
|
|
619
GATCATTCTCAACAATT
1-1-3-
GaTCAttctcaaCAaTT
619_8
-18.67
30602
|
7-2-1-2
|
|
619
GATCATTCTCAACAATT
5-7-1-
GATCAttctcaaCaATT
619_9
-20.82
30602
|
1-3
|
|
619
GATCATTCTCAACAATT
2-1-2-
GAtCAttctcaacAATT
619_10
-18.48
30602
|
8-4
|
|
620
AAGATCATTCTCAACAAT
4-1-1-
AAGAtCattctcAaCAAT
620_1
-20.71
30603
|
6-1-1-4
|
|
620
AAGATCATTCTCAACAAT
4-9-5
AAGAtcattctcaACAAT
620_2
-20.79
30603
|
|
620
AAGATCATTCTCAACAAT
2-2-2-
AAgaTCattctcAACAAT
620_3
-19.88
30603
|
6-6
|
|
620
AAGATCATTCTCAACAAT
4-1-1-
AAGAtCattctcaACaAT
620_4
-19.77
30603
|
7-2-1-2
|
|
620
AAGATCATTCTCAACAAT
2-1-3-
AAgATCattctcaaCAAT
620_5
-20.10
30603
|
8-4
|
|
620
AAGATCATTCTCAACAAT
4-1-1-
AAGAtCattctcAAcaAT
620_6
-18.96
30603
|
6-2-2-2
|
|
620
AAGATCATTCTCAACAAT
3-1-2-
AAGaTCattctcAaCAAT
620_7
-20.12
30603
|
6-1-1-4
|
|
620
AAGATCATTCTCAACAAT
2-1-3-
AAgATCattctcAaCAAT
620_8
-20.17
30603
|
6-1-1-4
|
|
620
AAGATCATTCTCAACAAT
1-1-1-
AaGatCattctcaACAAT
620_9
-18.21
30603
|
2-1-7-5
|
|
620
AAGATCATTCTCAACAAT
4-1-1-
AAGAtCattctcaaCAAT
620_10
-20.63
30603
|
8-4
|
|
621
AAAGATCATTCTCAACAA
1-1-1-
AaAgatcattctCAACAA
621_1
-18.13
30604
|
9-6
|
|
621
AAAGATCATTCTCAACAA
1-1-3-
AaAGAtcattctCAaCAA
621_2
-20.08
30604
|
7-2-1-3
|
|
621
AAAGATCATTCTCAACAA
1-3-2-
AaagATcattctCAaCAA
621_3
-18.11
30604
|
6-2-1-3
|
|
621
AAAGATCATTCTCAACAA
1-2-2-
AaaGAtcattctCaACAA
621_4
-18.07
30604
|
7-1-1-4
|
|
621
AAAGATCATTCTCAACAA
5-10-3
AAAGAtcattctcaaCAA
621_5
-18.65
30604
|
|
621
AAAGATCATTCTCAACAA
1-1-3-
AaAGAtcattctCAAcAA
621_6
-18.59
30604
|
7-3-1-2
|
|
621
AAAGATCATTCTCAACAA
4-8-2-
AAAGatcattctCAaCAA
621_7
-19.10
30604
|
1-3
|
|
621
AAAGATCATTCTCAACAA
3-1-1-
AAAgAtcattctCAaCAA
621_8
-18.35
30604
|
7-2-1-3
|
|
621
AAAGATCATTCTCAACAA
1-1-2-
AaAGatcattctCAaCAA
621_9
-18.37
30604
|
8-2-1-3
|
|
621
AAAGATCATTCTCAACAA
1-2-2-
AaaGAtcattctCAaCAA
621_10
-18.74
30604
|
7-2-1-3
|
|
621
AAAGATCATTCTCAACAA
5-7-1-
AAAGAtcattctCaaCAA
621_11
-19.32
30604
|
2-3
|
|
622
CAAAGATCATTCTCAACA
1-1-2-
CaAAgatcattcTCAACA
622_1
-20.93
30605
|
8-6
|
|
622
CAAAGATCATTCTCAACA
2-1-1-
CAaAgatcattctCAACA
622_2
-20.68
30605
|
9-5
|
|
622
CAAAGATCATTCTCAACA
1-4-1-
CaaagAtcattctCAACA
622_3
-18.86
30605
|
7-5
|
|
622
CAAAGATCATTCTCAACA
4-1-1-
CAAAgAtcattctCaaCA
622_4
-19.40
30605
|
7-1-2-2
|
|
622
CAAAGATCATTCTCAACA
3-1-2-
CAAaGAtcattctcaaCA
622_5
-19.67
30605
|
10-2
|
|
622
CAAAGATCATTCTCAACA
4-8-2-
CAAAgatcattcTCaaCA
622_6
-20.10
30605
|
2-2
|
|
622
CAAAGATCATTCTCAACA
1-1-2-
CaAAgAtcattctCAACA
622_7
-20.23
30605
|
1-1-7-5
|
|
622
CAAAGATCATTCTCAACA
2-1-1-
CAaAgatcattctCAaCA
622_8
-19.66
30605
|
9-2-1-2
|
|
622
CAAAGATCATTCTCAACA
3-2-1-
CAAagAtcattctCaACA
622_9
-19.21
30605
|
7-1-1-3
|
|
622
CAAAGATCATTCTCAACA
1-3-2-
CaaaGAtcattctCaaCA
622_10
-18.30
30605
|
7-1-2-2
|
|
623
CAAAGATCATTCTCAAC
3-8-6
CAAagatcattCTCAAC
623_1
-19.95
30606
|
|
623
CAAAGATCATTCTCAAC
2-1-1-
CAaAgatcattCTCAAC
623_2
-20.23
30606
|
7-6
|
|
623
CAAAGATCATTCTCAAC
2-2-1-
CAaaGatcattCTCAAC
623_3
-20.15
30606
|
6-6
|
|
623
CAAAGATCATTCTCAAC
1-2-2-
CaaAGatcattCTCAAC
623_4
-20.00
30606
|
6-6
|
|
623
CAAAGATCATTCTCAAC
5-6-1-
CAAAGatcattCtCAAC
623_5
-20.35
30606
|
1-4
|
|
623
CAAAGATCATTCTCAAC
4-7-3-
CAAAgatcattCTCaAC
623_6
-19.28
30606
|
1-2
|
|
623
CAAAGATCATTCTCAAC
3-1-1-
CAAaGatcattCtCAAC
623_7
-18.81
30606
|
6-1-1-4
|
|
623
CAAAGATCATTCTCAAC
2-1-1-
CAaAgatcattCtCAAC
623_8
-18.36
30606
|
7-1-1-4
|
|
623
CAAAGATCATTCTCAAC
1-2-2-
CaaAGatcattCtCAAC
623_9
-18.12
30606
|
6-1-1-4
|
|
623
CAAAGATCATTCTCAAC
4-8-5
CAAAgatcattcTCAAC
623_10
-19.31
30606
|
|
624
CTCAAAGATCATTCTCA
1-2-1-
CtcAaagatcaTTCTCA
624_1
-20.57
30608
|
7-6
|
|
624
CTCAAAGATCATTCTCA
1-1-1-
CtCaAagatcatTCtCA
624_2
-18.69
30608
|
1-1-7-
|
2-1-2
|
|
624
CTCAAAGATCATTCTCA
1-1-2-
CtCAaagatcaTtcTCA
624_3
-19.51
30608
|
7-1-2-3
|
|
624
CTCAAAGATCATTCTCA
3-10-
CTCaaagatcattCtCA
624_4
-19.23
30608
|
1-1-2
|
|
624
CTCAAAGATCATTCTCA
1-1-3-
CtCAAagatcattCTCA
624_5
-21.26
30608
|
8-4
|
|
624
CTCAAAGATCATTCTCA
1-1-3-
CtCAAagatcaTtCtCA
624_6
-19.82
30608
|
6-1-1-
|
1-1-2
|
|
624
CTCAAAGATCATTCTCA
4-7-1-
CTCAaagatcaTtctCA
624_7
-20.18
30608
|
3-2
|
|
624
CTCAAAGATCATTCTCA
1-2-2-
CtcAAagatcatTCTCA
624_8
-20.16
30608
|
7-5
|
|
624
CTCAAAGATCATTCTCA
1-1-2-
CtCAaagatcatTCtCA
624_9
-19.83
30608
|
8-2-1-2
|
|
624
CTCAAAGATCATTCTCA
3-10-4
CTCaaagatcattCTCA
624_10
-21.11
30608
|
|
625
TACACTTAATTATACTTCCA
1-2-1-
TacAcTtaattatACttcCA
625_1
-20.33
30666
|
1-1-7-
|
2-3-2
|
|
625
TACACTTAATTATACTTCCA
1-2-1-
TacActTaattatActtcCA
625_2
-19.15
30666
|
2-1-6-
|
1-4-2
|
|
625
TACACTTAATTATACTTCCA
1-4-1-
TacacTtaattatAcTtcCA
625_3
-19.30
30666
|
7-1-1-
|
1-2-2
|
|
625
TACACTTAATTATACTTCCA
1-1-1-
TaCacTTaattatActtcCA
625_4
-20.71
30666
|
2-2-6-
|
1-4-2
|
|
625
TACACTTAATTATACTTCCA
1-1-1-
TaCactTaattatacTtcCA
625_5
-20.00
30666
|
3-1-8-
|
1-2-2
|
|
625
TACACTTAATTATACTTCCA
1-2-1-
TacAcTTaattatacTtcCA
625_6
-20.50
30666
|
1-2-8-
|
1-2-2
|
|
625
TACACTTAATTATACTTCCA
1-2-1-
TacActtaattatacttCCA
625_7
-20.60
30666
|
13-3
|
|
625
TACACTTAATTATACTTCCA
1-4-1-
TacacTtaattatacttCCA
625_8
-20.96
30666
|
11-3
|
|
625
TACACTTAATTATACTTCCA
2-1-1-
TAcAcTtaattatacttcCA
625_9
-19.97
30666
|
1-1-12-
|
2
|
|
625
TACACTTAATTATACTTCCA
1-1-1-
TaCacTtaattatACttcCA
625_10
-20.87
30666
|
2-1-7-
|
2-3-2
|
|
625
TACACTTAATTATACTTCCA
1-2-1-
TacAcTTaattatAcTtcCA
625_11
-20.69
30666
|
1-2-6-
|
1-1-1-
|
2-2
|
|
625
TACACTTAATTATACTTCCA
1-2-1-
TacAcTtaattatacTtCCA
625_12
-21.63
30666
|
1-1-9-
|
1-1-3
|
|
625
TACACTTAATTATACTTCCA
1-1-1-
TaCactTaattatacttCCA
625_13
-21.86
30666
|
3-1-10-
|
3
|
|
625
TACACTTAATTATACTTCCA
2-1-2-
TAcACtTaattatacttcCA
625_14
-21.58
30666
|
1-1-11-
|
2
|
|
626
TTACACTTAATTATACTTCC
1-3-1-
TtacAcTtaattatACttCC
626_1
-19.98
30667
|
1-1-7-
|
2-2-2
|
|
626
TTACACTTAATTATACTTCC
1-5-1-
TtacacTtaattatAcTtCC
626_2
-18.96
30667
|
7-1-1-
|
1-1-2
|
|
626
TTACACTTAATTATACTTCC
2-4-1-
TTacacTtaattatacttCC
626_3
-19.49
30667
|
11-2
|
|
626
TTACACTTAATTATACTTCC
1-5-1-
TtacacTtaattatacTTCC
626_4
-20.26
30667
|
9-4
|
|
626
TTACACTTAATTATACTTCC
1-1-1-
TtAcacTtaattataCttCC
626_5
-19.43
30667
|
3-1-8-
|
1-2-2
|
|
626
TTACACTTAATTATACTTCC
1-1-2-
TtACacTtaattatActtCC
626_6
-19.72
30667
|
2-1-7-
|
1-3-2
|
|
626
TTACACTTAATTATACTTCC
3-1-1-
TTAcActtaattatactTCC
626_7
-21.33
30667
|
12-3
|
|
626
TTACACTTAATTATACTTCC
1-1-1-
TtAcAcTtaattatacTtCC
626_8
-19.10
30667
|
1-1-1-
|
1-9-1-
|
1-2
|
|
626
TTACACTTAATTATACTTCC
1-2-2-
TtaCAcTtaattatacttCC
626_9
-20.49
30667
|
1-1-11-
|
2
|
|
626
TTACACTTAATTATACTTCC
1-5-1-
TtacacTtaattatACtTCC
626_10
-20.82
30667
|
7-2-1-3
|
|
626
TTACACTTAATTATACTTCC
4-2-1-
TTACacTtaattatActtCC
626_11
-21.99
30667
|
7-1-3-2
|
|
626
TTACACTTAATTATACTTCC
1-1-1-
TtAcACTtaattataCttCC
626_12
-21.65
30667
|
1-3-8-
|
1-2-2
|
|
626
TTACACTTAATTATACTTCC
2-1-2-
TTaCActtaattatacTTCC
626_13
-23.23
30667
|
11-4
|
|
626
TTACACTTAATTATACTTCC
2-2-1-
TTacAcTtaattatacTtCC
626_14
-20.15
30667
|
1-1-9-
|
1-1-2
|
|
627
TTTACACTTAATTATACTTC
2-1-2-
TTtACacttaattAtACTTC
627_1
-20.02
30668
|
8-1-1-5
|
|
627
TTTACACTTAATTATACTTC
2-3-1-
TTtacActtaattATACtTC
627_2
-19.89
30668
|
7-4-1-2
|
|
627
TTTACACTTAATTATACTTC
1-2-1-
TttAcActtaattATaCTTC
627_3
-19.35
30668
|
1-1-7-
|
2-1-4
|
|
627
TTTACACTTAATTATACTTC
1-1-3-
TtTACacttaattATActTC
627_4
-20.58
30668
|
8-3-2-2
|
|
627
TTTACACTTAATTATACTTC
3-2-1-
TTTacActtaattATAcTTC
627_5
-20.76
30668
|
7-3-1-3
|
|
627
TTTACACTTAATTATACTTC
1-3-2-
TttaCActtaattATacTTC
627_6
-19.58
30668
|
7-2-2-3
|
|
627
TTTACACTTAATTATACTTC
3-2-1-
TTTacActtaattATaCTTC
627_7
-21.21
30668
|
7-2-1-4
|
|
627
TTTACACTTAATTATACTTC
3-1-1-
TTTaCacttaattAtaCTTC
627_8
-20.07
30668
|
8-1-2-4
|
|
627
TTTACACTTAATTATACTTC
6-7-1-
TTTACActtaattAtactTC
627_9
-20.56
30668
|
4-2
|
|
627
TTTACACTTAATTATACTTC
4-1-1-
TTTAcActtaattATACtTC
627_10
-22.36
30668
|
7-4-1-2
|
|
627
TTTACACTTAATTATACTTC
3-1-1-
TTTaCaCttaattATAcTTC
627_11
-22.29
30668
|
1-1-6-
|
3-1-3
|
|
627
TTTACACTTAATTATACTTC
2-1-3-
TTtACActtaattATActTC
627_12
-21.19
30668
|
7-3-2-2
|
|
627
TTTACACTTAATTATACTTC
3-1-2-
TTTaCActtaattATaCTTC
627_13
-23.30
30668
|
7-2-1-4
|
|
627
TTTACACTTAATTATACTTC
1-1-4-
TtTACActtaattAtaCTTC
627_14
-21.94
30668
|
7-1-2-4
|
|
628
ATTTACACTTAATTATACTT
2-1-1-
ATtTacActtaatTATaCTT
628_1
-21.21
30669
|
2-1-6-
|
3-1-3
|
|
628
ATTTACACTTAATTATACTT
3-1-1-
ATTtAcacttaatTAtACTT
628_2
-20.27
30669
|
8-2-1-4
|
|
628
ATTTACACTTAATTATACTT
1-1-2-
AtTTacActtaatTATAcTT
628_3
-20.33
30669
|
2-1-6-
|
4-1-2
|
|
628
ATTTACACTTAATTATACTT
1-3-1-
AtttAcActtaattATACTT
628_4
-19.30
30669
|
1-1-7-6
|
|
628
ATTTACACTTAATTATACTT
2-2-2-
ATttACacttaatTATacTT
628_5
-19.94
30669
|
7-3-2-2
|
|
628
ATTTACACTTAATTATACTT
4-1-2-
ATTTaCActtaatTAtacTT
628_6
-21.29
30669
|
6-2-3-2
|
|
628
ATTTACACTTAATTATACTT
1-1-4-
AtTTACacttaatTaTacTT
628_7
-19.33
30669
|
7-1-1-
|
1-2-2
|
|
628
ATTTACACTTAATTATACTT
2-2-3-
ATttACActtaatTatACTT
628_8
-20.97
30669
|
6-1-2-4
|
|
628
ATTTACACTTAATTATACTT
4-2-1-
ATTTacActtaatTataCTT
628_9
-19.73
30669
|
6-1-3-3
|
|
628
ATTTACACTTAATTATACTT
1-1-2-
AtTTaCActtaatTATAcTT
628_10
-22.43
30669
|
1-2-6-
|
4-1-2
|
|
628
ATTTACACTTAATTATACTT
3-2-2-
ATTtaCActtaatTAtaCTT
628_11
-21.72
30669
|
6-2-2-3
|
|
628
ATTTACACTTAATTATACTT
1-2-4-
AttTACActtaatTAtaCTT
628_12
-22.02
30669
|
6-2-2-3
|
|
628
ATTTACACTTAATTATACTT
2-1-1-
ATtTaCActtaatTaTACTT
628_13
-23.00
30669
|
1-2-6-
|
1-1-5
|
|
628
ATTTACACTTAATTATACTT
5-8-1-
ATTTAcacttaatTaTaCTT
628_14
-21.68
30669
|
1-1-1-3
|
|
629
TTCTACTATACTTTCCTCT
1-3-1-
TtctActatactTtCctCT
629_1
-21.04
30711
|
7-1-1-
|
1-2-2
|
|
629
TTCTACTATACTTTCCTCT
1-11-
TtctactatactTtCctCT
629_2
-20.85
30711
|
1-1-1-
|
2-2
|
|
629
TTCTACTATACTTTCCTCT
1-11-
TtctactatactTtcCtCT
629_3
-20.97
30711
|
1-2-1-
|
1-2
|
|
629
TTCTACTATACTTTCCTCT
1-1-1-
TtCtactatactTtcctCT
629_4
-21.06
30711
|
9-1-4-2
|
|
629
TTCTACTATACTTTCCTCT
1-1-1-
TtCtactatactttCctCT
629_5
-21.53
30711
|
11-1-2-
|
2
|
|
629
TTCTACTATACTTTCCTCT
1-3-1-
TtctActatactttCctCT
629_6
-20.74
30711
|
9-1-2-2
|
|
629
TTCTACTATACTTTCCTCT
1-4-1-
TtctaCtatactttCctCT
629_7
-21.54
30711
|
8-1-2-2
|
|
629
TTCTACTATACTTTCCTCT
1-13-
TtctactatactttCctCT
629_8
-20.55
30711
|
1-2-2
|
|
629
TTCTACTATACTTTCCTCT
1-1-1-
TtCtactatactttcCtCT
629_9
-21.65
30711
|
12-1-1-
|
2
|
|
629
TTCTACTATACTTTCCTCT
1-3-1-
TtctActatactttcCtCT
629_10
-20.86
30711
|
10-1-1-
|
2
|
|
629
TTCTACTATACTTTCCTCT
1-14-
TtctactatactttcCtCT
629_11
-20.67
30711
|
1-1-2
|
|
629
TTCTACTATACTTTCCTCT
1-1-1-
TtCtActatactTtCctCT
629_12
-22.02
30711
|
1-1-7-
|
1-1-1-
|
2-2
|
|
629
TTCTACTATACTTTCCTCT
1-1-1-
TtCtaCtatactttCctCT
629_13
-22.52
30711
|
2-1-8-
|
1-2-2
|
|
629
TTCTACTATACTTTCCTCT
1-3-2-
TtctACtatactttCctCT
629_14
-22.14
30711
|
8-1-2-2
|
|
629
TTCTACTATACTTTCCTCT
1-1-1-
TtCtActatactttcCtCT
629_15
-21.84
30711
|
1-1-10-
|
1-1-2
|
|
629
TTCTACTATACTTTCCTCT
1-1-1-
TtCtaCtatactttcCtCT
629_16
-22.64
30711
|
2-1-9-
|
1-1-2
|
|
630
GTTCTACTATACTTTCCTC
1-12-
GttctactatactTtCcTC
630_1
-20.78
30712
|
1-1-1-
|
1-2
|
|
630
GTTCTACTATACTTTCCTC
1-4-1-
GttctActatactttCcTC
630_2
-20.67
30712
|
9-1-1-2
|
|
630
GTTCTACTATACTTTCCTC
1-14-
GttctactatactttCcTC
630_3
-20.48
30712
|
1-1-2
|
|
631
GTTCTACTATACTTTCCT
1-2-1-
GttCtActatactTtcCT
631_1
-20.25
30713
|
1-1-7-
|
1-2-2
|
|
631
GTTCTACTATACTTTCCT
1-2-1-
GttCtactatactTtcCT
631_2
-20.06
30713
|
9-1-2-2
|
|
631
GTTCTACTATACTTTCCT
1-2-1-
GttCtactatactttCCT
631_3
-22.13
30713
|
11-3
|
|
631
GTTCTACTATACTTTCCT
1-4-1-
GttctActatactttCCT
631_4
-21.34
30713
|
9-3
|
|
631
GTTCTACTATACTTTCCT
1-14-3
GttctactatactttCCT
631_5
-21.15
30713
|
|
631
GTTCTACTATACTTTCCT
2-1-1-
GTtCtActatactttcCT
631_6
-21.50
30713
|
1-1-10-
|
2
|
|
631
GTTCTACTATACTTTCCT
2-1-1-
GTtCtactatactttcCT
631_7
-21.30
30713
|
12-2
|
|
631
GTTCTACTATACTTTCCT
1-2-1-
GttCtActatactttcCT
631_8
-19.95
30713
|
1-1-10-
|
2
|
|
631
GTTCTACTATACTTTCCT
1-2-1-
GttCtactatactttcCT
631_9
-19.76
30713
|
12-2
|
|
631
GTTCTACTATACTTTCCT
1-15-2
GttctactatactttcCT
631_10
-18.78
30713
|
|
631
GTTCTACTATACTTTCCT
1-2-1-
GttCtactatactTtCCT
631_11
-22.43
30713
|
9-1-1-3
|
|
631
GTTCTACTATACTTTCCT
2-1-1-
GTtCtActatactTtcCT
631_12
-21.80
30713
|
1-1-7-
|
1-2-2
|
|
631
GTTCTACTATACTTTCCT
1-2-2-
GttCTactatactTtcCT
631_13
-21.68
30713
|
8-1-2-2
|
|
631
GTTCTACTATACTTTCCT
1-2-1-
GttCtActatactttCCT
631_14
-22.32
30713
|
1-1-9-3
|
|
631
GTTCTACTATACTTTCCT
1-2-3-
GttCTActatactttcCT
631_15
-22.60
30713
|
10-2
|
|
632
AGTTCTACTATACTTTCC
1-12-
AgttctactatacTttCC
632_1
-19.37
30714
|
1-2-2
|
|
632
AGTTCTACTATACTTTCC
1-13-
AgttctactatactTtCC
632_2
-19.16
30714
|
1-1-2
|
|
632
AGTTCTACTATACTTTCC
1-1-1-
AgTtctactatactttCC
632_3
-19.51
30714
|
13-2
|
|
632
AGTTCTACTATACTTTCC
1-15-2
AgttctactatactttCC
632_4
-18.86
30714
|
|
632
AGTTCTACTATACTTTCC
1-1-1-
AgTtctactatacTttCC
632_5
-20.03
30714
|
10-1-2-
|
2
|
|
632
AGTTCTACTATACTTTCC
1-4-1-
AgttcTactatacTttCC
632_6
-20.31
30714
|
7-1-2-2
|
|
632
AGTTCTACTATACTTTCC
2-14-2
AGttctactatactttCC
632_7
-20.26
30714
|
|
632
AGTTCTACTATACTTTCC
1-2-1-
AgtTctactatactttCC
632_8
-19.23
30714
|
12-2
|
|
632
AGTTCTACTATACTTTCC
1-4-1-
AgttcTactatactttCC
632_9
-19.80
30714
|
10-2
|
|
632
AGTTCTACTATACTTTCC
2-10-1-
AGttctactataCtttCC
632_10
-21.25
30714
|
3-2
|
|
632
AGTTCTACTATACTTTCC
1-4-1-
AgttcTactataCtttCC
632_11
-20.79
30714
|
6-1-3-2
|
|
632
AGTTCTACTATACTTTCC
1-4-1-
AgttcTactatacTTtCC
632_12
-21.13
30714
|
7-2-1-2
|
|
632
AGTTCTACTATACTTTCC
1-1-1-
AgTtctactatactTtCC
632_13
-19.82
30714
|
11-1-1-
|
2
|
|
632
AGTTCTACTATACTTTCC
1-3-1-
AgttCtactatactttCC
632_14
-19.83
30714
|
11-2
|
|
633
CAACATTATTAACCACCTTA
1-13-
CaacattattaaccACCtTA
633_1
-22.44
33376
|
3-1-2
|
|
633
CAACATTATTAACCACCTTA
4-10-
CAACattattaaccAccTTA
633_2
-22.98
33376
|
1-2-3
|
|
633
CAACATTATTAACCACCTTA
2-2-1-
CAacAttattaaccaCcTTA
633_3
-21.97
33376
|
10-1-1-
|
3
|
|
633
CAACATTATTAACCACCTTA
1-4-2-
CaacaTTattaaccaCctTA
633_4
-21.08
33376
|
8-1-2-2
|
|
633
CAACATTATTAACCACCTTA
1-1-2-
CaACattattaaccaCctTA
633_5
-20.90
33376
|
11-1-2-
|
2
|
|
633
CAACATTATTAACCACCTTA
1-2-2-
CaaCAttattaaccacctTA
633_6
-20.76
33376
|
13-2
|
|
633
CAACATTATTAACCACCTTA
1-1-1-
CaAcAttattaaccacCtTA
633_7
-19.97
33376
|
1-1-11-
|
1-1-2
|
|
633
CAACATTATTAACCACCTTA
1-15-4
CaacattattaaccacCTTA
633_8
-21.21
33376
|
|
633
CAACATTATTAACCACCTTA
2-4-1-
CAacatTattaaccacctTA
633_9
-20.83
33376
|
11-2
|
|
634
CAACATTATTAACCACCTT
2-10-
CAacattattaaCCaccTT
634_1
-21.86
33377
|
2-3-2
|
|
634
CAACATTATTAACCACCTT
1-14-4
CaacattattaaccaCCTT
634_2
-21.36
33377
|
|
634
CAACATTATTAACCACCTT
1-1-1-
CaAcattattaaccAcCTT
634_3
-19.54
33377
|
11-1-1-
|
3
|
|
634
CAACATTATTAACCACCTT
3-1-1-
CAAcAttattaaccacCTT
634_4
-21.13
33377
|
11-3
|
|
634
CAACATTATTAACCACCTT
3-11-
CAAcattattaaccACcTT
634_5
-20.84
33377
|
2-1-2
|
|
634
CAACATTATTAACCACCTT
2-1-2-
CAaCAttattaaccAcCTT
634_6
-22.76
33377
|
9-1-1-3
|
|
634
CAACATTATTAACCACCTT
2-1-2-
CAaCAttattaaccaCcTT
634_7
-21.83
33377
|
10-1-1-
|
2
|
|
634
CAACATTATTAACCACCTT
1-1-2-
CaACattattaaccaCcTT
634_8
-19.70
33377
|
11-1-1-
|
2
|
|
634
CAACATTATTAACCACCTT
1-2-1-
CaaCattattaaccacCTT
634_9
-19.66
33377
|
12-3
|
|
635
GCAACATTATTAACCACCT
1-1-1-
GcAacAttattaACcacCT
635_1
-21.56
33378
|
2-1-6-
|
2-3-2
|
|
635
GCAACATTATTAACCACCT
1-1-2-
GcAAcAttattaAccAcCT
635_2
-21.14
33378
|
1-1-6-
|
1-2-1-
|
1-2
|
|
635
GCAACATTATTAACCACCT
1-11-
GcaacattattaACcAcCT
635_3
-21.59
33378
|
2-1-1-
|
1-2
|
|
635
GCAACATTATTAACCACCT
1-4-1-
GcaacAttattaAccaCCT
635_4
-22.69
33378
|
6-1-3-3
|
|
635
GCAACATTATTAACCACCT
1-1-1-
GcAaCattattaAccacCT
635_5
-21.01
33378
|
1-1-7-
|
1-4-2
|
|
635
GCAACATTATTAACCACCT
1-11-
GcaacattattaAcCacCT
635_6
-20.83
33378
|
1-1-1-
|
2-2
|
|
635
GCAACATTATTAACCACCT
2-3-1-
GCaacAttattaAccacCT
635_7
-22.63
33378
|
6-1-4-2
|
|
635
GCAACATTATTAACCACCT
1-1-1-
GcAacattattaaccAcCT
635_8
-20.05
33378
|
12-1-1-
|
2
|
|
635
GCAACATTATTAACCACCT
1-2-1-
GcaAcAttattaaccacCT
635_9
-20.30
33378
|
1-1-11-
|
2
|
|
636
AGCAACATTATTAACCACC
1-2-1-
AgcAacattattaACcACC
636_1
-22.13
33379
|
9-2-1-3
|
|
636
AGCAACATTATTAACCACC
1-11-
AgcaacattattAaCcaCC
636_2
-20.80
33379
|
1-1-1-
|
2-2
|
|
636
AGCAACATTATTAACCACC
1-4-1-
AgcaaCattattAAccaCC
636_3
-21.32
33379
|
6-2-3-2
|
|
636
AGCAACATTATTAACCACC
1-2-2-
AgcAAcattattAacCaCC
636_4
-21.29
33379
|
7-1-2-
|
1-1-2
|
|
636
AGCAACATTATTAACCACC
2-11-
AGcaacattattaAccaCC
636_5
-21.75
33379
|
1-3-2
|
|
636
AGCAACATTATTAACCACC
1-1-1-
AgCaAcattattaAccACC
636_6
-22.16
33379
|
1-1-8-
|
1-2-3
|
|
636
AGCAACATTATTAACCACC
1-2-1-
AgcAaCattattAaccACC
636_7
-21.33
33379
|
1-1-6-
|
1-3-3
|
|
636
AGCAACATTATTAACCACC
2-1-2-
AGcAAcattattaaccaCC
636_8
-22.02
33379
|
12-2
|
|
636
AGCAACATTATTAACCACC
1-15-3
AgcaacattattaaccACC
636_9
-20.45
33379
|
|
637
AGCAACATTATTAACCAC
2-1-1-
AGcAacattattaACCAC
637_1
-21.97
33380
|
9-5
|
|
637
AGCAACATTATTAACCAC
1-3-1-
AgcaAcattattAACCAC
637_2
-21.20
33380
|
7-6
|
|
637
AGCAACATTATTAACCAC
2-10-
AGcaacattattAAcCAC
637_3
-19.42
33380
|
2-1-3
|
|
637
AGCAACATTATTAACCAC
1-2-1-
AgcAacattattAaCCAC
637_4
-19.84
33380
|
8-1-1-4
|
|
637
AGCAACATTATTAACCAC
3-9-3-
AGCaacattattAACcAC
637_5
-20.94
33380
|
1-2
|
|
637
AGCAACATTATTAACCAC
1-1-3-
AgCAAcattattAACcAC
637_6
-20.15
33380
|
7-3-1-2
|
|
637
AGCAACATTATTAACCAC
1-1-3-
AgCAAcattattAAcCAC
637_7
-20.96
33380
|
7-2-1-3
|
|
637
AGCAACATTATTAACCAC
5-7-1-
AGCAAcattattAaccAC
637_8
-21.24
33380
|
3-2
|
|
637
AGCAACATTATTAACCAC
3-1-1-
AGCaAcattattaAccAC
637_9
-19.86
33380
|
8-1-2-2
|
|
638
GTTTCCATCTACTATTAAT
1-3-1-
GtttCcatctacTaTtAAT
638_1
-19.59
39806
|
7-1-1-
|
1-1-3
|
|
638
GTTTCCATCTACTATTAAT
1-1-1-
GtTtccatctacTAttaAT
638_2
-19.50
39806
|
9-2-3-2
|
|
638
GTTTCCATCTACTATTAAT
1-4-1-
GtttcCatctacTAttAAT
638_3
-20.09
39806
|
6-2-2-3
|
|
638
GTTTCCATCTACTATTAAT
1-3-1-
GtttCcatctactAttAAT
638_4
-18.30
39806
|
8-1-2-3
|
|
638
GTTTCCATCTACTATTAAT
3-1-1-
GTTtCcatctactAttaAT
638_5
-20.35
39806
|
8-1-3-2
|
|
638
GTTTCCATCTACTATTAAT
1-2-2-
GttTCcatctactattaAT
638_6
-18.88
39806
|
12-2
|
|
638
GTTTCCATCTACTATTAAT
1-1-1-
GtTtccatctactaTtAAT
638_7
-18.18
39806
|
11-1-1-
|
3
|
|
638
GTTTCCATCTACTATTAAT
2-2-1-
GTttCcatctactatTaAT
638_8
-20.16
39806
|
10-1-1-
|
2
|
|
638
GTTTCCATCTACTATTAAT
1-1-1-
GtTtCCatctactattAAT
638_9
-20.69
39806
|
1-2-10-
|
3
|
|
638
GTTTCCATCTACTATTAAT
2-2-1-
GTttCcatctacTattAAT
638_10
-20.69
39806
|
7-1-3-3
|
|
638
GTTTCCATCTACTATTAAT
1-1-1-
GtTtccatctactATtAAT
638_11
-19.08
39806
|
10-2-1-
|
3
|
|
638
GTTTCCATCTACTATTAAT
1-3-1-
GtttCcatctactAtTaAT
638_12
-18.72
39806
|
8-1-1-
|
1-1-2
|
|
638
GTTTCCATCTACTATTAAT
1-2-3-
GttTCCatctactAttAAT
638_13
-21.47
39806
|
7-1-2-3
|
|
638
GTTTCCATCTACTATTAAT
1-1-1-
GtTtCCatctactattaAT
638_14
-20.37
39806
|
1-2-11-
|
2
|
|
639
GTTTCCATCTACTATTAA
1-11-
GtttccatctacTAtTAA
639_1
-19.21
39807
|
2-1-3
|
|
639
GTTTCCATCTACTATTAA
1-3-1-
GtttCcatctacTaTTAA
639_2
-19.80
39807
|
7-1-1-4
|
|
639
GTTTCCATCTACTATTAA
3-1-1-
GTTtCcatctacTAttAA
639_3
-20.57
39807
|
7-2-2-2
|
|
639
GTTTCCATCTACTATTAA
2-2-1-
GTttCcatctacTaTtAA
639_4
-19.07
39807
|
7-1-1-
|
1-1-2
|
|
639
GTTTCCATCTACTATTAA
1-3-2-
GtttCCatctactATtAA
639_5
-19.67
39807
|
7-2-1-2
|
|
639
GTTTCCATCTACTATTAA
3-2-1-
GTTtcCatctacTattAA
639_6
-19.25
39807
|
6-1-3-2
|
|
639
GTTTCCATCTACTATTAA
1-1-3-
GtTTCcatctactAttAA
639_7
-18.04
39807
|
8-1-2-2
|
|
639
GTTTCCATCTACTATTAA
1-1-1-
GtTtCCatctactattAA
639_8
-18.62
39807
|
1-2-10-
|
2
|
|
639
GTTTCCATCTACTATTAA
3-1-1-
GTTtCcatctactaTTAA
639_9
-21.21
39807
|
9-4
|
|
639
GTTTCCATCTACTATTAA
1-3-2-
GtttCCatctacTAttAA
639_10
-20.39
39807
|
6-2-2-2
|
|
639
GTTTCCATCTACTATTAA
1-1-3-
GtTTCcatctacTaTtAA
639_11
-19.32
39807
|
7-1-1-
|
1-1-2
|
|
639
GTTTCCATCTACTATTAA
2-2-1-
GTttCcatctacTatTAA
639_12
-20.39
39807
|
7-1-2-3
|
|
639
GTTTCCATCTACTATTAA
2-2-1-
GTttCcatctactATtAA
639_13
-19.03
39807
|
8-2-1-2
|
|
639
GTTTCCATCTACTATTAA
1-1-1-
GtTtCCatctactaTTAA
639_14
-21.34
39807
|
1-2-8-4
|
|
640
TGTTTCCATCTACTATTA
1-1-1-
TgTttccatctactAtTA
640_1
-18.41
39808
|
11-1-1-
|
2
|
|
640
TGTTTCCATCTACTATTA
1-2-1-
TgtTtccatctacTAtTA
640_2
-20.03
39808
|
9-2-1-2
|
|
640
TGTTTCCATCTACTATTA
1-4-1-
TgtttCcatctacTatTA
640_3
-19.37
39808
|
7-1-2-2
|
|
640
TGTTTCCATCTACTATTA
1-4-1-
TgtttCcatctactATTA
640_4
-20.28
39808
|
8-4
|
|
640
TGTTTCCATCTACTATTA
1-4-1-
TgtttCcatctactAtTA
640_5
-18.52
39808
|
8-1-1-2
|
|
640
TGTTTCCATCTACTATTA
1-1-2-
TgTTtCcatctactatTA
640_6
-19.89
39808
|
1-1-10-
|
2
|
|
640
TGTTTCCATCTACTATTA
1-4-1-
TgtttCcatctactaTTA
640_7
-19.37
39808
|
9-3
|
|
640
TGTTTCCATCTACTATTA
1-2-1-
TgtTtCcatctactatTA
640_8
-18.73
39808
|
1-1-10-
|
2
|
|
640
TGTTTCCATCTACTATTA
1-4-1-
TgtttCcatctactatTA
640_9
-18.42
39808
|
10-2
|
|
640
TGTTTCCATCTACTATTA
1-4-1-
TgtttCcatctaCtATTA
640_10
-21.27
39808
|
6-1-1-4
|
|
640
TGTTTCCATCTACTATTA
2-1-1-
TGtTtccatctacTAtTA
640_11
-21.24
39808
|
9-2-1-2
|
|
640
TGTTTCCATCTACTATTA
1-3-2-
TgttTCcatctactAtTA
640_12
-19.51
39808
|
8-1-1-2
|
|
640
TGTTTCCATCTACTATTA
2-1-1-
TGtTtCcatctactatTA
640_13
-19.94
39808
|
1-1-10-
|
2
|
|
640
TGTTTCCATCTACTATTA
1-1-1-
TgTttCcatctactatTA
640_14
-19.08
39808
|
2-1-10-
|
2
|
|
641
ACTCTGCAATACACCAA
2-1-1-
ACtCtgcaatacACcAA
641_1
-19.61
44439
|
8-2-1-2
|
|
641
ACTCTGCAATACACCAA
2-2-1-
ACtcTgcaataCaCcAA
641_2
-19.77
44439
|
6-1-1-
|
1-1-2
|
|
641
ACTCTGCAATACACCAA
1-2-1-
ActCtgcaataCaCcAA
641_3
-18.35
44439
|
7-1-1-
|
1-1-2
|
|
641
ACTCTGCAATACACCAA
2-1-2-
ACtCTgcaataCAccAA
641_4
-22.21
44439
|
6-2-2-2
|
|
641
ACTCTGCAATACACCAA
1-3-1-
ActcTgcaatacAcCAA
641_5
-19.05
44439
|
7-1-1-3
|
|
641
ACTCTGCAATACACCAA
4-8-1-
ACTCtgcaatacAccAA
641_6
-20.30
44439
|
2-2
|
|
641
ACTCTGCAATACACCAA
2-1-2-
ACtCTgcaatacacCAA
641_7
-21.96
44439
|
9-3
|
|
641
ACTCTGCAATACACCAA
2-11-4
ACtctgcaatacaCCAA
641_8
-21.68
44439
|
|
641
ACTCTGCAATACACCAA
1-1-2-
AcTCtgcaatacacCAA
641_9
-20.07
44439
|
10-3
|
|
642
CTGTATACACCATCCCA
1-10-
CtgtatacaccAtCcCA
642_1
-21.99
46391
|
1-1-1-
|
1-2
|
|
642
CTGTATACACCATCCCA
1-10-
CtgtatacaccAtccCA
642_2
-21.22
46391
|
1-3-2
|
|
642
CTGTATACACCATCCCA
1-1-1-
CtGtatacaccAtccCA
642_3
-21.53
46391
|
8-1-3-2
|
|
642
CTGTATACACCATCCCA
1-2-1-
CtgTatacaccAtccCA
642_4
-22.31
46391
|
7-1-3-2
|
|
642
CTGTATACACCATCCCA
1-3-1-
CtgtAtacaccAtccCA
642_5
-21.32
46391
|
6-1-3-2
|
|
642
CTGTATACACCATCCCA
1-11-
CtgtatacaccaTCcCA
642_6
-23.06
46391
|
2-1-2
|
|
642
CTGTATACACCATCCCA
1-1-1-
CtGtAtacaccatCcCA
642_7
-22.35
46391
|
1-1-8-
|
1-1-2
|
|
642
CTGTATACACCATCCCA
1-1-1-
CtGtatacaccatCcCA
642_8
-22.25
46391
|
10-1-1-
|
2
|
|
642
CTGTATACACCATCCCA
1-2-1-
CtgTatacaccatCcCA
642_9
-23.02
46391
|
9-1-1-2
|
|
642
CTGTATACACCATCCCA
1-3-1-
CtgtAtacaccatCcCA
642_10
-22.04
46391
|
8-1-1-2
|
|
642
CTGTATACACCATCCCA
1-12-
CtgtatacaccatCcCA
642_11
-21.94
46391
|
1-1-2
|
|
642
CTGTATACACCATCCCA
2-2-1-
CTgtAtacaccatccCA
642_12
-22.95
46391
|
10-2
|
|
642
CTGTATACACCATCCCA
1-1-1-
CtGtAtacaccatccCA
642_13
-21.58
46391
|
1-1-10-
|
2
|
|
642
CTGTATACACCATCCCA
1-1-1-
CtGtatacaccatccCA
642_14
-21.48
46391
|
12-2
|
|
642
CTGTATACACCATCCCA
1-2-2-
CtgTAtacaccatccCA
642_15
-23.39
46391
|
10-2
|
|
642
CTGTATACACCATCCCA
1-3-1-
CtgtAtacaccatccCA
642_16
-21.27
46391
|
10-2
|
|
642
CTGTATACACCATCCCA
1-14-2
CtgtatacaccatccCA
642_17
-21.17
46391
|
|
642
CTGTATACACCATCCCA
1-3-1-
CtgtAtacaccATCcCA
642_18
-24.02
46391
|
6-3-1-2
|
|
642
CTGTATACACCATCCCA
1-1-1-
CtGtatacaccAtCcCA
642_19
-22.30
46391
|
8-1-1-
|
1-1-2
|
|
642
CTGTATACACCATCCCA
1-1-3-
CtGTAtacaccAtccCA
642_20
-24.64
46391
|
6-1-3-2
|
|
642
CTGTATACACCATCCCA
2-2-1-
CTgtAtacaccatCcCA
642_21
-23.72
46391
|
8-1-1-2
|
|
642
CTGTATACACCATCCCA
1-3-1-
CtgtAtacaccatcCCA
642_22
-23.55
46391
|
9-3
|
|
643
TCTGTATACACCATCCCA
1-4-1-
TctgtAtacaccatCcCA
643_1
-22.94
46391
|
8-1-1-2
|
|
644
TCTGTATACACCATCCC
2-10-
TCtgtatacaccAtcCC
644_1
-22.70
46392
|
1-2-2
|
|
644
TCTGTATACACCATCCC
1-11-
TctgtatacaccAtcCC
644_2
-21.11
46392
|
1-2-2
|
|
644
TCTGTATACACCATCCC
2-1-1-
TCtGtatacaccatcCC
644_3
-22.96
46392
|
11-2
|
|
644
TCTGTATACACCATCCC
2-13-2
TCtgtatacaccatcCC
644_4
-22.65
46392
|
|
644
TCTGTATACACCATCCC
3-9-1-
TCTgtatacaccAtcCC
644_5
-24.39
46392
|
2-2
|
|
644
TCTGTATACACCATCCC
2-1-1-
TCtGtatacaccAtcCC
644_6
-23.01
46392
|
8-1-2-2
|
|
645
TTCTGTATACACCATCCC
1-11-
TtctgtatacacCatcCC
645_1
-22.57
46392
|
1-3-2
|
|
645
TTCTGTATACACCATCCC
1-1-1-
TtCtgtatacaccAtcCC
645_2
-23.02
46392
|
10-1-2-
|
2
|
|
645
TTCTGTATACACCATCCC
1-3-1-
TtctGtatacaccAtcCC
645_3
-22.36
46392
|
8-1-2-2
|
|
645
TTCTGTATACACCATCCC
1-12-
TtctgtatacaccAtcCC
645_4
-22.05
46392
|
1-2-2
|
|
645
TTCTGTATACACCATCCC
1-15-2
TtctgtatacaccatcCC
645_5
-22.00
46392
|
|
645
TTCTGTATACACCATCCC
1-4-1-
TtctgTatacacCAtcCC
645_6
-25.12
46392
|
6-2-2-2
|
|
645
TTCTGTATACACCATCCC
1-3-1-
TtctGtatacaccAtCCC
645_7
-24.73
46392
|
8-1-1-3
|
|
645
TTCTGTATACACCATCCC
3-10-1-
TTCtgtatacaccAtcCC
645_8
-24.52
46392
|
2-2
|
|
645
TTCTGTATACACCATCCC
1-1-2-
TtCTgtatacaccAtcCC
645_9
-24.71
46392
|
9-1-2-2
|
|
645
TTCTGTATACACCATCCC
1-1-1-
TtCtGtatacaccAtcCC
645_10
-23.34
46392
|
1-1-8-
|
1-2-2
|
|
646
TTCTGTATACACCATCC
1-10-
TtctgtatacaCcatCC
646_1
-19.96
46393
|
1-3-2
|
|
646
TTCTGTATACACCATCC
1-12-4
TtctgtatacaccATCC
646_2
-21.16
46393
|
|
646
TTCTGTATACACCATCC
2-11-
TTctgtatacaccAtCC
646_3
-20.11
46393
|
1-1-2
|
|
646
TTCTGTATACACCATCC
1-2-1-
TtcTgtatacaccAtCC
646_4
-20.24
46393
|
9-1-1-2
|
|
646
TTCTGTATACACCATCC
1-3-1-
TtctGtatacaccAtCC
646_5
-19.54
46393
|
8-1-1-2
|
|
646
TTCTGTATACACCATCC
1-2-1-
TtcTgtatacacCatCC
646_6
-20.77
46393
|
8-1-2-2
|
|
646
TTCTGTATACACCATCC
1-12-
TtctgtatacaccAtCC
646_7
-19.23
46393
|
1-1-2
|
|
646
TTCTGTATACACCATCC
1-3-1-
TtctGtatacacCaTCC
646_8
-21.19
46393
|
7-1-1-3
|
|
646
TTCTGTATACACCATCC
1-1-1-
TtCtGtatacaccatCC
646_9
-20.47
46393
|
1-1-10-
|
2
|
|
646
TTCTGTATACACCATCC
1-1-1-
TtCtgtatacaccatCC
646_10
-20.16
46393
|
12-2
|
|
646
TTCTGTATACACCATCC
1-1-1-
TtCtgtatacaccaTCC
646_11
-21.28
46393
|
11-3
|
|
646
TTCTGTATACACCATCC
1-3-1-
TtctGtatacaccaTCC
646_12
-20.61
46393
|
9-3
|
|
646
TTCTGTATACACCATCC
1-13-3
TtctgtatacaccaTCC
646_13
-20.30
46393
|
|
646
TTCTGTATACACCATCC
3-1-1-
TTCtGtatacaccatCC
646_14
-21.96
46393
|
10-2
|
|
646
TTCTGTATACACCATCC
3-12-2
TTCtgtatacaccatCC
646_15
-21.65
46393
|
|
646
TTCTGTATACACCATCC
1-1-2-
TtCTgtatacaccatCC
646_16
-21.84
46393
|
11-2
|
|
646
TTCTGTATACACCATCC
1-2-1-
TtcTgtatacaccatCC
646_17
-20.19
46393
|
11-2
|
|
646
TTCTGTATACACCATCC
1-3-1-
TtctGtatacaccatCC
646_18
-19.49
46393
|
10-2
|
|
646
TTCTGTATACACCATCC
1-14-2
TtctgtatacaccatCC
646_19
-19.18
46393
|
|
646
TTCTGTATACACCATCC
3-8-1-
TTCtgtatacaCcatCC
646_20
-22.44
46393
|
3-2
|
|
646
TTCTGTATACACCATCC
1-3-1-
TtctGtatacaCcatCC
646_21
-20.27
46393
|
6-1-3-2
|
|
646
TTCTGTATACACCATCC
1-3-1-
TtctGtatacacCAtCC
646_22
-21.53
46393
|
7-2-1-2
|
|
646
TTCTGTATACACCATCC
1-1-1-
TtCtgtatacacCatCC
646_23
-20.74
46393
|
9-1-2-2
|
|
646
TTCTGTATACACCATCC
1-1-1-
TtCtgtatacaccAtCC
646_24
-20.21
46393
|
10-1-1-
|
2
|
|
647
AGCTTTTAACCAGAGT
2-10-4
AGcttttaaccaGAGT
647_1
-21.73
EX-EX
|
|
648
AGCTTTTAACCAGAGTG
2-11-4
AGcttttaaccagAGTG
648_1
-22.27
EX-EX
|
|
649
AGCTTTTAACCAGAGTGG
1-14-3
AgcttttaaccagagTGG
649_1
-21.63
EX-EX
|
|
650
AGCTTTTAACCAGAGTGGC
1-16-2
AgcttttaaccagagtgGC
650_1
-23.20
EX-EX
|
|
651
AGCTTTTAACCAGAGTGGCA
1-17-2
AgcttttaaccagagtggCA
651_1
-24.11
EX-EX
|
|
652
CAGCTTTTAACCAGAGT
2-12-3
CAgcttttaaccagAGT
652_1
-21.65
EX-EX
|
|
653
CAGCTTTTAACCAGAGTG
3-13-2
CAGcttttaaccagagTG
653_1
-22.27
EX-EX
|
|
654
CAGCTTTTAACCAGAGTGG
1-15-3
CagcttttaaccagagTGG
654_1
-22.97
EX-EX
|
|
655
CAGCTTTTAACCAGAGTGGC
1-17-2
CagcttttaaccagagtgGC
655_1
-24.53
EX-EX
|
|
656
CTTTTAACCAGAGTG
4-7-4
CTTTtaaccagAGTG
656_1
-20.12
EX-EX
|
|
657
CTTTTAACCAGAGTGG
4-9-3
CTTTtaaccagagTGG
657_1
-20.92
EX-EX
|
|
658
CTTTTAACCAGAGTGGC
4-11-2
CTTTtaaccagagtgGC
658_1
-22.48
EX-EX
|
|
659
CTTTTAACCAGAGTGGCA
1-14-3
CttttaaccagagtgGCA
659_1
-22.96
EX-EX
|
|
660
CTTTTAACCAGAGTGGCAT
3-13-3
CTTttaaccagagtggCAT
660_1
-24.65
EX-EX
|
|
661
CTTTTAACCAGAGTGGCATC
2-16-2
CTtttaaccagagtggcaTC
661_1
-23.19
EX-EX
|
|
662
GCTTTTAACCAGAGT
3-9-3
GCTtttaaccagAGT
662_1
-21.02
EX-EX
|
|
663
GCTTTTAACCAGAGTG
4-10-2
GCTTttaaccagagTG
663_1
-21.02
EX-EX
|
|
664
GCTTTTAACCAGAGTGG
1-12-4
GcttttaaccagaGTGG
664_1
-22.24
EX-EX
|
|
665
GCTTTTAACCAGAGTGGC
1-14-3
GcttttaaccagagtGGC
665_1
-23.42
EX-EX
|
|
666
GCTTTTAACCAGAGTGGCA
1-16-2
GcttttaaccagagtggCA
666_1
-22.94
EX-EX
|
|
667
GCTTTTAACCAGAGTGGCAT
1-16-3
GcttttaaccagagtggCAT
667_1
-25.01
EX-EX
|
|
668
TCAGCTTTTAACCAGAGT
2-13-3
TCagcttttaaccagAGT
668_1
-22.18
EX-EX
|
|
669
TCAGCTTTTAACCAGAGTG
2-14-3
TCagcttttaaccagaGTG
669_1
-23.15
EX-EX
|
|
670
TCAGCTTTTAACCAGAGTGG
2-16-2
TCagcttttaaccagagtGG
670_1
-23.41
EX-EX
|
|
671
TTCAGCTTTTAACCAGAGT
2-14-3
TTcagcttttaaccagAGT
671_1
-22.72
EX-EX
|
|
672
TTCAGCTTTTAACCAGAGTG
2-15-3
TTcagcttttaaccagaGTG
672_1
-23.69
EX-EX
|
|
673
TTTCAGCTTTTAACCAGAGT
2-15-3
TTtcagcttttaaccagAGT
673_1
-23.66
EX-EX
|
|
674
TTTTAACCAGAGTGGC
1-11-4
TtttaaccagagTGGC
674_1
-20.81
EX-EX
|
|
675
TTTTAACCAGAGTGGCA
3-11-3
TTTtaaccagagtgGCA
675_1
-22.30
EX-EX
|
|
676
TTTTAACCAGAGTGGCAT
4-11-3
TTTTaaccagagtggCAT
676_1
-23.21
EX-EX
|
|
677
TTTTAACCAGAGTGGCATC
4-13-2
TTTTaaccagagtggcaTC
677_1
-22.57
EX-EX
|
|
678
TTTTAACCAGAGTGGCATCC
2-16-2
TTttaaccagagtggcatCC
678_1
-24.58
EX-EX
|
|
679
ATCAATATCTTCTCACT
1-1-2-
AtCAatatcttCtCaCT
679_1
-19.16
5782
|
7-1-1-
|
1-1-2
|
|
679
ATCAATATCTTCTCACT
5-6-1-
ATCAAtatcttCtcACT
679_2
-21.49
5782
|
2-3
|
|
679
ATCAATATCTTCTCACT
1-1-1-
AtCaAtatcttcTCACT
679_3
-20.18
5782
|
1-1-7-5
|
|
679
ATCAATATCTTCTCACT
1-1-3-
AtCAAtatcttctCACT
679_4
-20.66
5782
|
8-4
|
|
679
ATCAATATCTTCTCACT
3-10-1-
ATCaatatcttctCaCT
679_5
-18.62
5782
|
1-2
|
|
680
TATCAATATCTTCTCACT
2-2-1-
TAtcAatatcttCtCaCT
680_1
-19.31
5782
|
7-1-1-
|
1-1-2
|
|
680
TATCAATATCTTCTCACT
1-1-2-
TaTCaatatcttCtCaCT
680_2
-19.89
5782
|
8-1-1-
|
1-1-2
|
|
680
TATCAATATCTTCTCACT
1-2-3-
TatCAAtatcttCtcACT
680_3
-20.66
5782
|
6-1-2-3
|
|
680
TATCAATATCTTCTCACT
1-2-3-
TatCAAtatcttcTCaCT
680_4
-20.99
5782
|
7-2-1-2
|
|
680
TATCAATATCTTCTCACT
2-1-1-
TAtCaatatcttctCACT
680_5
-20.89
5782
|
10-4
|
|
681
TATCAATATCTTCTCAC
4-7-2-
TATCaatatctTCtCAC
681_1
-21.30
5783
|
1-3
|
|
681
TATCAATATCTTCTCAC
1-2-2-
TatCAatatctTCtCAC
681_2
-19.73
5783
|
6-2-1-3
|
|
681
TATCAATATCTTCTCAC
2-1-1-
TAtCaatatcttCTCAC
681_3
-20.26
5783
|
8-5
|
|
681
TATCAATATCTTCTCAC
1-1-3-
TaTCAatatcttCTCAC
681_4
-21.74
5783
|
7-5
|
|
681
TATCAATATCTTCTCAC
5-9-3
TATCAatatcttctCAC
681_5
-20.83
5783
|
|
682
TTATCAATATCTTCTCAC
1-1-1-
TtAtCAatatctTCtcAC
682_1
-18.32
5783
|
1-2-6-
|
2-2-2
|
|
682
TTATCAATATCTTCTCAC
1-3-1-
TtatCaatatcttCTCAC
682_2
-19.71
5783
|
8-5
|
|
682
TTATCAATATCTTCTCAC
3-10-1-
TTAtcaatatcttCtCAC
682_3
-19.53
5783
|
1-3
|
|
682
TTATCAATATCTTCTCAC
2-1-2-
TTaTCaatatcttCtCAC
682_4
-20.20
5783
|
8-1-1-3
|
|
682
TTATCAATATCTTCTCAC
1-2-3-
TtaTCAatatcttctCAC
682_5
-19.47
5783
|
9-3
|
|
683
TTATCAATATCTTCTCACT
1-1-1-
TtAtCaatatcttCtCaCT
683_1
-19.45
5782
|
1-1-8-
|
1-1-1-
|
1-2
|
|
683
TTATCAATATCTTCTCACT
1-3-1-
TtatCaatatcttCtCaCT
683_2
-19.35
5782
|
8-1-1-
|
1-1-2
|
|
683
TTATCAATATCTTCTCACT
1-1-1-
TtAtCaatatcttCtcACT
683_3
-19.33
5782
|
1-1-8-
|
1-2-3
|
|
683
TTATCAATATCTTCTCACT
1-1-1-
TtAtcAatatcttCtcaCT
683_4
-18.18
5782
|
2-1-7-
|
1-3-2
|
|
683
TTATCAATATCTTCTCACT
1-1-1-
TtAtcAatatcttctCACT
683_5
-19.84
5782
|
2-1-9-4
|
|
684
ACCTTTCTTTAACCCTTT
2-1-1-
ACcTttctttaaCCcTTT
684_1
-25.24
8113
|
8-2-1-3
|
|
684
ACCTTTCTTTAACCCTTT
2-10-1-
ACctttctttaaCcCtTT
684_2
-22.31
8113
|
1-1-1-2
|
|
684
ACCTTTCTTTAACCCTTT
1-1-1-
AcCtttctttaaCcCtTT
684_3
-22.01
8113
|
9-1-1-
|
1-1-2
|
|
684
ACCTTTCTTTAACCCTTT
1-1-1-
AcCtTtctttaaccCtTT
684_4
-21.53
8113
|
1-1-9-
|
1-1-2
|
|
684
ACCTTTCTTTAACCCTTT
1-1-1-
AcCtttctttaaccCtTT
684_5
-21.23
8113
|
11-1-1-
|
2
|
|
685
TACCTTTCTTTAACCCTTT
1-2-1-
TacCtttctttaAcCctTT
685_1
-22.44
8113
|
8-1-1-
|
1-2-2
|
|
685
TACCTTTCTTTAACCCTTT
1-2-1-
TacCtTtctttaaCcCtTT
685_2
-23.32
8113
|
1-1-7-
|
1-1-1-
|
1-2
|
|
685
TACCTTTCTTTAACCCTTT
2-1-1-
TAcCtttctttaacCcTTT
685_3
-24.28
8113
|
10-1-1-
|
3
|
|
685
TACCTTTCTTTAACCCTTT
1-1-1-
TaCctttctttaaccCtTT
685_4
-22.13
8113
|
12-1-1-
|
2
|
|
685
TACCTTTCTTTAACCCTTT
1-2-1-
TacCtttctttaaccCtTT
685_5
-22.23
8113
|
11-1-1-
|
2
|
|
686
ATACCTTTCTTTAACCC
1-2-1-
AtaCctttcttTaAcCC
686_1
-20.53
8116
|
7-1-1-
|
1-1-2
|
|
686
ATACCTTTCTTTAACCC
1-3-1-
AtacCtttcttTaacCC
686_2
-20.21
8116
|
6-1-3-2
|
|
686
ATACCTTTCTTTAACCC
2-2-1-
ATacCtttctttAAcCC
686_3
-21.89
8116
|
7-2-1-2
|
|
686
ATACCTTTCTTTAACCC
1-1-1-
AtAcCtttctttaAcCC
686_4
-20.10
8116
|
1-1-8-
|
1-1-2
|
|
686
ATACCTTTCTTTAACCC
1-2-1-
AtaCctttctttaaCCC
686_5
-21.76
8116
|
10-3
|
|
687
ATACCTTTCTTTAACCCTT
1-3-2-
AtacCTttctttAacCCTT
687_1
-26.10
8114
|
6-1-2-4
|
|
687
ATACCTTTCTTTAACCCTT
1-1-1-
AtAcCtttctttaAcCcTT
687_2
-22.23
8114
|
1-1-8-
|
1-1-1-
|
1-2
|
|
687
ATACCTTTCTTTAACCCTT
1-2-1-
AtaCctttctttaAcCcTT
687_3
-21.93
8114
|
9-1-1-
|
1-1-2
|
|
687
ATACCTTTCTTTAACCCTT
1-2-1-
AtaCcTttctttaaCCcTT
687_4
-24.41
8114
|
1-1-8-
|
2-1-2
|
|
687
ATACCTTTCTTTAACCCTT
1-3-1-
AtacCtttctttaaccCTT
687_5
-22.51
8114
|
11-3
|
|
688
ATACCTTTCTTTAACCCTTT
1-3-1-
AtacCtttctttaAcCctTT
688_1
-22.83
8113
|
8-1-1-
|
1-2-2
|
|
688
ATACCTTTCTTTAACCCTTT
1-3-1-
AtacCtttctttaaCcCtTT
688_2
-23.41
8113
|
9-1-1-
|
1-1-2
|
|
688
ATACCTTTCTTTAACCCTTT
1-4-2-
AtaccTTtctttaaCccTTT
688_3
-23.98
8113
|
7-1-2-3
|
|
688
ATACCTTTCTTTAACCCTTT
1-1-1-
AtAcCtttctttaacCcTTT
688_4
-23.63
8113
|
1-1-10-
|
1-1-3
|
|
688
ATACCTTTCTTTAACCCTTT
1-2-1-
AtaCctttctttaaccCtTT
688_5
-22.52
8113
|
12-1-1-
|
2
|
|
689
ATACCTTTCTTTAACCCT
1-3-2-
AtacCTttctttAAccCT
689_1
-22.61
8115
|
6-2-2-2
|
|
689
ATACCTTTCTTTAACCCT
1-1-1-
AtAcCTttctttaaCcCT
689_2
-22.85
8115
|
1-2-8-
|
1-1-2
|
|
689
ATACCTTTCTTTAACCCT
1-2-1-
AtaCctttctttaaCcCT
689_3
-21.36
8115
|
10-1-1-
|
2
|
|
689
ATACCTTTCTTTAACCCT
1-2-3-
AtaCCTttctttaaccCT
689_4
-24.26
8115
|
10-2
|
|
689
ATACCTTTCTTTAACCCT
1-3-1-
AtacCtttctttaaccCT
689_5
-20.69
8115
|
11-2
|
|
690
TATACCTTTCTTTAACCCT
2-2-1-
TAtaCctttctttaaCcCT
690_1
-23.60
8115
|
10-1-1-
|
2
|
|
690
TATACCTTTCTTTAACCCT
1-4-1-
TatacCtttctttaaCcCT
690_2
-22.57
8115
|
9-1-1-2
|
|
690
TATACCTTTCTTTAACCCT
2-3-1-
TAtacCtttctttaaccCT
690_3
-22.92
8115
|
11-2
|
|
690
TATACCTTTCTTTAACCCT
1-3-1-
TataCctttctttaaccCT
690_4
-21.68
8115
|
12-2
|
|
690
TATACCTTTCTTTAACCCT
1-4-1-
TatacCtttctttaaccCT
690_5
-21.79
8115
|
11-2
|
|
691
TTATACCTTTCTTTAAC
4-7-2-
TTATacctttcTTtaAC
691_1
-18.49
8118
|
2-2
|
|
691
TTATACCTTTCTTTAAC
3-8-1-
TTAtacctttcTtTAAC
691_2
-18.07
8118
|
1-4
|
|
692
TTATACCTTTCTTTAACCC
2-10-1-
TTatacctttctTtAacCC
692_1
-21.94
8116
|
1-1-2-2
|
|
692
TTATACCTTTCTTTAACCC
1-1-1-
TtAtacctttctTtaacCC
692_2
-20.68
8116
|
9-1-4-2
|
|
692
TTATACCTTTCTTTAACCC
1-4-1-
TtataCctttcttTaacCC
692_3
-21.79
8116
|
7-1-3-2
|
|
692
TTATACCTTTCTTTAACCC
1-3-2-
TtatACctttctttAAcCC
692_4
-22.39
8116
|
8-2-1-2
|
|
692
TTATACCTTTCTTTAACCC
1-1-1-
TtAtaCctttctttaAcCC
692_5
-21.58
8116
|
2-1-9-
|
1-1-2
|
|
693
TTATACCTTTCTTTAACC
2-3-1-
TTataCctttctTtaaCC
693_1
-19.80
8117
|
6-1-3-2
|
|
693
TTATACCTTTCTTTAACC
1-1-1-
TtAtACctttctTtaaCC
693_2
-19.25
8117
|
1-2-6-
|
1-3-2
|
|
693
TTATACCTTTCTTTAACC
1-3-2-
TtatACctttcttTAaCC
693_3
-20.74
8117
|
7-2-1-2
|
|
693
TTATACCTTTCTTTAACC
1-1-1-
TtAtaCctttcttTaaCC
693_4
-19.08
8117
|
2-1-7-
|
1-2-2
|
|
693
TTATACCTTTCTTTAACC
1-2-1-
TtaTaCctttctttAACC
693_5
-20.26
8117
|
1-1-8-4
|
|
694
TTTATACCTTTCTTTAACC
2-1-1-
TTtAtacctttcTTtaaCC
694_1
-20.72
8117
|
8-2-3-2
|
|
694
TTTATACCTTTCTTTAACC
1-4-1-
TttatAcctttcTttAACC
694_2
-20.33
8117
|
6-1-2-4
|
|
694
TTTATACCTTTCTTTAACC
2-11-1-
TTtatacctttctTtAaCC
694_3
-19.72
8117
|
1-1-1-2
|
|
694
TTTATACCTTTCTTTAACC
1-1-2-
TtTAtacctttctTtaaCC
694_4
-20.65
8117
|
9-1-3-2
|
|
694
TTTATACCTTTCTTTAACC
1-3-2-
TttaTAcctttctTtaaCC
694_5
-20.88
8117
|
7-1-3-2
|
|
695
TTTATACCTTTCTTTAAC
3-9-3-
TTTatacctttcTTTaAC
695_1
-18.74
8118
|
1-2
|
|
695
TTTATACCTTTCTTTAAC
5-7-2-
TTTATacctttcTTtaAC
695_2
-20.31
8118
|
2-2
|
|
695
TTTATACCTTTCTTTAAC
1-1-3-
TtTATacctttctTtaAC
695_3
-18.98
8118
|
7-2-2-2
|
|
695
TTTATACCTTTCTTTAAC
4-8-1-
TTTAtacctttcTtTAAC
695_4
-19.89
8118
|
1-4
|
|
695
TTTATACCTTTCTTTAAC
2-3-1-
TTtatAcctttctTTAAC
695_5
-18.02
8118
|
7-5
|
|
696
TTTTATACCTTTCTTTAAC
2-3-1-
TTttaTacctttCTTtaAC
696_1
-19.79
8118
|
6-3-2-2
|
|
696
TTTTATACCTTTCTTTAAC
1-1-2-
TtTTatacctttCTtTaAC
696_2
-19.57
8118
|
8-2-1-
|
1-1-2
|
|
696
TTTTATACCTTTCTTTAAC
2-1-2-
TTtTAtacctttCTttAAC
696_3
-20.28
8118
|
7-2-2-3
|
|
696
TTTTATACCTTTCTTTAAC
3-9-1-
TTTtatacctttCtTTAAC
696_4
-20.62
8118
|
1-5
|
|
696
TTTTATACCTTTCTTTAAC
1-1-3-
TtTTAtacctttCtTtaAC
696_5
-19.08
8118
|
7-1-1-
|
1-2-2
|
|
697
TGTACTTTCCTTTACCA
2-9-1-
TGtactttcctTtacCA
697_1
-20.68
11462
|
3-2
|
|
697
TGTACTTTCCTTTACCA
1-2-1-
TgtActttcctTtacCA
697_2
-19.66
11462
|
7-1-3-2
|
|
697
TGTACTTTCCTTTACCA
1-3-1-
TgtaCtttcctTtacCA
697_3
-20.46
11462
|
6-1-3-2
|
|
697
TGTACTTTCCTTTACCA
2-2-1-
TGtaCtttcctttAcCA
697_4
-21.56
11462
|
8-1-1-2
|
|
697
TGTACTTTCCTTTACCA
1-3-1-
TgtaCtttcctttaCCA
697_5
-22.54
11462
|
9-3
|
|
698
TTATACACCATCATTAT
4-7-3-
TTATacaccatCATTAT
698_1
-21.13
11506
|
1-2
|
|
698
TTATACACCATCATTAT
4-7-2-
TTATacaccatCAtTAT
698_2
-21.64
11506
|
1-3
|
|
698
TTATACACCATCATTAT
3-8-1-
TTAtacaccatCaTTAT
698_3
-19.45
11506
|
1-4
|
|
698
TTATACACCATCATTAT
2-1-2-
TTaTAcaccatcATTAT
698_4
-20.61
11506
|
7-5
|
|
698
TTATACACCATCATTAT
5-9-3
TTATAcaccatcatTAT
698_5
-20.74
11506
|
|
699
TTATACACCATCATTATA
3-2-1-
TTAtaCaccatcATtaTA
699_1
-19.38
11505
|
6-2-2-2
|
|
699
TTATACACCATCATTATA
1-2-3-
TtaTACaccatcAtTATA
699_2
-20.93
11505
|
6-1-1-4
|
|
699
TTATACACCATCATTATA
4-1-1-
TTATaCaccatcaTTaTA
699_3
-21.44
11505
|
7-2-1-2
|
|
699
TTATACACCATCATTATA
2-1-2-
TTaTAcaccatcaTtATA
699_4
-19.71
11505
|
8-1-1-3
|
|
699
TTATACACCATCATTATA
3-2-1-
TTAtaCaccatcatTATA
699_5
-20.75
11505
|
8-4
|
|
700
TTTATACACCATCATTAT
2-1-2-
TTtATacaccatCATtAT
700_1
-20.67
11506
|
7-3-1-2
|
|
700
TTTATACACCATCATTAT
3-1-1-
TTTaTacaccatCAtTAT
700_2
-21.52
11506
|
7-2-1-3
|
|
700
TTTATACACCATCATTAT
1-3-2-
TttaTAcaccatCAtTAT
700_3
-20.70
11506
|
6-2-1-3
|
|
700
TTTATACACCATCATTAT
1-1-3-
TtTATacaccatcAtTAT
700_4
-20.05
11506
|
8-1-1-3
|
|
700
TTTATACACCATCATTAT
3-1-1-
TTTaTacaccatcaTTAT
700_5
-20.34
11506
|
9-4
|
|
701
TTTATACACCATCATTATA
4-8-1-
TTTAtacaccatCaTTaTA
701_1
-21.57
11505
|
1-2-1-2
|
|
701
TTTATACACCATCATTATA
2-2-1-
TTtaTacaccatCatTATA
701_2
-21.05
11505
|
7-1-2-4
|
|
701
TTTATACACCATCATTATA
1-1-1-
TtTaTacaccatcATTATA
701_3
-19.83
11505
|
1-1-8-
|
2-1-3
|
|
701
TTTATACACCATCATTATA
2-2-2-
TTtaTAcaccatcATtaTA
701_4
-20.24
11505
|
7-2-2-2
|
|
701
TTTATACACCATCATTATA
1-1-3-
TtTATacaccatcatTaTA
701_5
-20.30
11505
|
10-1-1-
|
2
|
|
702
ATTTATACACCATCATTAT
1-1-1-
AtTtaTacaccatCATTAT
702_1
-20.07
11506
|
2-1-7-
|
3-1-2
|
|
702
ATTTATACACCATCATTAT
1-1-2-
AtTTaTacaccatCAttAT
702_2
-20.07
11506
|
1-1-7-
|
2-2-2
|
|
702
ATTTATACACCATCATTAT
2-1-2-
ATtTAtacaccatCaTtAT
702_3
-19.74
11506
|
8-1-1-
|
1-1-2
|
|
702
ATTTATACACCATCATTAT
2-3-1-
ATttaTacaccatCatTAT
702_4
-20.07
11506
|
7-1-2-3
|
|
702
ATTTATACACCATCATTAT
1-1-1-
AtTtAtacaccatcaTTAT
702_5
-18.64
11506
|
1-1-10-
|
4
|
|
703
ATTTATACACCATCATTATA
1-4-1-
AtttaTacaccatCatTATA
703_1
-21.05
11505
|
7-1-2-4
|
|
703
ATTTATACACCATCATTATA
2-1-1-
ATtTatAcaccatcATtaTA
703_2
-20.32
11505
|
2-1-7-
|
2-2-2
|
|
703
ATTTATACACCATCATTATA
1-1-1-
AtTtaTacaccatcAtTaTA
703_3
-18.80
11505
|
2-1-8-
|
1-1-1-
|
1-2
|
|
703
ATTTATACACCATCATTATA
1-2-3-
AttTATacaccatcAtTaTA
703_4
-21.17
11505
|
8-1-1-
|
1-1-2
|
|
703
ATTTATACACCATCATTATA
3-1-1-
ATTtAtacaccatcAttATA
703_5
-19.97
11505
|
9-1-2-3
|
|
704
TATTTATACACCATCATTA
1-2-3-
TatTTAtacaccATcatTA
704_1
-20.37
11507
|
6-2-3-2
|
|
704
TATTTATACACCATCATTA
4-8-1-
TATTtatacaccAtCAtTA
704_2
-21.70
11507
|
1-2-1-2
|
|
704
TATTTATACACCATCATTA
1-1-1-
TaTtTatacaccAtCaTTA
704_3
-19.16
11507
|
1-1-7-
|
1-1-1-
|
1-3
|
|
704
TATTTATACACCATCATTA
2-2-1-
TAttTatacaccaTCatTA
704_4
-19.98
11507
|
8-2-2-2
|
|
704
TATTTATACACCATCATTA
2-2-1-
TAttTatacaccatcATTA
704_5
-19.99
11507
|
10-4
|
|
705
TATTTATACACCATCATTAT
2-2-1-
TAttTaTacaccatCAttAT
705_1
-21.49
11506
|
1-1-7-
|
2-2-2
|
|
705
TATTTATACACCATCATTAT
2-1-1-
TAtTtatacaccatCaTTAT
705_2
-21.44
11506
|
10-1-1-
|
4
|
|
705
TATTTATACACCATCATTAT
1-1-1-
TaTttAtacaccatCaTtAT
705_3
-18.27
11506
|
2-1-8-
|
1-1-1-
|
1-2
|
|
705
TATTTATACACCATCATTAT
2-1-2-
TAtTTatacaccatCattAT
705_4
-19.97
11506
|
9-1-3-2
|
|
705
TATTTATACACCATCATTAT
1-2-3-
TatTTAtacaccatcAtTAT
705_5
-21.11
11506
|
9-1-1-3
|
|
706
TTATTTATACACCATCATTA
2-3-1-
TTattTatacaccAtCaTTA
706_1
-20.54
11507
|
7-1-1-
|
1-1-3
|
|
706
TTATTTATACACCATCATTA
1-1-2-
TtATtTatacaccAtcATTA
706_2
-20.84
11507
|
1-1-7-
|
1-2-4
|
|
706
TTATTTATACACCATCATTA
1-1-1-
TtAttTatacaccaTCatTA
706_3
-19.52
11507
|
2-1-8-
|
2-2-2
|
|
706
TTATTTATACACCATCATTA
1-2-3-
TtaTTTatacaccaTcAtTA
706_4
-19.96
11507
|
8-1-1-
|
1-1-2
|
|
706
TTATTTATACACCATCATTA
3-1-1-
TTAtTtatacaccatcAtTA
706_5
-19.63
11507
|
11-1-1-
|
2
|
|
707
ATTATTTATACACCATCAT
2-2-2-
ATtaTTtatacaCCAtcAT
707_1
-22.41
11509
|
6-3-2-2
|
|
707
ATTATTTATACACCATCAT
2-3-1-
ATtatTtatacaCcaTCAT
707_2
-21.02
11509
|
6-1-2-4
|
|
707
ATTATTTATACACCATCAT
1-1-1-
AtTaTttatacacCATcAT
707_3
-20.01
11509
|
1-1-8-
|
3-1-2
|
|
707
ATTATTTATACACCATCAT
1-1-2-
AtTAtTtatacacCatCAT
707_4
-20.30
11509
|
1-1-7-
|
1-2-3
|
|
707
ATTATTTATACACCATCAT
2-1-2-
ATtATttatacaccAtCAT
707_5
-20.20
11509
|
9-1-1-3
|
|
708
ATTATTTATACACCATCA
2-2-2-
ATtaTTtatacaCCatCA
708_1
-20.96
11510
|
6-2-2-2
|
|
708
ATTATTTATACACCATCA
3-1-1-
ATTaTttatacaCcATCA
708_2
-21.19
11510
|
7-1-1-4
|
|
708
ATTATTTATACACCATCA
1-1-3-
AtTATttatacaCcatCA
708_3
-19.39
11510
|
7-1-3-2
|
|
708
ATTATTTATACACCATCA
1-1-1-
AtTatTtatacacCAtCA
708_4
-18.57
11510
|
2-1-7-
|
2-1-2
|
|
708
ATTATTTATACACCATCA
2-1-2-
ATtATttatacacCaTCA
708_5
-19.79
11510
|
8-1-1-3
|
|
709
ATTATTTATACACCATCATT
1-2-3-
AttATTtatacacCaTCaTT
709_1
-20.97
11508
|
7-1-1-
|
2-1-2
|
|
709
ATTATTTATACACCATCATT
1-1-1-
AtTatTTatacacCatcaTT
709_2
-19.29
11508
|
2-2-6-
|
1-4-2
|
|
709
ATTATTTATACACCATCATT
1-1-1-
AtTatTtatacaccATcATT
709_3
-19.70
11508
|
2-1-8-
|
2-1-3
|
|
709
ATTATTTATACACCATCATT
3-1-1-
ATTaTttatacaccAtCaTT
709_4
-20.09
11508
|
9-1-1-
|
1-1-2
|
|
709
ATTATTTATACACCATCATT
2-1-2-
ATTATtTatacaccAtcATT
709_5
-20.67
11508
|
1-1-7-
|
1-2-3
|
|
710
ATTATTTATACACCATC
5-6-3-
ATTATttatacACCaTC
710_1
-21.70
11511
|
1-2
|
|
710
ATTATTTATACACCATC
5-6-2-
ATTATttatacACcATC
710_2
-20.38
11511
|
1-3
|
|
710
ATTATTTATACACCATC
2-2-1-
ATtaTttatacaCCATC
710_3
-20.25
11511
|
7-5
|
|
710
ATTATTTATACACCATC
1-1-2-
AtTAtttatacaCCATC
710_4
-20.42
11511
|
8-5
|
|
710
ATTATTTATACACCATC
5-8-4
ATTATttatacacCATC
710_5
-21.04
11511
|
|
711
AATTATTTATACACCATC
2-2-2-
AAttATttatacACCaTC
711_1
-18.93
11511
|
6-3-1-2
|
|
711
AATTATTTATACACCATC
2-1-3-
AAtTATttatacAcCATC
711_2
-20.18
11511
|
6-1-1-4
|
|
711
AATTATTTATACACCATC
4-1-1-
AATTaTttatacaCCATC
711_3
-22.24
11511
|
7-5
|
|
711
AATTATTTATACACCATC
2-1-2-
AAtTAtttatacaCCATC
711_4
-21.17
11511
|
8-5
|
|
711
AATTATTTATACACCATC
1-1-4-
AaTTATttatacaCCaTC
711_5
-20.58
11511
|
7-2-1-2
|
|
712
AATTATTTATACACCATCA
1-2-1-
AatTaTttatacACCatCA
712_1
-20.42
11510
|
1-1-6-
|
3-2-2
|
|
712
AATTATTTATACACCATCA
2-2-1-
AAttAtttatacAcCAtCA
712_2
-18.54
11510
|
7-1-1-
|
2-1-2
|
|
712
AATTATTTATACACCATCA
1-1-3-
AaTTAtttatacAccATCA
712_3
-20.67
11510
|
7-1-2-4
|
|
712
AATTATTTATACACCATCA
2-1-2-
AAtTAtttatacaCCaTCA
712_4
-22.20
11510
|
8-2-1-3
|
|
712
AATTATTTATACACCATCA
3-1-1-
AATtAtttatacaCcaTCA
712_5
-19.50
11510
|
8-1-2-3
|
|
713
AAATTATTTATACACCATC
3-2-1-
AAAttAtttataCACcATC
713_1
-19.21
11511
|
6-3-1-3
|
|
713
AAATTATTTATACACCATC
1-2-3-
AaaTTAtttataCACcaTC
713_2
-20.01
11511
|
6-3-2-2
|
|
713
AAATTATTTATACACCATC
1-1-3-
AaATTatttataCAcCATC
713_3
-21.68
11511
|
7-2-1-4
|
|
713
AAATTATTTATACACCATC
2-1-2-
AAaTTatttataCaCCaTC
713_4
-19.63
11511
|
7-1-1-
|
2-1-2
|
|
713
AAATTATTTATACACCATC
1-1-2-
AaATtAtttatacaCCATC
713_5
-20.67
11511
|
1-1-8-5
|
|
714
AAATTATTTATACACCAT
1-1-4-
AaATTAtttataCAcCAT
714_1
-20.31
11512
|
6-2-1-3
|
|
714
AAATTATTTATACACCAT
2-2-2-
AAatTAtttataCaCCAT
714_2
-19.59
11512
|
6-1-1-4
|
|
714
AAATTATTTATACACCAT
1-1-3-
AaATTatttataCaCCAT
714_3
-20.00
11512
|
7-1-1-4
|
|
714
AAATTATTTATACACCAT
4-9-5
AAATtatttatacACCAT
714_4
-19.36
11512
|
|
714
AAATTATTTATACACCAT
3-1-2-
AAAtTAtttatacACCAT
714_5
-19.98
11512
|
7-5
|
|
715
AAAATTATTTATACACCAT
2-1-2-
AAaATtatttatACAcCAT
715_1
-19.29
11512
|
7-3-1-3
|
|
715
AAAATTATTTATACACCAT
1-3-2-
AaaaTTatttatACaCCAT
715_2
-19.68
11512
|
6-2-1-4
|
|
715
AAAATTATTTATACACCAT
3-2-1-
AAAatTatttatAcACCAT
715_3
-19.27
11512
|
6-1-1-5
|
|
715
AAAATTATTTATACACCAT
1-1-4-
AaAATTatttataCaCCAT
715_4
-20.75
11512
|
7-1-1-4
|
|
715
AAAATTATTTATACACCAT
2-1-2-
AAaATtatttatacACCAT
715_5
-19.38
11512
|
9-5
|
|
716
TAAAATTATTTATACACC
2-1-3-
TAaAATtatttaTACaCC
716_1
-18.88
11514
|
6-3-1-2
|
|
716
TAAAATTATTTATACACC
3-1-2-
TAAaATtatttatACACC
716_2
-18.95
11514
|
7-5
|
|
716
TAAAATTATTTATACACC
1-1-4-
TaAAATtatttatACACC
716_3
-18.33
11514
|
7-5
|
|
716
TAAAATTATTTATACACC
3-1-2-
TAAaATtatttataCACC
716_4
-18.35
11514
|
8-4
|
|
716
TAAAATTATTTATACACC
2-1-3-
TAaAATtatttataCACC
716_5
-18.35
11514
|
8-4
|
|
717
GTAAAATTATTTATACACC
2-1-3-
GTaAAAttatttATACaCC
717_1
-21.68
11514
|
6-4-1-2
|
|
717
GTAAAATTATTTATACACC
3-2-1-
GTAaaAttatttATacACC
717_2
-20.00
11514
|
6-2-2-3
|
|
717
GTAAAATTATTTATACACC
3-1-2-
GTAaAAttatttaTAcACC
717_3
-20.86
11514
|
7-2-1-3
|
|
717
GTAAAATTATTTATACACC
2-1-3-
GTaAAAttatttaTaCACC
717_4
-21.11
11514
|
7-1-1-4
|
|
717
GTAAAATTATTTATACACC
4-1-1-
GTAAaAttatttatACACC
717_5
-21.46
11514
|
8-5
|
|
718
GTAAAATTATTTATACAC
4-1-1-
GTAAaAttatttaTACAC
718_1
-18.17
11515
|
7-5
|
|
718
GTAAAATTATTTATACAC
3-1-2-
GTAaAAttatttaTACAC
718_2
-18.17
11515
|
7-5
|
|
719
GAGTATATTACCTCCA
3-10-3
GAGtatattacctCCA
719_1
-22.56
15162
|
|
719
GAGTATATTACCTCCA
2-1-1-
GAgTatattacctCCA
719_2
-22.24
15162
|
9-3
|
|
719
GAGTATATTACCTCCA
2-11-3
GAgtatattacctCCA
719_3
-21.15
15162
|
|
719
GAGTATATTACCTCCA
1-1-3-
GaGTAtattacctCCA
719_4
-22.93
15162
|
8-3
|
|
719
GAGTATATTACCTCCA
5-9-2
GAGTAtattacctcCA
719_5
-23.29
15162
|
|
720
CTTTTCTATAATCTCAC
2-2-1-
CTttTctataaTCTcAC
720_1
-18.54
30553
|
6-3-1-2
|
|
720
CTTTTCTATAATCTCAC
3-8-2-
CTTttctataaTCtCAC
720_2
-19.80
30553
|
1-3
|
|
720
CTTTTCTATAATCTCAC
1-1-3-
CtTTTctataaTcTCAC
720_3
-19.40
30553
|
6-1-1-4
|
|
720
CTTTTCTATAATCTCAC
4-8-5
CTTTtctataatCTCAC
720_4
-21.37
30553
|
|
720
CTTTTCTATAATCTCAC
1-3-1-
CtttTctataatCTCAC
720_5
-18.92
30553
|
7-5
|
|
721
CTTTTCTATAATCTCACA
2-3-1-
CTtttCtataatCtCaCA
721_1
-20.17
30552
|
6-1-1-
|
1-1-2
|
|
721
CTTTTCTATAATCTCACA
1-1-1-
CtTtTCtataatCtcACA
721_2
-20.15
30552
|
1-2-6-
|
1-2-3
|
|
721
CTTTTCTATAATCTCACA
1-2-1-
CttttCtataatcTCaCA
721_3
-19.50
30552
|
1-1-7-
|
2-1-2
|
|
721
CTTTTCTATAATCTCACA
1-1-3-
CtTTTctataatcTcACA
721_4
-19.49
30552
|
8-1-1-3
|
|
721
CTTTTCTATAATCTCACA
3-2-1-
CTTTTCtataatctCACA
721_5
-21.97
30552
|
8-4
|
|
722
TCTTTTCTATAATCTCACA
1-1-3-
TcTTTtctataaTcTcACA
722_1
-21.04
30552
|
7-1-1-
|
1-1-3
|
|
722
TCTTTTCTATAATCTCACA
1-4-1-
TctttTctataaTctCaCA
722_2
-18.81
30552
|
6-1-2-
|
1-1-2
|
|
722
TCTTTTCTATAATCTCACA
2-2-1-
TCttTtctataatCtcACA
722_3
-20.68
30552
|
8-1-2-3
|
|
722
TCTTTTCTATAATCTCACA
2-1-1-
TCtTttctataatCtcaCA
722_4
-20.13
30552
|
9-1-3-2
|
|
722
TCTTTTCTATAATCTCACA
2-13-1-
TCttttctataatctCaCA
722_5
-19.52
30552
|
1-2
|
|
723
TCTTTTCTATAATCTCAC
2-1-1-
TCtTttctataaTCtcAC
723_1
-18.51
30553
|
8-2-2-2
|
|
723
TCTTTTCTATAATCTCAC
3-10-1-
TCTtttctataatCtCAC
723_2
-20.36
30553
|
1-3
|
|
723
TCTTTTCTATAATCTCAC
1-2-3-
TctTTTctataatCtCAC
723_3
-19.57
30553
|
7-1-1-3
|
|
723
TCTTTTCTATAATCTCAC
2-2-2-
TCttTTctataatcTCAC
723_4
-20.57
30553
|
8-4
|
|
723
TCTTTTCTATAATCTCAC
1-1-4-
TcTTTTctataatcTCAC
723_5
-20.82
30553
|
8-4
|
|
724
ATCTTTTCTATAATCTCACA
1-1-1-
AtCtTttctataatCtCaCA
724_1
-20.93
30552
|
1-1-9-
|
1-1-1-
|
1-2
|
|
724
ATCTTTTCTATAATCTCACA
1-1-1-
AtCttttctataatCtcACA
724_2
-20.51
30552
|
11-1-2-
|
3
|
|
724
ATCTTTTCTATAATCTCACA
1-2-1-
AtcTtTtctataatCtcACA
724_3
-20.35
30552
|
1-1-8-
|
1-2-3
|
|
724
ATCTTTTCTATAATCTCACA
1-3-2-
AtctTTtctataatCtcaCA
724_4
-20.10
30552
|
8-1-3-2
|
|
724
ATCTTTTCTATAATCTCACA
1-1-1-
AtCttTtctataatctCaCA
724_5
-19.95
30552
|
2-1-10-
|
1-1-2
|
|
725
ATCTTTTCTATAATCTCAC
1-1-1-
AtCttttctataAtCtCAC
725_1
-19.62
30553
|
9-1-1-
|
1-1-3
|
|
725
ATCTTTTCTATAATCTCAC
1-2-2-
AtcTTttctataAtCtCAC
725_2
-19.97
30553
|
7-1-1-
|
1-1-3
|
|
725
ATCTTTTCTATAATCTCAC
1-1-2-
AtCTtTtctataaTCtcAC
725_3
-19.83
30553
|
1-1-7-
|
2-2-2
|
|
725
ATCTTTTCTATAATCTCAC
1-2-1-
AtcTtTtctataatcTCAC
725_4
-19.36
30553
|
1-1-9-4
|
|
725
ATCTTTTCTATAATCTCAC
3-13-3
ATCttttctataatctCAC
725_5
-20.25
30553
|
|
726
ATCTTTTCTATAATCTCA
1-1-2-
AtCTtttctataAtCtCA
726_1
-18.77
30554
|
8-1-1-
|
1-1-2
|
|
726
ATCTTTTCTATAATCTCA
3-1-1-
ATCtTttctataAtcTCA
726_2
-20.03
30554
|
7-1-2-3
|
|
726
ATCTTTTCTATAATCTCA
3-10-2-
ATCttttctataaTCtCA
726_3
-20.31
30554
|
1-2
|
|
726
ATCTTTTCTATAATCTCA
1-1-1-
AtCtTTtctataaTCtCA
726_4
-19.49
30554
|
1-2-7-
|
2-1-2
|
|
726
ATCTTTTCTATAATCTCA
1-1-3-
AtCTTttctataatCTCA
726_5
-21.14
30554
|
9-4
|
|
727
CATCTTTTCTATAATCTCAC
2-11-1-
CAtcttttctataAtCtcAC
727_1
-19.86
30553
|
1-1-2-2
|
|
727
CATCTTTTCTATAATCTCAC
1-1-2-
CaTCttttctataAtCtcAC
727_2
-20.49
30553
|
9-1-1-
|
1-2-2
|
|
727
CATCTTTTCTATAATCTCAC
1-3-1-
CatcTtTtctataatCtCAC
727_3
-20.97
30553
|
1-1-8-
|
1-1-3
|
|
727
CATCTTTTCTATAATCTCAC
1-2-1-
CatCtTttctataatCtcAC
727_4
-19.35
30553
|
1-1-9-
|
1-2-2
|
|
727
CATCTTTTCTATAATCTCAC
2-1-1-
CAtCttTtctataatctCAC
727_5
-21.92
30553
|
2-1-10-
|
3
|
|
728
CATCTTTTCTATAATCTCA
1-3-1-
CatcTtttctatAAtCtCA
728_1
-19.26
30554
|
7-2-1-
|
1-1-2
|
|
728
CATCTTTTCTATAATCTCA
2-3-1-
CAtctTttctatAAtcTCA
728_2
-20.74
30554
|
6-2-2-3
|
|
728
CATCTTTTCTATAATCTCA
1-2-1-
CatCttttctatAatCtCA
728_3
-19.21
30554
|
8-1-2-
|
1-1-2
|
|
728
CATCTTTTCTATAATCTCA
2-1-1-
CAtCtTttctataatCtCA
728_4
-20.86
30554
|
1-1-9-
|
1-1-2
|
|
728
CATCTTTTCTATAATCTCA
1-1-2-
CaTCttttctataatctCA
728_5
-19.23
30554
|
13-2
|
|
729
TCATCTTTTCTATAATCTCA
1-1-1-
TcAtcTtttctatAAtCtCA
729_1
-20.53
30554
|
2-1-7-
|
2-1-1-
|
1-2
|
|
729
TCATCTTTTCTATAATCTCA
2-4-1-
TCatctTttctatAAtctCA
729_2
-20.57
30554
|
6-2-3-2
|
|
729
TCATCTTTTCTATAATCTCA
2-2-1-
TCatCttttctatAatCtCA
729_3
-21.70
30554
|
8-1-2-
|
1-1-2
|
|
729
TCATCTTTTCTATAATCTCA
3-13-1-
TCAtcttttctataatCtCA
729_4
-22.07
30554
|
1-2
|
|
729
TCATCTTTTCTATAATCTCA
3-1-1-
TCAtCttttctataatctCA
729_5
-22.07
30554
|
13-2
|
|
730
TCATCTTTTCTATAATCTC
3-2-1-
TCAtcTtttctatAAtcTC
730_1
-20.15
30555
|
7-2-2-2
|
|
730
TCATCTTTTCTATAATCTC
3-1-1-
TCAtCttttctatAatcTC
730_2
-20.09
30555
|
8-1-3-2
|
|
730
TCATCTTTTCTATAATCTC
2-2-1-
TCatCttttctataAtcTC
730_3
-18.83
30555
|
9-1-2-2
|
|
730
TCATCTTTTCTATAATCTC
3-13-3
TCAtcttttctataatCTC
730_4
-20.65
30555
|
|
730
TCATCTTTTCTATAATCTC
2-2-2-
TCatCTtttctataatCTC
730_5
-21.35
30555
|
10-3
|
|
731
GTCATCTTTTCTATAATC
1-1-1-
GtCatCttttctATAaTC
731_1
-19.76
30557
|
2-1-6-
|
3-1-2
|
|
731
GTCATCTTTTCTATAATC
1-1-1-
GtCaTCttttctAtaATC
731_2
-19.19
30557
|
1-2-6-
|
1-2-3
|
|
731
GTCATCTTTTCTATAATC
4-9-1-
GTCAtcttttctaTaaTC
731_3
-20.42
30557
|
2-2
|
|
731
GTCATCTTTTCTATAATC
3-2-1-
GTCatCttttctatAATC
731_4
-20.51
30557
|
8-4
|
|
731
GTCATCTTTTCTATAATC
1-1-4-
GtCATCttttctataaTC
731_5
-20.23
30557
|
10-2
|
|
732
TGTCATCTTTTCTATAAT
2-1-1-
TGtCatcttttcTAtAAT
732_1
-19.36
30558
|
8-2-1-3
|
|
732
TGTCATCTTTTCTATAAT
2-1-2-
TGtCAtcttttcTAtaAT
732_2
-20.51
30558
|
7-2-2-2
|
|
732
TGTCATCTTTTCTATAAT
1-1-3-
TgTCAtcttttcTataAT
732_3
-19.51
30558
|
7-1-3-2
|
|
732
TGTCATCTTTTCTATAAT
4-10-4
TGTCatcttttctaTAAT
732_4
-21.42
30558
|
|
732
TGTCATCTTTTCTATAAT
2-2-1-
TGtcAtcttttctaTAAT
732_5
-18.57
30558
|
9-4
|
|
733
ACTTAATTATACTTCCA
5-6-2-
ACTTAattataCTtcCA
733_1
-21.55
30664
|
2-2
|
|
733
ACTTAATTATACTTCCA
2-1-2-
ACtTAattataCttCCA
733_2
-21.02
30664
|
6-1-2-3
|
|
733
ACTTAATTATACTTCCA
1-2-2-
ActTAattatacTTCCA
733_3
-20.65
30664
|
7-5
|
|
733
ACTTAATTATACTTCCA
4-8-1-
ACTTaattatacTtCCA
733_4
-21.09
30664
|
1-3
|
|
733
ACTTAATTATACTTCCA
1-1-1-
AcTtAattatactTCCA
733_5
-18.37
30664
|
1-1-8-4
|
|
734
CACTTAATTATACTTCC
2-1-2-
CAcTTaattatACttCC
734_1
-20.10
30665
|
6-2-2-2
|
|
734
CACTTAATTATACTTCC
5-6-1-
CACTTaattatActTCC
734_2
-21.76
30665
|
2-3
|
|
734
CACTTAATTATACTTCC
1-1-1-
CaCtTaattataCTtCC
734_3
-19.09
30665
|
1-1-7-
|
2-1-2
|
|
734
CACTTAATTATACTTCC
1-1-3-
CaCTTaattataCtTCC
734_4
-20.59
30665
|
7-1-1-3
|
|
734
CACTTAATTATACTTCC
2-1-2-
CAcTTaattatacTTCC
734_5
-20.52
30665
|
8-4
|
|
735
CACTTAATTATACTTCCA
2-2-1-
CActTaattataCTtCCA
735_1
-22.96
30664
|
7-2-1-3
|
|
735
CACTTAATTATACTTCCA
2-1-1-
CAcTtAattataCttcCA
735_2
-19.31
30664
|
1-1-6-
|
1-3-2
|
|
735
CACTTAATTATACTTCCA
1-1-3-
CaCTTaattatacTtCCA
735_3
-22.43
30664
|
8-1-1-3
|
|
735
CACTTAATTATACTTCCA
1-1-1-
CaCtTAattatacTtcCA
735_4
-19.51
30664
|
1-2-7-
|
1-2-2
|
|
735
CACTTAATTATACTTCCA
2-2-1-
CActTaattatactTCCA
735_5
-21.76
30664
|
9-4
|
|
736
ACACTTAATTATACTTCCA
1-1-2-
AcACtTaattatACttcCA
736_1
-20.93
30664
|
1-1-6-
|
2-3-2
|
|
736
ACACTTAATTATACTTCCA
2-2-1-
ACacTtaattatAcTtcCA
736_2
-19.38
30664
|
7-1-1-
|
1-2-2
|
|
736
ACACTTAATTATACTTCCA
1-1-1-
AcAcTtaattataCttCCA
736_3
-21.10
30664
|
1-1-8-
|
1-2-3
|
|
736
ACACTTAATTATACTTCCA
1-1-1-
AcActTaattatactTCCA
736_4
-21.31
30664
|
2-1-9-4
|
|
736
ACACTTAATTATACTTCCA
2-2-2-
ACacTTaattatacttcCA
736_5
-19.91
30664
|
11-2
|
|
737
ACACTTAATTATACTTCC
1-3-1-
AcacTtaattatACtTCC
737_1
-19.24
30665
|
7-2-1-3
|
|
737
ACACTTAATTATACTTCC
1-1-1-
AcAcTTaattatACttCC
737_2
-19.64
30665
|
1-2-6-
|
2-2-2
|
|
737
ACACTTAATTATACTTCC
2-1-2-
ACaCTtaattatAcTtCC
737_3
-20.12
30665
|
7-1-1-
|
1-1-2
|
|
737
ACACTTAATTATACTTCC
3-2-1-
ACActTaattatacTTCC
737_4
-21.53
30665
|
8-4
|
|
737
ACACTTAATTATACTTCC
1-1-2-
AcACtTaattatactTCC
737_5
-19.40
30665
|
1-1-9-3
|
|
738
ACACTTAATTATACTTC
5-7-5
ACACTtaattatACTTC
738_1
-20.47
30666
|
|
738
ACACTTAATTATACTTC
3-1-1-
ACAcTtaattatACTTC
738_2
-18.40
30666
|
7-5
|
|
738
ACACTTAATTATACTTC
2-1-2-
ACaCTtaattatACTTC
738_3
-18.51
30666
|
7-5
|
|
738
ACACTTAATTATACTTC
5-7-2-
ACACTtaattatACtTC
738_4
-18.77
30666
|
1-2
|
|
738
ACACTTAATTATACTTC
5-7-1-
ACACTtaattatAcTTC
738_5
-18.40
30666
|
1-3
|
|
738
ACACTTAATTATACTTC
5-8-4
ACACTtaattataCTTC
738_6
-19.88
30666
|
|
739
TACACTTAATTATACTTCC
3-2-1-
TACacTtaattatACttCC
739_1
-21.57
30665
|
7-2-2-2
|
|
739
TACACTTAATTATACTTCC
1-4-1-
TacacTtaattatAcTTCC
739_2
-19.87
30665
|
7-1-1-4
|
|
739
TACACTTAATTATACTTCC
1-2-3-
TacACTtaattataCttCC
739_3
-20.88
30665
|
8-1-2-2
|
|
739
TACACTTAATTATACTTCC
4-11-4
TACActtaattatacTTCC
739_4
-23.04
30665
|
|
739
TACACTTAATTATACTTCC
2-1-1-
TAcAcTtaattatactTCC
739_5
-20.03
30665
|
1-1-10-
|
3
|
|
740
TACACTTAATTATACTTC
4-1-1-
TACAcTtaattatACTTC
740_1
-20.63
30666
|
7-5
|
|
740
TACACTTAATTATACTTC
3-1-2-
TACaCTtaattatACTTC
740_2
-20.74
30666
|
7-5
|
|
740
TACACTTAATTATACTTC
2-1-3-
TAcACTtaattatACTTC
740_3
-20.21
30666
|
7-5
|
|
740
TACACTTAATTATACTTC
3-1-2-
TACaCTtaattataCTTC
740_4
-20.14
30666
|
8-4
|
|
740
TACACTTAATTATACTTC
1-1-4-
TaCACTtaattataCTTC
740_5
-20.48
30666
|
8-4
|
|
741
TTACACTTAATTATACTTC
2-1-2-
TTaCActtaattATACtTC
741_1
-21.41
30666
|
7-4-1-2
|
|
741
TTACACTTAATTATACTTC
5-7-3-
TTACActtaattATAcTTC
741_2
-22.67
30666
|
1-3
|
|
741
TTACACTTAATTATACTTC
4-1-1-
TTACaCttaattATaCTTC
741_3
-22.54
30666
|
6-2-1-4
|
|
741
TTACACTTAATTATACTTC
2-1-2-
TTaCActtaattATaCTTC
741_4
-21.48
30666
|
7-2-1-4
|
|
741
TTACACTTAATTATACTTC
5-7-1-
TTACActtaattAtACTTC
741_5
-22.04
30666
|
1-5
|
|
742
TTACACTTAATTATACTT
5-7-3-
TTACActtaattATAcTT
742_1
-20.18
30667
|
1-2
|
|
742
TTACACTTAATTATACTT
5-7-2-
TTACActtaattATaCTT
742_2
-20.62
30667
|
1-3
|
|
742
TTACACTTAATTATACTT
5-7-1-
TTACActtaattAtACTT
742_3
-19.54
30667
|
1-4
|
|
743
TTTACACTTAATTATACTT
4-1-1-
TTTAcActtaatTATAcTT
743_1
-21.26
30667
|
6-4-1-2
|
|
743
TTTACACTTAATTATACTT
3-1-2-
TTTaCActtaatTATaCTT
743_2
-22.57
30667
|
6-3-1-3
|
|
743
TTTACACTTAATTATACTT
4-8-2-
TTTAcacttaatTAtACTT
743_3
-20.48
30667
|
1-4
|
|
743
TTTACACTTAATTATACTT
1-1-4-
TtTACActtaatTAtaCTT
743_4
-21.20
30667
|
6-2-2-3
|
|
743
TTTACACTTAATTATACTT
2-2-2-
TTtaCActtaatTaTACTT
743_5
-21.02
30667
|
6-1-1-5
|
|
744
TTTACACTTAATTATACT
3-1-2-
TTTaCActtaatTATaCT
744_1
-20.75
30668
|
6-3-1-2
|
|
744
TTTACACTTAATTATACT
1-1-4-
TtTACActtaatTATaCT
744_2
-21.06
30668
|
6-3-1-2
|
|
744
TTTACACTTAATTATACT
2-1-3-
TTtACActtaatTAtACT
744_3
-19.03
30668
|
6-2-1-3
|
|
744
TTTACACTTAATTATACT
4-8-1-
TTTAcacttaatTaTACT
744_4
-19.42
30668
|
1-4
|
|
744
TTTACACTTAATTATACT
1-1-1-
TtTaCActtaatTaTACT
744_5
-19.12
30668
|
1-2-6-
|
1-1-4
|
|
745
ATTTACACTTAATTATACT
4-1-1-
ATTTaCacttaaTTATaCT
745_1
-22.20
30668
|
6-4-1-2
|
|
745
ATTTACACTTAATTATACT
2-1-3-
ATtTACacttaaTTAtACT
745_2
-21.43
30668
|
6-3-1-3
|
|
745
ATTTACACTTAATTATACT
5-7-2-
ATTTAcacttaaTTaTACT
745_3
-22.44
30668
|
1-4
|
|
745
ATTTACACTTAATTATACT
1-2-3-
AttTACacttaaTTaTACT
745_4
-20.95
30668
|
6-2-1-4
|
|
745
ATTTACACTTAATTATACT
3-1-2-
ATTtACacttaaTtATACT
745_5
-20.92
30668
|
6-1-1-5
|
|
746
ATTTACACTTAATTATAC
5-8-5
ATTTAcacttaatTATAC
746_1
-19.94
30669
|
|
746
ATTTACACTTAATTATAC
4-1-1-
ATTTaCacttaatTATAC
746_2
-19.40
30669
|
7-5
|
|
746
ATTTACACTTAATTATAC
2-1-3-
ATtTACacttaatTATAC
746_3
-19.70
30669
|
7-5
|
|
747
AATTTACACTTAATTATAC
3-1-2-
AATtTAcacttaATTaTAC
747_1
-19.51
30669
|
6-3-1-3
|
|
747
AATTTACACTTAATTATAC
1-1-4-
AaTTTAcacttaATTaTAC
747_2
-19.51
30669
|
6-3-1-3
|
|
747
AATTTACACTTAATTATAC
4-8-2-
AATTtacacttaATtATAC
747_3
-18.04
30669
|
1-4
|
|
747
AATTTACACTTAATTATAC
5-7-1-
AATTTacacttaAtTATAC
747_4
-19.79
30669
|
1-5
|
|
747
AATTTACACTTAATTATAC
2-1-3-
AAtTTAcacttaAtTATAC
747_5
-19.26
30669
|
6-1-1-5
|
|
748
AATTTACACTTAATTATACT
3-2-2-
AATttACacttaaTTATaCT
748_1
-21.50
30668
|
6-4-1-2
|
|
748
AATTTACACTTAATTATACT
5-1-1-
AATTTaCacttaaTTAtACT
748_2
-21.87
30668
|
6-3-1-3
|
|
748
AATTTACACTTAATTATACT
3-1-3-
AATtTACacttaaTTaTACT
748_3
-22.95
30668
|
6-2-1-4
|
|
748
AATTTACACTTAATTATACT
1-1-4-
AaTTTAcacttaaTTaTaCT
748_4
-20.23
30668
|
7-2-1-
|
1-1-2
|
|
748
AATTTACACTTAATTATACT
2-1-2-
AAtTTaCacttaaTtATACT
748_5
-20.55
30668
|
1-1-6-
|
1-1-5
|
|
749
TAATTTACACTTAATTATAC
2-1-4-
TAaTTTAcacttaATTAtAC
749_1
-20.98
30669
|
6-4-1-2
|
|
749
TAATTTACACTTAATTATAC
5-8-3-
TAATTtacacttaATTaTAC
749_2
-20.60
30669
|
1-3
|
|
749
TAATTTACACTTAATTATAC
2-2-3-
TAatTTAcacttaATTaTAC
749_3
-20.80
30669
|
6-3-1-3
|
|
749
TAATTTACACTTAATTATAC
4-1-2-
TAATtTAcacttaATtATAC
749_4
-21.41
30669
|
6-2-1-4
|
|
749
TAATTTACACTTAATTATAC
1-1-1-
TaAtTTacacttaAtTATAC
749_5
-18.92
30669
|
1-2-7-
|
1-1-5
|
|
750
TAATTTACACTTAATTAT
5-8-5
TAATTtacacttaATTAT
750_1
-18.27
30671
|
|
750
TAATTTACACTTAATTAT
4-1-1-
TAATtTacacttaATTAT
750_2
-18.18
30671
|
7-5
|
|
750
TAATTTACACTTAATTAT
2-1-3-
TAaTTTacacttaATTAT
750_3
-18.18
30671
|
7-5
|
|
750
TAATTTACACTTAATTAT
1-1-4-
TaATTTacacttaATTAT
750_4
-18.16
30671
|
7-5
|
|
751
TAATTTACACTTAATTATA
5-7-4-
TAATTtacacttAATTaTA
751_1
-18.87
30670
|
1-2
|
|
751
TAATTTACACTTAATTATA
5-7-2-
TAATTtacacttAAtTATA
751_2
-19.05
30670
|
1-4
|
|
751
TAATTTACACTTAATTATA
3-1-2-
TAAtTTacacttAAtTATA
751_3
-18.54
30670
|
6-2-1-4
|
|
751
TAATTTACACTTAATTATA
4-1-1-
TAATtTacacttAaTTATA
751_4
-19.40
30670
|
6-1-1-5
|
|
751
TAATTTACACTTAATTATA
2-1-3-
TAaTTTacacttAaTTATA
751_5
-19.41
30670
|
6-1-1-5
|
|
752
TTAATTTACACTTAATTATA
3-1-3-
TTAaTTTacacttAATTaTA
752_1
-20.61
30670
|
6-4-1-2
|
|
752
TTAATTTACACTTAATTATA
5-1-1-
TTAATtTacacttAATtATA
752_2
-20.28
30670
|
6-3-1-3
|
|
752
TTAATTTACACTTAATTATA
2-1-4-
TTaATTTacacttAAtTATA
752_3
-20.77
30670
|
6-2-1-4
|
|
752
TTAATTTACACTTAATTATA
3-2-2-
TTAatTTacacttAaTTATA
752_4
-20.28
30670
|
6-1-1-5
|
|
752
TTAATTTACACTTAATTATA
4-1-1-
TTAAtTtacacttaAtTATA
752_5
-18.80
30670
|
8-1-1-4
|
|
753
TTAATTTACACTTAATTAT
4-1-1-
TTAAtTtacactTAAtTAT
753_1
-18.65
30671
|
6-3-1-3
|
|
753
TTAATTTACACTTAATTAT
3-1-2-
TTAaTTtacactTAaTTAT
753_2
-19.52
30671
|
6-2-1-4
|
|
753
TTAATTTACACTTAATTAT
2-1-2-
TTaATttacactTAaTTAT
753_3
-18.68
30671
|
7-2-1-4
|
|
753
TTAATTTACACTTAATTAT
5-7-1-
TTAATttacactTaATTAT
753_4
-20.00
30671
|
1-5
|
|
753
TTAATTTACACTTAATTAT
2-1-3-
TTaATTtacactTaATTAT
753_5
-19.47
30671
|
6-1-1-5
|
|
754
TTTAATTTACACTTAATTA
3-1-2-
TTTaATttacacTTAaTTA
754_1
-19.46
30672
|
6-3-1-3
|
|
754
TTTAATTTACACTTAATTA
5-7-2-
TTTAAtttacacTTaATTA
754_2
-19.54
30672
|
1-4
|
|
754
TTTAATTTACACTTAATTA
4-1-1-
TTTAaTttacacTTaATTA
754_3
-19.46
30672
|
6-2-1-4
|
|
754
TTTAATTTACACTTAATTA
1-1-1-
TtTaATttacacTTaATTA
754_4
-18.11
30672
|
1-2-6-
|
2-1-4
|
|
754
TTTAATTTACACTTAATTA
1-1-4-
TtTAATttacactTAAtTA
754_5
-18.02
30672
|
7-3-1-2
|
|
755
TTTAATTTACACTTAATTAT
4-1-2-
TTTAaTTtacactTAAtTAT
755_1
-20.90
30671
|
6-3-1-3
|
|
755
TTTAATTTACACTTAATTAT
3-1-2-
TTTaATttacactTAaTTAT
755_2
-20.50
30671
|
7-2-1-4
|
755
TTTAATTTACACTTAATTAT
1-1-5-
TtTAATTtacactTAaTTAT
755_3
-21.34
30671
|
6-2-1-4
|
|
755
TTTAATTTACACTTAATTAT
5-8-1-
TTTAAtttacactTaATTAT
755_4
-20.58
30671
|
1-5
|
|
755
TTTAATTTACACTTAATTAT
2-2-3-
TTtaATTtacactTaATTAT
755_5
-20.05
30671
|
6-1-1-5
|
|
756
ATTTAATTTACACTTAATTA
5-1-1-
ATTTAaTttacacTTAAtTA
756_1
-21.11
30672
|
6-4-1-2
|
|
756
ATTTAATTTACACTTAATTA
3-2-2-
ATTtaATttacacTTAaTTA
756_2
-20.29
30672
|
6-3-1-3
|
|
756
ATTTAATTTACACTTAATTA
4-1-2-
ATTTaATttacacTTaATTA
756_3
-21.50
30672
|
6-2-1-4
|
|
756
ATTTAATTTACACTTAATTA
2-1-4-
ATtTAATttacacTTaaTTA
756_4
-20.39
30672
|
6-2-2-3
|
|
756
ATTTAATTTACACTTAATTA
2-1-4-
ATtTAATttacacttAATTA
756_5
-20.08
30672
|
8-5
|
|
757
ATTTAATTTACACTTAATT
5-7-3-
ATTTAatttacaCTTaATT
757_1
-20.52
30673
|
1-3
|
|
757
ATTTAATTTACACTTAATT
4-1-1-
ATTTaAtttacacTTaATT
757_2
-18.02
30673
|
7-2-1-3
|
|
757
ATTTAATTTACACTTAATT
2-1-3-
ATtTAAtttacacTTaATT
757_3
-18.04
30673
|
7-2-1-3
|
|
757
ATTTAATTTACACTTAATT
4-1-1-
ATTTaAtttacactTAATT
757_4
-18.34
30673
|
8-5
|
|
757
ATTTAATTTACACTTAATT
2-1-3-
ATtTAAtttacactTAATT
757_5
-18.37
30673
|
8-5
|
|
758
TATTTAATTTACACTTAAT
3-1-2-
TATtTAatttacACTTaAT
758_1
-20.16
30674
|
6-4-1-2
|
|
758
TATTTAATTTACACTTAAT
2-1-3-
TAtTTAatttacACtTAAT
758_2
-19.37
30674
|
6-2-1-4
|
|
758
TATTTAATTTACACTTAAT
1-1-4-
TaTTTAatttacACtTAAT
758_3
-19.19
30674
|
6-2-1-4
|
|
758
TATTTAATTTACACTTAAT
3-1-2-
TATtTAatttacAcTTAAT
758_4
-19.44
30674
|
6-1-1-5
|
|
758
TATTTAATTTACACTTAAT
2-1-3-
TAtTTAatttacAcTTAAT
758_5
-19.00
30674
|
6-1-1-5
|
|
759
TATTTAATTTACACTTAATT
2-1-4-
TAtTTAAtttacaCTTAaTT
759_1
-21.54
30673
|
6-4-1-2
|
|
759
TATTTAATTTACACTTAATT
5-1-1-
TATTTaAtttacaCTTaATT
759_2
-21.92
30673
|
6-3-1-3
|
|
759
TATTTAATTTACACTTAATT
4-1-2-
TATTtAAtttacacTTAaTT
759_3
-19.35
30673
|
7-3-1-2
|
|
759
TATTTAATTTACACTTAATT
3-1-3-
TATtTAAtttacacTTaATT
759_4
-20.28
30673
|
7-2-1-3
|
|
759
TATTTAATTTACACTTAATT
2-1-4-
TAtTTAAtttacactTAATT
759_5
-20.16
30673
|
8-5
|
|
760
CTATTTAATTTACACTT
5-6-1-
CTATTtaatttAcACTT
760_1
-19.07
30677
|
1-4
|
|
760
CTATTTAATTTACACTT
5-7-5
CTATTtaatttaCACTT
760_2
-20.97
30677
|
|
760
CTATTTAATTTACACTT
2-2-1-
CTatTtaatttaCACTT
760_3
-18.08
30677
|
7-5
|
|
760
CTATTTAATTTACACTT
5-7-2-
CTATTtaatttaCAcTT
760_4
-18.90
30677
|
1-2
|
|
760
CTATTTAATTTACACTT
5-7-1-
CTATTtaatttaCaCTT
760_5
-19.01
30677
|
1-3
|
|
761
CTATTTAATTTACACTTAA
2-1-3-
CTaTTTaatttaCACTtAA
761_1
-20.98
30675
|
6-4-1-2
|
|
761
CTATTTAATTTACACTTAA
3-1-2-
CTAtTTaatttaCACtTAA
761_2
-21.73
30675
|
6-3-1-3
|
|
761
CTATTTAATTTACACTTAA
4-1-1-
CTATtTaatttaCAcTTAA
761_3
-21.80
30675
|
6-2-1-4
|
|
761
CTATTTAATTTACACTTAA
5-7-2-
CTATTtaatttaCActTAA
761_4
-20.86
30675
|
2-3
|
|
761
CTATTTAATTTACACTTAA
2-1-3-
CTaTTTaatttaCaCTTAA
761_5
-21.29
30675
|
6-1-1-5
|
|
762
CTATTTAATTTACACTTA
5-7-3-
CTATTtaatttaCACtTA
762_1
-21.50
30676
|
1-2
|
|
762
CTATTTAATTTACACTTA
3-2-1-
CTAttTaatttaCACtTA
762_2
-20.17
30676
|
6-3-1-2
|
|
762
CTATTTAATTTACACTTA
3-1-1-
CTAtTtaatttaCAcTTA
762_3
-19.37
30676
|
7-2-1-3
|
|
762
CTATTTAATTTACACTTA
2-1-3-
CTaTTTaatttaCAcTTA
762_4
-20.43
30676
|
6-2-1-3
|
|
762
CTATTTAATTTACACTTA
2-1-3-
CTaTTTaatttaCaCTTA
762_5
-20.54
30676
|
6-1-1-4
|
|
763
CTATTTAATTTACACTTAAT
2-1-4-
CTaTTTAatttacACTtaAT
763_1
-21.79
30674
|
6-3-2-2
|
|
763
CTATTTAATTTACACTTAAT
4-1-2-
CTATtTAatttacACtTAAT
763_2
-23.29
30674
|
6-2-1-4
|
|
763
CTATTTAATTTACACTTAAT
1-2-4-
CtaTTTAatttacAcTTAAT
763_3
-20.68
30674
|
6-1-1-5
|
|
763
CTATTTAATTTACACTTAAT
3-1-3-
CTAtTTAatttacAcTTaAT
763_4
-21.14
30674
|
6-1-1-
|
2-1-2
|
|
763
CTATTTAATTTACACTTAAT
5-1-1-
CTATTtAatttacaCTTaAT
763_5
-22.14
30674
|
7-3-1-2
|
|
764
TCTATTTAATTTACACTTA
2-1-3-
TCtATTtaatttACACtTA
764_1
-21.94
30676
|
6-4-1-2
|
|
764
TCTATTTAATTTACACTTA
4-1-1-
TCTAtTtaatttACAcTTA
764_2
-22.47
30676
|
6-3-1-3
|
|
764
TCTATTTAATTTACACTTA
3-1-2-
TCTaTTtaatttaCAcTTA
764_3
-21.69
30676
|
7-2-1-3
|
|
764
TCTATTTAATTTACACTTA
1-1-4-
TcTATTtaatttaCActTA
764_4
-20.33
30676
|
7-2-2-2
|
|
764
TCTATTTAATTTACACTTA
3-2-1-
TCTatTtaatttaCaCTTA
764_5
-20.85
30676
|
7-1-1-4
|
|
765
TCTATTTAATTTACACTT
3-2-1-
TCTatTtaatttACaCTT
765_1
-19.21
30677
|
6-2-1-3
|
|
765
TCTATTTAATTTACACTT
3-1-2-
TCTaTTtaatttaCACTT
765_2
-21.53
30677
|
7-5
|
|
765
TCTATTTAATTTACACTT
2-1-3-
TCtATTtaatttaCACTT
765_3
-20.81
30677
|
7-5
|
|
765
TCTATTTAATTTACACTT
4-1-1-
TCTAtTtaatttaCAcTT
765_4
-19.64
30677
|
7-2-1-2
|
|
765
TCTATTTAATTTACACTT
1-1-4-
TcTATTtaatttaCAcTT
765_5
-19.12
30677
|
7-2-1-2
|
|
766
TCTATTTAATTTACACTTAA
2-1-2-
TCtATtTaatttaCACttAA
766_1
-20.25
30675
|
1-1-6-
|
3-2-2
|
|
766
TCTATTTAATTTACACTTAA
4-1-1-
TCTAtTtaatttaCAcTTAA
766_2
-22.62
30675
|
7-2-1-4
|
|
766
TCTATTTAATTTACACTTAA
1-1-1-
TcTaTTTaatttaCActTAA
766_3
-20.38
30675
|
1-3-6-
|
2-2-3
|
|
766
TCTATTTAATTTACACTTAA
3-1-2-
TCTaTTtaatttaCaCTtAA
766_4
-20.27
30675
|
7-1-1-
|
2-1-2
|
|
766
TCTATTTAATTTACACTTAA
2-3-2-
TCtatTTaatttaCaCtTAA
766_5
-19.51
30675
|
6-1-1-
|
1-1-3
|
|
767
ATCTATTTAATTTACACTT
2-1-2-
ATcTAtttaattTACAcTT
767_1
-21.49
30677
|
7-4-1-2
|
|
767
ATCTATTTAATTTACACTT
1-1-4-
AtCTATttaattTACaCTT
767_2
-23.18
30677
|
6-3-1-3
|
|
767
ATCTATTTAATTTACACTT
4-1-1-
ATCTaTttaattTAcACTT
767_3
-22.64
30677
|
6-2-1-4
|
|
767
ATCTATTTAATTTACACTT
5-7-2-
ATCTAtttaattTAcaCTT
767_4
-22.78
30677
|
2-3
|
|
767
ATCTATTTAATTTACACTT
1-1-4-
AtCTATttaattTaCACTT
767_5
-23.52
30677
|
6-1-1-5
|
|
768
ATCTATTTAATTTACACTTA
1-2-4-
AtcTATTtaatttACaCtTA
768_1
-21.10
30676
|
6-2-1-
|
1-1-2
|
|
768
ATCTATTTAATTTACACTTA
1-1-3-
AtCTAtTtaatttAcACTTA
768_2
-22.17
30676
|
1-1-6-
|
1-1-5
|
|
768
ATCTATTTAATTTACACTTA
3-2-2-
ATCtaTTtaatttAcACtTA
768_3
-20.60
30676
|
6-1-1-
|
2-1-2
|
|
768
ATCTATTTAATTTACACTTA
1-1-2-
AtCTaTTtaatttaCActTA
768_4
-20.80
30676
|
1-2-7-
|
2-2-2
|
|
768
ATCTATTTAATTTACACTTA
3-1-1-
ATCtAtTtaatttaCacTTA
768_5
-19.72
30676
|
1-1-7-
|
1-2-3
|
|
769
TATCTATTTAATTTACACTT
1-1-2-
TaTCtATttaattTACAcTT
769_1
-22.65
30677
|
1-2-6-
|
4-1-2
|
|
769
TATCTATTTAATTTACACTT
2-1-1-
TAtCtATttaattTAcACTT
769_2
-22.23
30677
|
1-2-6-
|
2-1-4
|
|
769
TATCTATTTAATTTACACTT
2-1-4-
TAtCTATttaattTAcacTT
769_3
-22.66
30677
|
6-2-3-2
|
|
769
TATCTATTTAATTTACACTT
1-3-3-
TatcTATttaattTaCACTT
769_4
-22.96
30677
|
6-1-1-5
|
|
769
TATCTATTTAATTTACACTT
1-1-3-
TaTCTaTttaattTacaCTT
769_5
-21.15
30677
|
1-1-6-
|
1-3-3
|
|
770
TATCTATTTAATTTACACT
2-1-3-
TAtCTAtttaatTTAcACT
770_1
-22.62
30678
|
6-3-1-3
|
|
770
TATCTATTTAATTTACACT
1-1-4-
TaTCTAtttaatTTAcACT
770_2
-22.62
30678
|
6-3-1-3
|
|
770
TATCTATTTAATTTACACT
2-2-2-
TAtcTAtttaatTTaCACT
770_3
-21.84
30678
|
6-2-1-4
|
|
770
TATCTATTTAATTTACACT
1-2-3-
TatCTAtttaatTtACACT
770_4
-21.72
30678
|
6-1-1-5
|
|
770
TATCTATTTAATTTACACT
4-1-1-
TATCtAtttaattTAcACT
770_5
-21.09
30678
|
7-2-1-3
|
|
771
TTATCTATTTAATTTACACT
2-4-1-
TTatctAtttaatTTACaCT
771_1
-20.22
30678
|
6-4-1-2
|
|
771
TTATCTATTTAATTTACACT
2-2-3-
TTatCTAtttaatTTAcaCT
771_2
-22.76
30678
|
6-3-2-2
|
|
771
TTATCTATTTAATTTACACT
1-1-5-
TtATCTAtttaatTTacACT
771_3
-22.87
30678
|
6-2-2-3
|
|
771
TTATCTATTTAATTTACACT
2-2-3-
TTatCTAtttaatTtaCACT
771_4
-22.94
30678
|
6-1-2-4
|
|
771
TTATCTATTTAATTTACACT
5-1-1-
TTATCtAtttaattTacACT
771_5
-21.68
30678
|
7-1-2-3
|
|
772
TTTATCTATTTAATTTACA
1-1-3-
TtTATctatttaATTTaCA
772_1
-19.96
30680
|
7-4-1-2
|
|
772
TTTATCTATTTAATTTACA
4-1-1-
TTTAtCtatttaATTtaCA
772_2
-19.70
30680
|
6-3-2-2
|
|
772
TTTATCTATTTAATTTACA
3-1-2-
TTTaTCtatttaATtTACA
772_3
-21.24
30680
|
6-2-1-4
|
|
772
TTTATCTATTTAATTTACA
5-7-2-
TTTATctatttaATttACA
772_4
-19.82
30680
|
2-3
|
|
772
TTTATCTATTTAATTTACA
1-1-4-
TtTATCtatttaAtTTACA
772_5
-21.42
30680
|
6-1-1-5
|
|
773
TTTTATCTATTTAATTTAC
2-1-3-
TTtTATctatttAATtTAC
773_1
-19.10
30681
|
6-3-1-3
|
|
773
TTTTATCTATTTAATTTAC
1-1-4-
TtTTATctatttAAtTTAC
773_2
-18.66
30681
|
6-2-1-4
|
|
773
TTTTATCTATTTAATTTAC
3-1-2-
TTTtATctatttAaTTTAC
773_3
-18.15
30681
|
6-1-1-5
|
|
773
TTTTATCTATTTAATTTAC
1-2-3-
TttTATctatttAaTTTAC
773_4
-18.29
30681
|
6-1-1-5
|
|
773
TTTTATCTATTTAATTTAC
2-1-3-
TTtTATctatttAatTTAC
773_5
-18.15
30681
|
6-1-2-4
|
|
774
TTTTATCTATTTAATTTACA
1-1-2-
TtTTaTctatttaATTTaCA
774_1
-19.84
30680
|
1-1-7-
|
4-1-2
|
|
774
TTTTATCTATTTAATTTACA
2-1-1-
TTtTaTCtatttaATTtACA
774_2
-20.79
30680
|
1-2-6-
|
3-1-3
|
|
774
TTTTATCTATTTAATTTACA
4-2-1-
TTTTatCtatttaATtTACA
774_3
-21.94
30680
|
6-2-1-4
|
|
774
TTTTATCTATTTAATTTACA
1-1-5-
TtTTATCtatttaATttaCA
774_4
-21.32
30680
|
6-2-3-2
|
|
774
TTTTATCTATTTAATTTACA
2-2-3-
TTttATCtatttaAttTACA
774_5
-20.67
30680
|
6-1-2-4
|
|
775
CTTTTATCTATTTAATTTA
5-7-4-
CTTTTatctattTAATtTA
775_1
-21.18
30682
|
1-2
|
|
775
CTTTTATCTATTTAATTTA
5-7-2-
CTTTTatctattTAaTTTA
775_2
-21.18
30682
|
1-4
|
|
775
CTTTTATCTATTTAATTTA
5-7-2-
CTTTTatctattTAatTTA
775_3
-20.23
30682
|
2-3
|
|
775
CTTTTATCTATTTAATTTA
3-1-1-
CTTtTatctattTaATTTA
775_4
-19.83
30682
|
7-1-1-5
|
|
775
CTTTTATCTATTTAATTTA
2-1-2-
CTtTTatctattTaAtTTA
775_5
-18.07
30682
|
7-1-1-
|
1-1-3
|
|
776
CTTTTATCTATTTAATTTAC
1-1-5-
CtTTTATctatttAATTtAC
776_1
-21.25
30681
|
6-4-1-2
|
|
776
CTTTTATCTATTTAATTTAC
3-1-1-
CTTtTatctatttAATtTAC
776_2
-20.13
30681
|
8-3-1-3
|
|
776
CTTTTATCTATTTAATTTAC
5-8-2-
CTTTTatctatttAAtTTAC
776_3
-21.02
30681
|
1-4
|
|
776
CTTTTATCTATTTAATTTAC
1-1-2-
CtTTtATctatttAAtTTAC
776_4
-19.49
30681
|
1-2-6-
|
2-1-4
|
|
776
CTTTTATCTATTTAATTTAC
2-1-4-
CTtTTATctatttAAttTAC
776_5
-21.33
30681
|
6-2-2-3
|
|
777
ACTTTTATCTATTTAATTT
4-1-1-
ACTTtTatctatTTAAtTT
777_1
-20.04
30683
|
6-4-1-2
|
|
777
ACTTTTATCTATTTAATTT
3-1-2-
ACTtTTatctatTTAaTTT
777_2
-20.48
30683
|
6-3-1-3
|
|
777
ACTTTTATCTATTTAATTT
5-7-2-
ACTTTtatctatTTaATTT
777_3
-20.54
30683
|
1-4
|
|
777
ACTTTTATCTATTTAATTT
2-2-2-
ACttTTatctatTTaATTT
777_4
-19.26
30683
|
6-2-1-4
|
|
777
ACTTTTATCTATTTAATTT
4-1-1-
ACTTtTatctatTtaATTT
777_5
-19.21
30683
|
6-1-2-4
|
|
778
ACTTTTATCTATTTAATTTA
2-3-1-
ACtttTatctattTAATtTA
778_1
-19.89
30682
|
7-4-1-2
|
|
778
ACTTTTATCTATTTAATTTA
1-1-4-
AcTTTTatctattTAaTtTA
778_2
-19.82
30682
|
7-2-1-
|
1-1-2
|
|
778
ACTTTTATCTATTTAATTTA
3-2-1-
ACTTTTatctattTAatTTA
778_3
-20.13
30682
|
7-2-2-3
|
|
778
ACTTTTATCTATTTAATTTA
4-9-1-
ACTTttatctattTaATTTA
778_4
-21.14
30682
|
1-5
|
|
778
ACTTTTATCTATTTAATTTA
2-1-3-
ACtTTTatctattTaATTTA
778_5
-21.49
30682
|
7-1-1-5
|
|
779
ACTTTTATCTATTTAATT
2-1-3-
ACtTTTatctatTTaATT
779_1
-18.25
30684
|
6-2-1-3
|
|
779
ACTTTTATCTATTTAATT
4-1-1-
ACTTtTatctattTAATT
779_2
-19.17
30684
|
7-5
|
|
779
ACTTTTATCTATTTAATT
3-1-2-
ACTtTTatctattTAATT
779_3
-19.17
30684
|
7-5
|
|
779
ACTTTTATCTATTTAATT
2-1-3-
ACtTTTatctattTAATT
779_4
-18.79
30684
|
7-5
|
|
779
ACTTTTATCTATTTAATT
1-1-4-
AcTTTTatctattTAATT
779_5
-18.42
30684
|
7-5
|
|
780
AACTTTTATCTATTTAATT
5-7-3-
AACTTttatctaTTTaATT
780_1
-19.61
30684
|
1-3
|
|
780
AACTTTTATCTATTTAATT
5-8-3-
AACTTttatctatTTAaTT
780_2
-18.68
30684
|
1-2
|
|
780
AACTTTTATCTATTTAATT
4-1-1-
AACTtTtatctatTTAaTT
780_3
-18.17
30684
|
7-3-1-2
|
|
780
AACTTTTATCTATTTAATT
1-1-4-
AaCTTTtatctatTTaATT
780_4
-18.45
30684
|
7-2-1-3
|
|
780
AACTTTTATCTATTTAATT
5-9-5
AACTTttatctattTAATT
780_5
-19.19
30684
|
|
781
AACTTTTATCTATTTAAT
5-8-5
AACTTttatctatTTAAT
781_1
-18.18
30685
|
|
782
AACTTTTATCTATTTAATTT
1-1-1-
AaCtTTTatctatTTAAtTT
782_1
-19.40
30683
|
1-3-6-
|
4-1-2
|
|
782
AACTTTTATCTATTTAATTT
4-2-1-
AACTttTatctatTTAaTTT
782_2
-20.41
30683
|
6-3-1-3
|
|
782
AACTTTTATCTATTTAATTT
5-1-1-
AACTTtTatctatTTaATTT
782_3
-21.20
30683
|
6-2-1-4
|
|
782
AACTTTTATCTATTTAATTT
2-1-4-
AAcTTTTatctatTtaATTT
782_4
-19.21
30683
|
6-1-2-4
|
|
782
AACTTTTATCTATTTAATTT
1-1-2-
AaCTtTTatctattTAaTTT
782_5
-19.40
30683
|
1-2-7-
|
2-1-3
|
|
783
TAACTTTTATCTATTTAAT
2-1-3-
TAaCTTttatctATTTaAT
783_1
-19.91
30685
|
6-4-1-2
|
|
783
TAACTTTTATCTATTTAAT
2-1-3-
TAaCTTttatctATtTAAT
783_2
-19.93
30685
|
6-2-1-4
|
|
783
TAACTTTTATCTATTTAAT
5-7-2-
TAACTtttatctATtTaAT
783_3
-18.79
30685
|
1-1-1-2
|
|
783
TAACTTTTATCTATTTAAT
1-1-4-
TaACTTttatctAtTTAAT
783_4
-19.16
30685
|
6-1-1-5
|
|
783
TAACTTTTATCTATTTAAT
5-9-5
TAACTtttatctatTTAAT
783_5
-19.60
30685
|
|
784
TAACTTTTATCTATTTAATT
4-1-1-
TAACtTttatctaTtTAaTT
784_1
-18.83
30684
|
7-1-1-
|
2-1-2
|
|
784
TAACTTTTATCTATTTAATT
2-1-4-
TAaCTTTtatctatTTAaTT
784_2
-20.71
30684
|
7-3-1-2
|
|
784
TAACTTTTATCTATTTAATT
2-1-3-
TAaCTTttatctatTTaATT
784_3
-19.87
30684
|
8-2-1-3
|
|
784
TAACTTTTATCTATTTAATT
1-1-5-
TaACTTTtatctatTTaATT
784_4
-20.35
30684
|
7-2-1-3
|
|
784
TAACTTTTATCTATTTAATT
5-10-5
TAACTtttatctattTAATT
784_5
-20.61
30684
|
|
785
TAACTTTTATCTATTTAA
5-7-2-
TAACTtttatctATtTAA
785_1
-18.07
30686
|
1-3
|
|
786
ATAACTTTTATCTATTTAA
3-1-2-
ATAaCTtttatcTATTtAA
786_1
-20.14
30686
|
6-4-1-2
|
|
786
ATAACTTTTATCTATTTAA
4-1-1-
ATAAcTtttatcTATtTAA
786_2
-20.03
30686
|
6-3-1-3
|
|
786
ATAACTTTTATCTATTTAA
2-1-3-
ATaACTtttatcTAtTTAA
786_3
-20.33
30686
|
6-2-1-4
|
|
786
ATAACTTTTATCTATTTAA
3-1-2-
ATAaCTtttatcTAttTAA
786_4
-19.84
30686
|
6-2-2-3
|
|
786
ATAACTTTTATCTATTTAA
5-7-1-
ATAACttttatcTaTTTAA
786_5
-20.30
30686
|
1-5
|
|
787
ATAACTTTTATCTATTTAAT
3-1-3-
ATAaCTTttatctATTtaAT
787_1
-20.73
30685
|
6-3-2-2
|
|
787
ATAACTTTTATCTATTTAAT
2-1-4-
ATaACTTttatctATtTAAT
787_2
-21.66
30685
|
6-2-1-4
|
|
787
ATAACTTTTATCTATTTAAT
3-1-2-
ATAaCTtttatctAttTAAT
787_3
-19.93
30685
|
7-1-2-4
|
|
787
ATAACTTTTATCTATTTAAT
4-2-1-
ATAActTttatctaTTTaAT
787_4
-18.98
30685
|
7-3-1-2
|
|
787
ATAACTTTTATCTATTTAAT
2-1-4-
ATaACTTttatctatTTAAT
787_5
-21.13
30685
|
8-5
|
|
788
TATAACTTTTATCTATTTA
1-1-2-
TaTAaCttttatCTATtTA
788_1
-21.10
30687
|
1-1-6-
|
4-1-2
|
|
788
TATAACTTTTATCTATTTA
2-2-2-
TAtaACttttatCTAtTTA
788_2
-20.60
30687
|
6-3-1-3
|
|
788
TATAACTTTTATCTATTTA
3-1-2-
TATaACttttatCTaTTTA
788_3
-22.09
30687
|
6-2-1-4
|
|
788
TATAACTTTTATCTATTTA
5-7-1-
TATAActtttatCtATTTA
788_4
-21.33
30687
|
1-5
|
|
788
TATAACTTTTATCTATTTA
4-1-1-
TATAaCttttatcTAttTA
788_5
-20.13
30687
|
7-2-2-2
|
|
789
TATAACTTTTATCTATTTAA
4-1-1-
TATAaCttttatcTATTtAA
789_1
-21.18
30686
|
7-4-1-2
|
|
789
TATAACTTTTATCTATTTAA
2-2-3-
TAtaACTtttatcTATtTAA
789_2
-21.32
30686
|
6-3-1-3
|
|
789
TATAACTTTTATCTATTTAA
1-1-5-
TaTAACTtttatcTAtTTAA
789_3
-21.97
30686
|
6-2-1-4
|
|
789
TATAACTTTTATCTATTTAA
3-1-2-
TATaACttttatcTaTtTAA
789_4
-19.86
30686
|
7-1-1-
|
1-1-3
|
|
789
TATAACTTTTATCTATTTAA
4-2-1-
TATAacTtttatcTatTTAA
789_5
-20.09
30686
|
6-1-2-4
|
|
790
TTATAACTTTTATCTATTT
2-1-3-
TTaTAActtttaTCTAtTT
790_1
-21.00
30688
|
6-4-1-2
|
|
790
TTATAACTTTTATCTATTT
5-7-2-
TTATAacttttaTCtaTTT
790_2
-20.52
30688
|
2-3
|
|
790
TTATAACTTTTATCTATTT
4-1-1-
TTATaActtttaTcTATTT
790_3
-21.08
30688
|
6-1-1-5
|
|
790
TTATAACTTTTATCTATTT
4-1-1-
TTATaActtttatCTAtTT
790_4
-20.46
30688
|
7-3-1-2
|
|
790
TTATAACTTTTATCTATTT
2-1-3-
TTaTAActtttatcTATTT
790_5
-19.98
30688
|
8-5
|
|
791
TTATAACTTTTATCTATT
5-7-3-
TTATAacttttaTCTaTT
791_1
-20.32
30689
|
1-2
|
|
791
TTATAACTTTTATCTATT
5-7-1-
TTATAacttttaTcTATT
791_2
-19.99
30689
|
1-4
|
|
791
TTATAACTTTTATCTATT
4-1-1-
TTATaActtttatCTATT
791_3
-20.40
30689
|
7-5
|
|
791
TTATAACTTTTATCTATT
4-9-5
TTATaacttttatCTATT
791_4
-19.98
30689
|
|
791
TTATAACTTTTATCTATT
2-1-3-
TTaTAActtttatCTATT
791_5
-19.81
30689
|
7-5
|
|
792
TTATAACTTTTATCTATTTA
1-2-1-
TtaTaACttttatCTAttTA
792_1
-20.10
30687
|
1-2-6-
|
3-2-2
|
|
792
TTATAACTTTTATCTATTTA
3-2-1-
TTAtaActtttatCtATtTA
792_2
-18.80
30687
|
7-1-1-
|
2-1-2
|
|
792
TTATAACTTTTATCTATTTA
4-1-2-
TTATaACttttatCtatTTA
792_3
-21.34
30687
|
6-1-3-3
|
|
792
TTATAACTTTTATCTATTTA
2-1-2-
TTaTAaCttttatcTAtTTA
792_4
-20.83
30687
|
1-1-7-
|
2-1-3
|
|
792
TTATAACTTTTATCTATTTA
1-1-4-
TtATAActtttatcTaTTTA
792_5
-19.94
30687
|
8-1-1-4
|
|
793
CTTATAACTTTTATCTATT
1-1-1-
CtTaTAacttttATCtaTT
793_1
-19.45
30689
|
1-2-6-
|
3-2-2
|
|
793
CTTATAACTTTTATCTATT
1-2-3-
CttATAacttttAtCTATT
793_2
-21.25
30689
|
6-1-1-5
|
|
793
CTTATAACTTTTATCTATT
3-2-1-
CTTatAacttttatCTATT
793_3
-20.78
30689
|
8-5
|
|
793
CTTATAACTTTTATCTATT
1-1-3-
CtTATaacttttatCTaTT
793_4
-19.82
30689
|
9-2-1-2
|
|
793
CTTATAACTTTTATCTATT
5-9-1-
CTTATaacttttatCtATT
793_5
-20.81
30689
|
1-3
|
|
794
CTTATAACTTTTATCTAT
5-7-3-
CTTATaacttttATCtAT
794_1
-21.02
30690
|
1-2
|
|
794
CTTATAACTTTTATCTAT
1-1-3-
CtTATaacttttAtCTAT
794_2
-20.04
30690
|
7-1-1-4
|
|
794
CTTATAACTTTTATCTAT
2-2-1-
CTtaTaacttttaTCTAT
794_3
-19.59
30690
|
8-5
|
|
794
CTTATAACTTTTATCTAT
3-1-2-
CTTaTAacttttatCTAT
794_4
-20.86
30690
|
8-4
|
|
794
CTTATAACTTTTATCTAT
5-10-3
CTTATaacttttatcTAT
794_5
-19.99
30690
|
|
795
CTTATAACTTTTATCTATTT
1-1-1-
CtTatAActtttaTCtAtTT
795_1
-18.22
30688
|
2-2-6-
|
2-1-1-
|
1-2
|
|
795
CTTATAACTTTTATCTATTT
1-1-1-
CtTaTAacttttatCTaTTT
795_2
-20.86
30688
|
1-2-8-
|
2-1-3
|
|
795
CTTATAACTTTTATCTATTT
2-1-2-
CTtATaActtttatCTatTT
795_3
-20.54
30688
|
1-1-7-
|
2-2-2
|
|
795
CTTATAACTTTTATCTATTT
3-2-1-
CTTatAacttttatCtAtTT
795_4
-18.19
30688
|
8-1-1-
|
1-1-2
|
|
795
CTTATAACTTTTATCTATTT
1-2-2-
CttATaActtttatctATTT
795_5
-18.61
30688
|
1-1-9-4
|
|
796
CTTATAACTTTTATCTA
5-6-2-
CTTATaactttTAtCTA
796_1
-21.44
30691
|
1-3
|
|
796
CTTATAACTTTTATCTA
5-6-1-
CTTATaactttTatCTA
796_2
-20.31
30691
|
2-3
|
|
796
CTTATAACTTTTATCTA
1-1-3-
CtTATaacttttATCTA
796_3
-19.90
30691
|
7-5
|
|
796
CTTATAACTTTTATCTA
3-1-1-
CTTaTaacttttaTCTA
796_4
-18.77
30691
|
8-4
|
|
796
CTTATAACTTTTATCTA
2-1-2-
CTtATaacttttaTCTA
796_5
-18.43
30691
|
8-4
|
|
797
GCTTATAACTTTTATCTA
2-2-2-
GCttATaactttTAtcTA
797_1
-21.32
30691
|
6-2-2-2
|
|
797
GCTTATAACTTTTATCTA
4-9-1-
GCTTataacttttAtCTA
797_2
-21.88
30691
|
1-3
|
|
797
GCTTATAACTTTTATCTA
2-12-4
GCttataacttttaTCTA
797_3
-20.47
30691
|
|
797
GCTTATAACTTTTATCTA
2-1-1-
GCtTaTaacttttatCTA
797_4
-20.94
30691
|
1-1-9-3
|
|
797
GCTTATAACTTTTATCTA
1-1-4-
GcTTATaacttttatcTA
797_5
-19.62
30691
|
10-2
|
|
798
GCTTATAACTTTTATCT
2-9-1-
GCttataacttTtaTCT
798_1
-18.54
30692
|
2-3
|
|
798
GCTTATAACTTTTATCT
2-10-5
GCttataactttTATCT
798_2
-20.90
30692
|
|
798
GCTTATAACTTTTATCT
4-8-1-
GCTTataactttTaTCT
798_3
-21.40
30692
|
1-3
|
|
798
GCTTATAACTTTTATCT
2-1-2-
GCtTAtaacttttATCT
798_4
-21.00
30692
|
8-4
|
|
798
GCTTATAACTTTTATCT
5-10-2
GCTTAtaacttttatCT
798_5
-20.68
30692
|
|
799
TGCTTATAACTTTTATC
3-8-3-
TGCttataactTTTaTC
799_1
-19.59
30693
|
1-2
|
|
799
TGCTTATAACTTTTATC
3-8-2-
TGCttataactTTtATC
799_2
-19.26
30693
|
1-3
|
|
799
TGCTTATAACTTTTATC
2-10-5
TGcttataacttTTATC
799_3
-18.08
30693
|
|
799
TGCTTATAACTTTTATC
5-8-4
TGCTTataactttTATC
799_4
-22.34
30693
|
|
799
TGCTTATAACTTTTATC
3-10-4
TGCttataactttTATC
799_5
-19.90
30693
|
|
800
TGCTTATAACTTTTATCT
3-9-3-
TGCttataacttTTAtCT
800_1
-22.27
30692
|
1-2
|
|
800
TGCTTATAACTTTTATCT
2-2-2-
TGctTAtaactttTATCT
800_2
-22.61
30692
|
7-5
|
|
800
TGCTTATAACTTTTATCT
3-10-1-
TGCttataactttTaTCT
800_3
-21.45
30692
|
1-3
|
|
800
TGCTTATAACTTTTATCT
1-1-1-
TgCtTAtaacttttATCT
800_4
-20.79
30692
|
1-2-8-4
|
|
800
TGCTTATAACTTTTATCT
4-1-1-
TGCTtAtaacttttatCT
800_5
-20.89
30692
|
10-2
|
|
801
CTGCTTATAACTTTTATC
2-1-1-
CTgCttataactTTtATC
801_1
-20.05
30693
|
8-2-1-3
|
|
801
CTGCTTATAACTTTTATC
4-8-1-
CTGCttataactTttaTC
801_2
-21.02
30693
|
3-2
|
|
801
CTGCTTATAACTTTTATC
2-1-1-
CTgCttataactttTATC
801_3
-20.69
30693
|
10-4
|
|
801
CTGCTTATAACTTTTATC
1-1-2-
CtGCttataactttTaTC
801_4
-18.86
30693
|
10-1-1-
|
2
|
|
801
CTGCTTATAACTTTTATC
1-1-4-
CtGCTTataacttttATC
801_5
-21.47
30693
|
9-3
|
|
802
CTCTGCTTATAACTTTT
1-1-1-
CtCtGcttataACtTTT
802_1
-18.92
30696
|
1-1-6-
|
2-1-3
|
|
802
CTCTGCTTATAACTTTT
1-1-1-
CtCtGcttataaCTtTT
802_2
-18.47
30696
|
1-1-7-
|
2-1-2
|
|
802
CTCTGCTTATAACTTTT
1-1-2-
CtCTgcttataaCtTTT
802_3
-19.44
30696
|
8-1-1-3
|
|
802
CTCTGCTTATAACTTTT
1-2-2-
CtcTGcttataaCtTTT
802_4
-19.02
30696
|
7-1-1-3
|
|
802
CTCTGCTTATAACTTTT
3-1-1-
CTCtGcttataacttTT
802_5
-18.16
30696
|
10-2
|
|
803
CCTCTGCTTATAACTTT
1-1-2-
CcTCtgcttatAAcTTT
803_1
-20.60
30697
|
7-2-1-3
|
|
803
CCTCTGCTTATAACTTT
2-9-1-
CCtctgcttatAactTT
803_2
-19.28
30697
|
3-2
|
|
803
CCTCTGCTTATAACTTT
2-2-1-
CCtcTgcttataActTT
803_3
-20.58
30697
|
7-1-2-2
|
|
803
CCTCTGCTTATAACTTT
1-2-1-
CctCtgcttataActTT
803_4
-18.06
30697
|
8-1-2-2
|
|
803
CCTCTGCTTATAACTTT
2-1-1-
CCtCtgcttataaCtTT
803_5
-21.12
30697
|
9-1-1-2
|
|
804
CTACTATACTTTCCTCT
3-8-2-
CTActatacttTCctCT
804_1
-22.54
30709
|
2-2
|
|
804
CTACTATACTTTCCTCT
1-1-1-
CtActatactttCCtCT
804_2
-21.39
30709
|
9-2-1-2
|
|
804
CTACTATACTTTCCTCT
1-2-1-
CtaCtatactttCctCT
804_3
-19.70
30709
|
8-1-2-2
|
|
804
CTACTATACTTTCCTCT
2-11-1-
CTactatactttcCtCT
804_4
-20.45
30709
|
1-2
|
|
804
CTACTATACTTTCCTCT
1-3-1-
CtacTatactttcCtCT
804_5
-19.77
30709
|
8-1-1-2
|
|
805
TCTACTATACTTTCCTCT
2-1-1-
TCtActatactttCctCT
805_1
-21.40
30709
|
9-1-2-2
|
|
805
TCTACTATACTTTCCTCT
2-2-1-
TCtaCtatactttCctCT
805_2
-22.20
30709
|
8-1-2-2
|
|
805
TCTACTATACTTTCCTCT
2-11-1-
TCtactatactttCctCT
805_3
-21.20
30709
|
2-2
|
|
805
TCTACTATACTTTCCTCT
2-1-1-
TCtActatactttcCtCT
805_4
-21.52
30709
|
10-1-1-
|
2
|
|
805
TCTACTATACTTTCCTCT
2-2-1-
TCtaCtatactttcCtCT
805_5
-22.32
30709
|
9-1-1-2
|
|
806
TTCTACTATACTTTCCT
1-1-1-
TtCtactatacTttcCT
806_1
-18.06
30711
|
8-1-3-2
|
|
806
TTCTACTATACTTTCCT
1-2-1-
TtcTactatacTttcCT
806_2
-18.02
30711
|
7-1-3-2
|
|
806
TTCTACTATACTTTCCT
1-1-1-
TtCtActatactTtCCT
806_3
-20.41
30711
|
1-1-7-
|
1-1-3
|
|
806
TTCTACTATACTTTCCT
1-1-1-
TtCtactatacttTCCT
806_4
-20.90
30711
|
10-4
|
|
806
TTCTACTATACTTTCCT
1-1-1-
TtCtActatactttCCT
806_5
-20.11
30711
|
1-1-9-3
|
|
807
TTCTACTATACTTTCCTC
1-2-1-
TtcTactatactTtCcTC
807_1
-19.51
30710
|
8-1-1-
|
1-1-2
|
|
807
TTCTACTATACTTTCCTC
1-1-1-
TtCtaCtatactTtccTC
807_2
-19.77
30710
|
2-1-6-
|
1-3-2
|
|
807
TTCTACTATACTTTCCTC
1-1-1-
TtCtActatactttCcTC
807_3
-19.44
30710
|
1-1-9-
|
1-1-2
|
|
807
TTCTACTATACTTTCCTC
1-1-1-
TtCtactatactttcCTC
807_4
-20.04
30710
|
12-3
|
|
807
TTCTACTATACTTTCCTC
1-2-1-
TtcTaCtatactttccTC
807_5
-19.43
30710
|
1-1-10-
|
2
|
|
808
TTTCCATCTACTATTAAT
1-1-3-
TtTCCatctactATTaAT
808_1
-21.43
39804
|
7-3-1-2
|
|
808
TTTCCATCTACTATTAAT
2-1-2-
TTtCCatctactAtTaAT
808_2
-19.50
39804
|
7-1-1-
|
1-1-2
|
|
808
TTTCCATCTACTATTAAT
1-1-4-
TtTCCAtctactAttAAT
808_3
-20.72
39804
|
6-1-2-3
|
|
808
TTTCCATCTACTATTAAT
2-1-2-
TTtCCatctactaTtAAT
808_4
-19.43
39804
|
8-1-1-3
|
|
808
TTTCCATCTACTATTAAT
4-1-1-
TTTCcAtctactatTAAT
808_5
-20.12
39804
|
8-4
|
|
809
TTTCCATCTACTATTAA
5-6-3-
TTTCCatctacTATTAA
809_1
-21.74
39805
|
1-2
|
|
809
TTTCCATCTACTATTAA
2-1-2-
TTtCCatctacTAtTAA
809_2
-20.76
39805
|
6-2-1-3
|
|
809
TTTCCATCTACTATTAA
1-1-3-
TtTCCatctacTaTTAA
809_3
-20.75
39805
|
6-1-1-4
|
|
809
TTTCCATCTACTATTAA
2-1-2-
TTtCCatctactATTAA
809_4
-20.54
39805
|
7-5
|
|
809
TTTCCATCTACTATTAA
5-9-3
TTTCCatctactatTAA
809_5
-20.18
39805
|
|
810
GTTTCCATCTACTATTA
3-9-2-
GTTtccatctacTAtTA
810_1
-20.81
39806
|
1-2
|
|
810
GTTTCCATCTACTATTA
1-1-1-
GtTtCcatctacTaTTA
810_2
-19.35
39806
|
1-1-7-
|
1-1-3
|
|
810
GTTTCCATCTACTATTA
2-2-1-
GTttCcatctacTatTA
810_3
-19.64
39806
|
7-1-2-2
|
|
810
GTTTCCATCTACTATTA
3-1-1-
GTTtCcatctactATTA
810_4
-21.37
39806
|
8-4
|
|
810
GTTTCCATCTACTATTA
1-2-2-
GttTCcatctactatTA
810_5
-18.14
39806
|
10-2
|
|
811
AATACAAAATCATCTTAC
3-1-2-
AATaCAaaatcaTcTTAC
811_1
-18.05
39836
|
6-1-1-4
|
|
811
AATACAAAATCATCTTAC
4-9-5
AATAcaaaatcatCTTAC
811_2
-18.25
39836
|
|
811
AATACAAAATCATCTTAC
3-1-2-
AATaCAaaatcatCTTAC
811_3
-19.20
39836
|
7-5
|
|
811
AATACAAAATCATCTTAC
2-1-3-
AAtACAaaatcatCTTAC
811_4
-18.12
39836
|
7-5
|
|
811
AATACAAAATCATCTTAC
1-1-4-
AaTACAaaatcatCTTAC
811_5
-19.50
39836
|
7-5
|
|
812
AATACAAAATCATCTTACA
2-2-2-
AAtaCAaaatcaTCTTaCA
812_1
-20.31
39835
|
6-4-1-2
|
|
812
AATACAAAATCATCTTACA
4-8-3-
AATAcaaaatcaTCTtaCA
812_2
-19.80
39835
|
2-2
|
|
812
AATACAAAATCATCTTACA
3-1-2-
AATaCAaaatcaTCtTACA
812_3
-21.91
39835
|
6-2-1-4
|
|
812
AATACAAAATCATCTTACA
1-1-4-
AaTACAaaatcatCTtaCA
812_4
-19.93
39835
|
7-2-2-2
|
|
812
AATACAAAATCATCTTACA
5-8-1-
AATACaaaatcatCtTACA
812_5
-20.93
39835
|
1-4
|
|
813
TAATACAAAATCATCTTA
1-1-4-
TaATACaaaatcATCtTA
813_1
-18.46
39837
|
6-3-1-2
|
|
813
TAATACAAAATCATCTTA
5-8-5
TAATAcaaaatcaTCTTA
813_2
-19.57
39837
|
|
813
TAATACAAAATCATCTTA
5-9-4
TAATAcaaaatcatCTTA
813_3
-18.44
39837
|
|
813
TAATACAAAATCATCTTA
2-1-3-
TAaTACaaaatcatCTTA
813_4
-18.20
39837
|
8-4
|
|
813
TAATACAAAATCATCTTA
1-1-4-
TaATACaaaatcatCTTA
813_5
-18.18
39837
|
8-4
|
|
814
TAATACAAAATCATCTTAC
2-1-3-
TAaTACaaaatcATCTtAC
814_1
-19.95
39836
|
6-4-1-2
|
|
814
TAATACAAAATCATCTTAC
4-1-1-
TAATaCaaaatcATCtTAC
814_2
-20.22
39836
|
6-3-1-3
|
|
814
TAATACAAAATCATCTTAC
1-2-3-
TaaTACaaaatcAtCTTAC
814_3
-19.14
39836
|
6-1-1-5
|
|
814
TAATACAAAATCATCTTAC
5-8-2-
TAATAcaaaatcaTCtTAC
814_4
-19.90
39836
|
1-3
|
|
814
TAATACAAAATCATCTTAC
4-1-1-
TAATaCaaaatcatCTTAC
814_5
-19.94
39836
|
8-5
|
|
815
TAATACAAAATCATCTTACA
3-2-2-
TAAtaCAaaatcaTCtTaCA
815_1
-20.84
39835
|
6-2-1-
|
1-1-2
|
|
815
TAATACAAAATCATCTTACA
2-3-1-
TAataCaaaatcatCTtACA
815_2
-18.77
39835
|
8-2-1-3
|
|
815
TAATACAAAATCATCTTACA
2-1-2-
TAaTAcAaaatcatCTtaCA
815_3
-19.66
39835
|
1-1-7-
|
2-2-2
|
|
815
TAATACAAAATCATCTTACA
1-1-1-
TaAtACaaaatcatCtTACA
815_4
-19.11
39835
|
1-2-8-
|
1-1-4
|
|
815
TAATACAAAATCATCTTACA
4-10-1-
TAATacaaaatcatCtTaCA
815_5
-19.22
39835
|
1-1-1-2
|
|
816
TCTGTATACACCATCCCA
2-10-1-
TCtgtatacaccAtCcCA
816_1
-24.49
46389
|
1-1-1-2
|
|
816
TCTGTATACACCATCCCA
2-3-1-
TCtgtAtacaccAtccCA
816_2
-23.81
46389
|
6-1-3-2
|
|
816
TCTGTATACACCATCCCA
2-10-1-
TCtgtatacaccAtccCA
816_3
-23.72
46389
|
3-2
|
|
816
TCTGTATACACCATCCCA
2-1-1-
TCtGtatacaccatCcCA
816_4
-24.75
46389
|
10-1-1-
|
2
|
|
816
TCTGTATACACCATCCCA
2-3-1-
TCtgtAtacaccatCcCA
816_5
-24.53
46389
|
8-1-1-2
|
|
816
TCTGTATACACCATCCCA
2-3-1-
TCtgtAtacaccatccCA
816_6
-23.76
46389
|
10-2
|
|
817
TTCTGACTCCCTATCCA
1-1-1-
TtCtgactccctatcCA
817_1
-22.56
46417
|
12-2
|
|
818
TTTCTGACTCCCTATCC
1-2-1-
TttCtgactccctatCC
818_1
-22.64
46418
|
11-2
|
|
Designs refer to the gapmer design, F-G-F′, where each number represents the number of consecutive modified nucleosides, e.g 2′ modified nucleosides (first number = 5′ flank), followed by the number of DNA nucleosides (second number = gap region), followed by the number of modified nucleosides, e.g 2′ modified nucleosides (third number = 3′ flank), optionally preceded by or followed by further repeated regions of DNA and LNA, which are not necessarily part of the contiguous sequence that is complementary to the target nucleic acid. For some oligonucleotides in table 3 the flanks are mixed flanks, such flanks start and end with a 2′ modified nucleosides, in these cases the gap region is the number above 5 not located at the 5′ or 3′ terminal in of the design.
|
For the oligonucleotide compounds capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, and 5-methyl DNA cytosines are presented by “e”, all internucleoside linkages are phosphorothioate internucleoside linkages.
Oligonucleotides with an EX-EX indication as Start on SEQ ID NO: 1 are exon-exon spanning oligonucleotides designed to be complementary across exon-exon junctions of SNHG14-023 (ENST00000554726). The oligonucleotides primarily span exon2 and exon3 (i.e. are complementary to a region in exon2 and a region in exon 3)
Oligonucleotide Synthesis
Oligonucleotide synthesis is generally known in the art. Below is a protocol which may be applied. The oligonucleotides of the present invention may have been produced by slightly varying methods in terms of apparatus, support and concentrations used.
Oligonucleotides are synthesized on uridine universal supports using the phosphoramidite approach on a MerMade12 or an Oligomaker DNA/RNA synthesizer at 1-4 μmol scale. At the end of the synthesis, the oligonucleotides are cleaved from the solid support using aqueous ammonia for 5-16 hours at 60° C. The oligonucleotides are purified by reverse phase HPLC (RP-HPLC) or by solid phase extractions and characterized by UPLC, and the molecular mass is further confirmed by ESI-MS.
Elongation of the Oligonucleotide:
The coupling of β-cyanoethyl-phosphoramidites (DNA-A(Bz), DNA-G(ibu), DNA-C(Bz), DNA-T, LNA-5-methyl-C(Bz), LNA-A(Bz), LNA-G(dmf), LNA-T or amino-C6 linker) is performed by using a solution of 0.1 M of the 5′-O-DMT-protected amidite in acetonitrile and DCI (4,5-dicyanoimidazole) in acetonitrile (0.25 M) as activator. For the final cycle a phosphoramidite with desired modifications can be used, e.g. a C6 linker for attaching a conjugate group or a conjugate group as such. Thiolation for introduction of phosphorthioate linkages is carried out by using xanthane hydride (0.01 M in acetonitrile/pyridine 9:1). Phosphordiester linkages can be introduced using 0.02 M iodine in THF/Pyridine/water 7:2:1. The rest of the reagents are the ones typically used for oligonucleotide synthesis.
Purification by RP-HPLC:
The crude compounds are purified by preparative RP-HPLC on a Phenomenex Jupiter C18 10μ 150×10 mm column. 0.1 M ammonium acetate pH 8 and acetonitrile is used as buffers at a flow rate of 5 mL/min. The collected fractions are lyophilized to give the purified compound typically as a white solid.
Abbreviations
DCI: 4,5-Dicyanoimidazole
DCM: Dichloromethane
DMF: Dimethylformamide
DMT: 4,4′-Dimethoxytrityl
THF: Tetrahydrofurane
Bz: Benzoyl
Ibu: Isobutyryl
RP-HPLC: Reverse phase high performance liquid chromatography
Tm Assay
Oligonucleotide and RNA target duplexes are diluted to 3 mM in 500 ml RNase-free water and mixed with 500 ml 2×Tm-buffer (200 mM NaCl, 0.2 mM EDTA, 20 mM Naphosphate, pH 7.0). The solution is heated to 95° C. for 3 min and then allowed to anneal in room temperature for 30 min. The duplex melting temperatures (Tm) is measured on a Lambda 40 UV/VIS Spectrophotometer equipped with a Peltier temperature programmer PTP6 using PE Templab software (Perkin Elmer). The temperature is ramped up from 20° C. to 95° C. and then down to 25° C., recording absorption at 260 nm. First derivative and the local maximums of both the melting and annealing are used to assess the duplex Tm.
Preparation of Mouse Primary Cortical Neuron Cell Cultures
Primary cortical neuron cultures were prepared from mouse embryo brains of 15 days of age according to standard procedure. In brief, culture plates were coated with Poly-L-Lysine (50 μg/ml Poly-L-Lysine, 10 mM Na-tetraborate, pH 8 buffer) for 2-3 hrs at room temperature. The plates were washed with 1×PBS before use. Harvested mouse embryo brains were dissected and homogenized by a razor blade and submerged into 38 ml dissection medium (HBSS, 0.01 M Hepes, Penicillin/Streptomycin). Then, 2 ml trypsin was added and cells were incubated for 30 min at 37° C. and centrifuged down. The cells were dissolved in 20 ml DMEM (+10% FBS) and passed through a syringe for further homogenization. This was followed by centrifugation at 500 rpm for 15 mins. The cells were dissolved in DMEM (+10% FBS) and seeded in 96 well plates (0.1×10{circumflex over ( )}6 cells/well in 100 μl). The neuronal cell cultures were ready for use directly after seeding.
Screening Oligonucleotides in Mouse Primary Cortical Neuron Cell Cultures
Cells were cultured in growth medium (Gibco Neurobasal medium, B27 supplement, Glutamax, Penicillin-streptomycin) in 96-well plates and incubated with oligonucleotides for 3 days at the desired concentrations. Total RNA was isolated from the cells and the knock-down efficacy was measured by qPCR analysis using the gScript™ XLT One-Step RT-qPCR ToughMix®, Low ROX™ kit from Quanta Bioscience (95134-500). A commercial taqman assays from Thermo Fisher Scientific was used to measure Ube3a_ATS including GAPDH for normalization.
Generation of Human Primary Neuronal Cell Cultures
Any cell lines at any described time point was incubated at 37° C., 5% CO2 concentration and 95% relative humidity.
Human Induced Pluripotent Stem Cells (hiPSC) Culture
Whole human blood samples were obtained from patients diagnosed with Angelman syndrome. The subsequent cultures of primary Peripheral Blood Mononuclear Cells (PMCSs) were enriched for erythroblasts. Patient-specific iPSC lines were generated by reprogramming erythroblast with CytoTune-iPS Sendai Reprogramming Kit (Thermo Fisher Scientific). Derived iPSC lines were maintained in feeder-free conditions using hESC-qualified Matrigel (Corning) in mTESR1 (STEMCELL Technologies) with daily medium replacement. Upon reaching confluence, colonies were dissociated into cell cluster of 50-200 μm in size using Gentle Cell Dissociation Reagent (STEMCELL Technologies) and subcultured at a ratio of 1:10-1:20 in the presence of 10 μM Y-27632 (Calbiochem).
Differentiation into Neural Progenitor Cells (NPC)
Upon induction of neural differentiation iPSC-derived cells were maintained in basal medium composed of equal volumes of DMEM:F12 Glutamax medium and Neurobasal medium (Gibco, Invitrogen), supplemented with 1×B27 (Gibco, Invitrogen), 1×N2 (Gibco, Invitrogen), 0.1 mM beta-mercaptoethanol (Gibco, Invitrogen) and indicated supplements.
Neural progenitor cells (NPCs) were derived from hiPSCs by dual SMAD inhibition and according to published procedures with slight modifications (Chambers et al. 2009 Nat Biotechnol. Vol. 3 pp. 275-80, Boissart et al., 2013 Transl Psychiatry. 3:e294). HiPSCs were dissociated with Accutase (Innovative Cell Technologies Inc.) into a single cell suspension and resuspended in basic medium further supplemented with 10 μM Y-27632 (Calbiochem), 5 ng/ml FGF (Peprotech), 10 μM SB-431542 (Calbiochem) and 100 nM LDN (Calbiochem). Single cell suspension was transferred to AggreWell800 plates (STEMCELL Technologies) enabling the formation of aggregates consisting of 8000 cells. After 5 days neural aggregates were transferred onto plates coated with poly-L-ornithine (Sigma) and laminin (Roche) and allowed to form neural rosettes under continued dual SMAD inhibition (SB-431542 and LDN) in basic medium supplemented with FGF. Neural rosettes were selectively isolated using STEMdiff™ Neural Rosette Selection Reagent (STEMCELL Technologies), replated onto dishes coated with poly-L-ornithine and Laminin521 (BioLamina) and expanded in basic medium supplemented with 10 ng/ml FGF (Peprotech), 10 ng/ml EGF (RnD), and 20 ng/ml BDNF (Peprotech). When reaching confluency, cells were enzymatically dissociated with 0.05% Trypsin/EDTA (Gibco, Invitrogen) and sub-cultured. Continued passaging in basic medium supplemented with FGF, EGF and BDNF leads to a stable neural progenitor cell line (NPC line) within 10 to 20 passages. A stable neural progenitor cell line is defined by its capacity to self-renew and by the expression of the developmental stage-specific markers Sox2 and Nestin. Upon specific stimuli, NPCs differentiate into neuronal (MAP2+, Tau+, HuC/D+) and astroglial (GFAP+) progenies (Dunkley et al., 2015 Proteomics Clin Appl. Vol. 7-8 pp. 684-94).
NPC Culture
Conditions for NPC culture have been described previously and were used with slight modifications (Boissart et al., 2013 Transl Psychiatry. 3:e294). In brief, cells were maintained in dishes coated with Laminin521 (BioLamina) and cultured in basic medium [composed of equal volumes of DMEM:F12 Glutamax medium and Neurobasal medium (Gibco, Invitrogen), supplemented with 1×B27 (Gibco, Invitrogen), 1×N2 (Gibco, Invitrogen), 0.1 mM beta-mercaptoethanol (Gibco, Invitrogen)] and supplemented with 10 ng/ml FGF (Peprotech), 10 ng/ml EGF (RnD), and 20 ng/ml BDNF (Peprotech).
Differentiation into Neuronal Cell Culture
To induce neuronal differentiation of NPC, cells were dissociated with 0.05% Trypsin/EDTA (Gibco, Invitrogen) into single cell suspension and seeded onto Laminin521 (BioLamina) coated dishes at a density of 12.000 cells/cm2 and maintained in basic medium supplemented with 200 ng/ml Shh (Peprotech), 100 ng/ml FGF8 (Peprotech), and 100 μM ascorbic acid phosphate (Sigma) for a period of 7 days. Subsequently, cells were replated in basal medium supplemented with 20 ng/ml BDNF (Peprotech), 10 ng/ml GDNF (Peprotech), 0.5 mM cAMP (BIOLOG Life Science), and 100 μM ascorbic acid phosphate (Sigma) at a density of 45000 cells/cm2 and differentiated for a period of 21 days. At day 21 of differentiation, differentiated neuronal cultures were replated onto the screening-compatible plate format. Replating was performed by dissociating the cultures with Accutase (Innovative Cell Technologies Inc.) into a single cell suspension. Cells were seeded at a density of 200.000 cells/cm2 in presence of 10 μM Y-27632 (a cell-permeable, reversible, inhibitor of Rho kinases from Calbiochem) into the 384 well microtiter plates for final oligonucleotides screening assay. Neuronal cultures were further differentiated for additional 7 days in basal medium supplemented with 20 ng/ml BDNF (Peprotech), 10 ng/ml GDNF (Peprotech), 0.5 mM cAMP (BIOLOG Life Science), and 100 μM ascorbic acid phosphate (Sigma). Differentiation medium was exchanged twice per week. After a total differentiation period of 35 days neuronal cell cultures were ready for oligonucleotide treatment.
Screening Oligonucleotides in Human Neuronal Cell Cultures—384 Well System
For screening, oligonucleotide stocks were pre-diluted to the indicated concentrations with water into 384 well microtiter plates (compound plate). The plate layout served as a treatment template. Two microliter oligonucleotide dilution from each well was transferred from the compound plate to a respective culture plate. All liquid handling was done under sterile conditions in a laminar flow using a semi-automated laboratory robotic system (Beckmancoulter). Neuronal cell cultures were incubated with oligonucleotides for 5 days without media change. Subsequently, neuronal cultures were lysed and processed for qPCR assay with RealTime ready Cell lysis and RNA Virus Master kit (Roche). Liquid handling was performed using a semi-automated laboratory robotic system (Beckmancoulter). Samples were analyzed by a Lightcycler480 real-time PCR system (Roche).
Activity of the oligonucleotides was assessed by qPCR monitoring transcript abundance of UBE3A using the following primers and probes
UBE3a-Sense:
|
Forward primer:
|
(SEQ ID NO: 837)
|
ATATGTGGAAGCCGGAATCT,
|
|
Reverse primer:
|
(SEQ ID NO: 838)
|
TCCCAGAACTCCCTAATCAGAA,
|
|
Internal probe labeled with dye FAM:
|
(SEQ ID NO: 839)
|
ATGACGGTGGCTATACCAGG
|
The RT-qPCR was multiplexed with PPIA (peptidylprolyl isomerase A) as housekeeping gene for normalization. PPIA primers and probe labeled with the dye VIC were purchased from Thermo Fisher Scientific (assay ID Hs99999904_m1). Each plate includes a non-targeting oligonucleotide (mock) as negative control (TTGaataagtggaTGT (SEQ ID NO: 846)) and a reference oligonucleotide CMP ID NO: 41_1, resulting in up-regulation of UBE3A mRNA.
Selectivity of oligonucleotides was verified by counter screening for SNORD 115 transcript, which is located upstream of SNORD109B on chromosome 15. Expression of SNORD115 was monitored by qPCR using the following primers and probe
Forward primer:
|
(SEQ ID NO: 840)
|
GGGTCAATGATGAGAACCTTAT,
|
|
Reverse primer
|
(SEQ ID NO: 841)
|
GGGCCTCAGCGTAATCCTATT,
|
|
Internal probe labeled with the dye FAM:
|
(SEQ ID NO: 842)
|
TTCTGAAGAGAGGTGATGACTTAAAA
|
The RT-qPCR was multiplexed with PPIA (Thermo Fisher Scientific) upon oligonucleotide treatment.
The reduction of the SNHG14 transcript downstream of SNORD109B (also termed the UBE3A suppressor) was measured by RT-qPCR using the following primers and probe
Forward primer:
|
(SEQ ID NO: 843)
|
ATCCGAGGCATGAATCTCAC,
|
|
Reverse primer:
|
(SEQ ID NO: 844)
|
CAGGCCCCCTTGATAA,
|
|
Internal probe labeled with dye FAM:
|
(SEQ ID NO: 845)
|
TTGCTGAGCATTTTTGCATC
|
The RT-qPCR was multiplexed with PPIA (Thermo Fisher Scientific).
Data are presented as average % expression relative to mock across all plates and normalized to the reference oligonucleotide to account for plate to plate variation.
Screening Oligonucleotides in Human Neuronal Cell Cultures—96 Well System
For screening, oligonucleotide stocks were pre-diluted to the indicated concentrations with water into 96 well microtiter plates (compound plate). The plate layout served as a treatment template. Two microliter oligonucleotide dilution from each well was transferred from the compound plate to a respective culture plate. All liquid handling was done under sterile conditions in a laminar flow using a semi-automated laboratory robotic system (Beckman Coulter). Neuronal cell cultures were incubated with oligonucleotides for 5 days without media change. Subsequently, neuronal cultures were lysed and RNA purified using RNA purification kit Pure Link Pro96 (12173011A) LifeTechnologies. Liquid handling was performed using a semi-automated laboratory robotic system (Beckmancoulter). qPCR analysis of Ube3a and Ube3a-ATS was carried out on a ViiA™ 7 Real-Time PCR System Thermo Fisher Scientific using the qScript™ XLT 1-Step RT-qPCR ToughMix Low ROX, from Quanta (95134-50).
The following primers and probes were used:
qPCR UBE3a-Sense:
Forward primer:
|
(SEQ ID NO: 697)
|
ATATGTGGAAGCCGGAATCT,
|
|
Reverse primer:
|
(SEQ ID NO: 698)
|
TCCCAGAACTCCCTAATCAGAA,
|
|
Internal probe labeled with dye FAM:
|
(SEQ ID NO: 699)
|
ATGACGGTGGCTATACCAGG
|
qPCR SNHG14 transcript downstream of SNORD109B (also termed the UBE3A suppressor):
Commercially available primer and probe set from ThermoFisher: Hs01372957_m1. These primers amplifies a 87 bp exon-exon spanning sequence in the Genbank transcript AF400500.1
qPCR GAPDH Transcript:
Commercially available primer and probe set from Thermofisher: Gene Symbol: with following assay details: RefSeq: NM_002046.3, Probe Exon Location: 3, Amplicon Size: 122 bp. Corresponding TaqMan Assay ID: Hs99999905_m1.
The RT-qPCR for both Ube3a and Ube3a-ATS was multiplexed with GAPDH as housekeeping gene for normalization. Each plate includes a non-targeting oligonucleotide (mock) as negative control (TTGaataagtggaTGT (SEQ ID NO: 846)) and a reference oligonucleotide CMP ID NO: 21_1, resulting in up-regulation of UBE3A mRNA. Moreover panel of oligos not targeting Ub3a or SNHG14 transcript downstream of SNORD109B (also termed the UBE3A suppressor) were included to monitor the assay noise and risk of detecting false positives. These were randomly distributed over the plates.
Control Oligonucleotides:
(SEQ ID NO: 819)
|
CGAaccactgaaCAA
|
|
(SEQ ID NO: 820)
|
CGAaccactgaacAAA
|
|
(SEQ ID NO: 821)
|
CGAagtgcacaCG
|
|
(SEQ ID NO: 822)
|
GCGtaaagagaGGT
|
|
(SEQ ID NO: 823)
|
GAGAaggcacagaCGG
|
|
(SEQ ID NO: 824)
|
GCGaagtgcacaCGG
|
|
(SEQ ID NO: 825)
|
GAGaaggcacagaCGG
|
|
(SEQ ID NO: 826)
|
CGAaccactgAACA
|
|
(SEQ ID NO: 827)
|
GAAccactgaacAAA
|
|
(SEQ ID NO: 828)
|
caGCGtaaagagaGG
|
|
(SEQ ID NO: 829)
|
GCgtaaagagAGG
|
|
(SEQ ID NO: 830)
|
CGAaccactgaAC
|
|
(SEQ ID NO: 831)
|
CGAAccactgaaCAAA
|
|
(SEQ ID NO: 832)
|
AGCgaagtgcacaCGG
|
|
(SEQ ID NO: 833)
|
AGGtgaagcgaAGTG
|
|
(SEQ ID NO: 834)
|
TAGTaaactgagCCA
|
|
(SEQ ID NO: 835)
|
AGAaggcacagaCGG
|
|
(SEQ ID NO: 836)
|
CCGcagtatggaTCG
|
Example 1—Oligonucleotide Activity in Mouse Primary Neuronal Cell Cultures
Oligonucleotides targeting the part of SNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA (position 55319 to 141053 of SEQ ID NO: 1) were tested for their ability to reduce the SNHG14 long non-coding RNA transcript preventing UBE3A expression (also termed UBE3A suppressor or UBE3A-SUP in the data table) and their ability to induce UBE3A mRNA re-expression in mouse primary cortical neuron cell cultures, obtained as described in the “Materials and methods” section above. The oligonucleotide concentration was 5 microM.
The oligonucleotides were screened according to the protocol for screening in mouse cortical neuron cell cultures described in the section “Materials and methods”. The results are shown in table 4.
TABLE 4
|
|
Oligonucleotide activity in primary mouse neuronal cell cultures.
|
CMP
% of Mock
% of Mock
|
ID NO
oligonucleotide
UBE3A_SUP
sd
UBE3A
sd
|
|
95_1
CTCAtacttgctttaAT
3.6
0.1
154.1
15.1
|
|
95_2
CTcatacttgctttaAT
15.9
2.6
119.8
12.4
|
|
96_1
ACatctcatacttGCTT
4.0
0.5
149.9
11.5
|
|
96_2
ACatctcatacttgcTT
9.3
3.9
139.9
36.4
|
|
96_3
ACatctcatacttgCTT
3.1
0.2
143.2
3.9
|
|
97_1
ACatctcatactTGCT
4.0
1.5
154.5
10.0
|
|
97_2
ACatctcatacttgCT
6.1
1.7
141.1
14.1
|
|
97_3
ACatctcatacttGCT
3.7
0.6
162.7
15.0
|
|
97_4
ACATctcatacttgCT
5.2
0.4
156.7
24.4
|
|
98_1
TAcatctcatactTGCT
5.0
0.9
159.0
15.6
|
|
98_2
TAcatctcatacttgCT
15.5
5.3
130.4
3.4
|
|
98_3
TACAtctcatacttgCT
4.7
0.4
140.3
38.2
|
|
101_1
TACatctcatactTGC
2.6
0.5
152.6
10.2
|
|
101_2
TAcatctcatacttGC
19.2
6.0
112.0
15.0
|
|
101_3
TAcatctcatactTGC
3.5
0.4
117.2
13.7
|
|
101_4
TACAtctcatacttGC
3.0
0.7
140.5
12.4
|
|
100_1
CTAcatctcatactTGC
5.4
0.8
160.4
4.1
|
|
100_2
CTacatctcatacttGC
9.6
3.7
159.2
14.5
|
|
100_3
CTacatctcatactTGC
3.0
0.1
133.2
5.9
|
|
99_2
CCtacatctcatacttGC
7.8
1.4
150.7
11.0
|
|
99_3
CCtacatctcatactTGC
3.2
0.6
134.7
12.5
|
|
99_4
CCtacatctcatacTTGC
2.7
0.2
145.2
4.7
|
|
102_1
CCTAcatctcatactTG
5.8
1.7
127.0
24.5
|
|
102_2
CCtacatctcatactTG
20.2
6.6
129.7
9.2
|
|
102_4
CCTacatctcatacTTG
4.0
0.6
140.2
7.2
|
|
102_3
CCTacatctcatactTG
3.9
1.0
133.3
10.0
|
|
104_1
CCTacatctcataCTT
6.6
1.5
136.5
8.7
|
|
104_3
CCtacatctcatACTT
3.5
0.4
131.4
6.0
|
|
103_1
ACCtacatctcataCTT
5.8
1.4
130.8
0.7
|
|
103_2
ACctacatctcatacTT
11.4
2.2
123.6
12.4
|
|
103_3
ACctacatctcatACTT
5.8
0.8
132.2
4.5
|
|
105_1
TACCtacatctcatacTT
5.2
0.8
152.3
7.2
|
|
106_1
TTAcctacatctcataCTT
13.3
3.0
140.1
17.5
|
|
106_2
TTacctacatctcatacTT
21.0
1.4
116.9
15.0
|
|
107_1
ACCTacatctcataCT
6.2
0.9
119.2
3.4
|
|
107_2
ACctacatctcataCT
14.3
7.4
142.9
13.7
|
|
108_1
TACCtacatctcataCT
5.6
1.0
127.0
10.7
|
|
108_2
TAcctacatctcataCT
21.4
12.5
117.1
8.5
|
|
109_1
TTacctacatctcaTACT
4.4
0.4
138.9
1.2
|
|
109_2
TTacctacatctcataCT
22.9
3.3
117.1
13.0
|
|
110_1
TTAcctacatctcaTAC
8.7
2.1
133.2
5.1
|
|
110_2
TTacctacatctcatAC
21.0
5.1
111.4
11.1
|
|
111_1
GTtacctacatctCATA
8.0
2.4
143.8
14.8
|
|
111_2
GTtacctacatctcaTA
19.0
2.3
115.4
4.1
|
|
112_1
GTTacctacatctCAT
6.6
1.4
145.5
16.8
|
|
112_2
GTtacctacatctcAT
15.8
4.5
120.3
8.1
|
|
126_1
TCACtttccagatatCA
8.0
1.9
133.8
5.4
|
|
126_3
TCactttccagatatCA
53.4
75.9
112.0
11.4
|
|
128_1
ACATgtccctttataTT
16.3
2.5
114.7
11.1
|
|
128_2
ACatgtccctttataTT
14.8
1.1
136.9
6.2
|
|
129_1
ACAtgtccctttaTAT
11.8
1.9
135.0
14.3
|
|
132_1
CTCAtccctccaagaAA
9.1
1.6
131.7
8.4
|
|
132_2
CTcatccctccaagaAA
11.2
3.9
159.3
17.7
|
|
Example 2—Oligonucleotide Activity in Human Neuronal Cell Cultures
Oligonucleotides targeting human SNHG14 in the region downstream of SNORD109B corresponding to position 25278410 to 25419462 on chromosome 15 (SEQ ID NO: 1) were tested in patient derived human neuronal cell cultures (see protocol in “Materials and methods” section). The oligonucleotides ability to reduce the SNHG14 transcript in the region downstream of SNORD109B (also termed UBE3A suppressor or UBE3A-SUP in the data table), without affecting expression of SNORD115 was analyzed. Furthermore, the ability to induce UBE3A mRNA re-expression was analyzed.
The oligonucleotides were screened according to the protocol for screening oligonucleotides in human neuronal cell cultures described in the section “Materials and methods” above.
The results are shown in table 5. The expression of UBE3A mRNA has been measured for all compounds, whereas the knock-down of the UBE3A suppressor and the maintenance of SNORD1115 levels have not been analyzed for all compounds.
TABLE 5
|
|
Oligonucleotide activity in patient derived human neuronal cell cultures.
|
Start
% of Mock
% of Mock
% of Mock
|
SEQ ID
CMP
Oligo conc
Oligo conc
Oligo conc
|
NO 1
ID NO
Target
0.2 μM
sd
1.0 μM
sd
5.0 μM
sd
|
|
1678
10_1
UBE3A
107
14
88
10
151
8
|
1679
12_2
UBE3A
100
9
87
14
158
16
|
1687
20_1
UBE3A
87
7
102
22
213
44
|
1712
21_1
UBE3A
127
23
166
6
178
13
|
1712
21_1
UBE3A-SUP
81
3
82
8
72
12
|
1712
21_1
SNORD115
115
6
142
24
169
26
|
4167
22_1
UBE3A
87
5
90
8
146
20
|
4170
27_1
UBE3A
94
16
106
11
170
10
|
4171
29_2
UBE3A
86
13
100
12
194
35
|
4172
30_1
UBE3A
96
6
121
12
209
27
|
9210
35_1
UBE3A
88
5
112
23
195
27
|
10838
37_1
UBE3A
77
7
85
9
169
24
|
15565
38_2
UBE3A
93
11
108
6
167
34
|
22209
42_1
UBE3A
125
16
143
14
180
17
|
22209
42_1
UBE3A-SUP
108
14
98
15
85
18
|
22209
42_1
SNORD115
101
14
93
25
127
21
|
30449
43_1
UBE3A
99
5
95
13
115
8
|
30451
44_1
UBE3A
99
15
80
20
141
17
|
30451
44_2
UBE3A
98
31
104
16
119
7
|
30697
46_1
UBE3A
91
8
87
5
167
20
|
36066
49_1
UBE3A
95
6
111
10
155
29
|
36066
49_1
UBE3A-SUP
76
7
84
24
110
31
|
36066
49_1
SNORD115
99
14
111
20
94
6
|
36068
50_1
UBE3A
109
15
105
11
92
14
|
36068
50_1
UBE3A-SUP
122
24
93
28
73
7
|
36068
50_1
SNORD115
120
15
113
12
99
6
|
37206
51_1
UBE3A
114
16
101
7
101
3
|
37206
51_1
UBE3A-SUP
128
21
67
9
84
13
|
37206
51_1
SNORD115
140
26
110
9
100
11
|
46130
52_1
UBE3A
139
3
160
1
236
36
|
46130
52_1
UBE3A-SUP
135
16
133
26
160
32
|
46130
52_1
SNORD115
104
8
119
14
100
8
|
48145
59_1
UBE3A
179
3
122
17
115
NA
|
48170
76_1
UBE3A
85
16
100
8
155
12
|
48171
80_1
UBE3A
120
7
114
10
172
20
|
48171
78_1
UBE3A
136
31
103
20
169
11
|
48172
82_2
UBE3A
96
11
121
4
186
32
|
48172
84_1
UBE3A
95
14
100
8
158
14
|
49343
85_1
UBE3A
97
22
121
10
189
17
|
49722
87_1
UBE3A
111
9
126
11
177
22
|
52417
92_1
UBE3A
133
7
140
30
140
8
|
52417
92_1
UBE3A-SUP
88
14
80
14
82
8
|
52417
92_1
SNORD115
102
8
114
20
91
9
|
52420
93_1
UBE3A
111
14
120
9
126
16
|
52420
93_1
UBE3A-SUP
104
23
82
20
79
8
|
52420
93_1
SNORD115
110
11
114
17
95
7
|
53953
94_1
UBE3A
117
12
147
15
166
15
|
53953
94_1
UBE3A-SUP
92
18
81
5
86
22
|
53953
94_1
SNORD115
124
33
122
17
106
14
|
60819
95_1
UBE3A
103
11
131
14
175
7
|
60819
95_1
UBE3A-SUP
93
13
87
3
74
6
|
60819
95_1
SNORD115
162
19
158
20
201
11
|
60819
95_2
UBE3A
147
10
129
20
117
2
|
60819
95_2
UBE3A-SUP
118
24
87
13
83
8
|
60819
95_2
SNORD115
104
17
118
10
129
6
|
60823
96_1
UBE3A
115
16
135
19
174
17
|
60823
96_1
UBE3A-SUP
104
25
93
32
91
11
|
60823
96_2
UBE3A
108
7
114
9
115
13
|
60823
96_2
UBE3A-SUP
99
17
92
19
93
10
|
60824
97_1
UBE3A
111
12
134
23
169
14
|
60824
97_1
UBE3A-SUP
110
27
105
33
92
10
|
60824
97_2
UBE3A
124
13
126
12
124
11
|
60824
97_2
UBE3A-SUP
113
17
107
33
96
20
|
60824
98_1
UBE3A
111
16
119
11
138
14
|
60824
98_1
UBE3A-SUP
118
34
98
23
82
19
|
60824
98_1
SNORD115
109
11
123
18
114
16
|
60824
98_2
UBE3A
128
10
109
7
136
12
|
60824
98_2
UBE3A-SUP
91
15
77
11
110
16
|
60824
98_2
SNORD115
101
3
110
7
124
11
|
60825
99_1
UBE3A
125
6
115
5
131
10
|
60825
99_1
UBE3A-SUP
139
18
121
34
127
45
|
60825
99_1
SNORD115
110
18
112
12
99
19
|
60825
99_2
UBE3A
120
21
111
11
135
22
|
60825
99_2
UBE3A-SUP
96
21
79
15
75
11
|
60825
99_2
SNORD115
104
34
113
22
131
24
|
60825
100_1
UBE3A
123
34
139
34
145
21
|
60825
100_1
UBE3A-SUP
104
37
127
46
99
17
|
60825
100_2
UBE3A
124
46
138
37
145
31
|
60825
100_2
UBE3A-SUP
111
36
120
47
92
11
|
60825
101_1
UBE3A
112
18
123
15
150
13
|
60825
101_1
UBE3A-SUP
96
18
102
14
88
12
|
60825
101_2
UBE3A
118
15
138
24
139
32
|
60825
101_2
UBE3A-SUP
100
29
110
39
92
10
|
60826
102_1
UBE3A
132
17
120
7
125
9
|
60826
102_1
UBE3A-SUP
113
16
83
5
88
18
|
60826
102_1
SNORD115
121
36
131
23
100
9
|
60826
102_2
UBE3A
90
6
116
23
103
7
|
60826
102_2
UBE3A-SUP
91
7
90
12
64
18
|
60826
102_2
SNORD115
116
15
146
27
183
28
|
60827
103_1
UBE3A
106
8
112
10
115
9
|
60827
103_1
UBE3A-SUP
99
15
110
28
94
8
|
60827
103_2
UBE3A
107
14
120
13
112
14
|
60827
103_2
UBE3A-SUP
97
14
118
38
93
20
|
60827
104_1
UBE3A
128
14
111
9
111
6
|
60827
104_1
UBE3A-SUP
111
12
97
9
87
19
|
60827
104_1
SNORD115
114
10
110
12
109
13
|
60827
104_2
UBE3A
108
10
111
16
109
10
|
60827
104_2
UBE3A-SUP
103
13
103
33
89
9
|
60827
105_1
UBE3A
122
13
121
12
121
4
|
60827
105_1
UBE3A-SUP
119
7
97
15
93
7
|
60827
105_1
SNORD115
114
21
128
12
118
9
|
60827
105_2
UBE3A
123
5
110
9
114
8
|
60827
105_2
UBE3A-SUP
110
11
89
17
94
21
|
60827
105_2
SNORD115
102
15
108
16
107
18
|
60827
106_1
UBE3A
114
17
133
23
125
9
|
60827
106_1
UBE3A-SUP
112
35
103
15
87
12
|
60827
106_2
UBE3A
110
12
130
22
123
14
|
60827
106_2
UBE3A-SUP
105
19
107
27
93
10
|
60828
107_1
UBE3A
83
11
117
13
112
6
|
60828
107_1
UBE3A-SUP
86
11
114
16
67
7
|
60828
107_1
SNORD115
108
17
130
21
137
24
|
60828
107_2
UBE3A
143
42
117
10
122
11
|
60828
107_2
UBE3A-SUP
116
12
92
4
100
8
|
60828
107_2
SNORD115
108
4
127
16
108
14
|
60828
108_1
UBE3A
120
7
127
31
132
31
|
60828
108_1
UBE3A-SUP
153
33
118
34
89
17
|
60828
108_1
SNORD115
114
9
114
9
105
15
|
60828
108_2
UBE3A
122
18
133
26
128
9
|
60828
108_2
UBE3A-SUP
101
19
100
28
89
17
|
60828
109_1
UBE3A
108
10
129
14
128
5
|
60828
109_1
UBE3A-SUP
106
21
107
24
84
8
|
60828
109_2
UBE3A
109
11
110
8
111
13
|
60828
109_2
UBE3A-SUP
95
15
86
14
83
9
|
60829
110_1
UBE3A
104
6
83
3
101
15
|
60829
110_1
UBE3A-SUP
100
13
95
12
79
4
|
60829
110_1
SNORD115
126
21
125
6
182
13
|
60829
110_2
UBE3A
92
7
87
8
96
7
|
60829
110_2
UBE3A-SUP
99
7
108
9
81
5
|
60829
110_2
SNORD115
118
15
139
22
198
39
|
60830
111_1
UBE3A
110
6
122
13
124
10
|
60830
111_1
UBE3A-SUP
104
14
90
28
79
11
|
60830
111_2
UBE3A
115
10
120
15
121
10
|
60830
111_2
UBE3A-SUP
114
20
89
19
87
9
|
60831
112_1
UBE3A
93
8
94
13
106
10
|
60831
112_1
UBE3A-SUP
97
1
68
29
82
7
|
60831
112_1
SNORD115
116
20
110
13
158
20
|
60831
112_2
UBE3A
83
8
78
7
83
6
|
60831
112_2
UBE3A-SUP
106
35
80
23
69
9
|
60831
112_2
SNORD115
107
6
106
8
159
21
|
62198
113_1
UBE3A
110
3
122
6
134
9
|
62198
113_1
UBE3A-SUP
113
20
85
19
79
24
|
62198
113_1
SNORD115
116
18
123
9
91
9
|
62284
115_1
UBE3A
105
14
98
19
141
36
|
62422
116_1
UBE3A
130
19
142
29
172
18
|
62423
117_1
UBE3A
76
8
93
13
171
17
|
62439
118_1
UBE3A
75
7
88
9
150
19
|
66378
119_1
UBE3A
96
14
93
5
110
10
|
77565
126_1
UBE3A
94
6
113
5
125
14
|
77565
126_1
UBE3A-SUP
83
17
95
33
85
5
|
77565
126_1
SNORD115
105
11
123
19
152
15
|
77565
126_2
UBE3A
95
5
126
9
111
2
|
77565
126_2
UBE3A-SUP
77
27
106
21
83
15
|
77565
126_2
SNORD115
115
17
157
13
180
15
|
92321
128_1
UBE3A
102
7
91
5
111
13
|
92321
128_1
UBE3A-SUP
115
3
104
25
91
13
|
92321
128_1
SNORD115
135
9
132
12
196
35
|
92321
128_2
UBE3A
91
5
96
8
104
8
|
92321
128_2
UBE3A-SUP
112
20
92
20
79
7
|
92321
128_2
SNORD115
125
7
111
13
169
12
|
92322
129_1
UBE3A
101
5
103
2
110
7
|
92322
129_1
UBE3A-SUP
99
39
113
12
94
13
|
92322
129_1
SNORD115
124
25
114
6
140
13
|
92322
129_2
UBE3A
93
2
100
4
113
16
|
92322
129_2
UBE3A-SUP
109
4
102
22
85
7
|
92322
129_2
SNORD115
103
11
99
9
152
31
|
97154
132_1
UBE3A
100
10
128
13
142
13
|
97154
132_1
UBE3A-SUP
103
9
115
8
109
6
|
97154
132_1
SNORD115
49
7
90
12
143
25
|
97154
132_2
UBE3A
111
8
128
17
128
17
|
97154
132_2
UBE3A-SUP
95
7
116
9
105
13
|
97154
133_2
SNORD115
86
7
106
9
121
9
|
97154
133_1
UBE3A
101
3
107
11
124
19
|
97154
133_1
UBE3A-SUP
112
9
117
7
146
25
|
97154
133_1
SNORD115
60
7
110
15
141
15
|
97154
133_2
UBE3A
94
13
116
14
138
12
|
97154
133_2
UBE3A-SUP
116
6
128
13
148
38
|
97154
132_2
SNORD115
70
5
108
9
160
34
|
106137
137_1
UBE3A
83
12
74
11
124
20
|
109404
138_1
UBE3A
80
20
92
7
120
21
|
110766
139_1
UBE3A
76
5
85
12
121
17
|
114826
140_1
UBE3A
87
10
88
11
136
9
|
118637
143_1
UBE3A
83
7
104
30
141
28
|
118639
144_1
UBE3A
74
17
31
39
106
33
|
124160
145_2
UBE3A
89
6
95
10
115
25
|
125499
146_1
UBE3A
83
13
76
7
124
16
|
125499
146_2
UBE3A
123
30
79
14
102
23
|
125538
150_2
UBE3A
82
17
82
7
119
24
|
|
Of the 187 compounds tested approximately 90% showed re-expression of UBE3A when compared to the mock oligonucleotide at the 5 micro Molar concentration. The number of oligonucleotides capable of inducing re-expression of UBE3A is higher in the region between position 1 to 55318 of SEQ ID NO: 1 (non-overlapping region) then in the region complementary to UBE3A coding region (overlapping region. FIG. 2 plots the distribution of the oligonucleotides according to their position on chromosome 15 versus the UBE3A mRNA expression relative to the mock oligonucleotide.
For the oligonucleotides where SNORD115 has been tested there is no significant down regulation when compared to mock at 1 and 5 microM.
Example 3—Activity of Oligonucleotides Targeting the SNHG14 Transcript in the Region Downstream of SNORD109B and Upstream of the Region Antisense to the UBE3A Pre-mRNA
Oligonucleotides targeting position 4806-54939 of SEQ ID NO: 1 were tested in patient derived human neuronal cell cultures (see protocol in “Materials and methods” section). The oligonucleotides ability to reduce the SNHG14 transcript in the region downstream of SNORD109B (also termed UBE3A suppressor or UBE3A-SUP in the data table. Furthermore, the ability to induce UBE3A mRNA re-expression was analyzed.
The oligonucleotides were screened according to the protocol for screening oligonucleotides in human neuronal cell cultures described in the section “Materials and methods”—“Screening oligonucleotides in human neuronal cell cultures—96 well system”
The results are shown in table 6.
TABLE 6
|
|
Oligonucleotide activity in patient
|
derived human neuronal cell cultures.
|
Start SEQ
CMP ID
Conc
% of Mock
% of Mock
|
ID NO 1
NO
μM
UBE3A-SUP
sd
UBE3A
sd
|
|
4806
151_1
0.2
66
2
125
NA
|
4806
151_1
1
53
10
NA
NA
|
4808
152_1
0.2
49
6
167
NA
|
4808
152_1
1
33
4
289
NA
|
4809
153_1
0.2
41
1
208
NA
|
4809
153_1
1
29
10
NA
NA
|
4811
154_1
0.2
48
3
282
NA
|
4811
154_1
1
37
5
331
NA
|
4812
155_1
0.2
35
5
286
64
|
4812
155_1
1
32
3
327
21
|
4972
156_1
0.2
60
6
145
6
|
4972
156_1
1
46
14
145
NA
|
4973
157_1
0.2
75
9
128
6
|
4973
157_1
1
59
NA
158
NA
|
4979
158_1
0.2
46
9
131
NA
|
4979
158_1
1
37
5
219
8
|
5058
159_1
0.2
69
6
133
19
|
5058
159_1
1
51
14
NA
NA
|
5071
160_1
0.2
55
8
98
NA
|
5071
160_1
1
39
7
136
34
|
5078
161_1
0.2
65
7
205
18
|
5078
161_1
1
51
10
306
31
|
5094
162_1
0.2
53
5
154
27
|
5094
162_1
1
34
8
300
65
|
5096
163_1
0.2
44
1
206
49
|
5096
163_1
1
36
6
316
NA
|
5100
164_1
0.2
34
3
220
NA
|
5100
164_1
1
30
3
227
32
|
5101
165_1
0.2
38
7
245
NA
|
5101
165_1
1
36
4
246
55
|
5218
166_1
0.2
45
4
240
NA
|
5218
166_1
1
36
6
280
44
|
5218
167_1
0.2
46
2
261
NA
|
5218
167_1
1
31
4
346
30
|
5224
168_1
0.2
39
3
377
40
|
5224
168_1
1
33
5
338
65
|
5224
169_1
0.2
37
4
313
NA
|
5224
169_1
1
31
2
308
3
|
5427
170_1
0.2
89
13
105
26
|
5427
170_1
1
117
35
124
NA
|
5434
171_1
0.2
51
5
164
10
|
5434
171_1
1
33
6
213
46
|
5785
172_1
0.2
46
5
210
NA
|
5785
172_1
1
38
4
342
NA
|
5786
173_1
0.2
54
4
292
61
|
5786
173_1
1
39
6
552
NA
|
6341
174_1
0.2
97
11
126
3
|
6341
174_1
1
90
33
NA
NA
|
6694
175_1
0.2
44
4
226
NA
|
6694
175_1
1
35
4
296
NA
|
6695
176_1
0.2
32
7
297
87
|
6695
176_1
1
29
4
263
9
|
6958
177_1
0.2
58
7
244
76
|
6958
177_1
1
47
NA
NA
NA
|
7159
179_1
0.2
33
4
282
NA
|
7159
179_1
1
29
5
289
7
|
7159
178_1
0.2
43
5
248
NA
|
7159
178_1
1
32
4
258
NA
|
7720
180_1
0.2
75
6
144
36
|
7720
180_1
1
54
7
233
26
|
7724
181_1
0.2
72
6
177
20
|
7724
181_1
1
45
19
224
62
|
7725
182_1
0.2
65
5
139
37
|
7725
182_1
1
47
4
208
76
|
7725
183_1
0.2
103
13
140
2
|
7725
183_1
1
74
6
NA
NA
|
7727
184_1
0.2
45
2
300
107
|
7727
184_1
1
35
2
272
16
|
8117
185_1
0.2
87
17
122
13
|
8117
185_1
1
63
17
175
NA
|
8118
186_1
0.2
40
5
368
105
|
8118
186_1
1
33
5
NA
NA
|
8119
187_1
0.2
62
5
197
NA
|
8119
187_1
1
43
13
517
143
|
8120
188_1
0.2
96
10
136
41
|
8120
188_1
1
79
22
146
19
|
8571
189_1
0.2
53
11
204
NA
|
8571
189_1
1
49
24
298
15
|
8573
190_1
0.2
54
9
140
9
|
8573
190_1
1
50
10
267
4
|
8574
191_1
0.2
56
1
117
NA
|
8574
191_1
1
57
13
199
NA
|
8575
192_1
0.2
56
9
165
10
|
8575
192_1
1
54
13
246
NA
|
8576
193_1
0.2
56
6
185
7
|
8576
193_1
1
52
8
330
35
|
8585
194_1
0.2
47
2
302
NA
|
8585
194_1
1
39
7
NA
NA
|
8819
195_1
0.2
62
10
155
10
|
8819
195_1
1
41
3
192
7
|
8820
196_1
0.2
55
12
237
69
|
8820
196_1
1
40
3
278
26
|
8887
197_1
0.2
69
15
301
59
|
8887
197_1
1
58
7
383
92
|
9150
198_1
0.2
49
6
NA
NA
|
9150
198_1
1
43
3
365
38
|
9201
199_1
0.2
79
23
88
42
|
9201
199_1
1
64
24
140
22
|
9202
201_1
0.2
61
10
NA
NA
|
9202
201_1
1
45
8
343
27
|
9202
200_1
0.2
47
3
287
76
|
9202
200_1
1
41
4
281
NA
|
9203
202_1
0.2
55
17
166
92
|
9203
202_1
1
40
5
297
54
|
9209
203_1
0.2
60
1
122
NA
|
9209
203_1
1
40
14
204
8
|
9210
204_1
0.2
43
2
216
NA
|
9210
204_1
1
37
3
409
NA
|
9210
205_1
0.2
45
8
187
NA
|
9210
205_1
1
37
22
336
18
|
9211
206_1
0.2
51
10
384
17
|
9211
206_1
1
42
3
381
35
|
9211
207_1
0.2
65
8
301
28
|
9211
207_1
1
50
5
272
53
|
9212
35_2
0.2
42
11
203
16
|
9212
35_2
1
44
18
335
NA
|
9212
208_1
0.2
64
5
147
58
|
9212
208_1
1
50
6
260
73
|
9213
209_1
0.2
57
7
NA
NA
|
9213
209_1
1
49
4
346
31
|
9214
210_1
0.2
49
7
139
NA
|
9214
210_1
1
45
7
223
59
|
10832
211_1
0.2
70
6
147
10
|
10832
211_1
1
56
9
200
38
|
10837
212_1
0.2
59
9
146
46
|
10837
212_1
1
41
6
226
47
|
10838
213_1
0.2
50
8
247
69
|
10838
213_1
1
44
12
307
NA
|
10877
214_1
0.2
108
21
115
1
|
10877
214_1
1
92
37
88
32
|
11434
215_1
0.2
97
12
81
23
|
11434
215_1
1
80
26
111
11
|
11435
216_1
0.2
90
16
87
NA
|
11435
216_1
1
82
29
82
21
|
11436
217_1
0.2
87
6
83
11
|
11436
217_1
1
68
26
123
NA
|
11438
218_1
0.2
57
5
133
NA
|
11438
218_1
1
44
16
188
NA
|
11439
219_1
0.2
84
1
93
NA
|
11439
219_1
1
66
22
113
29
|
11464
220_1
0.2
67
9
209
51
|
11464
220_1
1
41
6
256
33
|
11507
221_1
0.2
59
6
237
NA
|
11507
221_1
1
40
63
320
NA
|
11508
222_1
0.2
53
7
195
NA
|
11508
222_1
1
48
12
302
NA
|
11511
223_1
0.2
41
3
210
6
|
11511
223_1
1
37
9
273
NA
|
11513
224_1
0.2
22
8
288
91
|
11513
224_1
1
26
5
360
46
|
11514
225_1
0.2
98
17
98
31
|
11514
225_1
1
68
16
129
11
|
11736
226_1
0.2
69
8
197
80
|
11736
226_1
1
55
7
329
66
|
12361
227_1
0.2
48
8
183
56
|
12361
227_1
1
37
4
193
46
|
12794
228_1
0.2
38
9
201
71
|
12794
228_1
1
32
2
362
48
|
12795
229_1
0.2
50
12
161
30
|
12795
229_1
1
34
7
301
35
|
12796
230_1
0.2
44
12
237
86
|
12796
230_1
1
32
3
379
106
|
12894
232_1
0.2
91
17
79
27
|
12894
232_1
1
66
10
99
24
|
12894
231_1
0.2
80
5
89
NA
|
12894
231_1
1
57
14
164
31
|
12895
234_1
0.2
88
11
75
32
|
12895
234_1
1
68
19
91
24
|
12895
233_1
0.2
57
5
199
37
|
12895
233_1
1
38
7
249
57
|
12896
235_1
0.2
72
3
176
9
|
12896
235_1
1
45
3
251
42
|
13223
236_1
0.2
40
3
267
66
|
13223
236_1
1
31
3
270
23
|
13224
238_1
0.2
33
3
265
NA
|
13224
238_1
1
28
4
265
6
|
13224
237_1
0.2
38
2
212
NA
|
13224
237_1
1
31
1
254
31
|
13225
239_1
0.2
42
5
317
113
|
13225
239_1
1
29
7
215
26
|
13226
240_1
0.2
38
7
223
NA
|
13226
240_1
1
32
5
232
16
|
15115
241_1
0.2
61
8
377
15
|
15115
241_1
1
41
3
377
43
|
15258
242_1
0.2
66
14
133
35
|
15258
242_1
1
55
10
170
17
|
15568
243_1
0.2
62
13
192
58
|
15568
243_1
1
41
11
309
5
|
15570
244_1
0.2
53
17
252
59
|
15570
244_1
1
44
5
332
52
|
15572
245_1
0.2
57
21
321
122
|
15572
245_1
1
49
7
407
77
|
15573
246_1
0.2
47
16
348
129
|
15573
246_1
1
40
7
410
69
|
15574
247_1
0.2
48
14
326
116
|
15574
247_1
1
44
8
411
36
|
15722
248_1
0.2
51
3
258
17
|
15722
248_1
1
36
3
230
NA
|
16597
249_1
0.2
66
19
111
39
|
16597
249_1
1
54
14
174
44
|
16603
250_1
0.2
67
26
89
31
|
16603
250_1
1
56
6
172
32
|
16730
251_1
0.2
36
5
354
41
|
16730
251_1
1
31
2
326
75
|
16849
252_1
0.2
74
17
188
81
|
16849
252_1
1
48
17
282
1
|
17089
253_1
0.2
70
17
98
37
|
17089
253_1
1
62
19
153
13
|
17401
254_1
0.2
42
6
209
83
|
17401
254_1
1
29
3
327
49
|
24290
255_1
0.2
106
13
105
36
|
24290
255_1
1
109
21
136
NA
|
24296
256_1
0.2
92
20
117
30
|
24296
256_1
1
93
15
138
21
|
24811
257_1
0.2
85
12
126
4
|
24811
257_1
1
74
12
137
17
|
25032
258_1
0.2
50
11
329
131
|
25032
258_1
1
39
5
411
53
|
25033
259_1
0.2
40
10
343
50
|
25033
259_1
1
31
3
483
84
|
25250
260_1
0.2
33
10
279
42
|
25250
260_1
1
33
4
338
65
|
25251
261_1
0.2
40
8
209
97
|
25251
261_1
1
34
3
370
57
|
25718
262_1
0.2
56
20
113
48
|
25718
262_1
1
45
8
198
65
|
25720
263_1
0.2
84
7
121
39
|
25720
263_1
1
72
11
88
10
|
25721
264_1
0.2
83
15
87
40
|
25721
264_1
1
84
22
NA
NA
|
26331
265_1
0.2
93
5
88
38
|
26331
265_1
1
81
8
NA
NA
|
27165
266_1
0.2
63
3
117
39
|
27165
266_1
1
46
9
174
15
|
27248
267_1
0.2
81
10
124
17
|
27248
267_1
1
59
10
190
112
|
29330
268_1
0.2
109
4
124
48
|
29330
268_1
1
98
28
114
35
|
29635
269_1
0.2
45
1
218
50
|
29635
269_1
1
33
9
267
NA
|
29635
270_1
0.2
55
5
225
41
|
29635
270_1
1
45
8
NA
NA
|
29636
271_1
0.2
48
2
285
56
|
29636
271_1
1
40
7
359
99
|
29636
272_1
0.2
48
3
166
5
|
29636
272_1
1
35
8
293
40
|
29637
273_1
0.2
56
5
255
47
|
29637
273_1
1
46
4
300
105
|
29637
274_1
0.2
67
7
134
35
|
29637
274_1
1
54
7
234
19
|
29661
275_1
0.2
51
3
167
15
|
29661
275_1
1
42
11
251
NA
|
29661
276_1
0.2
54
5
127
17
|
29661
276_1
1
39
8
229
NA
|
29684
277_1
0.2
40
3
168
73
|
29684
277_1
1
31
13
NA
NA
|
29684
278_1
0.2
46
7
179
2
|
29684
278_1
1
36
8
NA
NA
|
30455
279_1
0.2
102
20
96
34
|
30455
279_1
1
86
22
118
23
|
30456
280_1
0.2
94
23
91
28
|
30456
280_1
1
83
18
134
36
|
30457
281_1
0.2
89
23
97
37
|
30457
281_1
1
94
23
106
39
|
30458
282_1
0.2
99
14
77
27
|
30458
282_1
1
103
17
96
20
|
30462
283_1
0.2
66
26
98
36
|
30462
283_1
1
56
14
129
13
|
30465
284_1
0.2
73
11
114
47
|
30465
284_1
1
57
10
197
63
|
30601
285_1
0.2
41
31
311
29
|
30601
285_1
1
30
16
373
40
|
30605
286_1
0.2
40
2
221
86
|
30605
286_1
1
33
6
375
NA
|
30609
287_1
0.2
43
3
267
65
|
30609
287_1
1
37
5
332
27
|
30610
288_1
0.2
46
6
253
79
|
30610
288_1
1
38
3
338
NA
|
30667
289_1
0.2
38
15
325
144
|
30667
289_1
1
36
3
461
68
|
30668
290_1
0.2
74
19
124
54
|
30668
290_1
1
58
14
183
20
|
30669
291_1
0.2
86
18
98
40
|
30669
291_1
1
78
12
133
26
|
30670
292_1
0.2
93
10
86
31
|
30670
292_1
1
94
16
127
22
|
30679
293_1
0.2
85
19
83
21
|
30679
293_1
1
87
21
113
23
|
30681
294_1
0.2
92
17
78
20
|
30681
294_1
1
100
19
86
22
|
30682
295_1
0.2
93
22
101
40
|
30682
295_1
1
94
33
101
8
|
30699
296_1
0.2
80
24
134
6
|
30699
296_1
1
47
21
232
36
|
30700
297_1
0.2
53
5
146
26
|
30700
297_1
1
32
8
NA
NA
|
30700
298_1
0.2
47
4
221
NA
|
30700
298_1
1
38
0
294
NA
|
30701
299_1
0.2
49
4
140
NA
|
30701
299_1
1
23
NA
NA
NA
|
30701
300_1
0.2
50
9
163
19
|
30701
300_1
1
39
11
346
11
|
30702
301_1
0.2
66
9
116
36
|
30702
301_1
1
44
14
230
51
|
30711
302_1
0.2
41
14
288
120
|
30711
302_1
1
40
5
422
132
|
30714
303_1
0.2
45
9
355
94
|
30714
303_1
1
31
5
355
8
|
30715
305_1
0.2
39
4
292
56
|
30715
305_1
1
34
12
253
5
|
30715
304_1
0.2
50
13
263
87
|
30715
304_1
1
43
7
285
12
|
31630
306_1
0.2
92
32
134
48
|
31630
306_1
1
85
25
177
26
|
31632
307_1
0.2
94
24
92
32
|
31632
307_1
1
86
17
109
33
|
31633
308_1
0.2
92
18
78
13
|
31633
308_1
1
102
23
98
7
|
32755
310_1
0.2
47
12
220
40
|
32755
310_1
1
40
16
285
NA
|
32755
309_1
0.2
62
6
167
NA
|
32755
309_1
1
40
10
225
NA
|
32756
311_1
0.2
55
9
128
9
|
32756
311_1
1
56
NA
224
NA
|
33366
312_1
0.2
64
23
121
4
|
33366
312_1
1
56
10
137
1
|
33367
313_1
0.2
81
7
91
NA
|
33367
313_1
1
79
22
115
12
|
33368
314_1
0.2
70
4
103
NA
|
33368
314_1
1
57
15
157
NA
|
33369
315_1
0.2
73
12
87
20
|
33369
315_1
1
67
19
155
NA
|
33375
316_1
0.2
79
18
100
18
|
33375
316_1
1
51
14
159
39
|
33377
317_1
0.2
46
21
248
72
|
33377
317_1
1
41
9
313
NA
|
33378
318_1
0.2
38
17
273
63
|
33378
318_1
1
36
7
321
1
|
36606
319_1
0.2
79
10
154
21
|
36606
319_1
1
48
9
233
65
|
36607
320_1
0.2
60
9
157
18
|
36607
320_1
1
49
9
206
25
|
38092
321_1
0.2
51
10
221
59
|
38092
321_1
1
41
5
328
39
|
38297
322_1
0.2
43
9
298
31
|
38297
322_1
1
34
6
365
91
|
39173
323_1
0.2
98
8
119
27
|
39173
323_1
1
82
20
177
21
|
39174
324_1
0.2
89
8
139
24
|
39174
324_1
1
84
23
192
15
|
39175
325_1
0.2
93
18
167
13
|
39175
325_1
1
68
17
203
33
|
39176
326_1
0.2
79
12
185
83
|
39176
326_1
1
55
17
374
107
|
39228
327_1
0.2
75
12
151
29
|
39228
327_1
1
57
8
207
32
|
39230
328_1
0.2
65
11
176
19
|
39230
328_1
1
52
19
357
NA
|
39231
329_1
0.2
63
19
150
35
|
39231
329_1
1
46
6
257
43
|
39563
330_1
0.2
69
10
116
34
|
39563
330_1
1
56
11
196
NA
|
39808
331_1
0.2
40
8
201
17
|
39808
331_1
1
25
5
300
NA
|
39808
332_1
0.2
40
14
282
109
|
39808
332_1
1
33
7
404
81
|
39931
333_1
0.2
80
11
107
53
|
39931
333_1
1
70
16
112
26
|
41114
334_1
0.2
64
4
113
NA
|
41114
334_1
1
28
NA
179
NA
|
41444
335_1
0.2
57
17
165
39
|
41444
335_1
1
46
4
290
40
|
41445
336_1
0.2
51
2
134
NA
|
41445
336_1
1
42
15
238
NA
|
41446
337_1
0.2
63
1
108
NA
|
41446
337_1
1
56
14
151
22
|
41725
338_1
0.2
91
16
130
50
|
41725
338_1
1
75
23
154
27
|
41726
339_1
0.2
66
20
142
23
|
41726
339_1
1
55
14
193
NA
|
41728
340_1
0.2
60
16
137
23
|
41728
340_1
1
51
13
233
NA
|
42167
341_1
0.2
70
9
138
7
|
42167
341_1
1
51
11
182
20
|
42168
343_1
0.2
67
9
210
92
|
42168
343_1
1
52
6
193
NA
|
42168
342_1
0.2
51
6
183
NA
|
42168
342_1
1
46
10
275
14
|
42169
344_1
0.2
55
1
231
32
|
42169
344_1
1
35
3
NA
NA
|
42169
345_1
0.2
55
7
164
41
|
42169
345_1
1
45
5
284
27
|
42287
346_1
0.2
66
7
144
32
|
42287
346_1
1
53
5
279
34
|
42289
347_1
0.2
75
20
125
10
|
42289
347_1
1
68
7
241
69
|
43452
348_1
0.2
62
12
231
92
|
43452
348_1
1
48
23
257
72
|
43453
349_1
0.2
52
11
142
41
|
43453
349_1
1
44
23
257
34
|
43562
350_1
0.2
50
13
148
35
|
43562
350_1
1
36
10
NA
NA
|
43565
351_1
0.2
71
10
116
43
|
43565
351_1
1
60
11
154
37
|
43566
352_1
0.2
65
19
139
14
|
43566
352_1
1
44
8
255
23
|
43634
353_1
0.2
63
25
172
75
|
43634
353_1
1
51
22
214
NA
|
44180
355_1
0.2
60
6
165
8
|
44180
355_1
1
57
25
145
NA
|
44180
354_1
0.2
76
17
149
55
|
44180
354_1
1
48
10
240
29
|
44181
356_1
0.2
60
5
170
27
|
44181
356_1
1
43
15
154
55
|
44183
357_1
0.2
50
15
214
33
|
44183
357_1
1
37
17
196
19
|
44184
358_1
0.2
57
5
155
31
|
44184
358_1
1
47
10
257
94
|
44439
359_1
0.2
46
4
220
53
|
44439
359_1
1
45
2
347
52
|
44440
360_1
0.2
48
9
261
37
|
44440
360_1
1
44
6
NA
NA
|
44440
361_1
0.2
43
5
218
46
|
44440
361_1
1
29
3
291
19
|
44441
362_1
0.2
50
5
192
60
|
44441
362_1
1
45
7
290
58
|
44441
363_1
0.2
45
10
185
51
|
44441
363_1
1
43
10
247
NA
|
44442
364_1
0.2
54
8
124
24
|
44442
364_1
1
39
5
271
54
|
44442
365_1
0.2
59
6
166
9
|
44442
365_1
1
44
8
313
47
|
44443
367_1
0.2
55
10
161
29
|
44443
367_1
1
40
7
314
67
|
44443
366_1
0.2
51
5
202
44
|
44443
366_1
1
41
10
300
31
|
44477
368_1
0.2
73
6
155
58
|
44477
368_1
1
52
3
362
141
|
44478
369_1
0.2
82
18
130
35
|
44478
369_1
1
58
11
228
66
|
44776
370_1
0.2
60
7
128
20
|
44776
370_1
1
46
5
274
NA
|
45216
371_1
0.2
50
10
149
33
|
45216
371_1
1
41
8
260
59
|
45217
372_1
0.2
59
7
132
45
|
45217
372_1
1
39
4
270
12
|
45217
373_1
0.2
47
3
167
52
|
45217
373_1
1
38
4
330
62
|
45218
374_1
0.2
51
9
189
27
|
45218
374_1
1
42
9
359
93
|
45246
375_1
0.2
61
8
175
29
|
45246
375_1
1
50
7
257
NA
|
45247
376_1
0.2
84
4
116
40
|
45247
376_1
1
74
10
144
NA
|
45248
378_1
0.2
61
10
226
2
|
45248
378_1
1
50
5
367
141
|
45248
377_1
0.2
74
11
138
29
|
45248
377_1
1
62
4
251
NA
|
45249
379_1
0.2
48
5
232
NA
|
45249
379_1
1
50
NA
312
NA
|
45249
380_1
0.2
54
4
203
16
|
45249
380_1
1
53
1
353
12
|
45250
381_1
0.2
48
6
230
25
|
45250
381_1
1
40
7
387
79
|
45250
382_1
0.2
60
7
153
30
|
45250
382_1
1
46
3
288
43
|
45258
383_1
0.2
46
4
211
NA
|
45258
383_1
1
34
6
307
29
|
45266
385_1
0.2
80
34
85
8
|
45266
385_1
1
55
13
128
25
|
45266
384_1
0.2
92
4
128
50
|
45266
384_1
1
79
12
108
23
|
45267
386_1
0.2
93
23
105
13
|
45267
386_1
1
80
23
139
14
|
45268
387_1
0.2
90
17
111
1
|
45268
387_1
1
109
9
122
44
|
45270
388_1
0.2
97
7
146
47
|
45270
388_1
1
88
9
113
22
|
45271
390_1
0.2
79
12
141
14
|
45271
390_1
1
58
14
197
38
|
45271
389_1
0.2
70
3
97
28
|
45271
389_1
1
53
6
150
26
|
45272
391_1
0.2
61
4
128
24
|
45272
391_1
1
55
14
208
39
|
45560
392_1
0.2
86
22
97
26
|
45560
392_1
1
71
19
125
18
|
45627
393_1
0.2
48
14
150
64
|
45627
393_1
1
39
1
209
35
|
45628
394_1
0.2
51
4
174
34
|
45628
394_1
1
44
8
309
30
|
45629
395_1
0.2
60
5
151
24
|
45629
395_1
1
48
7
297
43
|
45629
396_1
0.2
86
24
139
55
|
45629
396_1
1
64
13
203
38
|
45635
397_1
0.2
50
10
289
61
|
45635
397_1
1
46
2
401
56
|
45709
398_1
0.2
47
6
207
61
|
45709
398_1
1
49
6
233
NA
|
45709
399_1
0.2
56
6
206
13
|
45709
399_1
1
45
4
287
93
|
46215
400_1
0.2
78
14
122
13
|
46215
400_1
1
60
9
114
19
|
46256
401_1
0.2
62
7
164
56
|
46256
401_1
1
45
5
213
20
|
46257
404_1
0.2
44
4
207
44
|
46257
404_1
1
41
3
288
45
|
46257
402_1
0.2
48
5
197
57
|
46257
402_1
1
41
1
300
11
|
46257
403_1
0.2
51
4
265
50
|
46257
403_1
1
44
5
382
NA
|
46259
405_1
0.2
46
4
NA
NA
|
46259
405_1
1
39
10
359
10
|
46260
406_1
0.2
52
9
153
63
|
46260
406_1
1
48
7
262
71
|
46263
407_1
0.2
52
9
148
9
|
46263
407_1
1
41
5
262
45
|
46264
408_1
0.2
51
17
269
72
|
46264
408_1
1
42
8
280
55
|
46392
409_1
0.2
38
10
359
91
|
46392
409_1
1
38
8
NA
NA
|
46393
410_1
0.2
39
12
295
30
|
46393
410_1
1
32
12
NA
NA
|
46420
411_1
0.2
75
10
69
3
|
46420
411_1
1
86
3
101
21
|
46505
412_1
0.2
65
11
97
7
|
46505
412_1
1
53
5
226
59
|
46505
413_1
0.2
74
16
124
19
|
46505
413_1
1
69
13
117
11
|
46506
414_1
0.2
75
7
149
17
|
46506
414_1
1
71
10
169
118
|
46507
415_1
0.2
86
31
119
36
|
46507
415_1
1
66
17
129
28
|
46508
416_1
0.2
86
22
87
22
|
46508
416_1
1
67
10
142
16
|
47364
417_1
0.2
49
2
166
22
|
47364
417_1
1
47
13
295
NA
|
47365
418_1
0.2
54
3
131
29
|
47365
418_1
1
41
3
230
42
|
48110
419_1
0.2
77
9
101
45
|
48110
419_1
1
58
8
178
68
|
48111
420_1
0.2
63
7
121
32
|
48111
420_1
1
51
2
238
59
|
48186
421_1
0.2
69
5
176
52
|
48186
421_1
1
44
12
307
62
|
48221
422_1
0.2
58
15
149
63
|
48221
422_1
1
39
6
235
50
|
48222
423_1
0.2
60
12
143
9
|
48222
423_1
1
43
10
209
57
|
49345
85_1
0.2
43
14
242
38
|
49345
85_2
1
37
5
275
NA
|
50282
424_1
0.2
75
20
138
19
|
50282
424_1
1
56
9
226
62
|
51241
426_1
0.2
61
6
144
NA
|
51241
426_1
1
46
9
264
44
|
51241
425_1
0.2
46
8
164
22
|
51241
425_1
1
44
4
244
35
|
51242
428_1
0.2
57
6
138
30
|
51242
428_1
1
48
7
290
39
|
51242
427_1
0.2
40
15
341
NA
|
51242
427_1
1
30
8
286
63
|
51244
429_1
0.2
46
5
184
25
|
51244
429_1
1
44
6
283
4
|
51245
430_1
0.2
47
7
203
9
|
51245
430_1
1
37
5
271
29
|
51358
431_1
0.2
51
7
265
10
|
51358
431_1
1
40
4
363
70
|
51358
432_1
0.2
60
4
202
51
|
51358
432_1
1
37
7
275
NA
|
51359
433_1
0.2
40
3
238
20
|
51359
433_1
1
32
3
NA
NA
|
51359
434_1
0.2
39
6
424
83
|
51359
434_1
1
35
6
360
NA
|
51438
435_1
0.2
78
15
144
62
|
51438
435_1
1
60
14
201
27
|
51438
436_1
0.2
71
4
125
32
|
51438
436_1
1
54
6
205
71
|
51953
437_1
0.2
46
6
217
35
|
51953
437_1
1
37
4
277
52
|
52150
438_1
0.2
67
6
131
39
|
52150
438_1
1
53
13
177
NA
|
52549
439_1
0.2
56
5
162
31
|
52549
439_1
1
50
10
215
39
|
52550
440_1
0.2
69
13
137
40
|
52550
440_1
1
50
5
156
53
|
52551
441_1
0.2
66
3
132
8
|
52551
441_1
1
49
5
169
27
|
52579
442_1
0.2
38
7
280
60
|
52579
442_1
1
37
5
257
51
|
53012
443_1
0.2
79
10
197
61
|
53012
443_1
1
65
7
212
36
|
53013
445_1
0.2
64
6
211
13
|
53013
445_1
1
56
4
264
42
|
53013
444_1
0.2
68
11
137
33
|
53013
444_1
1
58
9
198
35
|
53014
446_1
0.2
59
6
125
NA
|
53014
446_1
1
47
3
216
22
|
53014
447_1
0.2
53
2
188
94
|
53014
447_1
1
51
10
192
47
|
54198
448_1
0.2
54
15
161
66
|
54198
448_1
1
48
11
243
NA
|
54199
449_1
0.2
63
12
166
20
|
54199
449_1
1
45
8
185
41
|
54232
450_1
0.2
84
17
112
67
|
54232
450_1
1
83
8
157
15
|
54233
451_1
0.2
67
14
118
44
|
54233
451_1
1
51
8
192
34
|
54235
452_1
0.2
50
3
162
NA
|
54235
452_1
1
42
7
190
NA
|
54236
453_1
0.2
47
21
234
17
|
54236
453_1
1
42
5
295
NA
|
54238
454_1
0.2
76
14
85
NA
|
54238
454_1
1
48
12
162
NA
|
54239
455_1
0.2
62
6
132
69
|
54239
455_1
1
46
7
149
57
|
54609
456_1
0.2
66
10
130
57
|
54609
456_1
1
56
11
141
60
|
54924
457_1
0.2
78
3
137
29
|
54924
457_1
1
61
4
178
25
|
|
Example 4—Activity of Oligonucleotides Targeting the SNHG14 Transcript in the Region Antisense to the UBE3A Pre-mRNA
Oligonucleotides targeting position 55337-136214 of SEQ ID NO: 1 were tested in patient derived human neuronal cell cultures (see protocol in “Materials and methods” section). The oligonucleotides ability to reduce the SNHG14 transcript in the region downstream of SNORD109B (also termed UBE3A suppressor or UBE3A-SUP in the data table). Furthermore, the ability to induce UBE3A mRNA re-expression was analyzed.
The oligonucleotides were screened according to the protocol for screening oligonucleotides in human neuronal cell cultures described in the section “Materials and methods”—“Screening oligonucleotides in human neuronal cell cultures—96 well system”.
The results are shown in table 7.
TABLE 7
|
|
Oligonucleotide activity in patient
|
derived human neuronal cell cultures.
|
Start SEQ
CMP ID
Conc
% of Mock
% of Mock
|
ID NO 1
NO
μM
UBE3A-SUP
sd
UBE3A
sd
|
|
55337
458_1
0.2
64
0
177
6
|
55337
458_1
1
50
10
233
9
|
55338
459_1
0.2
48
1
186
6
|
55338
459_1
1
44
9
213
NA
|
59565
460_1
0.2
66
4
110
24
|
59565
460_1
1
66
9
131
23
|
59574
461_1
0.2
56
5
162
19
|
59574
461_1
1
45
13
149
6
|
59575
462_1
0.2
56
7
114
84
|
59575
462_1
1
39
11
101
13
|
59576
463_1
0.2
82
19
52
NA
|
59576
463_1
1
65
15
95
18
|
60012
464_1
0.2
47
5
129
71
|
60012
464_1
1
41
3
160
64
|
60298
465_1
0.2
49
7
206
95
|
60298
465_1
1
37
9
222
44
|
60448
466_1
0.2
47
7
130
NA
|
60448
466_1
1
33
8
167
31
|
60821
467_1
0.2
87
1
73
NA
|
60821
467_1
1
62
18
101
3
|
61925
468_1
0.2
108
19
105
19
|
61925
468_1
1
95
17
101
19
|
62287
469_1
0.2
62
8
180
57
|
62287
469_1
1
48
5
196
38
|
62422
470_1
0.2
71
2
130
20
|
62422
470_1
1
57
9
116
18
|
62443
471_1
0.2
51
2
NA
NA
|
62443
471_1
1
43
2
160
34
|
64113
472_1
0.2
95
4
83
22
|
64113
472_1
1
76
14
74
36
|
64461
473_1
0.2
79
23
141
22
|
64461
473_1
1
59
12
279
53
|
64462
474_1
0.2
80
12
138
3
|
64462
474_1
1
84
15
202
3
|
65272
475_1
0.2
77
3
104
2
|
65272
475_1
1
75
23
113
10
|
66840
476_1
0.2
67
5
86
5
|
66840
476_1
1
72
10
100
12
|
67426
477_1
0.2
62
15
101
8
|
67426
477_1
1
65
13
170
52
|
68194
478_1
0.2
53
10
109
6
|
68194
478_1
1
59
4
178
7
|
68328
479_1
0.2
74
6
94
2
|
68328
479_1
1
79
16
111
38
|
68805
480_1
0.2
58
15
157
63
|
68805
480_1
1
49
2
190
26
|
68921
481_1
0.2
58
7
210
58
|
68921
481_1
1
55
10
281
NA
|
70133
482_1
0.2
50
9
149
6
|
70133
482_1
1
54
8
247
41
|
72377
483_1
0.2
44
2
143
NA
|
72377
483_1
1
52
6
195
37
|
72378
484_1
0.2
47
12
111
8
|
72378
484_1
1
56
3
201
NA
|
72826
485_1
0.2
54
12
116
0
|
72826
485_1
1
64
13
172
1
|
72861
486_1
0.2
52
9
93
6
|
72861
486_1
1
54
6
167
16
|
72887
487_1
0.2
55
3
128
5
|
72887
487_1
1
59
4
193
24
|
73474
488_1
0.2
55
10
132
20
|
73474
488_1
1
55
5
202
56
|
73992
489_1
0.2
60
7
146
17
|
73992
489_1
1
67
7
197
31
|
74791
490_1
0.2
42
5
167
65
|
74791
490_1
1
46
6
277
19
|
74851
491_1
0.2
69
14
78
1
|
74851
491_1
1
73
6
114
11
|
74853
492_1
0.2
64
6
84
1
|
74853
492_1
1
68
5
136
25
|
75840
493_1
0.2
40
10
90
6
|
75840
493_1
1
61
8
155
32
|
75841
494_1
0.2
65
10
131
30
|
75841
494_1
1
57
4
119
16
|
76238
495_1
0.2
70
9
109
41
|
76238
495_1
1
50
8
156
22
|
76254
496_1
0.2
67
13
134
34
|
76254
496_1
1
55
7
201
NA
|
76811
497_1
0.2
83
7
134
41
|
76811
497_1
1
77
8
148
32
|
77114
498_1
0.2
59
2
128
13
|
77114
498_1
1
64
10
206
NA
|
80468
499_1
0.2
55
2
105
34
|
80468
499_1
1
61
6
151
42
|
81047
500_1
0.2
103
17
80
6
|
81047
500_1
1
143
25
122
7
|
82233
501_1
0.2
57
NA
104
NA
|
82233
501_1
1
61
3
199
39
|
84166
502_1
0.2
49
6
89
0
|
84166
502_1
1
57
5
115
NA
|
85392
503_1
0.2
61
6
90
14
|
85392
503_1
1
62
8
118
15
|
86974
504_1
0.2
73
7
82
4
|
86974
504_1
1
79
3
104
19
|
87728
505_1
0.2
79
14
76
2
|
87728
505_1
1
80
19
97
35
|
87810
506_1
0.2
69
9
101
20
|
87810
506_1
1
73
6
155
2
|
88417
507_1
0.2
45
NA
116
3
|
88417
507_1
1
61
14
168
6
|
88991
508_1
0.2
51
6
113
20
|
88991
508_1
1
59
2
154
31
|
90228
509_1
0.2
65
6
76
10
|
90228
509_1
1
62
7
118
4
|
90474
510_1
0.2
71
7
83
14
|
90474
510_1
1
81
3
125
NA
|
91625
511_1
0.2
57
17
105
3
|
91625
511_1
1
65
11
150
NA
|
91885
512_1
0.2
57
5
105
1
|
91885
512_1
1
66
7
155
30
|
92976
513_1
0.2
67
6
136
44
|
92976
513_1
1
68
11
138
38
|
94304
514_1
0.2
81
11
110
7
|
94304
514_1
1
87
6
153
28
|
94528
515_1
0.2
48
5
128
6
|
94528
515_1
1
55
3
191
25
|
95653
516_1
0.2
57
3
108
7
|
95653
516_1
1
62
3
131
16
|
96751
517_1
0.2
63
9
90
19
|
96751
517_1
1
62
4
106
NA
|
97636
518_1
0.2
49
5
107
14
|
97636
518_1
1
44
9
137
NA
|
98480
519_1
0.2
55
1
106
NA
|
98480
519_1
1
54
5
112
23
|
98481
520_1
0.2
55
2
116
6
|
98481
520_1
1
62
4
129
6
|
99646
521_1
0.2
74
10
105
1
|
99646
521_1
1
87
13
119
27
|
100334
522_1
0.2
49
7
157
28
|
100334
522_1
1
57
2
120
37
|
101110
523_1
0.2
51
10
96
10
|
101110
523_1
1
72
14
114
25
|
101898
524_1
0.2
85
11
79
3
|
101898
524_1
1
93
21
92
46
|
102558
525_1
0.2
82
9
104
8
|
102558
525_1
1
86
18
104
30
|
103589
526_1
0.2
85
17
114
14
|
103589
526_1
1
94
39
126
6
|
104309
527_1
0.2
63
11
148
2
|
104309
527_1
1
70
26
155
NA
|
105686
528_1
0.2
66
11
91
24
|
105686
528_1
1
66
14
140
36
|
107972
529_1
0.2
84
15
109
15
|
107972
529_1
1
94
14
127
24
|
108257
530_1
0.2
63
7
114
19
|
108257
530_1
1
67
12
141
40
|
109407
531_1
0.2
84
24
87
16
|
109407
531_1
1
82
11
127
26
|
110210
532_1
0.2
72
12
91
14
|
110210
532_1
1
80
14
122
40
|
110768
533_1
0.2
67
8
126
16
|
110768
533_1
1
87
21
176
45
|
111811
534_1
0.2
77
2
98
17
|
111811
534_1
1
74
6
143
14
|
111812
535_1
0.2
64
4
97
0
|
111812
535_1
1
77
3
136
37
|
112149
536_1
0.2
73
2
63
2
|
112149
536_1
1
77
18
127
36
|
112150
537_1
0.2
76
6
78
8
|
112150
537_1
1
90
29
91
11
|
112945
538_1
0.2
69
4
121
2
|
112945
538_1
1
83
14
102
39
|
113533
539_1
0.2
95
17
85
2
|
113533
539_1
1
91
27
87
17
|
114274
540_1
0.2
89
11
103
17
|
114274
540_1
1
87
26
132
20
|
114495
541_1
0.2
76
5
88
1
|
114495
541_1
1
83
15
120
6
|
114831
542_1
0.2
59
3
76
4
|
114831
542_1
1
74
3
104
4
|
115355
543_1
0.2
66
8
91
9
|
115355
543_1
1
74
16
110
NA
|
116105
544_1
0.2
55
12
77
NA
|
116105
544_1
1
74
6
110
8
|
116106
545_1
0.2
58
18
96
9
|
116106
545_1
1
66
8
130
10
|
117096
546_1
0.2
69
9
118
20
|
117096
546_1
1
65
4
146
NA
|
117189
547_1
0.2
69
6
98
9
|
117189
547_1
1
74
11
146
25
|
117476
548_1
0.2
59
4
87
5
|
117476
548_1
1
65
3
104
10
|
118293
549_1
0.2
55
8
92
3
|
118293
549_1
1
66
10
105
24
|
118294
550_1
0.2
55
18
90
4
|
118294
550_1
1
72
21
119
5
|
118756
551_1
0.2
60
13
86
18
|
118756
551_1
1
88
24
120
26
|
119621
552_1
0.2
77
21
117
4
|
119621
552_1
1
102
19
146
NA
|
120655
553_1
0.2
55
9
124
19
|
120655
553_1
1
57
7
185
14
|
123733
554_1
0.2
74
6
87
14
|
123733
554_1
1
77
4
127
4
|
124163
555_1
0.2
89
12
117
46
|
124163
555_1
1
67
20
152
13
|
125512
556_1
0.2
70
5
114
26
|
125512
556_1
1
69
11
119
47
|
126882
557_1
0.2
78
15
106
8
|
126882
557_1
1
84
10
113
33
|
127105
558_1
0.2
71
7
91
13
|
127105
558_1
1
68
5
108
28
|
127809
559_1
0.2
59
4
74
NA
|
127809
559_1
1
58
7
101
26
|
129020
560_1
0.2
82
11
103
39
|
129020
560_1
1
77
9
103
27
|
129205
561_1
0.2
75
24
78
16
|
129205
561_1
1
89
11
102
23
|
129928
562_1
0.2
57
0
98
21
|
129928
562_1
1
63
9
107
18
|
130020
563_1
0.2
65
5
85
9
|
130020
563_1
1
65
3
145
12
|
130884
564_1
0.2
81
24
117
31
|
130884
564_1
1
83
4
139
17
|
130886
565_1
0.2
80
8
103
13
|
130886
565_1
1
69
7
122
11
|
131404
566_1
0.2
79
4
85
3
|
131404
566_1
1
80
7
116
24
|
132514
567_1
0.2
71
8
98
28
|
132514
567_1
1
69
9
97
29
|
133367
568_1
0.2
78
9
88
16
|
133367
568_1
1
91
17
88
32
|
136198
569_1
0.2
88
5
87
2
|
136198
569_1
1
81
6
109
35
|
|
Example 5—Activity of Oligonucleotides Targeting the SNHG14 Transcript in the Region Downstream of SNORD109B and Upstream of the Region Antisense to the UBE3A Pre-mRNA
Oligonucleotides targeting position 5224-51257 of SEQ ID NO: 1 were tested in patient derived human neuronal cell cultures (see protocol in “Materials and methods” section). The oligonucleotides ability to reduce the SNHG14 transcript in the region downstream of SNORD109B (also termed UBE3A suppressor or UBE3A-SUP in the data table. Furthermore, the ability to induce UBE3A mRNA re-expression was analyzed.
The oligonucleotides were screened according to the protocol for screening oligonucleotides in human neuronal cell cultures described in the section “Materials and methods” “Screening oligonucleotides in human neuronal cell cultures—96 well system” with the following modifications:
UBE3a-Sense Primer
Using commercially available primers and probe from ThermoFisher: Hs00166580_m1 amplifying a 94 bp sequence in position 838 of refseq ID NM_000462.3.
Each plate include PBS controls (instead on a non-targeting oligonucleotide) and a positive control oligonucleotide CMP ID NO: 271_1, resulting in up-regulation of UBE3A mRNA. The additional control oligonucleotides were not included.
Data are presented as average % expression relative to PBS controls across all plates and normalized to the positive control oligonucleotide to manage plate to plate variation in efficacy levels. The results are shown in table 8.
TABLE 8
|
|
Oligonucleotide activity in patient
|
derived human neuronal cell cultures.
|
Start SEQ
CMP
Conc
% of Mock
% of Mock
|
ID NO 1
ID NO
μM
UBE3A-SUP
sd
UBE3A
sd
|
|
5224
169_2
7.5 μM
49
4
209
9
|
5224
169_3
7.5 μM
47
5
282
5
|
5224
169_4
7.5 μM
57
14
202
12
|
5224
169_5
7.5 μM
84
36
148
4
|
5224
169_6
7.5 μM
42
1
285
16
|
5224
169_7
7.5 μM
52
6
233
27
|
5224
169_8
7.5 μM
51
7
278
11
|
5224
169_9
7.5 μM
51
4
228
20
|
5224
169_10
7.5 μM
78
17
143
5
|
5224
169_11
7.5 μM
74
15
146
2
|
5224
169_12
7.5 μM
47
1
277
26
|
5224
169_13
7.5 μM
56
23
244
42
|
5224
169_14
7.5 μM
74
16
141
1
|
5224
169_15
7.5 μM
95
32
122
13
|
5224
169_16
7.5 μM
44
4
276
23
|
5224
169_17
7.5 μM
85
5
118
5
|
5224
169_18
7.5 μM
75
18
131
4
|
5224
169_19
7.5 μM
95
18
126
11
|
5224
169_20
7.5 μM
61
12
169
20
|
5224
169_21
7.5 μM
79
18
156
3
|
5224
169_22
7.5 μM
63
14
173
16
|
5224
169_23
7.5 μM
43
2
233
27
|
5224
169_24
7.5 μM
56
1
183
9
|
5224
169_25
7.5 μM
48
0
220
24
|
5224
169_26
7.5 μM
41
1
244
39
|
5224
169_27
7.5 μM
55
16
260
42
|
5224
169_28
7.5 μM
48
1
265
65
|
5224
169_29
7.5 μM
56
2
197
18
|
5224
169_30
7.5 μM
57
12
189
12
|
5224
169_31
7.5 μM
53
4
196
9
|
5224
169_32
7.5 μM
50
1
220
3
|
5224
169_33
7.5 μM
64
19
227
8
|
5224
169_34
7.5 μM
58
4
193
10
|
5224
169_35
7.5 μM
45
2
229
3
|
5224
169_36
7.5 μM
44
6
262
14
|
5224
169_37
7.5 μM
55
2
180
21
|
5224
169_38
7.5 μM
75
22
158
13
|
5224
169_39
7.5 μM
76
15
159
17
|
5224
169_40
7.5 μM
60
18
232
31
|
5224
169_41
7.5 μM
46
3
230
10
|
5224
169_42
7.5 μM
47
3
240
11
|
5224
169_43
7.5 μM
48
9
273
30
|
5224
169_44
7.5 μM
83
32
196
11
|
5224
169_45
7.5 μM
69
4
185
20
|
5224
169_46
7.5 μM
45
9
256
3
|
5224
169_47
7.5 μM
41
2
304
4
|
5224
169_48
7.5 μM
44
1
260
16
|
5224
169_49
7.5 μM
38
1
245
32
|
5224
169_50
7.5 μM
35
2
314
28
|
5224
169_51
7.5 μM
41
5
281
5
|
5224
169_52
7.5 μM
36
1
282
1
|
5224
169_53
7.5 μM
38
7
301
7
|
5224
169_54
7.5 μM
36
3
304
6
|
5224
169_55
7.5 μM
52
5
246
23
|
5224
169_56
7.5 μM
33
15
302
15
|
5224
169_57
7.5 μM
34
16
273
16
|
5784
570_1
7.5 μM
47
0
274
7
|
5784
570_2
7.5 μM
47
8
232
8
|
5784
570_3
7.5 μM
55
25
280
54
|
5784
570_4
7.5 μM
61
11
235
54
|
5784
570_5
7.5 μM
72
10
198
30
|
5784
570_6
7.5 μM
66
8
244
50
|
5784
570_7
7.5 μM
42
1
284
13
|
5784
570_8
7.5 μM
43
6
257
11
|
5784
570_9
7.5 μM
32
9
242
30
|
5785
571_1
7.5 μM
40
1
269
35
|
5785
571_2
7.5 μM
42
3
187
6
|
5785
571_3
7.5 μM
46
6
242
8
|
5785
571_4
7.5 μM
37
4
282
19
|
5785
571_5
7.5 μM
48
16
296
2
|
5785
571_6
7.5 μM
37
6
274
10
|
5785
571_7
7.5 μM
39
1
260
8
|
5785
571_8
7.5 μM
35
1
252
3
|
5785
571_9
7.5 μM
30
5
297
10
|
5786
572_1
7.5 μM
34
4
279
29
|
5786
572_2
7.5 μM
63
10
152
4
|
5786
572_3
7.5 μM
39
0
280
42
|
5786
572_4
7.5 μM
40
1
283
14
|
5786
572_5
7.5 μM
38
6
310
11
|
5786
572_6
7.5 μM
33
1
316
18
|
5786
572_7
7.5 μM
35
1
318
11
|
5786
572_8
7.5 μM
47
9
310
19
|
5786
572_9
7.5 μM
31
7
321
12
|
8116
573_1
7.5 μM
39
8
316
28
|
8116
573_2
7.5 μM
49
15
305
41
|
8116
573_3
7.5 μM
46
13
308
3
|
8116
573_4
7.5 μM
39
3
332
6
|
8116
573_5
7.5 μM
34
6
278
12
|
8116
573_6
7.5 μM
42
1
285
10
|
8116
573_7
7.5 μM
38
0
289
33
|
8116
573_8
7.5 μM
40
4
311
20
|
8116
573_9
7.5 μM
57
9
315
5
|
8117
574_1
7.5 μM
40
2
291
35
|
8117
574_2
7.5 μM
42
3
343
18
|
8117
574_3
7.5 μM
36
6
325
8
|
8117
574_4
7.5 μM
38
1
279
15
|
8117
574_5
7.5 μM
42
6
308
10
|
8117
574_6
7.5 μM
47
8
340
11
|
8117
574_7
7.5 μM
43
0
308
42
|
8117
574_8
7.5 μM
44
6
268
10
|
8117
574_9
7.5 μM
41
8
241
22
|
8118
575_1
7.5 μM
47
0
198
28
|
8118
575_2
7.5 μM
83
26
253
31
|
8118
575_3
7.5 μM
48
4
348
5
|
8118
575_4
7.5 μM
37
2
269
7
|
8118
575_5
7.5 μM
43
6
258
17
|
8118
575_6
7.5 μM
50
6
286
3
|
8118
575_7
7.5 μM
37
2
331
30
|
8118
575_8
7.5 μM
47
7
264
1
|
8118
575_9
7.5 μM
64
23
243
3
|
8119
576_1
7.5 μM
47
1
272
14
|
8119
576_2
7.5 μM
109
31
119
3
|
8119
576_3
7.5 μM
36
3
287
6
|
8119
576_4
7.5 μM
35
3
285
23
|
8119
576_5
7.5 μM
49
10
222
1
|
8119
576_6
7.5 μM
79
12
132
10
|
8119
576_7
7.5 μM
76
4
132
3
|
8119
576_8
7.5 μM
62
1
147
5
|
8119
576_9
7.5 μM
43
3
230
5
|
8120
577_1
7.5 μM
57
3
158
15
|
8120
577_2
7.5 μM
39
4
279
60
|
8120
577_3
7.5 μM
38
1
290
68
|
8120
577_4
7.5 μM
77
11
148
11
|
8120
577_5
7.5 μM
31
6
272
36
|
8120
577_6
7.5 μM
38
8
228
32
|
8120
577_7
7.5 μM
40
8
246
39
|
8120
577_8
7.5 μM
43
11
256
26
|
8120
577_9
7.5 μM
85
32
109
6
|
8584
578_1
7.5 μM
57
7
199
7
|
8584
578_2
7.5 μM
40
5
263
3
|
8584
578_3
7.5 μM
40
2
289
23
|
8584
578_4
7.5 μM
43
8
199
16
|
8584
578_5
7.5 μM
42
1
256
15
|
8584
578_6
7.5 μM
42
6
241
10
|
8584
578_7
7.5 μM
42
5
329
20
|
8584
578_8
7.5 μM
49
7
271
13
|
8584
578_9
7.5 μM
45
3
222
3
|
8585
579_1
7.5 μM
45
0
208
8
|
8585
579_2
7.5 μM
51
4
226
6
|
8585
579_3
7.5 μM
54
5
178
8
|
8585
579_4
7.5 μM
41
4
328
13
|
8585
579_5
7.5 μM
50
5
272
3
|
8585
579_6
7.5 μM
86
12
161
0
|
8585
579_7
7.5 μM
72
5
155
15
|
8585
579_8
7.5 μM
57
3
230
14
|
8585
579_9
7.5 μM
83
0
123
1
|
8586
580_1
7.5 μM
37
2
313
13
|
8586
580_2
7.5 μM
43
1
266
3
|
8586
580_3
7.5 μM
42
5
303
5
|
8586
580_4
7.5 μM
57
4
225
26
|
8586
580_5
7.5 μM
51
4
228
35
|
8586
580_6
7.5 μM
44
4
253
15
|
8586
580_7
7.5 μM
50
1
241
10
|
8586
580_8
7.5 μM
44
0
227
26
|
8586
580_9
7.5 μM
31
5
323
31
|
8587
581_1
7.5 μM
50
6
223
30
|
8587
581_2
7.5 μM
66
7
199
19
|
8587
581_3
7.5 μM
56
8
197
9
|
8587
581_4
7.5 μM
57
12
270
24
|
8587
581_5
7.5 μM
51
12
259
12
|
8587
581_6
7.5 μM
39
4
282
2
|
8587
581_7
7.5 μM
38
11
263
5
|
8587
581_8
7.5 μM
45
10
203
19
|
8587
581_9
7.5 μM
43
2
234
10
|
9209
582_1
7.5 μM
61
7
225
7
|
9209
582_2
7.5 μM
46
9
341
36
|
9209
582_3
7.5 μM
44
9
306
38
|
9209
582_4
7.5 μM
43
1
249
5
|
9209
582_5
7.5 μM
33
16
306
6
|
9209
582_6
7.5 μM
37
8
329
19
|
9209
582_7
7.5 μM
44
9
289
4
|
9209
582_8
7.5 μM
39
3
314
20
|
9209
582_9
7.5 μM
41
4
299
25
|
9210
583_1
7.5 μM
43
5
319
25
|
9210
583_2
7.5 μM
53
9
352
5
|
9210
583_3
7.5 μM
42
2
362
42
|
9210
583_4
7.5 μM
46
5
225
13
|
9210
583_5
7.5 μM
39
6
343
21
|
9210
583_6
7.5 μM
44
9
298
8
|
9210
583_7
7.5 μM
37
5
332
9
|
9210
583_8
7.5 μM
42
6
343
25
|
9210
583_9
7.5 μM
36
2
341
9
|
9211
584_1
7.5 μM
45
5
343
39
|
9211
584_2
7.5 μM
42
2
298
22
|
9211
584_3
7.5 μM
44
10
321
2
|
9211
584_4
7.5 μM
50
1
299
5
|
9211
584_5
7.5 μM
44
1
319
25
|
9211
584_6
7.5 μM
50
6
323
13
|
9211
584_7
7.5 μM
42
4
316
27
|
9211
584_8
7.5 μM
53
3
217
11
|
9212
208_2
7.5 μM
44
7
312
26
|
9212
208_3
7.5 μM
38
2
331
21
|
9212
208_4
7.5 μM
47
3
353
11
|
9212
208_5
7.5 μM
54
11
348
14
|
9212
208_6
7.5 μM
51
12
310
8
|
9212
208_7
7.5 μM
60
9
224
11
|
9213
209_2
7.5 μM
44
12
242
21
|
9213
209_3
7.5 μM
37
12
335
12
|
9213
209_4
7.5 μM
55
7
350
2
|
9213
209_5
7.5 μM
47
7
337
19
|
9213
209_6
7.5 μM
51
8
300
19
|
9213
209_7
7.5 μM
47
15
342
23
|
9213
209_8
7.5 μM
45
12
289
5
|
9213
209_9
7.5 μM
41
1
368
37
|
9213
209_10
7.5 μM
40
4
315
1
|
11511
585_1
7.5 μM
41
7
350
12
|
11511
585_2
7.5 μM
44
4
233
7
|
11511
585_3
7.5 μM
40
8
310
31
|
11511
585_4
7.5 μM
33
8
324
41
|
11511
585_5
7.5 μM
29
3
314
23
|
11511
585_6
7.5 μM
38
4
332
15
|
11511
585_7
7.5 μM
30
2
315
15
|
11511
585_8
7.5 μM
36
11
328
37
|
11511
585_9
7.5 μM
39
5
303
49
|
11512
586_1
7.5 μM
60
3
236
5
|
11512
586_2
7.5 μM
40
9
282
53
|
11512
586_3
7.5 μM
36
1
279
11
|
11512
586_4
7.5 μM
34
3
288
21
|
11512
586_5
7.5 μM
30
1
270
4
|
11512
586_6
7.5 μM
29
5
269
24
|
11512
586_7
7.5 μM
33
4
263
6
|
11512
586_8
7.5 μM
32
4
270
4
|
11512
586_9
7.5 μM
33
5
310
48
|
11513
587_1
7.5 μM
45
2
237
34
|
11513
587_2
7.5 μM
44
3
307
4
|
11513
587_3
7.5 μM
37
1
285
24
|
11513
587_4
7.5 μM
44
1
252
41
|
11513
587_5
7.5 μM
51
7
220
29
|
11513
587_6
7.5 μM
41
2
262
35
|
11513
587_7
7.5 μM
39
7
280
21
|
11513
587_8
7.5 μM
48
9
230
11
|
11513
587_9
7.5 μM
41
5
270
9
|
11514
588_1
7.5 μM
54
9
204
25
|
11514
588_2
7.5 μM
98
5
143
4
|
11514
588_3
7.5 μM
55
9
180
1
|
11514
588_4
7.5 μM
113
24
109
17
|
11514
588_5
7.5 μM
66
26
150
5
|
11514
588_6
7.5 μM
74
1
131
1
|
11514
588_7
7.5 μM
79
4
140
9
|
11514
588_8
7.5 μM
49
2
235
2
|
11514
588_9
7.5 μM
51
10
281
2
|
11515
589_1
7.5 μM
61
2
154
9
|
11515
589_2
7.5 μM
70
9
126
12
|
11515
589_3
7.5 μM
53
3
212
32
|
11515
589_4
7.5 μM
93
14
108
14
|
11515
589_5
7.5 μM
69
11
191
7
|
11515
589_6
7.5 μM
53
9
183
20
|
11515
589_7
7.5 μM
45
8
257
4
|
11515
589_8
7.5 μM
35
5
213
5
|
11515
589_9
7.5 μM
41
2
290
22
|
13223
236_2
7.5 μM
39
6
286
21
|
13223
236_3
7.5 μM
32
10
256
29
|
13223
236_4
7.5 μM
37
5
285
12
|
13223
236_5
7.5 μM
33
8
280
19
|
13223
236_6
7.5 μM
40
16
295
7
|
13223
236_7
7.5 μM
45
10
254
50
|
13223
236_8
7.5 μM
41
22
306
50
|
13223
236_9
7.5 μM
32
11
292
47
|
13223
236_10
7.5 μM
31
10
307
3
|
13223
236_11
7.5 μM
52
32
198
29
|
13223
236_12
7.5 μM
31
7
261
18
|
13223
236_13
7.5 μM
34
3
279
32
|
13223
236_14
7.5 μM
38
0
285
75
|
13223
236_15
7.5 μM
40
17
307
53
|
13223
236_16
7.5 μM
41
6
321
30
|
13224
237_2
7.5 μM
49
18
251
38
|
13224
237_3
7.5 μM
53
14
236
33
|
13224
237_4
7.5 μM
39
0
283
26
|
13224
237_5
7.5 μM
43
2
243
2
|
13224
237_6
7.5 μM
39
10
265
48
|
13224
237_7
7.5 μM
50
3
302
19
|
13224
237_8
7.5 μM
46
7
327
43
|
13224
237_9
7.5 μM
38
9
287
12
|
13224
237_10
7.5 μM
35
6
248
35
|
13224
237_11
7.5 μM
41
1
259
24
|
13224
237_12
7.5 μM
33
6
303
35
|
13224
237_13
7.5 μM
26
4
265
53
|
13224
237_14
7.5 μM
30
8
321
15
|
13224
237_15
7.5 μM
33
11
315
24
|
13224
237_16
7.5 μM
36
11
292
19
|
13225
239_2
7.5 μM
35
16
291
30
|
13225
239_3
7.5 μM
40
15
311
42
|
13225
239_4
7.5 μM
81
6
144
16
|
13225
239_5
7.5 μM
90
16
127
11
|
13225
239_6
7.5 μM
49
29
282
3
|
13225
239_7
7.5 μM
35
4
296
23
|
13225
239_8
7.5 μM
40
1
292
48
|
13225
239_9
7.5 μM
36
1
318
44
|
13225
239_10
7.5 μM
49
NA
304
NA
|
13225
239_11
7.5 μM
45
NA
258
NA
|
13225
239_12
7.5 μM
43
1
285
1
|
13225
239_13
7.5 μM
31
1
308
31
|
13225
239_14
7.5 μM
41
8
253
6
|
13225
239_15
7.5 μM
28
3
291
16
|
13225
239_16
7.5 μM
29
3
314
14
|
13226
590_1
7.5 μM
34
1
283
18
|
13226
590_2
7.5 μM
49
7
213
17
|
13226
590_3
7.5 μM
40
1
274
51
|
13226
590_4
7.5 μM
36
1
300
2
|
13226
590_5
7.5 μM
37
3
280
36
|
13226
590_6
7.5 μM
38
2
204
17
|
13226
590_7
7.5 μM
38
5
245
16
|
13226
590_8
7.5 μM
30
6
219
34
|
13226
590_9
7.5 μM
33
1
269
2
|
13226
590_10
7.5 μM
33
2
258
49
|
13226
590_11
7.5 μM
48
17
297
31
|
13226
590_12
7.5 μM
33
4
317
65
|
13226
590_13
7.5 μM
35
7
337
43
|
13226
590_14
7.5 μM
25
1
306
22
|
13226
590_15
7.5 μM
30
5
299
2
|
15113
591_1
7.5 μM
43
3
313
14
|
15113
591_2
7.5 μM
52
2
295
24
|
15114
592_1
7.5 μM
53
2
232
17
|
15114
592_2
7.5 μM
39
1
309
23
|
15114
592_3
7.5 μM
46
1
278
12
|
15114
592_4
7.5 μM
36
1
328
13
|
15114
592_5
7.5 μM
49
9
295
40
|
15114
592_6
7.5 μM
46
3
297
10
|
15114
592_7
7.5 μM
75
21
160
23
|
15114
592_8
7.5 μM
41
10
325
23
|
15114
592_9
7.5 μM
55
15
265
3
|
15115
241_2
7.5 μM
66
18
168
2
|
15115
241_3
7.5 μM
51
15
265
11
|
15115
241_4
7.5 μM
49
4
239
7
|
15115
241_5
7.5 μM
52
11
314
20
|
15115
241_6
7.5 μM
41
13
307
7
|
15115
241_7
7.5 μM
38
6
344
33
|
15115
241_8
7.5 μM
39
10
329
9
|
15115
241_9
7.5 μM
50
11
321
32
|
15115
241_10
7.5 μM
48
9
316
1
|
15563
593_1
7.5 μM
38
10
282
14
|
15563
593_2
7.5 μM
31
5
279
16
|
15563
593_3
7.5 μM
34
7
281
16
|
15563
593_4
7.5 μM
32
16
318
2
|
15563
594_1
7.5 μM
40
2
320
21
|
15563
594_2
7.5 μM
54
7
237
14
|
15563
594_3
7.5 μM
35
6
300
45
|
15563
594_4
7.5 μM
37
7
254
6
|
15564
596_1
7.5 μM
47
7
225
35
|
15564
596_2
7.5 μM
49
2
184
14
|
15564
596_3
7.5 μM
34
8
271
18
|
15564
596_4
7.5 μM
45
8
277
29
|
15564
595_1
7.5 μM
42
4
254
6
|
15564
595_2
7.5 μM
36
9
277
35
|
15564
595_3
7.5 μM
40
8
295
31
|
15564
595_4
7.5 μM
45
5
173
20
|
15566
597_1
7.5 μM
48
6
296
22
|
15566
597_2
7.5 μM
44
12
293
8
|
15566
597_3
7.5 μM
41
6
318
23
|
15566
597_4
7.5 μM
60
9
340
72
|
15567
38_3
7.5 μM
41
3
306
14
|
15567
38_4
7.5 μM
45
1
303
48
|
15567
38_5
7.5 μM
39
15
292
28
|
15567
38_6
7.5 μM
46
12
261
40
|
15567
598_1
7.5 μM
42
2
257
31
|
15567
598_2
7.5 μM
41
12
272
46
|
15567
598_3
7.5 μM
54
9
281
29
|
15567
598_4
7.5 μM
45
8
307
6
|
15568
599_1
7.5 μM
47
3
326
68
|
15568
599_2
7.5 μM
60
14
307
30
|
15568
599_3
7.5 μM
50
8
274
24
|
15568
599_4
7.5 μM
45
6
250
12
|
15568
600_1
7.5 μM
37
6
251
1
|
15568
600_2
7.5 μM
45
11
267
15
|
15568
600_3
7.5 μM
44
5
278
1
|
15568
600_4
7.5 μM
41
10
265
5
|
15569
601_1
7.5 μM
42
12
271
18
|
15569
601_2
7.5 μM
38
6
269
24
|
15569
601_3
7.5 μM
39
4
260
34
|
15569
601_4
7.5 μM
56
8
146
1
|
15570
244_2
7.5 μM
46
1
338
6
|
15570
244_3
7.5 μM
47
0
275
47
|
15570
244_4
7.5 μM
47
8
281
67
|
15570
244_5
7.5 μM
41
8
258
52
|
15570
39_2
7.5 μM
53
4
339
25
|
15570
39_3
7.5 μM
65
5
200
17
|
15570
39_4
7.5 μM
47
7
321
6
|
15570
39_5
7.5 μM
46
3
289
20
|
15571
602_1
7.5 μM
34
5
278
29
|
15571
602_2
7.5 μM
39
8
254
37
|
15571
602_3
7.5 μM
41
10
266
23
|
15571
602_4
7.5 μM
42
8
256
40
|
15571
40_2
7.5 μM
58
0
325
4
|
15571
40_3
7.5 μM
58
2
326
35
|
15571
40_4
7.5 μM
54
1
306
3
|
15571
40_5
7.5 μM
44
2
322
4
|
15571
40_6
7.5 μM
43
4
293
17
|
15571
40_7
7.5 μM
53
7
343
20
|
15571
40_8
7.5 μM
52
1
337
17
|
15572
604_1
7.5 μM
58
1
289
3
|
15572
604_2
7.5 μM
63
12
230
5
|
15572
604_3
7.5 μM
57
3
306
23
|
15572
604_4
7.5 μM
46
6
324
4
|
15572
603_1
7.5 μM
60
7
339
31
|
15572
603_2
7.5 μM
70
0
279
19
|
15572
603_3
7.5 μM
59
9
290
48
|
15572
603_4
7.5 μM
85
11
123
24
|
15573
605_1
7.5 μM
56
5
288
3
|
15573
605_2
7.5 μM
58
4
286
6
|
15573
605_3
7.5 μM
59
3
261
9
|
15573
605_4
7.5 μM
69
24
328
17
|
15573
606_1
7.5 μM
50
4
282
19
|
15573
606_2
7.5 μM
112
NA
133
NA
|
15573
606_3
7.5 μM
55
22
254
43
|
15573
606_4
7.5 μM
107
59
116
2
|
15574
607_1
7.5 μM
56
2
337
31
|
15574
607_2
7.5 μM
59
1
254
10
|
15574
607_3
7.5 μM
53
0
295
26
|
15574
607_4
7.5 μM
48
3
268
15
|
25248
608_1
7.5 μM
86
7
189
5
|
25248
608_2
7.5 μM
102
13
136
3
|
25248
608_3
7.5 μM
54
17
280
12
|
25248
608_4
7.5 μM
71
8
219
31
|
25248
608_5
7.5 μM
59
20
179
16
|
25248
608_6
7.5 μM
71
2
198
0
|
25248
608_7
7.5 μM
47
3
230
21
|
25248
608_8
7.5 μM
55
12
287
13
|
25248
608_9
7.5 μM
66
19
297
18
|
25249
609_1
7.5 μM
58
19
264
7
|
25249
609_2
7.5 μM
88
6
156
5
|
25249
609_3
7.5 μM
76
19
140
13
|
25249
609_4
7.5 μM
50
15
185
6
|
25249
609_5
7.5 μM
95
29
139
1
|
25249
609_6
7.5 μM
86
15
126
7
|
25249
609_7
7.5 μM
72
9
174
1
|
25249
609_8
7.5 μM
64
3
189
18
|
25249
609_9
7.5 μM
77
12
223
35
|
25250
610_1
7.5 μM
55
17
233
7
|
25250
610_2
7.5 μM
52
15
233
9
|
25250
610_3
7.5 μM
77
5
151
11
|
25250
610_4
7.5 μM
48
0
242
21
|
25250
610_5
7.5 μM
59
8
234
0
|
25250
610_6
7.5 μM
59
12
208
23
|
25250
610_7
7.5 μM
69
7
216
5
|
25250
610_8
7.5 μM
70
16
211
2
|
25250
610_9
7.5 μM
77
22
157
19
|
25251
611_1
7.5 μM
43
4
306
10
|
25251
611_2
7.5 μM
43
1
300
36
|
25251
611_3
7.5 μM
43
17
306
6
|
25251
611_4
7.5 μM
40
1
320
37
|
25251
611_5
7.5 μM
48
9
273
7
|
25251
611_6
7.5 μM
51
2
302
26
|
25251
611_7
7.5 μM
40
8
326
8
|
25251
611_8
7.5 μM
55
10
330
17
|
25251
611_9
7.5 μM
40
3
297
11
|
25252
612_1
7.5 μM
58
9
219
5
|
25252
612_2
7.5 μM
54
9
282
4
|
25252
612_3
7.5 μM
56
13
265
35
|
25252
612_4
7.5 μM
81
16
239
51
|
25252
612_5
7.5 μM
57
2
234
25
|
25252
612_6
7.5 μM
76
18
221
8
|
25252
612_7
7.5 μM
45
7
285
11
|
25252
612_8
7.5 μM
50
8
231
4
|
25252
612_9
7.5 μM
51
3
305
17
|
29636
271_1
7.5 μM
35
4
345
29
|
29636
271_1
7.5 μM
32
6
383
31
|
29636
271_1
7.5 μM
42
7
292
13
|
29636
271_1
7.5 μM
40
1
309
41
|
29636
271_1
7.5 μM
41
10
339
17
|
29636
271_1
7.5 μM
35
8
306
40
|
29636
271_1
7.5 μM
33
1
320
12
|
29636
271_1
7.5 μM
43
1
347
7
|
29636
271_1
7.5 μM
36
2
339
19
|
29636
271_1
7.5 μM
36
1
315
5
|
29636
271_1
7.5 μM
41
1
326
16
|
29636
271_1
7.5 μM
38
2
344
1
|
29636
271_1
7.5 μM
34
6
341
8
|
29636
271_1
7.5 μM
42
9
320
1
|
29636
271_1
7.5 μM
31
8
344
37
|
29636
271_1
7.5 μM
44
2
335
11
|
29636
271_1
7.5 μM
32
0
316
17
|
29636
271_1
7.5 μM
43
11
323
2
|
29636
271_1
7.5 μM
35
7
340
2
|
29636
271_1
7.5 μM
43
1
340
8
|
29636
271_1
7.5 μM
33
4
296
27
|
29636
271_1
7.5 μM
38
5
334
4
|
29636
271_1
7.5 μM
36
4
341
22
|
29636
271_1
7.5 μM
48
4
334
3
|
29636
271_1
7.5 μM
36
8
303
13
|
29636
271_1
7.5 μM
36
0
343
7
|
29636
271_1
7.5 μM
39
1
326
1
|
29636
271_1
7.5 μM
38
2
346
14
|
29636
271_1
7.5 μM
32
0
332
11
|
29636
271_1
7.5 μM
39
4
330
23
|
29636
271_1
7.5 μM
39
7
346
33
|
29636
271_1
7.5 μM
40
1
329
14
|
29636
271_1
7.5 μM
34
6
316
38
|
29636
271_1
7.5 μM
33
4
317
14
|
29636
271_1
7.5 μM
41
6
328
11
|
29636
271_1
7.5 μM
45
2
345
3
|
29636
271_1
7.5 μM
37
1
330
3
|
29636
271_1
7.5 μM
45
7
322
18
|
29636
271_1
7.5 μM
36
3
334
13
|
29636
271_1
7.5 μM
33
8
333
3
|
29636
271_1
7.5 μM
35
10
321
43
|
29636
271_1
7.5 μM
41
3
323
18
|
29636
271_1
7.5 μM
39
8
354
39
|
29636
271_1
7.5 μM
35
2
327
23
|
30599
613_1
7.5 μM
73
29
172
22
|
30599
613_2
7.5 μM
87
40
114
9
|
30599
613_3
7.5 μM
59
23
168
23
|
30599
613_4
7.5 μM
43
15
281
31
|
30599
613_5
7.5 μM
51
3
271
28
|
30600
614_1
7.5 μM
56
11
179
22
|
30600
614_2
7.5 μM
96
40
100
7
|
30600
614_3
7.5 μM
41
7
246
27
|
30600
614_4
7.5 μM
47
19
283
14
|
30600
614_5
7.5 μM
52
21
209
16
|
30600
615_1
7.5 μM
61
19
197
12
|
30600
615_2
7.5 μM
45
11
287
25
|
30600
615_3
7.5 μM
102
NA
115
NA
|
30600
615_4
7.5 μM
72
NA
170
NA
|
30600
615_5
7.5 μM
95
NA
138
NA
|
30601
285_2
7.5 μM
83
NA
165
NA
|
30601
285_3
7.5 μM
124
NA
111
NA
|
30601
285_4
7.5 μM
69
NA
183
NA
|
30601
285_5
7.5 μM
47
23
211
7
|
30601
285_6
7.5 μM
46
12
183
6
|
30601
617_1
7.5 μM
67
26
190
19
|
30601
617_2
7.5 μM
74
35
137
6
|
30601
617_3
7.5 μM
51
16
211
4
|
30601
617_4
7.5 μM
65
22
142
11
|
30601
617_5
7.5 μM
43
8
298
26
|
30601
616_1
7.5 μM
50
22
181
12
|
30601
616_2
7.5 μM
37
13
276
33
|
30601
616_3
7.5 μM
38
16
264
9
|
30601
616_4
7.5 μM
43
NA
304
NA
|
30601
616_5
7.5 μM
50
NA
229
NA
|
30602
619_1
7.5 μM
90
43
131
22
|
30602
619_2
7.5 μM
78
40
138
2
|
30602
619_3
7.5 μM
66
22
123
8
|
30602
619_4
7.5 μM
100
43
96
5
|
30602
619_5
7.5 μM
75
17
157
5
|
30602
618_1
7.5 μM
46
16
226
12
|
30602
618_2
7.5 μM
68
NA
151
NA
|
30602
618_3
7.5 μM
52
4
207
18
|
30602
618_4
7.5 μM
57
12
223
2
|
30602
618_5
7.5 μM
54
2
211
3
|
30603
620_1
7.5 μM
106
23
110
16
|
30603
620_2
7.5 μM
48
10
243
18
|
30603
620_3
7.5 μM
53
1
174
32
|
30603
620_4
7.5 μM
81
0
138
15
|
30603
620_5
7.5 μM
56
5
218
9
|
30604
621_1
7.5 μM
39
4
304
10
|
30604
621_2
7.5 μM
35
7
311
3
|
30604
621_3
7.5 μM
67
18
142
8
|
30604
621_4
7.5 μM
34
6
273
21
|
30604
621_5
7.5 μM
36
5
266
18
|
30605
622_1
7.5 μM
42
1
242
28
|
30605
622_2
7.5 μM
31
10
300
8
|
30605
622_3
7.5 μM
35
3
319
11
|
30605
622_4
7.5 μM
37
4
281
5
|
30605
622_5
7.5 μM
39
5
306
11
|
30606
623_1
7.5 μM
47
3
287
1
|
30606
623_2
7.5 μM
74
23
166
7
|
30606
623_3
7.5 μM
82
1
149
8
|
30606
623_4
7.5 μM
66
9
135
8
|
30606
623_5
7.5 μM
78
7
128
12
|
30608
624_1
7.5 μM
84
13
185
25
|
30608
624_2
7.5 μM
35
2
245
9
|
30608
624_3
7.5 μM
31
3
267
9
|
30608
624_4
7.5 μM
39
16
257
13
|
30608
624_5
7.5 μM
34
3
283
4
|
30666
625_1
7.5 μM
45
5
286
39
|
30666
625_2
7.5 μM
39
3
280
13
|
30666
625_3
7.5 μM
40
10
258
9
|
30666
625_4
7.5 μM
41
14
234
39
|
30666
625_5
7.5 μM
42
5
293
26
|
30666
625_6
7.5 μM
44
0
284
25
|
30666
625_7
7.5 μM
46
3
271
4
|
30666
625_8
7.5 μM
47
5
256
17
|
30666
625_9
7.5 μM
40
7
302
2
|
30667
626_1
7.5 μM
38
1
279
10
|
30667
626_2
7.5 μM
39
21
329
22
|
30667
626_3
7.5 μM
59
12
265
65
|
30667
626_4
7.5 μM
39
5
318
25
|
30667
626_5
7.5 μM
36
2
302
33
|
30667
626_6
7.5 μM
36
6
273
34
|
30667
626_7
7.5 μM
30
0
299
29
|
30667
626_8
7.5 μM
35
4
277
43
|
30667
626_9
7.5 μM
32
3
275
22
|
30668
627_1
7.5 μM
71
3
131
11
|
30668
627_2
7.5 μM
49
4
226
30
|
30668
627_3
7.5 μM
64
5
147
8
|
30668
627_4
7.5 μM
52
6
176
9
|
30668
627_5
7.5 μM
78
14
108
3
|
30668
627_6
7.5 μM
40
1
183
23
|
30668
627_7
7.5 μM
85
8
116
2
|
30668
627_8
7.5 μM
45
1
128
7
|
30668
627_9
7.5 μM
42
5
215
36
|
30669
628_1
7.5 μM
90
11
120
15
|
30669
628_2
7.5 μM
73
12
124
4
|
30669
628_3
7.5 μM
88
2
115
4
|
30669
628_4
7.5 μM
54
4
190
18
|
30669
628_5
7.5 μM
64
1
138
3
|
30669
628_6
7.5 μM
62
4
138
11
|
30669
628_7
7.5 μM
55
1
138
13
|
30669
628_8
7.5 μM
62
1
140
5
|
30669
628_9
7.5 μM
79
10
134
22
|
30711
629_1
7.5 μM
42
1
252
47
|
30711
629_2
7.5 μM
40
2
295
30
|
30711
629_3
7.5 μM
46
1
302
78
|
30711
629_4
7.5 μM
41
3
260
16
|
30711
629_5
7.5 μM
41
1
284
3
|
30711
629_6
7.5 μM
43
0
262
1
|
30711
629_7
7.5 μM
43
3
278
65
|
30711
629_8
7.5 μM
53
5
234
24
|
30711
629_9
7.5 μM
37
4
289
1
|
30711
629_10
7.5 μM
47
6
292
6
|
30711
629_11
7.5 μM
50
5
224
20
|
30712
630_1
7.5 μM
44
2
282
22
|
30712
630_2
7.5 μM
45
6
297
23
|
30712
630_3
7.5 μM
46
2
272
10
|
30713
631_1
7.5 μM
45
2
294
10
|
30713
631_2
7.5 μM
42
0
285
14
|
30713
631_3
7.5 μM
38
3
319
21
|
30713
631_4
7.5 μM
43
3
282
4
|
30713
631_5
7.5 μM
54
2
173
17
|
30713
631_6
7.5 μM
37
0
315
10
|
30713
631_7
7.5 μM
40
4
317
2
|
30713
631_8
7.5 μM
44
1
275
5
|
30713
631_9
7.5 μM
47
2
233
8
|
30713
631_10
7.5 μM
108
18
101
3
|
30714
632_1
7.5 μM
48
4
210
4
|
30714
632_2
7.5 μM
53
5
256
5
|
30714
632_3
7.5 μM
60
5
224
19
|
30714
632_4
7.5 μM
89
12
117
11
|
30714
632_5
7.5 μM
39
6
312
6
|
30714
632_6
7.5 μM
40
2
278
31
|
30714
632_7
7.5 μM
86
1
160
21
|
30714
632_8
7.5 μM
57
17
278
40
|
30714
632_9
7.5 μM
51
7
236
13
|
30715
304_2
7.5 μM
53
5
206
18
|
30715
304_3
7.5 μM
70
11
142
24
|
30715
304_4
7.5 μM
88
1
120
10
|
30715
304_5
7.5 μM
82
15
123
7
|
30715
304_6
7.5 μM
43
4
264
12
|
30715
304_7
7.5 μM
41
5
266
49
|
30715
304_8
7.5 μM
43
1
291
12
|
30715
304_9
7.5 μM
36
3
285
18
|
30715
304_10
7.5 μM
42
1
280
40
|
33376
633_1
7.5 μM
53
1
234
50
|
33376
633_2
7.5 μM
45
5
301
7
|
33376
633_3
7.5 μM
53
7
263
17
|
33376
633_4
7.5 μM
53
4
229
22
|
33376
633_5
7.5 μM
43
3
264
36
|
33376
633_6
7.5 μM
53
5
247
12
|
33376
633_7
7.5 μM
49
6
289
6
|
33376
633_8
7.5 μM
64
11
238
24
|
33376
633_9
7.5 μM
63
2
249
28
|
33377
634_1
7.5 μM
57
9
250
14
|
33377
634_2
7.5 μM
53
10
265
3
|
33377
634_3
7.5 μM
48
2
275
10
|
33377
634_4
7.5 μM
39
6
287
12
|
33377
634_5
7.5 μM
49
1
255
22
|
33377
634_6
7.5 μM
51
2
291
15
|
33377
634_7
7.5 μM
47
5
297
16
|
33377
634_8
7.5 μM
42
9
311
14
|
33377
634_9
7.5 μM
47
5
271
23
|
33378
635_1
7.5 μM
56
11
257
3
|
33378
635_2
7.5 μM
56
5
213
23
|
33378
635_3
7.5 μM
61
8
215
8
|
33378
635_4
7.5 μM
58
15
232
16
|
33378
635_5
7.5 μM
48
3
316
20
|
33378
635_6
7.5 μM
59
5
262
30
|
33378
635_7
7.5 μM
55
7
287
15
|
33378
635_8
7.5 μM
42
1
284
3
|
33378
635_9
7.5 μM
40
0
277
23
|
33379
636_1
7.5 μM
50
2
239
7
|
33379
636_2
7.5 μM
74
16
204
10
|
33379
636_3
7.5 μM
55
4
201
3
|
33379
636_4
7.5 μM
54
2
238
7
|
33379
636_5
7.5 μM
52
5
207
43
|
33379
636_6
7.5 μM
47
3
249
6
|
33379
636_7
7.5 μM
48
5
241
1
|
33379
636_8
7.5 μM
37
7
304
12
|
33379
636_9
7.5 μM
62
9
245
5
|
33380
637_1
7.5 μM
39
1
219
25
|
33380
637_2
7.5 μM
59
1
197
11
|
33380
637_3
7.5 μM
56
1
250
19
|
33380
637_4
7.5 μM
53
7
244
36
|
33380
637_5
7.5 μM
73
13
297
34
|
33380
637_6
7.5 μM
65
1
124
17
|
33380
637_7
7.5 μM
74
5
133
5
|
33380
637_8
7.5 μM
53
2
207
7
|
33380
637_9
7.5 μM
54
15
226
26
|
39806
638_1
7.5 μM
37
7
283
31
|
39806
638_2
7.5 μM
49
11
291
30
|
39806
638_3
7.5 μM
41
1
270
20
|
39806
638_4
7.5 μM
42
13
267
9
|
39806
638_5
7.5 μM
50
1
184
5
|
39806
638_6
7.5 μM
38
1
276
15
|
39806
638_7
7.5 μM
56
1
292
4
|
39806
638_8
7.5 μM
41
4
267
11
|
39806
638_9
7.5 μM
41
4
218
33
|
39807
639_1
7.5 μM
48
15
293
30
|
39807
639_2
7.5 μM
38
3
269
2
|
39807
639_3
7.5 μM
72
5
167
3
|
39807
639_4
7.5 μM
69
38
242
36
|
39807
639_5
7.5 μM
47
6
303
36
|
39807
639_6
7.5 μM
53
6
179
5
|
39807
639_7
7.5 μM
51
3
189
8
|
39807
639_8
7.5 μM
42
3
185
19
|
39807
639_9
7.5 μM
45
3
202
15
|
39808
640_1
7.5 μM
39
5
265
7
|
39808
640_2
7.5 μM
37
4
272
56
|
39808
640_3
7.5 μM
38
3
260
17
|
39808
640_4
7.5 μM
33
4
255
2
|
39808
640_5
7.5 μM
38
3
253
3
|
39808
640_6
7.5 μM
40
8
216
10
|
39808
640_7
7.5 μM
39
8
310
7
|
39808
640_8
7.5 μM
41
6
282
21
|
39808
640_9
7.5 μM
40
5
269
12
|
44439
641_1
7.5 μM
35
6
336
32
|
44439
641_2
7.5 μM
67
20
161
6
|
44439
641_3
7.5 μM
34
9
317
30
|
44439
641_4
7.5 μM
62
18
193
9
|
44439
641_5
7.5 μM
34
4
280
3
|
44439
641_6
7.5 μM
43
1
315
45
|
44439
641_7
7.5 μM
45
17
307
53
|
44439
641_8
7.5 μM
41
0
294
41
|
44439
641_9
7.5 μM
37
2
334
43
|
44440
361_2
7.5 μM
36
1
303
15
|
44440
361_3
7.5 μM
32
3
315
12
|
44440
361_4
7.5 μM
41
1
299
7
|
44440
361_5
7.5 μM
40
5
295
6
|
44440
361_6
7.5 μM
40
2
296
30
|
44440
361_7
7.5 μM
39
1
300
55
|
44440
361_8
7.5 μM
45
6
285
45
|
44440
361_9
7.5 μM
44
6
321
26
|
44440
361_10
7.5 μM
46
7
290
18
|
44441
362_2
7.5 μM
50
4
277
4
|
44441
362_3
7.5 μM
40
6
296
8
|
44441
362_4
7.5 μM
37
5
340
18
|
44441
362_5
7.5 μM
45
2
266
21
|
44441
362_6
7.5 μM
39
7
263
0
|
44441
362_7
7.5 μM
41
12
262
36
|
44441
362_8
7.5 μM
35
13
313
6
|
44441
362_9
7.5 μM
36
8
300
20
|
44441
362_10
7.5 μM
48
10
293
1
|
46391
642_1
7.5 μM
51
25
278
6
|
46391
642_2
7.5 μM
46
2
303
4
|
46391
642_3
7.5 μM
48
3
297
11
|
46391
642_4
7.5 μM
45
11
320
37
|
46391
642_5
7.5 μM
71
32
303
40
|
46391
642_6
7.5 μM
47
15
298
16
|
46391
642_7
7.5 μM
38
6
277
5
|
46391
642_8
7.5 μM
38
3
280
20
|
46391
642_9
7.5 μM
51
20
285
16
|
46391
642_10
7.5 μM
32
7
293
20
|
46391
642_11
7.5 μM
42
2
291
2
|
46391
642_12
7.5 μM
40
3
317
19
|
46391
642_13
7.5 μM
39
11
295
5
|
46391
642_14
7.5 μM
52
20
295
16
|
46391
642_15
7.5 μM
39
8
316
38
|
46391
642_16
7.5 μM
35
2
294
30
|
46391
642_17
7.5 μM
51
5
292
8
|
46391
643_1
7.5 μM
39
4
276
16
|
46392
644_1
7.5 μM
39
0
321
7
|
46392
644_2
7.5 μM
46
4
308
4
|
46392
644_3
7.5 μM
44
1
317
3
|
46392
644_4
7.5 μM
38
6
315
11
|
46392
645_1
7.5 μM
46
5
342
42
|
46392
645_2
7.5 μM
37
5
292
25
|
46392
645_3
7.5 μM
46
16
317
30
|
46392
645_4
7.5 μM
47
8
381
102
|
46392
645_5
7.5 μM
42
2
269
4
|
46393
646_1
7.5 μM
49
4
295
2
|
46393
646_2
7.5 μM
49
9
304
38
|
46393
646_3
7.5 μM
44
6
298
50
|
46393
646_4
7.5 μM
43
1
296
41
|
46393
646_5
7.5 μM
35
1
260
3
|
46393
646_6
7.5 μM
40
2
281
67
|
46393
646_7
7.5 μM
38
1
278
44
|
46393
646_8
7.5 μM
42
6
262
49
|
46393
646_9
7.5 μM
38
3
289
24
|
46393
646_10
7.5 μM
38
1
317
4
|
46393
646_11
7.5 μM
42
1
320
34
|
46393
646_12
7.5 μM
36
5
323
8
|
46393
646_13
7.5 μM
41
3
262
27
|
46393
646_14
7.5 μM
46
13
315
18
|
46393
646_15
7.5 μM
42
4
340
27
|
46393
646_16
7.5 μM
45
8
360
14
|
46393
646_17
7.5 μM
44
1
303
3
|
46393
646_18
7.5 μM
50
2
304
28
|
46393
646_19
7.5 μM
54
10
217
25
|
51241
425_2
7.5 μM
49
12
296
3
|
51241
425_3
7.5 μM
48
6
297
10
|
51241
425_4
7.5 μM
52
5
275
25
|
51241
425_5
7.5 μM
40
6
284
29
|
51241
425_6
7.5 μM
39
5
301
22
|
51241
425_7
7.5 μM
39
4
263
13
|
51241
425_8
7.5 μM
32
5
188
13
|
51241
425_9
7.5 μM
42
5
286
2
|
51241
425_10
7.5 μM
34
3
165
17
|
|
Example 6—Activity of Exon-Exon Spanning Oligonucleotides
Oligonucleotides designed to be complementary across exon-exon junctions of SNHG14-023 (ENST00000554726) were tested for their ability to reduce the SNHG14 transcript in the region downstream of SNORD109B (also termed UBE3A suppressor or UBE3A-SUP in the data table). Furthermore, the ability to induce UBE3A mRNA re-expression was analyzed. The oligonucleotides primarily span exon2 and exon3 (i.e. are complementary to a region in exon2 and a region in exon 3),
The oligonucleotides were screened according to the protocol for screening oligonucleotides in human neuronal cell cultures described in the section Example 5.
The results are shown in table 9.
TABLE 9
|
|
Oligonucleotide activity in patient
|
derived human neuronal cell cultures.
|
CMP ID
Conc
% of Mock
% of Mock
|
NO
μM
UBE3A-SUP
sd
UBE3A
sd
|
|
674_1
7.5 μM
47
2
214
12
|
675_1
7.5 μM
44
6
265
10
|
676_1
7.5 μM
44
3
284
16
|
677_1
7.5 μM
55
19
351
18
|
678_1
7.5 μM
41
11
257
1
|
656_1
7.5 μM
46
3
140
19
|
657_1
7.5 μM
35
7
218
27
|
658_1
7.5 μM
38
12
253
43
|
659_1
7.5 μM
39
7
274
6
|
660_1
7.5 μM
38
8
275
29
|
661_1
7.5 μM
43
13
246
21
|
662_1
7.5 μM
27
10
290
5
|
663_1
7.5 μM
28
0
287
23
|
664_1
7.5 μM
27
2
288
14
|
665_1
7.5 μM
37
9
321
47
|
666_1
7.5 μM
54
1
259
10
|
667_1
7.5 μM
47
8
236
2
|
647_1
7.5 μM
19
3
300
25
|
648_1
7.5 μM
22
7
320
3
|
649_1
7.5 μM
34
8
326
2
|
650_1
7.5 μM
44
4
292
7
|
651_1
7.5 μM
36
5
254
9
|
652_1
7.5 μM
21
2
314
18
|
653_1
7.5 μM
24
5
299
41
|
654_1
7.5 μM
31
2
344
41
|
655_1
7.5 μM
60
9
301
3
|
668_1
7.5 μM
21
3
297
11
|
669_1
7.5 μM
24
5
296
27
|
670_1
7.5 μM
30
3
274
55
|
671_1
7.5 μM
27
6
263
35
|
672_1
7.5 μM
27
6
280
50
|
673_1
7.5 μM
33
2
290
19
|
|
Example 7—Testing In Vitro Efficacy and Potency of Selected Oligonucleotides
Based on the screenings in examples 2 to 5 above 52 oligonucleotides were selected for potency and efficacy testing.
The oligonucleotides were screened in human AS patient derived cells as described in the Materials and Method section “Screening oligonucleotides in human neuronal cell cultures—96 well system” with the following modifications:
For UBE3a-Sense primer commercially available primers and probe from ThermoFisher: Hs00166580_m1 amplifying a 94 bp sequence in position 838 of refseq ID NM_000462.3 were used.
Each plate include PBS controls (instead on a non-targeting oligonucleotide) and the positive control oligonucleotides CMP ID NO: 186_1 and 39_1 identified in previous screens were included. The additional control oligonucleotides described in the materials and method section were not included. Oligonucleotide test concentrations were from 31.6 μM to 1 nM using a 10 point half-log dilution. All oligonucleotides were tested in 5 independent experiments in 5 different weeks. In the data QC process some plates were removed from the analysis if these were obvious outliers e.g. no PCR product detected. After this filtration there is a minimum of three independent experiments behind each the reported values.
The EC50 (UBE3A mRNA re-expression) and IC50 (reduction of the SNHG14 transcript in the region downstream of SNORD109B, also termed UBE3A suppressor or UBE3A-SUP in the data table) were determined after curve fitting using a 4 parameter sigmoidal dose-response model. Fitting was executed using the fit engine available inside the Biobook software by IDBS (XLfit). From the curve-fitting the maximum obtainable up-regulation of UBE3A (UBE3A Max Up) and the maximum obtainable knockdown of UBE3A-SUP (UBE3A-SUP max Kd) were determined. Both are shown as % of control (PBS treated cells). The results are shown in table 10, values are reported as geometric means of each biological replicate.
TABLE 10
|
|
Oligonucleotide EC50 and IC 50 values and maximum
|
UBE3A upregulation and UBE3A suppressor knock down.
|
CMP
EC50
IC50
UBE3A
UBE3A-SUP
|
ID NO
↑ UBE3A
Sd
↓ UBE3A-SUP
Sd
Max Kd
Sd
max Kd
Sd
|
|
586_9
0.02
0.02
0.01
0.00
329.4
25.5
33.5
3.8
|
585_1
0.03
0.01
0.03
0.02
301.6
18.3
31.0
5.3
|
572_7
0.03
0.00
0.01
0.03
294.1
30.4
31.3
3.5
|
591_1
0.03
0.02
0.01
0.00
387.3
46.0
41.4
2.8
|
585_8
0.04
0.02
0.02
0.01
312.3
23.1
35.2
3.3
|
626_7
0.04
0.02
0.02
0.00
362.5
44.6
38.7
3.3
|
621_2
0.04
0.03
0.02
0.01
264.5
19.6
24.7
3.9
|
624_3
0.04
0.03
0.04
0.03
288.1
19.2
29.7
5.2
|
169_52
0.04
0.04
0.02
0.01
303.4
23.1
27.3
1.8
|
624_5
0.04
0.07
0.01
0.01
249.2
16.3
16.4
1.4
|
586_5
0.04
0.01
0.01
0.00
364.4
43.9
30.4
3.3
|
626_8
0.04
0.03
0.01
0.01
338.7
24.0
39.1
2.6
|
169_50
0.05
0.02
0.02
0.02
280.3
23.0
28.3
2.4
|
572_6
0.05
0.01
0.01
0.02
298.5
22.4
36.3
4.0
|
639_5
0.05
0.03
0.01
0.00
327.7
22.0
38.2
3.6
|
592_2
0.05
0.03
0.02
0.05
364.9
27.1
36.4
3.6
|
586_8
0.05
0.03
0.02
0.01
366.6
35.1
38.0
3.9
|
625_6
0.06
0.03
0.01
0.00
335.5
34.7
32.5
1.9
|
644_3
0.06
0.04
0.01
0.02
298.5
22.0
25.3
1.6
|
586_4
0.06
0.03
0.01
0.01
354.3
31.5
33.0
2.3
|
642_12
0.06
0.05
0.02
0.01
289.2
14.8
24.7
3.0
|
572_5
0.07
0.09
0.02
0.00
312.7
25.9
31.5
3.0
|
592_4
0.07
0.06
0.03
0.01
341.1
31.9
35.7
1.8
|
622_3
0.07
0.04
0.02
0.01
300.9
21.0
27.6
3.6
|
622_5
0.07
0.01
0.02
0.01
306.2
13.5
24.4
4.0
|
616_4
0.07
0.04
0.03
0.02
293.8
17.9
29.1
5.0
|
304_6
0.08
0.08
0.02
0.00
318.1
39.2
43.8
3.9
|
638_8
0.08
0.01
0.01
0.01
354.8
30.6
42.4
4.1
|
622_4
0.08
0.07
0.02
0.01
330.3
24.8
29.5
2.4
|
642_13
0.08
0.07
0.04
0.03
268.4
21.0
26.8
2.5
|
573_8
0.08
0.01
0.04
0.02
320.1
34.4
34.3
3.4
|
241_9
0.09
0.04
0.04
0.03
352.6
26.4
34.1
2.3
|
304_10
0.09
0.07
0.03
0.01
289.5
19.9
28.3
2.8
|
636_8
0.10
0.08
0.03
0.04
330.8
34.1
53.9
13.4
|
598_4
0.11
0.06
0.03
0.04
295.0
15.1
41.3
2.2
|
586_6
0.11
0.10
0.02
0.02
316.2
21.2
23.8
3.5
|
621_1
0.11
0.21
0.02
0.01
311.9
19.2
27.5
5.2
|
331_1
0.12
0.02
0.03
0.02
293.6
49.0
25.1
5.4
|
626_9
0.13
0.12
0.02
0.03
302.2
32.6
34.4
2.2
|
169_56
0.14
0.18
0.02
0.01
356.5
22.3
26.8
2.2
|
631_6
0.14
0.30
0.04
0.00
292.9
25.1
33.5
4.9
|
186_1
0.16
0.02
0.04
0.05
371.7
70.1
32.5
5.5
|
611_7
0.16
0.15
0.02
0.01
369.2
29.3
37.2
3.9
|
165_1
0.17
0.02
0.07
0.12
266.3
NA
26.7
NA
|
646_16
0.18
0.15
0.03
0.02
306.0
9.0
30.6
2.9
|
640_4
0.20
0.10
0.02
0.01
328.4
31.0
40.4
7.0
|
631_1
0.22
0.07
0.07
0.02
324.6
1.6
47.5
8.1
|
590_13
0.23
0.59
0.02
0.02
353.4
22.3
31.8
2.2
|
172_1
0.24
0.10
0.11
0.14
254.2
NA
34.2
NA
|
35_2
0.26
0.02
0.06
0.09
257.9
NA
22.3
NA
|
425_5
0.26
0.14
0.08
0.08
317.3
33.9
32.9
2.4
|
359_1
0.27
0.03
0.03
0.08
260.5
NA
31.3
NA
|
209_1
0.28
0.08
0.03
0.03
339.9
30.6
48.2
11.6
|
123_1
0.28
0.13
0.26
0.08
235.9
NA
51.8
NA
|
361_1
0.29
0.10
0.06
0.02
331.9
17.2
30.7
6.3
|
602_1
0.31
0.33
0.15
0.20
340.3
21.7
42.2
5.0
|
NA
0.44
0.12
0.15
0.18
251.3
NA
24.6
NA
|
287_1
0.45
0.09
0.04
0.02
318.1
45.2
28.8
9.3
|
303_1
0.46
0.05
0.09
0.15
259.9
NA
30.9
NA
|
379_1
0.47
0.02
0.08
0.16
247.2
NA
22.5
NA
|
405_1
0.48
0.42
0.04
0.01
323.0
56.2
32.5
11.9
|
39_1
0.51
0.20
0.06
0.06
341.2
30.3
40.4
4.7
|
206_1
0.52
0.07
0.14
0.31
262.9
NA
30.5
NA
|
155_1
0.53
0.10
NA
0.53
260.8
NA
26.7
NA
|
362_1
0.57
0.25
0.09
0.02
328.1
57.3
27.4
8.6
|
178_1
0.58
0.35
0.11
0.04
334.3
50.8
26.6
8.0
|
48_1
0.59
0.02
0.07
0.56
262.7
NA
27.2
NA
|
200_1
0.62
0.51
0.15
0.06
331.0
54.3
33.1
6.2
|
361_5
0.67
0.18
0.07
0.00
307.1
22.9
32.1
4.5
|
597_4
0.67
0.51
0.10
0.06
325.3
17.3
35.3
2.7
|
85_1
0.68
0.06
0.28
0.41
255.5
NA
35.1
NA
|
278_1
0.69
0.67
0.08
0.09
313.8
33.4
27.2
4.6
|
271_1
0.69
0.00
0.03
0.65
247.3
NA
24.0
NA
|
403_1
0.77
0.57
0.11
0.09
296.4
55.0
28.8
7.0
|
204_1
0.78
0.59
0.05
0.05
316.1
35.5
36.3
7.9
|
116_1
0.91
0.05
0.09
0.43
240.6
NA
31.6
NA
|
124_1
0.92
0.29
0.55
0.94
190.0
NA
43.9
NA
|
237_8
0.93
0.66
0.05
0.03
376.2
32.8
33.6
3.7
|
378_1
0.95
0.64
0.13
0.09
317.7
30.1
48.5
6.1
|
126_2
0.95
0.05
0.12
0.70
219.7
NA
45.0
NA
|
373_1
1.03
0.63
0.13
0.08
321.7
38.6
27.5
4.8
|
641_5
1.16
1.36
0.07
0.06
335.1
28.9
26.6
5.1
|
207_1
1.18
0.58
0.18
0.06
318.5
42.9
44.0
7.2
|
19_1
1.50
0.19
0.24
1.07
261.7
NA
28.4
NA
|
175_1
1.51
0.42
0.17
0.11
333.5
23.8
29.2
5.2
|
304_1
1.55
0.09
0.08
0.11
297.8
26.2
32.5
5.7
|
399_1
1.86
2.50
0.44
0.26
340.1
52.2
39.6
4.3
|
38_1
2.12
0.10
0.34
0.43
257.3
NA
45.1
NA
|
222_1
2.29
0.75
0.28
0.12
298.2
34.9
26.8
5.6
|
187_1
2.30
1.39
1.00
0.91
315.3
38.4
28.6
6.2
|
272_1
2.32
1.39
0.24
0.16
330.4
41.2
37.1
6.1
|
18_1
2.42
0.21
0.24
2.00
271.0
NA
29.3
NA
|
118_1
2.78
0.30
0.31
0.07
205.4
NA
40.4
NA
|
35_1
2.93
4.94
3.61
1.52
258.4
NA
48.2
NA
|
233_1
3.14
1.68
0.35
0.16
330.3
20.1
29.3
5.2
|
220_1
3.47
0.99
1.02
0.48
315.5
27.4
29.6
7.6
|
33_1
3.97
0.41
1.07
NA
265.7
NA
32.2
NA
|
109_1
4.06
1.45
1.33
0.67
231.7
44.7
39.6
3.9
|
40_1
4.17
0.05
0.12
3.74
263.6
NA
38.3
NA
|
115_1
4.98
0.15
0.25
NA
184.2
NA
47.0
NA
|
161_1
6.55
3.20
1.25
1.24
294.0
24.8
32.1
7.4
|
105_4
6.61
1.62
1.38
4.20
NA
NA
50.6
NA
|
19_2
6.66
1.17
3.17
1.52
201.7
NA
57.7
NA
|
104_1
7.75
6.77
1.67
1.05
267.9
25.5
42.5
4.1
|
18_2
20.00
1.67
3.50
NA
245.9
NA
46.4
NA
|
108_1
20.00
0.61
1.27
NA
219.6
NA
51.2
NA
|
129_2
20.00
0.08
1.10
NA
165.8
NA
56.5
NA
|
141_1
20.00
0.03
0.15
NA
159.0
NA
64.1
NA
|
142_1
20.00
1.04
1.12
NA
133.1
NA
57.6
NA
|
145_1
20.00
1.30
1.81
NA
139.0
NA
56.9
NA
|
|
Patent Grant
11320421
