Identification of tissue/cell specific marker genes and use thereof

FIELD OF THE INVENTION

The present invention relates to a method for the identification of tissue cell specific marker genes, a method for the determination of a disease state or developmental status of cells/tissue as well as to gene expression profiling of cartilage tissue. More specifically, the invention relates to microarrays containing a plurality of selected human chondrocyte specific sequences and their use for classification of cartilage donor tissue or generation of characteristic gene expression profiles of in vitro chondrocyte cultures. Such DNA arrays find use as a standard tool of molecular biology research and clinical diagnostics for all cartilaginous or related tissues.

BACKGROUND OF THE INVENTION

Limitation on Current Microarray Technologies

DNA array technology, also known as biochip or microarray technology, is currently revolutionizing modern biology. In this technology, a biological sample is applied to a glass slide or chip covered with an array of immobilized DNA probes. Sample nucleic acid complementary to specific probes on the array hybridizes and can be detected with high sensitively with automated, computerized detectors. In this manner, hundreds to thousands of different individual hybridization experiments can be performed simultaneously. This allows assays of enormous complexity to be carried out—for example, an analysis of the entire gene expression profile of a cancer cell—with simplicity unimaginable only a few years ago. As a consequence many patents as well as scientific publications have accumulated during the last years. U.S. Pat. No. 6,194,158 discloses characteristic genes and gene expression useful in screening for, diagnosis of, monitoring of, and therapeutic treatment of brain cancer. U.S. Pat. No. 6,218,122 discloses methods for determining or monitoring the progression of disease states or the efficacy of therapeutic regimens within human patients. U.S. Pat. No. 6,077,673 discloses mouse arrays having a plurality of probe polynucleotides corresponding to a key mouse gene for expression analysis of critical mouse genes. A list of representative scientific papers dealing with monitoring the expression level of a large number of transcripts within a cell at any time are as follows: Schena et al., 1995, Quantitative monitoring of gene expression patterns with a complementary DNA-microarray, Science 270: 467-470; Lockhart et al., 1996, Expression monitoring by hybridization to high-density oligonucleotide arrays, Nature Biotechnology 14:1675-1680; Blanchard et al., 1996, Sequence to array: Probing the genome's secrets, Nature Biotechnology 14:1649. Qi et al., 2003, Identification of genes responsible for osteoblast differentiation from human mesodermal progenitor cells PNAS 18; 100 (6):3305-10. While this list of scientific papers and patents reflects without any doubt the great potential of microarrays, there are a couple of yet unsolved problems that are more and more discussed among the scientific community. Especially, these problems are data overflow, representative sample collection, RNA processing and inappropriate data analysis. It is even suspected that within next five years, many of conclusions drawn from published data will be revised or refuted. Thus there remains a real and unmet need for advanced microarray solutions, targeted to specific tissues above all with respect to simplification and substantiation of the process of data generation and data handling. With respect to this issue the disclosed invention has made considerable contribution in the cartilage area with a cartilage-specific microarray containing a manageable number of cartilage relevant genes.

Limitation on the Number of Cartilage Relevant Genes

Until today the number of cartilage-relevant genes (genes that have been associated a potential functional role on cartilage biology, homeostasis or pathology) is very limited. Approximately, 100-200 genes have been described in the literature in any relationship to cartilage tissue. While existing publications e.g. Heller et al PNAS, 94; 2150-2155; 1997 have described analysis of inflammatory diseases of cartilage and Sekiya et al PNAS 99; 43974402; 2001 cartilage formation from stem cells with microarrays, a comprehensive analysis and determination of characteristic gene expression profiles for 2D, 3D, fetal, adult and pathological chondrocytes cell cultures cultivated under different conditions has not been performed up to now. While in patent WO01/24833 A2 a few markers have been determined that are associated with chondorcytes and their phenotype stability, it will not be possible to perform a detailed gene expression analysis and to define specific fingerprints. Therefore the possibility of characterizing culture conditions or cartilage tissue samples can not be thoroughly addressed.

Completion of the human genome first project draft on 2000 has revealed that the human genome comprises ˜30000-35000 human genes. Estimates show that the number and type of active genes vary significantly between different tissues and may increase up to a couple of 10000 for complex tissues, e.g. brain. As a consequence, many genes albeit fully sequenced may have yet not been, disclosed to be functionally up- or down regulated in cartilage or cartilage derived cells. The inventive approach described herein has made possible to up to now disclose a total of 467 known and additional genes being differentially expressed in a significant and objective manner within chondrocytes or chondrogenic cells.

By means of the already known and additionally found to be cartilage related genes, a strategy to best address and represent chondrocytes cultured under different conditions has been developed in the scope of the present invention.

SUMMARY OF THE INVENTION

In a first aspect the present invention relates to a method for the identification of tissue/cell specific marker genes comprising

- a) taking tissue and/or cells of at least one developmental stage and/or at least one disease state, and/or
- cultivating said tissue and/or cells in vitro under at least one culture condition,
- b) determination of gene expression profiles of said tissue/cells and/or in vitro cultivated tissue/cells and
- c) identification of specific marker genes by bioinformatic analysis of said gene expression profiles.

In particular, the first aspect relates to a method for the identification of tissue/cell specific marker genes comprising cultivating tissue/cells of different developmental stages and/or health conditions in vitro under different culture conditions, determination of gene expression profiles of said in vitro cultivated cartilage tissue and identification of specific marker genes by bioinformatic analysis of said gene expression profiles.

In a preferred embodiment said tissue is selected from the group consisting of fetal tissue, adolescent tissue, adult tissue, healthy tissue, pathological tissue, progenitor cells such as stem cells or cells derived from the same precursor lineage. Preferred culture conditions are 2D and 3D in vitro cultures and the gene expression profiles are preferably determined by means of a micro-array. The bioinformatic analysis of said gene expression profiles is preferably done by cluster software such as e.g cluster analysis.

In a preferred embodiment said tissue is cartilage.

A second aspect of the present invention relates to a method for the determination of a disease state or developmental status of cells/tissue or the physiological potential of cells/tissue. Said method comprises establishing a profile of cellular constituents, preferably a gene expression profile, of said cells or tissue, comparison of said resulting gene expression profile with gene expression profiles characteristic for a particular status or physiological potential of the examined cells or tissue.

Said method can e.g be used to assess the redifferentiation potential of cells or tissue, the assessment of the quality of tissue biopsies for diagnostic and prognostic purposes regarding in vitro tissue engineering applications, the assessment of the quality of in vitro produced cells such as e.g. mesenchymal cells, stem cells or embryonic cells or of in vitro produced tissue for therapeutical applications and for determining the effect of one or more growth factors, media compositions or drugs on cells or tissue. Based on said method it is e.g. possible to set up different in vitro culture conditions for cells/tissue allowing the cultivation of cells/tissue which retain their potential for differentiation.

In a preferred embodiment said cells or tissue is cartilage tissue or chondrocytes and the array comprises polynucleotide probes of tissue specific marker genes.

In a further preferred embodiment said profile is a gene expression profile which is determined by means of a micro-array.

A further object of the present invention is a method for the determination of characteristic profits for clinical use comprising correlating the patient data of the biopsy donor with the gene expression profile of said biopsy cells/tissue. Preferably said gene expression profile has been determined according to the above disclosed method. The resulting profiles of said method are suitable tools in the clinic allowing an evaluation of further treatments of a patient.

The present invention provides characteristic gene expression profiles experimentally determined by using cartilaginous tissues as from individual human donors of various ages (fetal, adolescent, adult) and health conditions (healthy and arthritic) or cells thereof cultivated under different in vitro culture conditions (2D and 3D in vitro cultures, time follow ups). From these different gene expression profiles a set of hitherto 467 markers has been deduced that can be used to design and produce a cartilage specific microarray for commercial applications in the field of R&D, such as culture media development, drug screening etc., but also for clinical applications.

Gene expression analysis performed with such microarrays and the corresponding analytical procedure thereof can be used to assess quality control of human donor cartilage, e.g. biopsy and therefore optimization of any downstream tissue engineering process, for diagnostic evaluation of the patient and its candidate treatment methods, to ensure a cost-optimized procedure, to investigate and assess all kind of 2D- and 3D in vitro cultures performed with human chondrocytes or chondrogenic cells, e.g. stem cells, to screen all kind of drugs, e.g. hormones, growth factors within the above mentioned in vitro cultures regarding a potential beneficial effect and quality assessment of in vitro produced tissue performed by tissue engineered procedures.

In a further aspect the present invention provides a cartilage array comprising a plurality of different polynucleotide probe spots stably associated with a solid surface of a carrier, whereby each of said spots is made of a unique polynucleotide that corresponds to one specific cartilage marker gene.

A preferred cartilage array of the present invention comprises at least two spots that have different nucleotide sequences but of the same cartilage marker gene, more preferably at least 10 spots indicative for one tissue or cell status, whereby said at least 10 spots can be selected from different sequences of one gene or from different genes or a combination thereof.

In a preferred embodiment said polynucleotides of the array do not cross hybridize under stringent conditions with each other.

In a preferred embodiment of the present invention the cartilage array comprises spots that are indicative for at least two tissue or cell status, preferably 3.

A further preferred inventive cartilage array is an array wherein at least part of the cartilage marker genes are selected from the 467 genes listed in the description, preferably at least 10%, more preferably at least 50%, most preferably about 100%.

A further preferred inventive cartilage array is an array wherein at least part of the cartilage marker genes are selected from a subgroup of the 467 genes listed in the description, wherein said subgroup consists of the most tissue specific 200 genes.

In another preferred embodiment the status is selected from biopsies and/or 2D cultures and/or 3D cultures of healthy adult, healthy fetal/infant, undesired adult, undesired fetal/infant or progenitor cells like e.g. stem cells or cells derived from the same precursor lineage.

In a further preferred embodiment of the present invention the polynucleotide probes of the cartilage array have a length of at least 10 nucleotides, preferably at least 20 nucleotides. The probes can also have a length of 30 nucleotides, 50 nucleotides or 70 nucleotides. It is as well possible to use PCR derived products produced from cDNA clones.

In a preferred embodiment the carrier of the inventive cartilage array is attached to coated glass, nylon or any other material.

A further object of the present invention is a kit for use in a hybridization assay, wherein said kit comprises a cartilage array of the present invention. In a preferred embodiment said kit comprises reagents for generating a labelled target polynucleotide sample, a hybridization buffer and a wash medium.

DESCRIPTION OF THE FIGURES

The present invention will be further understood from the following description with reference to the tables and figures where:

Tab. I shows the determined number of all genes in the corresponding SOM analysis being differentially expressed according to microarray analyses of a variety of in vitro chondrocyte cultures according to predefined criteria. From these data sets specific expression profiles can be deduced that are characteristic for different cell culture conditions.

Tab. II shows the extracted and reviewed genes deduced from Tab I in order to have only single entry numbers. Since most of these genes have never been described in any relationship to cartilage, they can be considered as novel cartilage marker (positive/negative markers) or key cartilage genes.

Tab III shows a subset of marker genes form Tab. II that has been used for the production of a micro-array. Included is a subset from Tab II and genes known from the literature.

Tab IV shows the results of the analysis of the 467 cartilage specific marker genes.

Tab V shows the samples used in Examples 1, 2 and 3. Human chondrocytes isolated from 4 different donors were proliferated and kept in 3D-like pellet culture for 7 and 14 days resulting in a total number of 12 samples.

FIG. 1 shows a classical result from an analysis performed with self-organizing-maps. This software clusters all genes together in sub clusters that show a similar expression profile. The number of marker genes for the corresponding analysis e.g. 2D vs. 3D cultures (see also Tab I) corresponds to the total number of genes in the sub clusters.

FIG. 2 shows an example of a graphical presentation of a cluster analysis and viewed by the software treeview. This shows how cells from different origin and potential for in vitro cartilage formation are related to each other and allow a clearer classification of the cell sources. Fetal cells clearly produce different gene clusters compared to adult chondrocytes, while failures are characterized by other gene clusters. Furthermore 3D cell cultures analyzed in a time dependent manner from different donors can be distinguished among each other and gene expression profiles will be grouped accordingly.

FIG. 3: SOM analysis of all culture conditions and samples described in Example 2 and in Tab V.

FIG. 4: SOM analysis for proliferated chondrocytes (t0) only, for the 4 donors. Gene expression pattern corresponding to donor 2 (the second spot from left hand side in every cluster) behaves different in most clusters.

FIG. 5: SOM analysis of chondrocytes kept in 3D culture condition for 7 days (t7). Gene expression pattern from donor 3 (the third spot from left hand side in every cluster) is different for example in clusters c2 and c5.

FIG. 6 shows self organized maps (SOM) of chondrocytes from same patients of FIGS. 4 and 5 kept under 3D culture condition for 14 days (t14).

FIG. 7: cluster analysis of all culture conditions and samples described in Example 2 and in Tab V. This figure shows a subset of 88 hierarchical clustered genes (rows) and samples (columns) demonstrating similar gene expression behavior of chondrocytes under different culture conditions. For example proliferated cells (#1, #2, #4, #5, #7, #8, #10, #11) can easily be discriminated from cells kept in 3D-like pellet culture for 14 days (3#, 6#, 9#, 12#).

FIG. 8: cluster analysis of human aortic fibroblasts vs. chondrocytes. This figure shows a subset of selected clusters of human aortic fibroblasts cells compared to human chondrocytes both kept in 3D pellet cultures for 14 days. The dendrogram in the upper part of the figure shows the ability of CART-CHIP™ 300 microarray described in this invention to discriminate between different cell lines.

FIG. 9: cluster analysis of Interleukin-1 treated vs. untreated human chondrocytes. This figure demonstrates a subset of representative gene clusters allowing differentiation between cells treated with Interleukin-1 from untreated cells both kept in 3D pellet cultures as well as for proliferated cells.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

2D cultures as used in the scope of the present invention are anchorage dependent chondrocyte cultures cultivated on plastic culture devices.

3D cultures as used in the scope of the present invention are chondrocytes cultured in a three dimensional environment, namely either a) scaffold-free, such as small high density pellet cultures (0.25-3.0*10⁶cells) or as high density cultures using 50*10⁶cells/ml or aliquots thereof; or b) by using a synthetic scaffold such as PGA, PLA, or mixtures thereof or biological substances such as agarose, alginate, chitosan or collagen.

failures as used in the scope of the present invention are chondrocytes cultured in a three dimensional environment that are not able to synthesize new extracellular matrix thereby compromising the production of new living tissue engineered cartilage equivalents.

gene expression profile as used in the scope of the present invention is a profile of genes that are up or down regulated according to different cell conditions.

fingerprint as used in the scope of the present invention refers to a gene expression profile characteristic for a cellular status.

tissue or cell status as used in the scope of the present invention refers to a tissue or cells therof having a certain metabolic or activity status.

new extracellular matrix as used in the scope of the present invention designates living cartilage-like tissue.

micro-array as used in the scope of the present invention is used in its original scope that encompasses embodiments today sometimes refused to as “macro-arrays”.

The Invention

The present invention provides cartilage-specific gene arrays as well as methods for their use. In the subject cartilage arrays, a plurality of polynucleotide probe spots are stably associated with the surface of a solid carrier, preferably a surface of a microscope glass slide. Each different polynucleotide probe spot is made of a unique polynucleotide that corresponds to a key cartilage gene of interest. Thus, the subject arrays find particular use in gene expression assays of key cartilage genes. In further describing the subject of the invention, the cartilage specific microarrays are first discussed, followed by a review of representative applications in which the subject arrays may be employed.

Arrays of the Subject Invention-General Description

Selection of Novel Key Cartilage Specific Genes:

A critical feature of the subject arrays is that all of the probe polynucleotide spots of the array correspond to human key cartilage genes that have been found through unique selection processes and criteria. As a result of said processes, up to now 467 different key human cartilage genes that are under tight transcriptional role have been discovered, some of them being not described before in any relationship to cartilage. In more detail, different microarray analyses were performed by using cartilaginous tissues as from individual human donors of various ages (fetal, adolescent, adult) and health conditions (healthy and arthritic) or cells thereof cultivated under different in vitro culture conditions (2D and 3D in vitro cultures, time follow ups). This variety of cartilage cell sources and different culture conditions was set up to grasp the highest possible number of genes differentially expressed and thus being indicative of a potential role.

It has been found that specific chondrocyte culture conditions are of great importance for the present invention that discloses a plurality of novel key cartilage genes as well as characteristic and meaningful gene expression patterns. For this reason, the strategy and criteria of the analysed in vitro human chondrocyte cultures are described in more detail. The principal experimental setup included both the cultivation of chondrocytes in an anchorage dependent condition, known as 2D cultures for expansion of cells e.g. where the passages is variable but at least more then one, as well as cultivation of chondrocytes in an anchorage independent condition, known as 3D cultures for (re-)differentiation and de novo tissue formation of cells. These are the key steps of any tissue engineering process where autologous tissue equivalents are produced. Since the cell source is either a small biopsy, a small bone marrow aspirate in case of mesenchymal stem cells or other tissue with a limited number of pre-chondrogenic cells, it is first necessary to isolate those cells in order to be able to multiply the cell number drastically. In case of a cartilage biopsy, cells are released from their surrounding extracellular matrix by collagenase digestion and then seeded onto the surface of plastic tissue culture flasks. The proliferation may take place either in the presence or absence of fetal serum combined with conventional DMEM/F12 medium. Cells can then be passaged by trypsin treatment over several rounds. As a major drawback of this necessary cell expansion, the cells loose their differentiated phenotype and assume a de-differentiated phenotype with altered gene expression. It is further known that with increasing number of passages the state of de-differentiation also advances. As a consequence, genes being transcriptionally upregulated under such artificial culture conditions are cartilage relevant in a manner being indicative of an undesired cellular status. It is also quite common to designate these genes as de-differentiation or negative markers. While healthy tissue in general has been found to re-differentiate in 3D culture after up to 4 passages in 2D cultures, tissue of undesired cellular status cultivated under usual conditions, such as usual culture media, usually does not re-differentiate in 3D culture after at most 4 passages in 2D culture.

Subculture modulated chondrocytes that do not express differentiation markers reexpress the differentiated phenotype in response to the anchorage—independence resulting from various 3D culture models, e.g. high density cultures, agarose or alginate cultures, or cultures within synthetic scaffolds such as made of polyglycolic acid (PGA), polylactic acid (PLA) or mixtures thereof. To set up three dimensional cell cultures the cells are detached after proliferation by trypsin treatment and embedded either in gel-like substances such as alginate, seeded within a porous scaffold such as PGA or cultivated as high-density cultures, only. The time for the analysis may vary and ideally addresses several time points (up to several weeks). Thus 3D in vitro chondrocyte cultures support the differentiated phenotype of chondrocytes and can be used to discover cartilage relevant genes or differentiation markers. It should be noted however, that reversibility of the de-differentiation process is dependent on the number of passages and can become irreversible or at least partially irreversible at higher passage numbers (under usual conditions at most about 4 passages). As a rule the time course of de- and re-differentiation are similar. During skeletal development, cartilage serves as a template for bone formation. Chondrocytes of fetal or infant (<1 year) or growth plate cartilage pass through different stages and exhibit several distinct phenotypes, such as resting, proliferating, and hypertrophic chondrocytes. Progression through each of these phases is accompanied by profound changes in gene expression patterns. Further, evidence has accumulated that the successful sequence of cartilage repair via tissue engineering recapitulates aspects of embryonic tissue formation. For these reasons, it is important to consider fetal and infant cartilaginous tissue. Cells isolated from human fetal/infant cartilage that are cultivated in 2D and 3D culture systems as described above are especially helpful to understand the mechanisms underlying the phenotypic instability of chondrocytes and the related gene expression patterns. These 2D and 3D culture system may then be analyzed to deduce gene expression profiles and to define marker genes that are characteristic for the (re-)differentiation process. Thus maintenance of chondrocyte-specific phenotype being crucial for normal structure and biomechanical properties of articular cartilage may be better understood and have important implications for modern therapeutic biological applications.

The above mentioned experimental setup for 2D and 3D cultures may be even expanded to compare human adult cells with human fetal/infant chondrocytic cells of age <1 year. The comparison of gene expression profiles of adult versus fetal/infant human chondrocytes during the in vitro cartilage formation process is an important aspect since marker genes associated with developmental aspects are revealed. This can be of further interest when 3D cell cultures need to be optimized for their in vitro performance for the production of new tissue by e.g. adding growth factors that are found to play a major role during the early onset of cartilage formation in vivo.

Another experimental setup found in the scope of this invention includes the in vitro culture of cells harvested from cartilaginous areas of arthritic knee joints. Osteoarthritis (OA) results from the failure of chondrocytes within the joint to maintain the balance between synthesis and degradation of extracellular matrix. OA is a multifactorial disorder in which aging, genetic, hormonal and mechanical factors are all major contributors to its onset and progression. With progressing disease state, the articular chondrocytes ability to maintain homeostasis and functionality is increasingly disappearing. As a consequence, the phenotype of osteoarthritic chondrocytes compared with normal chondrocytes exhibits remarkable changes. Gene expression profiling allows characterization of the osteoarthritic cellular phenotype, a key determinant for understanding and manipulation of osteoarthritic processes. By studying and comparing the gene expression profiles of chondrocytes harvested from pathological and healthy human cartilage areas it becomes possible to identify marker genes that are able to predict the future outcome of cell cultures used for in vitro tissue engineering applications. This also relates to the very critical question of the assessment of the quality of the starting biopsy material that is being used for downstream applications like tissue engineering. By having this important information before performing any downstream applications like e.g. proliferation and consecutive 3D in vitro tissue formation, the further steps of any process can then be adapted or even not performed at all because of inadequate quality of biopsy material. Such decision may be of high relevance when tissue-engineering processes are transferred or applied in the clinic. Gene expression profiling of chondrocytes may then be used as a diagnostic tool to allow and to choose that therapeutic approach with the most promising clinical outcome.

A further important aspect of the invention is the observation that chondrocytes derived from osteoarthritic patient material always qualify for anchorage dependent proliferation in 2D over several passages. These cells however, if subsequently induced to re-differentiate by culturing them as 3D high density pellets, do not survive over an extended time period, in most cases they die in culture by undergoing apoptosis. It is assumed that these cells, due to an altered phenotype, are not capable of producing the critical survival factors in the appropriate concentrations, above all extracellular matrix components providing intercellular spaces as they occur in native cartilage. Cells that are not suitable to be cultured within 3D high density cultures are herein referred to as “failures”. These impaired cell cultures can be used to set up representative “failure” systems, where cells from different pathological cartilage sources are harvested, proliferated and cultivated in 3D high density pellet culture systems. After each of these experimental steps, RNA can be isolated from the different cell sources and combined to create “failure pools”. These failure pools are very well suitable to identify general marker genes being indicative of the onset of osteoarthritis.

For finding cartilage relevant genes, and for determining their presence dependent on the specific cartilage type such as age, health etc., sufficient material must be generated, e.g. by 2D culturing over several passages, and optionally 3D culturing. Said material then can on be subjected to usual gene analyses, and the tissue specific genes determined. Cartillage samples are classified prior to culturing and/or after culturing to get the information needed for later interpretation of the gene expression profile.

A further experimental setup of the current inventions discloses the analysis of chondrocytes grown in 3D cultures isolated from pathological human cartilage and analyzed in a time dependent manner. This experimental set-up allows to study the apoptotic process and to further define additional dynamic and characteristic gene expression profiles, useful for deducing and further assessment of the quality of the biopsy material.

The microarray process and strategy for disclosing all the cartilage relevant genes with the above-mentioned tissues and cell culture criteria will be described in the following. An important issue of the inovative strategy used by the inventors of the present inventions is to use various microarrays containing a high number of genes comprising different functional categories preferentially by representing the whole genome. The broader the microarray regarding the coverage of the human genome the more genes associated with chondrocyte cell cultures can be determined. The chosen strategy of the inventors was not obvious to a person skilled in the art.

RNA isolated from the above mentioned different cell cultures conditions may be radioactive labeled with e.g. 33P or fluorescence like e.g. Cy3 and hybridized to the corresponding filters or microarrays. After hybridization each array may then be scanned and the corresponding signals measured (Tab IV). This raw data file needs then to be calibrated and normalized in a manner to create an input file for the further downstream analysis process. In principle if the data are normalized an expression profile is created. To identify the key cartilage marker genes being differentially expressed under the chosen criteria, tedious bioinformatic analysis are conducted. Corresponding cell cultures and their expression profiles are therefore compared and analyzed accordingly and the different clusters of marker genes determined by software analysis e.g. self-organizing maps (herein referred to as SOM). A representative example of a result for the comparison of different gene expression profiles from different cell culture conditions performed by SOM analysis is given in FIG. 1. By performing SOM analysis genes that are similarly expressed are clustered together in so-called sub clusters. The total amount of marker genes for one analysis corresponds to the total amount of sub clusters containing the corresponding genes. Table I in the appendix summarize the results of all the different analysis performed and encompasses all the genes determined for every set of cell culture analysis.

By performing this analytical procedure the analysis reveals several characteristic up and down regulated marker genes for different cellular culture conditions. From these marker genes characteristic expression profiles can then be deduced and used as a benchmark for the comparison or further characterization of other cell cultures.

Hence, on the one hand previously unknown cartilage—relevant genes associated with different culture conditions and on the other hand characteristic gene expression profiles (cellular fingerprints) indicative of a stage of development, a disease state or a particular selected cell culture condition are revealed. These fingerprints are part of the current invention and are of major importance for the classification and characterization of chondrocytes cultivated under different culture conditions.

Since the gene clusters from all the different analysis contain repetitive gene entries, they have been further processed so that only single entry genes are recorded (see Tab II). This 467 selected sequences are thus all key cartilage genes that are activated and thus differentially expressed according to a stage of development, a disease state or a particular selected cell culture condition and are part of the current invention. A list of all 467 genes with their Pubmed accession no. and a description is given below See also Tables II and III):

List of Table II Related Sequences:

PubmedAccesion NoDescriptionAA283693Human osteoclast stimulating factor mRNA, complete cdsAA845156Serine protease inhibitor, Kazal type 1R52548Human superoxide dismutase (SOD-1) mRNA, complete cdsT67128ARYLAMINE N-ACETYLTRANSFERASE, MONOMORPHICAA845015Elastase 1, pancreatic (elastase IIA)AA937895Antigen identified by monoclonal antibodies 12E7, F21 and O13AA844998Pancreatic polypeptideAA844818Amylase, alpha 2A; pancreaticAA894557Creatine kinase BAA872001Annexin VI (p68)H09590Human mRNA for eukaryotic initiation factor 4AIAA868278Testis specific protein 1 (probe H4-1 p3-1)AA490855Acid finger protein ZNF173H05820Human MRL3 mRNA for ribosomal protein L3 homologue (MRL3 = mammalianribosome L3)N57766Agammaglobulinaemia protein-tyrosine kinase atkAA873885Alkaline phosphatase, liver/bone/kidneyAA878880Interferon (gamma)-induced cell line; protein 10 fromR54818Human eukaryotic initiation factor 2B-epsilon mRNA, partial cdsAA458630RENIN PRECURSOR, RENALW37864Phosphatase and tensin homolog (mutated in multiple advanced cancers 1)N63192Phenylethanolamine N-methyltransferaseR55789Human X11 protein mRNA, partial cdsR56871Human chromatin assembly factor-I p60 subunit mRNA, complete cdsAA448659M-PHASE INDUCER PHOSPHATASE 2AA235388TropomodulinW37769Chromogranin B (secretogranin 1)AA421701H. sapiens mRNA for MUF1 proteinN81029Collagen, type XVIII, alpha 1AA644128Nuclear autoantigenic sperm protein (histone-binding)N26536ATPase, Cu++ transporting, beta polypeptide (Wilson disease)AA890663Human protein kinase PAK1 mRNA, complete cdsAA405987Glycerol kinase 2 (testis specific)AA888182Ribosomal protein S4, X-linkedH09730Adenylate kinase 2 (adk2)AA285155CDC46 HOMOLOGAA873351Ribosomal protein L35aH12320CAMP-RESPONSE ELEMENT BINDING PROTEINAA856556Ribosomal protein S28R43581Human guanine nucleotide-binding protein G-s, alpha subunit mRNA, partial cdsAA63376860S RIBOSOMAL PROTEIN L24AA496880Ribosomal protein L5AA625632Ubiquitin A-52 residue ribosomal protein fusion product 1R40850H. sapiens mRNA for alpha-centractinAA486072Small inducible cytokine A5 (RANTES)N80129Metallothionein 1LT67270UBIQUINOL-CYTOCHROME C REDUCTASE COMPLEX SUBUNIT VI REQUIRINGPROTEINAA77536460S RIBOSOMAL PROTEIN L30AA464743Ribosomal protein L21AA663983Triosephosphate isomerase 1AA63400840S RIBOSOMAL PROTEIN S23AA68305040S RIBOSOMAL PROTEIN S8AA77587460S RIBOSOMAL PROTEIN L18AA029934Integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)AA872397GALECTIN-2AA428195Protein tyrosine phosphatase, non-receptor type 2AA478724Insulin-like growth factor binding protein 6T40541H. sapiens mRNA for human giant larvae homologN33214H. sapiens mRNA for membrane-type matrix metalloproteinase 1W69399Homo sapiens adenosine triphosphatase mRNA, complete cdsH85454Homo sapiens delayed-rectifier K+ channel alpha subunit (KCNS1) mRNA, completecdsT71284Complement component 1, q subcomponent, beta polypeptideN95418Human FK-506 binding protein homologue (FKBP38) mRNA, complete cdsAA430675Human DNA repair protein XRCC9 (XRCC9) mRNA, complete cdsAA682851Homo sapiens mRNA for ERp28 proteinAA427433PROTEIN PHOSPHATASE PP2A, 65 KD REGULATORY SUBUNIT, ALPHAISOFORMAA100296H. sapiens PAP mRNAAA070997Proteasome (prosome, macropain) subunit, beta type, 6R27585Proteasome component C2N71628Spi-B transcription factor (Spi-1/PU.1 related)AA464566Human mRNA for LDL-receptor related proteinAA043228Calponin 3, acidicAA478273APEX nuclease (multifunctional DNA repair enzyme)H05619Homo sapiens GDNF family receptor alpha 2 (GFRalpha2) mRNA, complete cdsAA405562Protein phosphatase 4 (formerly X), catalytic subunitAA147043Homo sapiens CAGH1a (CAGH1) mRNA, partial cdsAA035384Homo sapiens mRNA for small subunit of cytochrome b in succinate dehydrogenasecomplex, complete cdsR60150Human mRNA for histidyl-tRNA synthetase (HRS)N64051Homo sapiens Werner syndrome gene, complete cdsAA405748SPLICING FACTOR U2AF 65 KD SUBUNITAA461110Homo sapiens growth-arrest-specific protein (gas) mRNA, complete cdsAA845167ELASTASE IIIA PRECURSORAA443118Homo sapiens mRNA for CD151, complete cdsN92319Glycoprotein Ib (platelet), beta polypeptideAA187148Core-binding factor, beta subunitAA253413Friedreich ataxiaAA046701ATP SYNTHASE LIPID-BINDING PROTEIN P1 PRECURSORAA164562Homo sapiens actin-related protein Arp3 (ARP3) mRNA, complete cdsAA496357Homo sapiens SKB1Hs mRNA, complete cdsAA180742TUBULIN ALPHA-4 CHAINAA454743Human protease M mRNA, complete cdsAA437226Interleukin 10 receptorAA458849Homo sapiens placental bikunin mRNA, complete cdsAA504891Crystallin, alpha BAA609655Homo sapiens mRNA for SCP-1, complete cdsAA599158MULTIFUNCTIONAL AMINOACYL-TRNA SYNTHETASEAA052932Homo sapiens casein kinase I gamma 2 mRNA, complete cdsAA789328Homo sapiens (clone PK2J) CDC2-related protein kinase (PISSLRE) mRNA,complete cdsAA129537Human GAP SH3 binding protein mRNA, complete cdsAA486209Low density lipoprotein-related protein-associated protein 1 (alpha-2-macroglobulinreceptor-associated protein 1H39018H. sapiens Syt V gene (genomic and cDNA sequence)AA464217V-akt murine thymoma viral oncogene homolog 1T95053Homo sapiens Rigui (RIGUI) mRNA, complete cdsAA454646LYMPHOTOXIN-BETA RECEPTOR PRECURSORAA448400Human plectin (PLEC1) mRNA, complete cdsH13691Major histocompatibility complex, class II, DM betaAA132086Homo sapiens RCL (Rcl) mRNA, complete cdsAA488073Mucin 1, transmembraneN40945H. sapiens mRNA for DRES9 proteinR55705Homo sapiens orexin receptor-1 mRNA, complete cdsH50114Homo sapiens NMDA receptor mRNA, complete cdsAA452841Human K-CI cotransporter (hKCC1) mRNA, complete cdsW73790IMMUNOGLOBULIN-RELATED 14.1 PROTEIN PRECURSORN30302POSSIBLE GTP-BINDING PROTEIN HSR1AA291556Human ras inhibitor mRNA, 3′ endAA598510Human APRT gene for adenine phosphoribosyltransferaseAA453787Human TFIIB related factor hBRF (HBRF) mRNA, complete cdsH05655Human transcriptional activator mRNA, complete cdsAA419177INTEGRAL MEMBRANE PROTEIN E16AA458807Human retinal protein (HRG4) mRNA, complete cdsAA293218Cleavage stimulation factor, 3′ pre-RNA, subunit 2, 64 kDW44860Human calmodulin mRNA, complete cdsAA629862Homo sapiens mRNA for smallest subunit of ubiquinol-cytochrome c reductase,complete cdsAA447674Homo sapiens HIV-Nef associated acyl CoA thioesterase (hNAACTE) mRNA,complete cdsT52484Nerve growth factor betaAA496810Protein kinase C substrate 80K-HAA486233G1 to S phase transition 1AA079775TYROSINE-PROTEIN KINASE CSKW73889Tetranectin (plasminogen-binding protein)R50337Solute carrier family 19 (folate transporter), member 1R55046MpV17 transgene, murine homolog, glomerulosclerosisR46821T-COMPLEX PROTEIN 1, ALPHA SUBUNITR87763Human telencephalin precursor mRNA, complete cdsH69583Human BTG2 (BTG2) mRNA, complete cdsR56046Guanine nucleotide binding protein (G protein), alpha z polypeptideAA922705Glycogen phosphorylase B (brain form)AA487571Surfactant, pulmonary-associated protein CAA402440Homo sapiens exportin t mRNA, complete cdsH29521ATP-binding cassette 3AA490911Homo sapiens drp1 mRNA, complete cdsAA486082Homo sapiens sgk geneAA6780652,3-bisphosphoglycerate mutaseR43509Human Gu binding protein mRNA, partial cdsN57553Adenosine receptor A2AA676955Aplysia ras-related homolog 12R14692Human Na/H antiporter (APNH1) mRNA, complete cdsAA488979Homo sapiens nucleolar protein (MSP58) mRNA, complete cdsAA443630Aldehyde dehydrogenase 8AA027840H. sapiens mRNA for RIT proteinAA456830Diacylglycerol kinase, alpha (80 kD)AA453015H. sapiens L23-related mRNAAA074446Human GTP cyclohydrolase I feedback regulatory protein gene, complete cdsAA027042DNA-DIRECTED RNA POLYMERASE II 23 KD POLYPEPTIDEAA629923Human mRNA for pM5 proteinAA460830Homo sapiens (clone mf.18) RNA polymerase II mRNA, complete cdsAA454218Homo sapiens transcription factor SL1 mRNA, complete cdsAA046523H. sapiens mRNA for centrin geneR51346Human eIF-2-associated p67 homolog mRNA, complete cdsAA029964Human ataxin-2 related protein mRNA, partial cdsAA489219DUTP pyrophosphataseAA043133Solute carrier family 16 (monocarboxylic acid transporters), member 1AA812973Human mRNA for testis-specific TCP20, complete cdsAA453471GANGLIOSIDE GM2 ACTIVATOR PRECURSORAA284693Transcription factor AP-4 (activating enhancer-binding protein 4)N90281Human B7 mRNA, complete cdsAA629542Brush-1AA679345Human BTK region clone ftp-3 mRNAH37774TuberinT97181Platelet factor 4AA454879Plasminogen activator, urokinase receptorAA147640Phosphorylase, glycogen; liver (Hers disease, glycogen storage disease type VI)AA757429Human serotonin N-acetyltransferase mRNA, complete cdsAA490991Homo sapiens HnRNP F protein mRNA, complete cdsAA422058H. sapiens mRNA for D1075-like geneN66208Human (ard-1) mRNA, complete cdsAA630776Human AP-3 complex delta subunit mRNA, complete cdsAA827287Human interferon-induced leucine zipper protein (IFP35) mRNA, partial cdsAA488084Superoxide dismutase 2, mitochondrialR89715Protein kinase C, gammaAA490501H. sapiens mRNA; UV Radiation Resistance Associated GeneN32199Human melanoma antigen recognized by T-cells (MART-1) mRNAAA434404DNA primase polypeptide 2A (58 kD)N93686Aldehyde dehydrogenase 7AA292676Human metargidin precursor mRNA, complete cdsAA464417INTERFERON-INDUCIBLE PROTEIN 1-8UAA442092Catenin (cadherin-associated protein), beta 1 (88 kD)AA026644Transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47)AA481464Peptidylprolyl isomerase B (cyclophilin B)T68859Alpha-2-plasmin inhibitor (alpha-2-PI)AA699560Surfeit 1AA705069Human mRNA for receptor of retinoic acidAA457739Homo sapiens putative OSP like protein mRNA, partial cdsH99843Homo sapiens mRNA for quinolinate phosphoribosyl transferase, complete cdsAA399410Signal transducer and activator of transcription 3 (acute-phase response factor)AA443039HEAT SHOCK 70 KD PROTEIN 1AA164440Human autoantigen pericentriol material 1 (PCM-1) mRNA, complete cdsAA446453Human mRNA for c-myc binding protein, complete cdsAA280692Diacylglycerol kinase deltaAA031514Matrix metalloproteinase 7 (matrilysin, uterine)R33154Msh (Drosophila) homeo box homolog 1 (formerly homeo box 7)AA487452Human DNA fragmentation factor-45 mRNA, complete cdsAA400329Human gene for neurofilament subunit M (NF-M)AA454668Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase andcyclooxygenase)AA486393Cytokine receptor family II, member 4R52541unknown ESTAA171613Homo sapiens carbonic anhydrase precursor (CA 12) mRNA, complete cdsAA235706Human TATA-binding protein associated factor 30 kDa subunit (tafII30) mRNA,complete cdsAA668527Human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) mRNA, completecdsT54144Homo sapiens homolog of the Aspergillus nidulans sudD gene product mRNA,complete cdsR14080Calcium modulating ligandAA609599Homo sapiens SSX3 (SSX3) mRNA, complete cdsAA489201H. sapiens mRNA for PHAPI2b proteinR08876Human 26S proteasome-associated pad1 homolog (POH1) mRNA, complete cdsH46425H. sapiens Pur (pur-alpha) mRNA, complete cdsR56149Human putative transmembrane protein (nma) mRNA, complete cdsAA454619Homo sapiens mRNA for Hic-5, partial cdsH15445H. sapiens mRNA for SEX geneAA705225Myosin, light polypeptide 4, alkali; atrial, embryonicAA191488Human high-affinity copper uptake protein (hCTR1) mRNA, complete cdsN64862Human SLP-76 associated protein mRNA, complete cdsR45413Human transmembrane 4 superfamily protein (SAS) mRNA, complete cdsR77293Intercellular adhesion molecule 1 (CD54), human rhinovirus receptorAA436187Integrin, alpha M (complement component receptor 3, alpha; also known as CD11b(p170), macrophage antigen alpha polypeptide)AA676470H. sapiens IAI.3B mRNAAA443634Homo sapiens ubiquitin conjugating enzyme G2 (UBE2G2) mRNA, complete cdsAA664180Glutathione peroxidase 3 (plasma)W58658H. sapiens mRNA for CLPPH54023Homo sapiens monocyte/macrophage Ig-related receptor MIR-10 (MIR cl-10) mRNA,complete cdsH73724Cyclin-dependent kinase 6T70031Human neutral amino acid transporter B mRNA, complete cdsAA481758DNAJ PROTEIN HOMOLOG 1AA521431Human profilin mRNA, complete cdsAA446103ERGIC-53 PROTEIN PRECURSORN92646Immunoglobulin gamma 3 (Gm marker)AA453789Protein-tyrosine kinase 7AA425299Homo sapiens ezrin-radixin-moesin binding phosphoprotein-50 mRNA, complete cdsAA868929Troponin T1, skeletal, slowR60019Homolog 2 of Drosophila large discsAA857343Human putative RNA binding protein (RBP56) mRNA, complete cdsAA481438Complement component 1 inhibitor (angioedema, hereditary)AA399674Human small proline rich protein (sprII) mRNA, clone 1292T98887Glucose-6-phosphataseAA676404Peptidylprolyl isomerase C (cyclophilin C)H15747Human HU-K4 mRNA, complete cdsH16958Human glyceraldehyde 3-phosphate dehydrogenase mRNAAA936783Eukaryotic translation initiation factor 3 (eIF-3) p36 subunitAA884709Cytochrome P450 11 betaH24688Human SWI/SNF complex 170 KDa subunit (BAF170) mRNA, complete cdsAA884403Human cardiotrophin-1 (CTF1) mRNA, complete cdsAA4046195′ nucleotidase (CD73)AA598611IMMEDIATE-EARLY RESPONSE PROTEIN NOTH72875GATA-binding protein 3H63361Eukaryotic translation initiation factor 2B (eIF-2B) alpha subunitR39221Human MAP kinase mRNA, complete cdsR02346U1 snRNP 70K proteinR51835unknown ESTR33031H. sapiens mRNA for sigma 3B proteinAA412053CD9 antigenAA001897Erythroid alpha-spectrinW81191Homo sapiens nucleolar autoantigen No55 mRNA, complete cdsAA430552Homo sapiens proline-rich Gla protein 2 (PRGP2) mRNA, complete cdsAA394130Human transducin-like protein mRNA, complete cdsN92864Human cleavage and polyadenylation specificity factor mRNA, complete cdsAA457123VALYL-TRNA SYNTHETASER43320Human guanine nucleotide-binding regulatory protein (Go-alpha) geneAA670430Glutamate receptor, metabotropic 3H65066Visinin-like 1AA458785GUANYLATE CYCLASE SOLUBLE, BETA-1 CHAINAA485871H. sapiens mRNA for myosin-I betaT39411Human 53K isoform of Type II phosphatidylinositol-4-phosphate 5-kinase (PIPK)mRNA, complete cdsR00855Homo sapiens 59 protein mRNA, 3′ endH98666Metallopeptidase 1 (33 kD)H72028GELSOLIN PRECURSOR, PLASMAAA679177Human follistatin-related protein precursor mRNA, complete cdsN21576Human mitochondrial 1,25-dihydroxyvitamin D3 24-hydroxylase mRNA, complete cdsAA007419Human RGP4 mRNA, complete cdsT49657Homo sapiens TWIK-related acid-sensitive K+ channel (TASK) mRNA, complete cdsN38959Homo sapiens chaperonin containing t-complex polypeptide 1, beta subunit (Cctb)mRNA, complete cdsR51912Human somatostatin I gene and flanksH90415Breast cancer 1, early onsetH41489Adaptin, beta 1 (beta prime)H15456CALPAIN 1, LARGEW45415ELASTASE IIIB PRECURSORAA447751Tyrosine hydroxylaseAA487486Cyclin D1 (PRAD1; parathyroid adenomatosis 1)R56604Cholinergic receptor, nicotinic, alpha polypeptide 4T65772pulmonary surfactant protein (SP5)H15085ADP-ribosylation factor 4-likeR61295Human ADP/ATP translocase mRNA, 3′ end, clone pHAT8T61256H. sapiens KHK mRNA for ketohexokinase, clone pHKHK3aAA405731Phosphoenolpyruvate carboxykinase 1 (soluble)T71879Complement component C2R59927Human mRNA for cytochrome c oxidase subunit VIcAA496780Human small GTP binding protein Rab7 mRNA, complete cdsAA176688Human mRNA for lysosomal sialoglycoprotein, complete cdsAA436163Homo sapiens Pig12 (PIG12) mRNA, complete cdsAA428778Human placenta LERK-2 (EPLG2) mRNA, complete cdsAA463225Bone morphogenetic protein 4AA485426Interferon (alpha, beta and omega) receptor 2W47485Human sigma receptor mRNA, complete cdsH84982Human checkpoint suppressor 1 mRNA, complete cdsAA504615Homo sapiens mRNA for CAB1, complete cdsH94487Cathepsin EAA448959Homo sapiens NADH: ubiquinone oxidoreductase 15 kDa IP subunit mRNA, nucleargene encoding mitochondrial protein, complete cdsAA070358Transketolase (Wernicke-Korsakoff syndrome)AA453401Human PH-20 homolog (LUCA2) mRNA, partial cdsN66737Collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal dysplasia,congenital)AA666180Human v-erbA related ear-2 geneAA857131Human Tat-SF1 mRNA, complete cdsAA479102Protein kinase C, beta 1AA456077Homo sapiens mRNA for p27, complete cdsR87497H. sapiens mRNA for 2.19 geneAA718910Human tax1-binding protein TXBP181 mRNA, complete cdsAA406269Nuclear factor I/X (CCAAT-binding transcription factor)N74623Insulin-like growth factor 2 (somatomedin A)H99364Human chloride channel protein (CLCN7) mRNA, partial cdsAA447684Small proline-rich protein 1B (cornifin)AA282301Homo sapiens nuclear dual-specificity phosphatase (SBF1) mRNA, partial cdsH99588Human lymphoid nuclear protein (LAF-4) mRNA, complete cdsN53512Homo sapiens alpha 2 delta calcium channel subunit isoform I mRNA, complete cdsAA683321Homo sapiens PAR-5 mRNA, probable 5′ endAA608557Damage-specific DNA binding protein 1 (127 kD)AA757764Homo sapiens mRNA for DNA-binding protein, complete cdsAA406064Homo sapiens testis-specific Basic Protein Y 1 (BPY1) mRNA, complete cdsN54596Human Krueppel-related zinc finger protein (H-plk) mRNA, complete cdsAA481988Transcription factor 7 (T-cell specific)N62394Gap junction protein, beta 1, 32 kD (connexin 32, Charcot-Marie-Tooth neuropathy, X-linked)N26148Zinc finger protein 148 (pHZ-52)AA496678B-cell CLL/lymphoma 3AA400973NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN PRECURSORAA497027Human mRNA, clone HH109 (screened by the monoclonal antibody of insulinreceptor substrate-1 (IRS-1))N64508Homo sapiens podocalyxin-like protein mRNA, complete cdsAA033564H. sapiens mRNA for DGCR6 proteinAA446108Endoglin (Osler-Rendu-Weber syndrome 1)AA159577Mucin 5, subtype B, tracheobronchialR36958unknown ESTAA629808Ribosomal protein L6AA482067Human tazarotene-induced gene 2 (TIG2) mRNA, complete cdsAA669314ATP synthase, H+ transporting, mitochondrial F1 complex, delta subunitAA775241Aldolase AR73584Homo sapiens hydroxysteroid sulfotransferase SULT2B1a (HSST2) mRNA, completecdsH28984PHOSPHATIDYLSERINE SYNTHASE IR44202Homo sapiens catechol-O-methyltransferase (COMT) mRNA, complete cdsW70051H. sapiens mRNA for M-phase phosphoprotein, mpp9AA401972Human RalGDS-like 2 (RGL2) mRNA, partial cdsAA236164CATHEPSIN S PRECURSORR22412Platelet/endothelial cell adhesion molecule (CD31 antigen)AA424804MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 1AA669443Eukaryotic translation initiation factor 5 (elF5)N69689RAS-RELATED PROTEIN RAB-1AH24316AQUAPORIN-CHIPAA074224RecoverinR36571Human U1 snRNP-specific protein A geneAA056465Human 54 kDa protein mRNA, complete cdsAA633811H. sapiens E4BP4 geneAA457155Human zinc-finger protein C2H2-150 mRNA, complete cdsAA45910460S RIBOSOMAL PROTEIN L13R40212Human coatomer protein (HEPCOP) mRNA, complete cdsAA086476Adenosine monophosphate deaminase 1 (isoform M)AA663310Thymidylate synthaseAA455640Homo sapiens signalosome subunit 3 (Sgn3) mRNA, complete cdsAA496879Human (clone E5.1) RNA-binding protein mRNA, complete cdsAA085749Homo sapiens mRNA for ATP binding protein, complete cdsAA425755Homo sapiens mRNA for leukemia associated gene 1N52350H. sapiens mRNA for protein-tyrosine-phosphatase (tissue type: testis)AA630104Lipase A, lysosomal acid, cholesterol esterase (Wolman disease)AA454854ALPHA-AMYLASE 2B PRECURSORW73406DIHYDROPRYRIDINE-SENSITIVE L-TYPE, SKELETAL MUSCLE CALCIUMCHANNEL GAMMA SUBUNITR12802Human cytochrome bc-1 complex core protein II mRNA, complete cdsAA465355Homo sapiens mRNA for U3 snoRNP associated 55 kDa proteinAA829383DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 3AA629189Keratin 4AA430512Homo sapiens cytoplasmic antiproteinase 3 (CAP3) mRNA, complete cdsAA456439Human homozygous deletion target in pancreatic carcinoma (DPC4) mRNA,complete cdsH27864SECRETOGRANIN II PRECURSORAA644657MHC class I protein HLA-A (HLA-A28, -B40, -Cw3)R40460Homo sapiens phosphatidylinositol 4-kinase mRNA, complete cdsW96058Human hnRNP H mRNA, complete cdsT72202Human transcription factor IL-4 Stat mRNA, complete cdsAA598794Connective tissue growth factorAA599178Ribosomal protein L27aR88247Adrenergic, beta, receptor kinase 1T98612Alpha-1 type 3 collagenAA454856Phospholipid hydroperoxide glutathione peroxidaseN67048Type 3 iodothyronine deiodinaseAA778675Homo sapiens mRNA for calmegin, complete cdsH51117Human calmodulin dependent phosphodiesterase PDE1B1 mRNA, complete cdsN361745-HYDROXYTRYPTAMINE 2B RECEPTORAA777187Homo sapiens Cyr61 mRNA, complete cdsR09561Decay accelerating factor for complement (CD55, Cromer blood group system)R16849Human HsPex13p mRNA, complete cdsAA884167ANNEXIN XIIIAA136983Cadherin 11 (OB-cadherin)AA488622Human signal transducing adaptor molecule STAM mRNA, complete cdsAA699427Fructose-bisphosphatase 1AA490459Transcobalamin IIAA626787Human ras-related C3 botulinum toxin substrate (rac) mRNA, complete cdsN62179Human methylmalonate semialdehyde dehydrogenase gene, complete cdsN27190UBIQUITIN CARBOXYL-TERMINAL HYDROLASE ISOZYME L3AA441895Human glutathione-S-transferase homolog mRNA, complete cdsAA463924FACTOR VIII INTRON 22 PROTEINN78843Homo sapiens cyclophilin-33A (CYP-33) mRNA, complete cdsAA629719Cytochrome c oxidase VIIc subunitAA464755Ankyrin 1, erythrocyticAA459351H. sapiens sds22-like mRNAAA488346MYOSIN LIGHT CHAIN ALKALI, SMOOTH-MUSCLE ISOFORMAA427899Human mRNA fragment encoding beta-tubulin. (from clone D-beta-1)AA453813H. sapiens mRNA for Gal-beta(1-3/1-4)GlcNAc alpha-2.3-sialyltransferaseAA397824Dopachrome tautomerase (dopachrome delta-isomerase, tyrosine-related protein 2)AA633901Transforming growth factor, beta-induced, 68 kDAA181334Troponin I (skeletal fast)AA292410Clusterin (complement lysis inhibitor; testosterone-repressed prostate message 2;apolipoprotein J)AA253434HEAT SHOCK FACTOR PROTEIN 2AA455056H. sapiens mRNA for MAP kinase activated protein kinaseR55188Human pre-T/NK cell associated protein (3B3) mRNA, 3′ endAA465723Homo sapiens mRNA for protein phosphatase 2C gammaN49856SODIUM-AND CHLORIDE-DEPENDENT BETAINE TRANSPORTERAA455272H. sapiens mRNA for ITBA1 proteinAA459292CDC28 protein kinase 1AA878561Ubiquitin A-52 residue ribosomal protein fusion product 1AA772066Human phosphatidylinositol (4,5)bisphosphate 5-phosphatase homolog mRNA,partial cdsN78621H. sapiens mRNA for gamma-adaptinAA291490H. sapiens mRNA for processing a-glucosidase IN46828Homo sapiens mRNA for inositol 1,4,5-trisphosphate 3-kinase isoenzyme, partial cdsAA150487Alkaline phosphatase, placental (Regan isozyme)AA282537MYOCYTE-SPECIFIC ENHANCER FACTOR 2AA707922Human mRNA for cone-specific cGMP phosphodiesterase gamma subunit, completecdsAA443638Homo sapiens breast cancer-specific protein 1 (BCSG1) mRNA, complete cdsW73892Human putative tumor suppressor (LUCA15) mRNA, complete cdsN70734Troponin T2 (cardiac)H57136Human phospholemman chloride channel mRNA, complete cdsAA709414Nidogen (enactin)W65461Human protein tyrosine phosphatase mRNA, complete cdsAA436564Human cellular proto-oncogene (c-mer) mRNA, complete cdsAA029042Human hSIAH2 mRNA, complete cdsAA427725Homo sapiens carboxypeptidase Z precursor, mRNA, complete cdsN51280ADP-ribosylation factor like 1AA281347H. sapiens mRNA for MHC class I promoter binding proteinAA402960Human HLA class III region containing NOTCH4 gene, partial sequence, homeoboxPBX2 (HPBX) gene, receptor for advanced glycosylation end products (RAGE) gene,complete cds, and 6 unidentified cdsN98485Human forkhead protein FREAC-2 mRNA, partial cdsAA490209H. sapiens mRNA for Sop2p-like proteinW61361Homo sapiens cytoplasmic antiproteinase 2 (CAP2) mRNA, complete cdsN51018BiglycanAA455281DEFENDER AGAINST CELL DEATH 1W69471V-ski avian sarcoma viral oncogene homologAA486321VimentinAA458982Solute carrier family 9 (sodium/hydrogen exchanger), isoform 1 (antiporter, Na+/H+,amiloride sensitive)AA442095NEDD-4 PROTEINN99003Active BCR-related geneAA609284Homo sapiens mRNA for Eph-family protein, complete cdsAA195036Human Ro/SSA ribonucleoprotein homolog (RoRet) mRNA, complete cdsAA478268Human CtBP mRNA, complete cdsAA608583Homo sapiens mRNA for OTK27, complete cdsAA486435Homo sapiens mRNA for CDEP, complete cdsAA505045Human L2-9 transcript of unrearranged immunoglobulin V(H)5 pseudogeneAA487893TUMOR-ASSOCIATED ANTIGEN L6AA292226Homo sapiens creatine transporter mRNA, complete cdsH87106Homo sapiens T245 protein (T245) mRNA, complete cdsW96450Human putative tRNA synthetase-like protein mRNA, complete cdsN33331Human peroxisome proliferator activated receptor mRNA, complete cdsAA405800Dodecenoyl-Coenzyme A delta isomerase (3,2 trans-enoyl-Coenzyme A isomerase)T51539Macrophage stimulating 1 (hepatocyte growth factor-like)N59764Human guanosine 5′-monophosphate synthase mRNA, complete cdsAA521346H. sapiens mRNA for Ndr protein kinaseAA428551Homo sapiens SOX22 protein (SOX22) mRNA, complete cdsAA489383Bone morphogenetic protein 2AA490172Collagen, type I, alpha-2AA504477Human cytoskeleton associated protein (CG22) mRNA, complete cds

List of Table III related sequences:

Accession_—mrgdNAMEGeneM98539Human prostaglandin D2 synthase gene, exon 7AB004922Homo sapiens gene for Smad 3, exon 1, partial sequenceAB006000Homo sapiens mRNA for chondromodulin-I precursor, complete cdsAB017364Homo sapiens mRNA for frizzled-2, complete cdsAB020236Homo sapiens gene for ribosomal protein L27A, complete cdsRibosomal protein L27aAB042820Homo sapiens RPL6 gene for ribosomal protein L6, complete cdsRibosomal protein L6AB043547Homo sapiens gene for SMAD4, partial cdsAB080265Homo sapiens CYP2J2 mRNA for cytochrome P450 2J2, complete cdsCytochrome P450, subfamily IIJ(arachidonic acid epoxygenase) polypeptide 2AF000979Homo sapiens testis-specific Basic Protein Y 1 (BPY1) mRNA, complete cdsHomo sapiens testis-specific Basic ProteinY 1 (BPY1) mRNA, complete cdsAF001450Homo sapiens core binding factor alpha1subunit (CBFA1) gene, exon 7 and complete cdsAF004231Homo sapiens monocyte/macrophage Ig-related receptor MIR-10 (MIR cl-10)Homo sapiens monocyte/macrophage Ig-relatedmRNA, complete cdsreceptor MIR-10 (MIR cl-10) mRNA,complete cdsAF009801Homo sapiens homeodomain protein (BAPX1) mRNA, complete cdsAF010126Homo sapiens breast cancer-specific protein 1 (BCSG1) mRNA, complete cdsHomo sapiens breast cancer-specificprotein 1 (BCSG1) mRNA, complete cdsAF010316Homo sapiens Pig12 (PIG12) mRNA, complete cdsHomo sapiens Pig12 (PIG12) mRNA,complete cdsAF013591Homo sapiens homolog of the Aspergillus nidulans sudD gene product mRNA,Homo sapiens homolog of thecomplete cdsAspergillus nidulans sudD gene productmRNA, complete cdsAF037204Homo sapiens RING zinc finger protein (RZF) mRNA, complete cdsAF043339Homo sapiens macrophageinflammatory protein 1 alpha (MIP1a) mRNA, partial cdsAF049656Homo sapiens inducible nitric oxide synthase (iNOS) mRNA, complete cdsAF072872Homo sapiens frizzled 1 mRNA, complete cdsAF188285Homo sapiens bone morphogenetic protein 9 (BMP9) mRNA, complete cdsAF189279Homo sapiens group IIE secretory phospholipase A2 mRNA, complete cdsAF248634Homo sapiens syndecan 3 (SDC3) mRNA, complete cdsAF304431Homo sapiens hypoxia-inducible factor1 alpha subunit (HIF1A) mRNA, complete cdsAF339054Homo sapiens BCL2-associated X protein (BAX) gene, exons 1, 2 and partial cdsAF348700Homo sapiens ubiquitin A-52 residue ribosomal protein fusion product 1Ubiquitin A-52 residue ribosomal protein(UBA52), mRNA, complete cdsfusion product 1AF395008Homo sapiens interleukin 4 (IL4) gene, complete cdsAF405705Homo sapiens matrix metalloproteinase 3(stromelysin 1, progelatinase) (MMP3) gene, complete cdsAF411526Homo sapiens nerve growth factor beta (NGFB) mRNA, complete cdsNerve growth factor betaAF469046Homo sapiens macrophage migration inhibitory factor (MIF) mRNA, complete cdsAF477981Homo sapiens osterix mRNA, complete cdsAJ279016Homo sapiens mRNA for chondrocyte expressed protein 68 kDa (CEP-68 gene)AY043326Homo sapiens keratin 4 (KRT4) gene, complete cdsKeratin 4AY044847Homo sapiens aggrecanase 1 (ADAMTS4) gene, complete cdsD13748Human mRNA for eukaryotic initiation factor 4AIHuman mRNA for eukaryoticinitiation factor 4AID38255Homo sapiens mRNA for CAB1, complete cdsHomo sapiens mRNA for CAB1, complete cdsD45399Human mRNA for cone-specific cGMP phosphodiesterase gamma subunit,Human mRNA for cone-specific cGMPcomplete cdsphosphodiesterase gamma subunit,complete cdsD49738Human cytoskeleton associated protein (CG22) mRNA, complete cdsHuman cytoskeleton associated protein(CG22) mRNA, complete cdsD49835Homo sapiens mRNA for DNA-binding protein, complete cdsHomo sapiens mRNA for DNA-bindingprotein, complete cdsD90040Human mRNA for arylamine N-acetyltransferase (EC 2.3.1.5)ARYLAMINE N-ACETYLTRANSFERASE,MONOMORPHICJ00306Human somatostatin I gene and flanksHuman somatostatin I gene and flanksJ03191Human profilin mRNA, complete cdsHuman profilin mRNA, complete cdsJ03592Human ADP/ATP translocase mRNA, 3′ end, clone pHAT8Human ADP/ATP translocase mRNA,3′ end, clone pHAT8J04111Human c-jun proto oncogene (JUN), complete cds, clone hCJ-1J04177Human alpha-1 type XI collagen (COL11A1) mRNA, complete cdsJ04973Human cytochrome bc-1 complex core protein II mRNA, complete cdsHuman cytochrome bc-1 complex coreprotein II mRNA, complete cdsJ05036Human cathepsin E mRNA, complete cdsCathepsin EK00065Human superoxide dismutase (SOD-1) mRNA, complete cdsHuman superoxide dismutase (SOD-1) mRNA,complete cdsK00650Human fos proto-oncogene (c-fos), complete cdsL05095Homo sapiens ribosomal protein L30 mRNA, complete cds60S RIBOSOMAL PROTEIN L30L08895Homo sapiens MADS/MEF2-familytranscription factor (MEF2C) mRNA, complete cdsL10347Human pro-alpha1 type II collagen (COL2A1) gene exons 1-54, complete cdsL11566Homo sapiens ribosomal protein L18 (RPL18) mRNA, complete cds60S RIBOSOMAL PROTEIN L18L13286Human mitochondrial 1,25-dihydroxyvitamin D3 24-hydroxylase mRNA,Human mitochondrial 1,25-dihydroxyvitamincomplete cdsD3 24-hydroxylase mRNA, complete cdsL13463Human helix-loop-helix basic phosphoprotein (G0S8) mRNA, complete cdsL13616Human focal adhesion kinase (FAK) mRNA, complete cdsL13720Homo sapiens growth-arrest-specific protein (gas) mRNA, complete cdsHomo sapiens growth-arrest-specific protein(gas) mRNA, complete cdsL22009Human hnRNP H mRNA, complete cdsHuman hnRNP H mRNA, complete cdsL28997Homo sapiens ARL1 mRNA, complete cdsADP-ribosylation factor like 1L31409Homo sapiens creatine transporter mRNA, complete cdsHomo sapiens creatine transporter mRNA,complete cdsL33930Homo sapiens CD24 signal transducer mRNA, complete cds and 3′ regionL34059Homo sapiens cadherin-4 mRNA, complete cdsL41162Homo sapiens collagen alpha 3 type IX (COL9A3) mRNA, complete cdsL47647Homo sapiens creatine kinase B mRNA, complete cdsCreatine kinase BM13994Human B-cell leukemia/lymphoma 2 (bcl-2) proto-oncogenemRNA encoding bcl-2-alpha protein, complete cdsM14144Human vimentin gene, complete cdsVimentinM14631Human guanine nucleotide-binding protein G-s, alpha subunit mRNA, partialHuman guanine nucleotide-binding protein G-s,cdsalpha subunit mRNA, partial cdsM16652Human pancreatic elastase IIA mRNA, complete cdsElastase 1, pancreatic (elastase IIA)M20137Human interleukin 3 (IL-3) mRNA, complete cds, clone pcD-SR-alphaM22636Human U1 small nuclear ribonucleoprotein 70 kd protein mRNA, complete cdsU1 snRNP 70K proteinM37825Human fibroblast growth factor-5 (FGF-5) mRNA, complete cdsM57293Human parathyroid hormone-related peptide(PTHRP) gene, exons 1A, 1B, 1C, and 2M58458Human ribosomal protein S4 (RPS4X) isoform mRNA, complete cdsRibosomal protein S4, X-linkedM58525Homo sapiens catechol-O-methyltransferase (COMT) mRNA, complete cdsHomo sapiens catechol-O-methyltransferase(COMT) mRNA, complete cdsM58549Human matrix Gla protein (MGP) mRNA, complete cdsM61877Human erythroid alpha-spectrin (SPTA1) mRNA, complete cdsErythroid alpha-spectrinM62402Human insulin-like growth factor binding protein 6 (IGFBP6) mRNA, completeInsulin-like growth factor binding protein 6cdsM65062Human insulin-like growth factor binding protein 5 (IGFBP-5) mRNA, complete cdsM65217Human heat shock factor 2 (HSF2) mRNA, complete cdsHEAT SHOCK FACTOR PROTEIN 2M76701Homo sapiens zinc finger protein 35 (ZNF35) gene, exon 1M77016Human tropomodulin mRNA, complete cdsTropomodulinM81768Human Na/H antiporter (APNH1) mRNA, complete cdsHuman Na/H antiporter (APNH1) mRNA,complete cdsM84489Human extracellular signal-regulated kinase 2 mRNA, complete cdsM84721Human AMP deaminase (AMPD3) mRNA, complete cdsAdenosine monophosphate deaminase(isoform E)M87842Human S-lac lectin L-14-II (LGALS2) mRNA, complete cdsGALECTIN-2M92934Human connective tissue growth factor, complete cdsConnective tissue growth factorM95610Human alpha 2 type IX collagen (COL9A2) mRNA, partial cdsM96684H. sapiens Pur (pur-alpha) mRNA, complete cdsH. sapiens Pur (pur-alpha) mRNA,complete cdsM97676Homo sapiens (region 7) homeobox protein (HOX7) mRNA, complete cdsNM_000194Homo sapiens hypoxanthine phosphoribosyltransferase1 (Lesch-Nyhan syndrome) (HPRT1), mRNANM_000213Homo sapiens integrin, beta 4 (ITGB4), mRNANM_000221Homo sapiens ketohexokinase (fructokinase) (KHK), transcript variant a,H. sapiens KHK mRNA for ketohexokinase,mRNAclone pHKHK3aNM_000235Homo sapiens lipase A, lysosomal acid, cholesterol esterase (WolmanLipase A, lysosomal acid, cholesterol esterasedisease) (LIPA), mRNA(Wolman disease)NM_000358Homo sapiens transforming growth factor, beta-induced, 68 kD (TGFBI), mRNATransforming growth factor,beta-induced, 68 kDNM_000364Homo sapiens troponin T2, cardiac (TNNT2), mRNATroponin T2 (cardiac)NM_000537Homo sapiens renin (REN), mRNARENIN PRECURSOR, RENALNM_000574Homo sapiens decay accelerating factor for complement (CD55, Cromer bloodDecay accelerating factor for complementgroup system) (DAF), mRNA(CD55, Cromer blood group system)NM_000600Homo sapiens interleukin 6 (interferon, beta 2) (IL6), mRNANM_000618Homo sapiens insulin-like growth factor 1 (somatomedia C) (IGF1), mRNANM_000632Homo sapiens Integrin, alpha M (complement component receptor 3, alpha;Integrin, alpha M (complement componentalso known as CD11b (p170), macrophage antigen alpha polypeptide)receptor 3, alpha; also known as CD11b(ITGAM), mRNA(p170), polypeptide) macrophage antigen alphaNM_000711Homo sapiens bone gamma-carboxyglutamate(gla) protein (osteocalcin) (BGLAP), mRNANM_000962Homo sapiens prostaglandin-endoperoxide synthase 1 (prostaglandin G/HProstaglandin-endoperoxide synthase 1synthase and cyclooxygenase) (PTGS1), transcript variant 1, mRNA(prostaglandin G/H synthase andcyclooxygenase)MM_000977Homo sapiens ribosomal protein L13 (RPL13), transcript variant 1, mRNA60S RIBOSOMAL PROTEIN L13NM_000996Homo sapiens ribosomal protein L35a (RPL35A), mRNARibosomal protein L35aNM_001012Homo sapiens ribosomal protein S8 (RPS8), mRNA40S RIBOSOMAL PROTEIN S8NM_001025Homo sapiens ribosomal protein S23 (RPS23), mRNA40S RIBOSOMAL PROTEIN S23NM_001064Homo sapiens transketolase (Wernicke-Korsakoff syndrome) (TKT), mRNATransketolase (Wernicke-Korsakoff syndrome)NM_001127Homo sapiens adaptor-related protein complex 1, beta 1 subunitAdaptin, beta 1 (beta prime)AP1B1), mRNANM_001200Homo sapiens bone morphogenetic protein 2 (BMP2), mRNABone morphogenetic protein 2NM_001229Homo sapiens caspase 9, apoptosis-related cysteine protease(CASP9), transcript variant alpha, mRNANM_001511Homo sapiens GRO1 oncogene (melanoma growthstimulating activity, alpha) (GRO1), mRNANM_001565Homo sapiens small inducible cytokine subfamily B (Cys-X-Cys), member 10Interferon (gamma)-induced cell line;(SCYB10), mRNAprotein 10 fromNM_001632Homo sapiens alkaline phosphatase, placental (Regan isozyme) (ALPP),Alkaline phosphatase, placentalmRNA(Regan isozyme)NM_001687Homo sapiens ATP synthase, H+ transporting, mitochondrial F1 complex, deltaATP synthase, H+ transporting,subunit (ATP5D), mRNAmitochondrial F1 complex, delta subunitNM_001718Homo sapiens bone morphogenetic protein 6 (BMP6), mRNANM_001745Homo sapiens calcium modulating ligand (CAMLG), mRNACalcium modulating ligandNM_001797Homo sapiens cadherin 11, type 2, OB-cadherin(osteoblast) (CDH11), transcript variant 1, mRNANM_001844Homo sapiens collagen, type II, alpha 1 (primary osteoarthritis,spondyloepiphyseal dysplasia, congenital) (COL2A1), transcript variant 1, mRNANM_001912Homo sapiens cathepsin L (CTSL), mRNANM_001969Homo sapiens eukaryotic translation initiation factor 5 (EIF5), mRNAEukaryotic translation initiation factor 5 (eIF5)NM_002073Homo sapiens guanine nucleotide binding protein (G protein), alpha zGuanine nucleotide binding proteinpolypeptide (GNAZ), mRNApolypeptide (G protein), alpha zNM_002094Homo sapiens G1 to S phase transition 1 (GSPT1), mRNAG1 to S phase transition 1NM_002160Homo sapiens hexabrachion (tenascin C, cytotactin) (HXB), mRNANM_002211Homo sapiens integrin, beta 1 (fibronectin receptor, beta polypeptide,antigen CD29 includes MDF2, MSK12) (ITGB1), mRNANM_002379Homo sapiens matrilin 1, cartilage matrix protein (MATN1), mRNANM_002381Homo sapiens matrilin 3 (MATN3) precursor, mRNANM_002421Homo sapiens matrix metalloproteinase 1 (interstitial collagenase) (MMP1), mRNANM_002424Homo sapiens matrix metalloproteinase 8 (neutrophil collagenase) (MMP8), mRNANM_002427Home sapiens matrix metalloproteinase 13 (collagenase 3) (MMP13), mRNANM_002591Homo sapiens phosphoenolpyruvate carboxykinase 1 (soluble) (PCK1), mRNAPhosphoenolpyruvate carboxykinase 1 (soluble)mRNA carboxykinase 1 (soluble)NM_002619Home sapiens platelet factor 4 (PF4), mRNAPlatelet factor 4NM_002722Homo sapiens pancreatic polypeptide (PPY), mRNANM_002738Homo sapiens protein kinase C, beta 1 (PRKCB1), mRNAProtein kinase C, beta 1NM_002903Homo sapiens recoverin (RCV1), mRNARecoverinNM_003036Homo sapiens v-ski sarcoma viral oncogene homolog (avian) (SKI), mRNAV-ski avian sarcoma viral oncogene homologNM_003282Homo sapiens troponin I, skeletal, fast (TNNI2), mRNATroponin I (skeletal fast)NM_003385Homo sapiens visinin-like 1 (VSNL1),Visinin-like 1NM_003395Homo sapiens wingless-type MMTV integrationsite family, member 14 (WNT14), mRNANM_004613Homo sapiens transglutaminase 2 (C polypeptide,protein-glutamine-gamma-glutamyltransferase) (TGM2), mRNANM_004832Homo sapiens glutathione-S-transferase like; glutathione transferase omegaHuman glutathione-S-transferase homolog(GSTTLp28), mRNAcds mRNA, completeNM_004994Homo sapiens matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase,92 kD type IV collagenase) (MMP9), mRNANM_004995Homo sapiens matrix metalloproteinase 14 (membrane-inserted) (MMP14), mRNANM_005038Homo sapiens peptidylprolyl isomerase D (cyclophilin D) (PPID), mRNA40 KD PEPTIDYL-PROLYL CIS-TRANSISOMERASENM_005186Homo sapiens calpain 1, (mu/l) large subunit (CAPN1), mRNACALPAIN 1, LARGENM_005346Homo sapiens heat shock 70 kD protein 1B (HSPA1B), mRNAHEAT SHOCK 70 KD PROTEIN 1NM_005438Homo sapiens FOS-like antigen 1 (FOSL1), mRNANM_005506Homo sapiens CD36 antigen (collagen type I receptor, thrombospondinreceptor)-like 2 (lysosomal integral membrane protein II) (CD36L2), mRNANM_006289Homo sapiens talin 1 (TLN1), mRNANM_006988Homo sapiens a disintegrin-like and metalloprotease (reprolysin type)with thrombospondin type 1 motif, 1 (ADAMTS1), mRNANM_007306Homo sapiens breast cancer 1, early onset (BRCA1), transcript variantBreast cancer 1, early onsetBRCA1-exon4, mRNANM_007352Homo sapiens elastase 3B, pancreatic (ELA3B), MrnaELASTASE IIIB PRECURSORNM_014000Homo sapiens vinculin (VCL), transcript variant meta-VCL, mRNANM_014470Homo sapiens GTP-binding protein (RHO6), mRNANM_018952Homo sapiens homeo box B6 (HOXB6), mRNANM_021019Homo sapiens myosin, light polypeptide 6, alkali, smooth muscle and non-MYOSIN LIGHT CHAIN ALKALI,muscle (MYL6), transcript variant 1, mRNASMOOTH-MUSCLE ISOFORMNM_033150Homo sapiens collagen, type II, alpha 1 (primary osteoarthritis,spondyloepiphyseal dysplasia, congenital) (COL2A1), transcript variant 2, mRNANM_053056Homo sapiens cyclin D1 (PRAD1: parathyroid adenomatosis 1) (CCND1),Cyclin D1 (PRAD1; parathyroidmRNAadenomatosis 1)NM_080682Homo sapiens vascular cell adhesionmolecule 1 (VCAM 1), transcript variant 2, mRNAS79854Homo sapiens type 3 iodothyronine deiodinase mRNA, complete cdsType 3 iodothyronine deiodinaseS83308SOX5 = Sry-related HMG box gene {alternativelyspliced} [human, testis, mRNA, 1473 nt]U07424Human putative tRNA synthetase-like protein mRNA, complete cdsHuman putative tRNA synthetase-likeprotein mRNA, complete cdsU07620Human MAP kinase mRNA, complete cdsHuman MAP kinase mRNA, complete cdsU08023Human cellular proto-oncogene (c-mer) mRNA, complete cdsHuman cellular proto-oncogene (c-mer)mRNA, complete cdsU09303Human T cell leukemia LERK-2 (EPLG2) mRNA, complete cdsU09577Homo sapiens lysosomal hyaluronidase (LUCA2/HYAL2) mRNA, complete cdsHuman PH-20 homolog (LUCA2) mRNA,partial cdsU09825Human acid finger protein mRNA, complete cdsAcid finger protein ZNF173U13261Homo sapiens eIF-2-associated p67 homolog mRNA, complete cdsHuman eIF-2-associated p67 homologmRNA, complete cdsU13660Human cartilage-derived morphogenetic protein 1 (CDMP-1) mRNA, complete cdsU13991Human TATA-binding protein associated factor 30 kDa subunit (tafII30) mRNA,Human TATA-binding protein associatedcomplete cdsfactor 30 kDa subunit (tafII30) mRNA,complete cdsU14966Human ribosomal protein L5 mRNA, complete cdsRibosomal protein L5U14971Human ribosomal protein S9 mRNA, complete cdsU15085Human HLA-DMB mRNA, complete cdsMajor histocompatibility complex,class II, DM betaU16031Human transcription factor IL-4 Stat mRNA, complete cdsHuman transcription factor IL-4 StatmRNA, complete cdsU16261Human MDA-7 (mda-7) mRNA, complete cdsU18299Human damage-specific DNA binding protein DDBa p127 subunit (DDB1)Damage-specific DNA binding proteinmRNA, complete cds1 (127 kD)U20980Human chromatin assembly factor-I p60 subunit mRNA, complete cdsHuman chromatin assembly factor-Ip60 subunit mRNA, complete cdsU22409Human parathyroid hormone/PTH-related peptide receptor(PTH/PTHrP) gene, exon 14 and complete cdsU23028Human eukaryotic initiation factor 2B-epsilon mRNA, partial cdsHuman eukaryotic initiation factor2B-epsilon mRNA, partial cdsU23946Human putative tumor suppressor (LUCA15) mRNA, complete cdsHuman putative tumor suppressor(LUCA15) mRNA, complete cdsU24152Human p21-activated protein kinase (Pak1) gene, complete cdsHuman protein kinase PAK1mRNA, complete cdsU25789Human ribosomal protein L21 mRNA, complete cdsRibosomal protein L21U27699Human pephBGT-1 betaine-GABA transporter mRNA, complete cdsSODIUM-AND CHLORIDE-DEPENDENTBETAINE TRANSPORTERU31202Human noggin (NOGGIN) gene, complete cds, (NOG)U32169Human pro-a2 chain of collagen type XI (COL11A2) gene, complete cdsU32907Human p37NB mRNA, complete cdsHuman p37NB mRNA, complete cdsU33822Human tax1-binding protein TXBP181 mRNA, complete cdsHuman tax1-binding protein TXBP181mRNA, complete cdsU37012Human cleavage and polyadenylation specificity factor mRNA, complete cdsHuman cleavage and polyadenylationspecificity factor mRNA, complete cdsU38864Human zinc-finger protein C2H2-150 mRNA, complete cdsHuman zinc-finger protein C2H2-150mRNA, complete cdsU40373Human cell surface glycoprotein CD44 mRNA, complete cdsU41517Human channel-like integral membrane protein (AQP-1) mRNA, clone AQP-1-AQUAPORIN-CHIP1656, complete cdsU43148Human patched homolog (PTC) mRNA, complete cdsU43747Human frataxin (FRDA) mRNA, complete cdsFriedreich ataxiaU43842Homo sapiens bone morphogenetic protein-4 (hBMP-4) gene, complete cdsBone morphogenetic protein 4U45975Human phosphatidylinositol (4,5)bisphosphate 5-phosphatase homolog mRNA,Human phosphatidylinositolpartial cds(4,5)bisphosphate 5- phosphatase homologmRNA, partial cdsU53204Human plectin (PLEC1) mRNA, complete cdsHuman plectin (PLEC1) mRNA, complete cdsU53347Human neutral amino acid transporter B mRNA, complete cdsHuman neutral amino acid transporter BmRNA, complete cdsU59289Human H-cadherin mRNA, complete cdsU59423Human Smad1 mRNA, complete cdsU63717Homo sapiens osteoclast stimulating factor mRNA, complete cdsHuman osteoclast stimulating factormRNA, complete cdsU68723Human checkpoint suppressor 1 mRNA, complete cdsU70312Homo sapiens integrin binding protein Del-1 (Del1) mRNA, complete cdsU72245Human phospholemman chloride channel mRNA, complete cdsHuman phospholemman chloride channelmRNA, complete cdsU75283Human sigma receptor mRNA, complete cdsHuman sigma receptor mRNA, complete cdsU76992Human Tat-SF1 mRNA, complete cdsHuman Tat-SF1 mRNA, complete cdsU80998Human basic helix-loop-helix DNA binding protein (TWIST) gene, complete cdsU83460Human high-affinity copper uptake protein (hCTR1) mRNA, complete cdsHuman high-affinity copper uptake protein(hCTR1) mRNA, complete cdsU90547Human Ro/SSA ribonucleoprotein homolog (RoRet) mRNA, complete cdsHuman Ro/SSA ribonucleoprotein homolog(RoRet) mRNA, complete cdsU92268Homo sapiens mitogen activated protein kinase p38-2 mRNA, complete cdsU93181Homo sapiens nuclear dual-specificity phosphatase (SBF1) mRNA, partial cdsHomo sapiens nuclear dual-specificityphosphatase (SBF1) mRNA, partial cdsX00129Human mRNA for retinol binding protein (RBP)X00588Human mRNA for precursor of epidermal growth factor receptorX02910Human gene for tumor necrosis factor (TNF-alpha)X03742Human gene for L apoferritin exons 1 and 2X04412Human mRNA for plasma gelsolinGELSOLIN PRECURSOR, PLASMAX06614Human mRNA for receptor of retinoic acidHuman mRNA for receptor of retinoic acidX12794Human v-erbA related ear-2 geneHuman v-erbA related ear-2 geneX14420Human mRNA for pro-alpha-1 type 3 collagenX51801Human OP-1 mRNA for osteogenic proteinX54412Human mRNA for alpha1(IX) collagen (long form)X55654Homo sapiens mitochondrial coxII mRNA for cytochrome C oxidase II subunitX55764Human mRNA for cytochrome P-450 (11 Beta)Cytochrome P450 11 betaX58399Human L2-9 transcript of unrearranged immunoglobulin V(H)5 pseudogeneHuman L2-9 transcript of unrearrangedimmunoglobulin V(H)5 pseudogeneX58957H. sapiens atk mRNA for agammaglobulinaemia tyrosine kinaseAgammaglobulinaemia protein-tyrosinekinase atkX60188Human ERK1 mRNA for protein serine/threonine kinaseX60382H. sapiens COL10A1 gene for collagen (alpha-1 type X)X67337H. sapiens HPBRII-4 mRNAH. sapiens HPBRII-4 mRNAX70683H. sapiens mRNA for SOX-4 proteinX71661H. sapiens ERGIC-53 mRNAERGIC-53 PROTEIN PRECURSORX74795H. sapiens P1-Cdc46 mRNACDC46 HOMOLOGX76770H. sapiens PAP mRNAH. sapiens PAP mRNAX78712H. sapiens mRNA for glycerol kinase testis specific 2Glycerol kinase 2 (testis specific)X87237H. sapiens mRNA for processing a-glucosidase IH. sapiens mRNA for processinga-glucosidase IX87342H. sapiens mRNA for human giant larvae homologH. sapiens mRNA for humangiant larvae homologX92475H. sapiens mRNA for ITBA1 proteinH. sapiens mRNA for ITBA1 proteinX94216H. sapiens mRNA for VEGF-C proteinXM_001306Homo sapiens solute carrier family 16 (monocarboxylic acid transporters),Solute carrier family 16 (monocarboxylicmember 1 (SLC16A1), mRNAacid transporters), member 1XM_001316Homo sapiens adenosine monophosphate deaminase 1 (isoform M) (AMPD1),Adenosine monophosphatemRNAdeaminase 1 (isoform M)XM_001324Homo sapiens calponin 3, acidic (CNN3), mRNACalponin 3, acidicXM_001782Homo sapiens fibromodulin (FMOD), mRNAXM_001826Homo sapiens alkaline phosphatase, liver/bone/kidney (ALPL), mRNAAlkaline phosphatase, liver/bone/kidneyXM_002321Homo sapiens glypican 1 (GPC1), mRNAGlypican 1XM_003059Homo sapiens peroxisome proliferativeactivated receptor, gamma (PPARG), mRNAXM_003222Homo sapiens catenin (cadherin-associatedprotein), beta 1 (88 kD) (CTNNB1), mRNAXM_003730Homo sapiens cytochrome c oxidase subunit VIIc (COX7C), mRNACytochrome c oxidase VIIc subunitXM_003752Homo sapiens interleukin 3 (colony-stimulating factor, multiple) (IL3), mRNAXM_003913Homo sapiens integrin, alpha 2 (CD49B, alpha2 subunit of VLA-2 receptor) (ITGA2), mRNAXM_004063Homo sapiens early growth response 1 (EGR1), mRNAXM_006121Homo sapiens cathepsin D (lysosomal aspartyl protease) (CTSD), mRNAXM_009336Homo sapiens cartilage oligomeric matrix protein (pseudoachondroplasia,epiphyseal dysplasia 1, multiple) (COMP), mRNAXM_009915Homo sapiens leukemia inhibitory factor(cholinergic differentiation factor) (LIF), mRNAXM_010702Homo sapiens cathepsin K (pycnodysostosis) (CTSK), mRNAXM_012503Homo sapiens matrix metalloproteinase 2 (gelatinase A, 72 kDgelatinase, 72 kD type IV collagenase) (MMP2), mRNAXM_012651Homo sapiens collagen, type I, alpha 1 (COL1A1), mRNAXM_015434Homo sapiens chitinase 3-like 1 (cartilage glycoprotein-39) (CHI3L1), mRNAXM_016181Homo sapiens wingless-type MMTVintegration site family, member 5A (WNT5A), mRNAXM_017096Homo sapiens active BCR-related gene (ABR), mRNAXM_017384Homo sapiens matrix metalloproteinase 7 (matrilysin, uterine) (MMP7), mRNAMatrix metalloproteinase 7 (matrilysin, uterine)XM_017591Homo sapiens annexin A6 (ANXA6), mRNAAnnexin VI (p68)XM_028204Homo sapiens nuclear factor of kappa light polypeptide geneenhancer in B-cells 1 (p105) (NFKB1), mRNAXM_028642Homo sapiens integrin, alpha 5(fibronectin receptor, alpha polypeptide) (ITGA5), mRNAXM_029245Homo sapiens collagen, type I, alpha 2 (COL1A2), mRNACollagen, type I, alpha-2XM_029796Homo sapiens frizzled-related protein (FRZB), mRNAXM_031221Homo sapiens interleukin 1, alpha (IL1A), mRNAXM_031288Homo sapiens aggrecan 1 (chondroitin sulfate proteoglycan 1, largeaggregating proteoglycan, antigen identified by monoclonalantibody A0122) (AGC1), mRNAXM_031289Homo sapiens interleukin 8 (IL8), mRNAXM_032902Homo sapiens integrin, alpha 1 (ITGA1), mRNAXM_033470Homo sapiens defender against cell death 1 (DAD1), mRNADEFENDER AGAINST CELL DEATH 1XM_033657Homo sapiens heparan sulfate proteoglycan 2 (perlecan) (HSPG2), mRNAXM_033878Homo sapiens tissue inhibitor of metalloproteinase 1 (erythroid potentiatingactivity, collagenase inhibitor) (TIMP1), mRNAXM_034023Homo sapiens regulator of G-protein signalling 4 (RGS4), mRNAHuman RGP4 mRNA, complete cdsXM_034556Homo sapiens chloride channel 7 (CLCN7), mRNAXM_034845Homo sapiens phosphatase and tensin homolog (mutated in multiple advancedPhosphatase and tensin homologcancers 1) (PTEN), mRNA(mutated in multiple advanced cancers 1)XM_034890Homo sapiens fibrillin 1 (Marfan syndrome) (FBN1), mRNAXM_035662Homo sapiens cathepsin B (CTSB), mRNAXM_035842Homo sapiens small inducible cytokine A5 (RANTES) (SCYA5), mRNASmall inducible cytokine A5 (RANTES)XM_036107Homo sapiens integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associatedantigen 1; macrophage antigen 1 (mac-1) beta subunit) (ITGB2), mRNAXM_036175Homo sapiens collagen, type XVIII, alpha 1 (COL18A1), mRNACollagen, type XVIII, alpha 1XM_037087Homo sapiens ATP binding protein associated with cell differentiationHomo sapiens mRNA for ATP binding(APACD), mRNAprotein, complete cdsXM_037646Homo sapiens msh homeo box homolog 2 (Drosophila) (MSX2), mRNAXM_037965Homo sapiens chondroadherin (CHAD), mRNAXM_038584Homo sapiens tissue inhibitor of metalloproteinase 3(Sorsby fundus dystrophy, pseudoinflammatory) (TIMP3), mRNAXM_039094Homo sapiens SRY (sex determining region Y)-box 9(campomelic dysplasia, autosomal sex-reversal) (SOX9), mRNAXM_040037Homo sapiens adrenergic, beta, receptor kinase 1 (ADRBK1), mRNAAdrenergic, beta, receptor kinase 1XM_040385Homo sapiens S-adenosylmethionine decarboxylase 1 (AMD1), mRNAS-adenosylmethionine decarboxylase 1XM_042153Homo sapiens biglycan (BGN), mRNABiglycanXM_042664Homo sapiens nuclear autoantigenic sperm protein (histone-binding) (NASP),Nuclear autoantigenic spermmRNAprotein (histone-binding)XM_044120Homo sapiens fibroblast growth factor receptor 3(achondroplasia, thanatophoric dwarfism) (FGFR3), mRNAXM_045089Homo sapiens ATPase, Cu++ transporting, beta polypeptide (Wilson disease)ATPase, Cu++ transporting,(ATP7B), mRNAbeta polypeptide (Wilson disease)XM_045802Homo sapiens paxillin (PXN), MrnaXM_045890Homo sapiens ADP-ribosylation factor 4-like (ARF4L), mRNAADP-ribosylation factor 4-likeXM_045925Homo sapiens decorin (DCN), mRNADecorinXM_045926Homo sapiens lumican (LUM), mRNAXM_046035Homo sapiens integrin, alpha L (antigen CD11A (p180), lymphocyte function-Integrin, alpha L (antigenassociated antigen 1; alpha polypeptide) (ITGAL), mRNACD11A (p180), lymphocyte function-associatedantigen 1; alpha polypeptide)XM_046758Homo sapiens tensin (TNS), mRNAXM_046765Homo sapiens thymidylate synthetase (TYMS), mRNAThymidylate synthaseXM_047231Homo sapiens fibulin 1 (FBLN1), mRNAXM_047719Homo sapiens transcription factor 7 (T-cell specific, HMG-box) (TCF7), mRNATranscription factor 7 (T-cell specific)XM_047802Homo sapiens a disintegrin-like and metalloprotease (reprolysin type)with thrombospondin type 1 motif, 5 (aggrecanase-2) (ADAMTS5), mRNAXM_048167Homo sapiens troponin T1, skeletal, slow (TNNT1), mRNATroponin T1, skeletal, slowXM_048201Homo sapiens metallothionein 1L (MT1L), mRNAMetallothionein 1LXM_049177Homo sapiens vascular endothelial growth factor B (VEGFB), mRNAXM_049518Homo sapiens intercellular adhesion molecule 1 (CD54), human rhinovirusIntercellular adhesion moleculereceptor (ICAM1), mRNAreceptor 1 (CD54), human rhinovirusXM_049534Homo sapiens amylase, alpha 2A; pancreatic (AMY2A), mRNAAmylase, alpha 2A; pancreaticXM_049690Homo sapiens coatomer protein complex, subunit alpha (COPA), mRNAHuman coatomer protein (HEPCOP)mRNA, complete cdsXM_049864Homo sapiens colony stimulating factor 3 (granulocyte) (CSF3), mRNAXM_049937Homo sapiens insulin-like growth factor binding protein 4 (IGFBP4), mRNAXM_050846Homo sapiens Indian hedgehog homolog (Drosophila) (IHH), mRNAXM_053809Homo sapiens similar to chondroitin sulfate proteoglycan 2(versican)(H. sapiens) (LOC153633), mRNAXM_054566Homo sapiens collagen, type VI, alpha 1 (COL6A1), mRNAXM_054686Homo sapiens caspase 3, apoptosis-related cysteine protease (CASP3), mRNAXM_055254Homo sapiens fibronectin 1 (FN1), mRNAXM_058069Homo sapiens matrix metalloproteinase 12 (macrophage elastase) (MMP12), mRNAXM_084239Homo sapiens retinoic acid receptor responder (tazarotene induced) 2Human tazarotene-induced(RARRES2), Mrnagene 2 (TIG2) mRNA, complete cdsXM_084263Homo sapiens cytochrome c oxidase subunit VIc (COX6C), mRNAHuman mRNA forcytochrome c oxidase subunit VIcXM_084285Homo sapiens integral membrane protein 2A (ITM2A), mRNAXM_085705Homo sapiens tissue inhibitor of metalloproteinase 2 (TIMP2), mRNAXM_086368Homo sapiens MUF1 protein (MUF1), mRNAH. sapiens mRNA for MUF1 proteinXM_096277Homo sapiens collagen, type V, alpha 1 (COL5A1), mRNAY00985Human mRNA for manganese-containing superoxide dismutaseY07566H. sapiens mRNA for RIT proteinH. sapiens mRNA for RIT proteinY07570H. sapiens mRNA for PHAPI2b proteinH. sapiens mRNA for PHAPI2b proteinY08999H. sapiens mRNA for Sop2p-like proteinH. sapiens mRNA for Sop2p-like proteinY12692Homo sapiens mRNA for WNT11 geneY13936Homo sapiens mRNA for protein phosphatase 2C gammaHomo sapiens mRNA forprotein phosphatase 2C gammaY15227Homo sapiens mRNA for leukemia associated gene 1Homo sapiens mRNA forleukemia associated gene 1Z22865H. sapiens dermatopontin mRNA, complete CDSZ50781H. sapiens mRNA for leucine zipper proteinZ50853H. sapiens mRNA for CLPPH. sapiens mRNA for CLPP

The current invention also encompasses the process of down compression of previously determined 467 genes to a lower number that is still able to characterize the desired number of different cellular status. At present, for the determination of 7 different cell types or development stages, a minimum of 26 spots of different marker genes are preferred, much preferred about 200 such spots. For full information, at least one spot for each of the presently 467 genes (markers) is preferred. A reduction of spot number can be of relevance e.g. if under certain conditions only a small subset of those genes listed in Tab II is required for analysis e.g. in clinical applications. This down compression can be achieved by determining the ratio of actual to target number of genes and then choosing from each cluster accordingly to the determined ratio the necessary number of genes to fulfill the requirement. This process requires to group the number of genes for each analysis of e.g. Tab. I into representative cluster familys from where representative genes can be selected. Such clusters familys can be determined as shown in FIG. 1, namely by grouping clusters together that show a similar expression pattern. For each cluster family a representative number of genes may be choosen according to the compression factor that has been defined. It can easily be seen that for larger clusters like e.g. “A” in Tab I more genes are available to select while in other clusters like e.g. “E” in Tab I less are present. At the end of the process one needs to balance the procedure in order to preserve the characteristics of the expression profile. In order to do so the amount of genes for each analysis should at least be greater than 2 sequences or spots, respectively, of different genes and for the total array at least 30. In order to control such a process classical hierarchical clustering (Stanford) analysis can be performed and checked on graphical presentations like treeview (Stanford). Cluster analysis may group similar expression profiles in families and will allow distinguishing between different cell sources and allows classification of these cell cultures (see FIG. 2). If the cell sources are not properly represented in the cluster analysis it means that the selected marker genes are not balanced.

Example of an Cartilage Specific Micro Array Structure:

To produce a microarray with printed oligonucleotides sequences of approx. at least 10 mers, preferably at least 25 mers, some sequences of table II need to be further processed. Since some of the determined sequences in Tab II are only expressed sequence tags (herein referred to as EST), they do not correspond to or represent the full-length cDNA. Therefore the EST preferably is BLAST searched with the public database at NCBI and the corresponding full-length cDNA determined. Only by having the correct and full-length cDNA it is possible to design oligomeric sequences that are balanced to each other and minimize any cross reactivity. Exemplary polynucleotide sequences (targets) are provided in the sequence listing of Table III. The cartilage related polynucleotide sequences as e.g. listed in Table III and other polynucleotide sequences known as key cartilage genes from the literature can be immobilized on a substrate and used as hybridizable array elements in a microarray format. Such microarrays can be composed of a subset of oligonucleotides representing e.g. sequences listed on Tab. II but modified to represent only full-length cDNA sequences. The used polynucleotides for the production of such a microarray can either be 50mer or also PCR (polymerase chain reaction) products but at least need to be longer then 10 bases. It should be noted that for microarray production also PCR products from the corresponding determined sequences directly or the full length cDNA can be used and it is not restricted just to oligonucleotides.

Methods to anchor such oligonucleotides or polynucleotides on a solid support are described in literature, together with information on length dependent distances between each oligo or polynucleotides and spots. (see e.g. Principal and Practice, DNA microarrays: gene expression analysis B. Jordan, Springer, 2001)

When polynucleotides are employed as hybridizable array elements in a microarray and depending on the software used, the array elements may be organized in an ordered fashion so that each element is present at a specified location on the substrate. If the array elements are at specified locations on the substrate, the hybridization patterns and intensities (which together create a unique expression profile) can be interpreted in terms of expression levels of particular genes. This expression profile can then be used and may be correlated with any effect associated with a tissue and/or compound or to be investigated with regard to a specific tissue and/or compound and allows comparison with already existing data.

One of such useful application of using ordered polynucleotides on microarrays is e.g. the comparison of gene expression profiles from a new sample e.g. a tissue biopsy, with already determined characteristic gene expression profiles that are preferably stored in a database. Such stored gene expression profiles are e.g. of major importance if microarrays are applied in the clinic. In this case advantageously a database is set up that stores the corresponding gene expression profiles and advantageously also all patient informations, e.g. history, blood pressure etc. By including all patient data and gene expression profiles in the analysis process and then starting a comparison with an expression profile from a new biopsy, it becomes possible to achieve a stronger correlation with the clinical outcome. This will allow to determine which therapy shall be applied, or even to modify an existing therapy, e.g. to add growth factor x at a concentration y during the ex vivo tissue engineering phase. It may also be the case that the biopsy sample will demonstrate a poor gene expression profile that precludes the successful application of a modern therapeutic cell/tissue approach. Such cases would then only qualify for traditional surgical approaches, and hence would not obtain the benefits of the tissue engineering process.

In analogy, the assessment of in vitro produced cartilage can also be performed. In the same way as mentioned above cell culture parameters, like e.g. culture media conditions, growth factor concentration, are preferably stored in a data base together with the corresponding gene expression profiles. Comparison of the database entry with new profiles of new samples can then be used to assess the quality of the new in vitro produced tissue.

Subject Arrays and Their Use:

It should be noted that the invention described here is not dependent on any special array format rather than the possibility to select from an extended list of 467 novel key cartilage genes as well as meaningful gene expression patterns. A presently preferred subject array is a novel cartilage specific microarray that includes 187 genes that in the scope of this invention have been determined to be cartilage related and 140 genes that have been connected to cartilage in literature (see also Tab II). Normally, in high-density array procedures up to 10000 genes are usually applied and are not specific for certain applications. As one major general drawback, this results in massive data overflow and impaired data analysis due to difficult data handling and procedures. A preferred array has in its current state a minimal number of 150 genes, presently much preferred at most 333 genes, all of those with demonstrated relevance within cartilage tissue. Another major limitation has become apparent. While the invention WO01/24833 A2 describes a few marker genes associated with cartilage phenotype stability they do not allo w to extensively describe chondrocyte cultures in details. No comprehensive classification of the different cell populations and culture conditions is possible as well as no gene expression profile or fingerprint can be achieved. Gene expression profiles determined with a set of genes represented in Tab II may allow to perform a more comprehensive analysis of different cell cultures conditions. Furthermore it may allow to compare and classify different tissue or the result of the different applied cell culture conditions. The above mentioned topics may only be possible with the disclosed invention as outlined within the following applications.

The inventive array CART-CHIP 300 ™ may be applied to classify (quality control) any source material, such as human cartilage biopsies, mesenchymal stem cell containing bone marrow aspirate, or pre-chondrogenic cells containing tissue according to pre-defined categories with respect to their capacity to re-build or re-organize a hyaline cartilage-like matrix in vitro. A rough subdivision could be for example “A”, “B”, or “C”. While “A” will easily produce cartilage-like matrix, “B” will require special treatment to achieve an implantable construct, and “C” will represent those cases that do yet not qualify for such a procedure. This biopsy classification system will allow:

- Quality control of the starting biopsy material and therefore optimization of the downstream process regarding e.g. in vitro tissue engineering applications
- Diagnostic evaluation of the patient and candidate treatment methods (e.g. CARTIGRAF™) to ensure a cost-optimized procedure
- Quality control of in vitro tissue engineered products

The subject array of the present invention can be employed for all kind of research and developmental studies related to in vitro tissue engineering of cartilage. The possibility to assess proliferation, differentiation or re-differentiation as well as de novo matrix formation processes through analyses and comparison of a plurality of key cartilage genes (positive/negative markers) within one single experiment replaces current trial and error approaches and is thus far more rational.

The subject array can be applied to screen all kind of drugs, e.g. hormones, growth factors, within in vitro chondrocyte cultures regarding a potential beneficial effect on proliferation, differentiation, de novo matrix formation. The deduced expression profiles can then be compared with existing data of e.g. native cartilage tissue and used to further optimize the process. Additionally the expression profiles can be compared with data from human adult and human infant cartilage to deduce a pathway or a strategy of how to induce more tissue formation in vitro.

The subject array of the preferred embodiment is very well suitable to better understand reaction pathways leading to new responses of chondrocytes in vitro. Only key cartilage genes comprising the whole spectrum of functional gene categories are to be investigated. This can be used to study the complexity of degenerative cartilage process in vitro and the respective influence of potential beneficial drugs.

The subject array may be used to optimize cultures for in vitro cartilage formation starting from human cell sources other than cartilage like e.g. mesenchymal stem cells or bon marrow aspirates.

This subject array will be preferably used as powerful alternative for conventional molecular biology tools beside more established histological and biochemical analyses. By focusing on the most prominent cartilage marker genes being either positive or negative, it is possible to characterize cartilage or cartilage related tissues as well as cell cultures thereof. In this respect, the subject array can replace conventional RT-PCR studies performed to check for cartilage marker gene expression, e.g. collagen I versus collagen II, aggrecan versus versican. By applying this subject array the set of markers will be easily increased by simultaneously simplifying the experimental procedure and enhancing the outcome.

The subject arrays of the present invention have several advantages compared to existing microarrays as well as to conventional gene expression tools such as RT-PCR, Northern Blots etc.

Most importantly, the subject arrays are all based on key cartilage genes. Beyond all the key cartilage genes known from the literature (˜100-200 genes), 467 additional cartilage relevant genes have been discovered. Thus a significantly increased pool of cartilage key genes exists to choose from for various applications. For instance, to understand degenerative processes as they occur in OA or RA by study of complex biological reaction pathways, it is important to follow expression of a relatively large number of genes.

EXAMPLES

The examples are described for the purposes of illustration and are not intended to limit the scope of the invention.

Example 1
Analysis of Various Human Cartilage Samples

Useful for characterizing chondrocyte cultures derived from different human cartilage samples (adult and fetal), where adult samples are different with respect to their capacity to form living tissue engineered equivalents under high density culture conditions.

Adult chondrocytes show different gene expression clusters compared to fetal chondrocytes and can be further distinguished from samples that will not produce living cartilage constructs (failures).

Human chondrocytes from adult and fetal articular cartilage were proliferated in DMEM-F12 medium containing 10% FCS over several passages and transferred to pellet cultures (0.5*10⁶cells) in serum free DMEM-F12 medium supplemented with Ascorbate and Insulin medium. Proliferated cells were directly lyzed with RLT buffer (RNeasy® Mini Kit, Qiagen) after trypsin release from plastic substrate, shredded (QIAshredder, Qiagen) and kept frozen at −80° C. in lysis buffer for later processing. High density pellet cultures were cultivated for 2 weeks if not otherwise specified, subsequently washed with phosphate buffered saline (PBS) and lyzed in RLT Buffer (supplied with RNeasy® Kit). Total RNA was isolated from all samples as described in the manual provided with the RNeasy kit and stored at −80° C.

Fluorescent labeled aRNA (amplified RNA) constructs were obtained by in vitro reverse transcription of the RNA followed by an in vitro amplification reaction.

2 μg of isolated total RNA were used per sample to amplify RNA by applying only one cycle of in vitro transcription (IVT, Millenium Biologix AG, Application Note).

2 μg of total RNA from each sample was primed with oligo(dT)_24-mer(containing a T7 RNA Polymerase Promotor) and reverse transcribed using 400 Units SuperScript II reverse transcriptase enzyme, nucleotides, 5× Reaction Buffer and Dithiothreithol (DTT) as described in protocol provided with the enzyme. For ribonuclease protection 1 μL RNase inhibitor (10 Units) was used to prevent RNA degradation during first strand synthesis. This first strand synthesis reaction was incubated for 1 hour at 42° C.

To the first strand synthesis reaction 93 μl nuclease free water, 30 μl second strand buffer (Invitrogen, Basel, Switzerland) and 1.5 μl nuclotide mix (dATP, dTTP, dGTP, dCTP, 25 mM each) was added.

Second strand synthesis reaction mix was obtained by adding 40 Units E. coli polymerase I (New England Biolabs, BioConcept, Allschwil, Switzerland), 10 Units E. coli DNA Ligase (New England Biolabs, BioConcept, Allschwil, Switzerland) and 2.5 Units Ribonuclease H (Fermentas, Labforce AG, Nunningen, Switzerland). Reaction was incubated for 2 hours at 16° C.

After this incubation step remaining RNA was degraded by adding 7.5 μl 1M sodium hydroxid containing 2 mM EDTA (Ethylenediaminetetraacetic acid) for 10 minutes at 65° C. 7.5 μl 1M Hydrochloric acid was added to neutralize the reaction.

The obtained double strand DNA was purified in a QIAquick® PCR purification kit (Qiagen, Hilden, Germany) and concentrated to 7.5 μl. To this concentrated RNA following reagents were added to obtain aRNA synthesis mix: 2 μl ATP (Adenosine triphosphate, 75 mM), 2 μl GTP (Cytidin triphosphate, 75 mM), 2 μl GTP (Guanosin triphosphate, 75 mM), 2 μl UTP (Uridin triphosphate, 75 mM), 1.5 μl 5-(3-aminoallyl)-Uridin triphosphate and 2 μ, reaction buffer and 2 μl Enzyme mix (both provided with Ambion MegaScript Kit, Ambion, Cambridgeshire, United Kingdom).

This aRNA synthesis mix was incubated for 4 hours at 37° C. Remaining double strand DNA was digested by adding 1 μl Dnase I for 15 min at 37° C. aRNA was cleaned and concentrated with an RNeasy® Mini Kit column (Qiagen, Hilden Germany) and then concentrated to a final volume of 9 μl.

Fluorescent dye molecules were coupled to the reactive aminoallyl groups of the incorporated a 5-(3-aminoallyl)-Uridin triphosphate molecules. One aliquot of either Cy3™- or Cy5™-mono reactive dye (Amersham Biosciences, Buckinghamshire, United Kingdom) was diluted in 40 μl water free Dimethyl sulfonoxide. 10 μl, of one of the diluted Cy™ mono reactive dyes was added to each sample buffered in 100 mM Carbonate buffer (pH 9.00). Reaction was quenched after 1 hour by adding 10.4 μl Ethanol amine for 15 min at room temperature.

Unincorporated dye molecules were removed by ethanol precipitation. 2 μl Glycogen (Invitrogen, Basel, Switzerland) was added as carrier during precipitation. After precipitation aRNA pellet was washed with 80% ethanol, dried and resuspended in 50 μl 1× Fragmentation buffer (200 mM Tris(hydroxymethyl)aminomethane hydrochloride, 500 mM Potassium acetate, 150 mM Magnesium acetate). aRNA was fragmented for 35 min at 94° C. and placed on ice immediately. Fragmented aRNA was dissolved in 900 μl hybridization buffer.

For denaturation aRNA was incubated for 5 min at 98° C. and centrifuged for 30 sec at full speed in a microcentrifuge.

One CART-CHIP™ 300 (Millenium Biologix AG, Switzerland) was placed face down in a standard hybridization chamber. Hybridization solution containing the denatured and labeled aRNA sample was injected using a standard micropipet whereas Cy3™ and Cy5™ samples were hybridized together in one hybridization chamber (Millenium Biologix AG, Switzerland). The microarrays were incubated overnight at 42° C. in a PCR thermal cycler (TGradient, Whatman Biometra GmbH, Göttingen, Germany).

After incubation unspecific aRNA probe was washed away with 1×SSC, 0.1% SDS for 5 min at room temperature, followed by another wash step in 1×SSC, 0.1% SDS for 5 min and rinsed with 1×SSC without SDS for 1 minute to remove excessive SDS. 1×SSC was discarded. Remaining 1×SSC buffer on the slide surface was removed by centrifuge the slide for 2 min at 1500×g.

The dried CART-CHIP™ 300 were then scanned using an Affymetrix 418 microarray scanner.

Expression level raw data for every spot was obtained with ImageQuaNT (Molecular Dynamics). Raw data was normalized by dividing every expression value by total expression value of all spots for every sample and filtered by setting all values below the 25 percentile to the value of this 25 percentile to remove noise (25 percentile threshold).

For each sample (e.g. de-differentiated and re-differentiated chondorcytes) a list of all measured genes was generated. This so called gene expression profile was then used for subsequent analyses.

Further data analysis was performed using either hierarchical clustering with cluster.exe (written by Michael Eisen, Stanford University) or Self Organizing Maps (SOM), such as GeneCluster developed by Whitehead Institute (Massachusetts Institute of Technology, MIT). The settings of the software were optimized until a reasonable number of clusters resulted that were able to represent the comparison thoroughly. In the following example the parameters were as following:

Basic parameters: SOM rows 6; SOM col: 4; #epochs=3000; #seeds=1

Advanced parameters: initialization: random vectors; neighborhood: bubble; alpha 1=2; alpha f=0.005; sigma 1=3000; sigma f=2.

FIG. 1 shows a typical result from a SOM analysis with the above mentioned basic parameters, whereas FIG. 2 shows an example of a graphical presentation of a cluster analysis and viewed by the software treeview.

Example 2
Quality Control and Human Cartilage Sample Classification

Useful to demonstrate how CART-CHIP™ 300 can be used to differentiate between diverse cell culture conditions, to distinguish different patients, to study the influence of 3D culture conditions and to serve as a quality control tool during any tissue engineering process.

Human chondrocytes isolated from 4 different donors were proliferated over one passage (P1) and then cultivated as high density pellets (0.5*10⁶cells) in 3D culture for 7 and 14 days. RNA samples were taken from proliferated as well as from 3D cultured cells resulting in totally 12 different samples as shown in FIG. 8. RNA isolated from this samples was shreddered in a QIAshredder (QIAGEN, Hilden, Germany), amplified, hybridized, washed and scanned as described in Example 1.

Data sets for all 12 samples were extracted and normalized as described in Example 1 to perform cluster and SOM analysis as noted below. Cluster analysis was performed using normalized data computed with GeneCluster.

FIG. 3 shows a picture of such a cluster analysis for all 12 samples (#1-#12) consisting of 20 clusters (c0-c19)

Every cluster represents a typical gene expression pattern for all 12 samples indicated by a point, starting from sample #1 on the left hand side to sample #12 on the right hand side in every cluster. For example cluster c0 represents the expression level of 104 genes in all 12 samples in a given range indicated by the lines located above and below the computed points.

Another example for gene expression levels that behave similar for different culture conditions and donors are depicted in clusters c3, c4, c9 and c10. Meaning that every subset of the three donor specific points #143, #4-#6, #7-#9, #10-#12 (see Tab V for detailed description) have gene clusters that behave similar in all analyzed samples.

An example of differently behaving genes is indicated in cluster c13, representing 10 genes that behave similar in donor #1 and #2 but show a different gene expression patterns for donors #3 and #4.

More detailed analyses are shown in FIG. 4, FIG. 5, and FIG. 6. The clusters produced in these figures clearly demonstrate differences as well as similarities in cell behavior for either t0, t7 or t14 days, respectively.

Another software algorithm that can be applied for analysis of large amounts of data coming from gene microarrays is called hierarchical cluster analysis, whereas genes and/or different conditions with similar behavior in gene expression are clustered together. All hierarchical cluster analyses were performed using Cluster software described in Eisen et al. (1998) PNAS 95:14863) and displayed using treeview.exe developed by same author.

FIG. 7 shows such a cluster of selected genes for all 12 samples analyzed. Every square is representing one single gene expression value. Different intensity means different expression levels. Dark squares are representing samples without any significant change in gene expression compare to the other samples or patients. Bright squares are indicating samples in which genes are up- or down-regulated relative to other samples analyzed. A so called cluster of genes is a group of genes that behave similar from one donor to the other donors.

Not only genes but also samples can be clustered together. These clusters are called similarity dendrograms, shown in the top part of FIG. 7. These tree-like structures illustrates similarities in gene expression between different samples or donors. The closer a sample (#1 . . . #12) is located to another sample in this dendrogram the more similar gene pattern they have.

Interestingly to see is that the seven samples located at the right side of the dendrogram (samples #1, #2, #5, #7, #8, #10 and #11) are clustered together. This samples are representing t0 and t7 conditions as described above (illustrated in Tab V), whereas a cluster of 4 samples in the middle of the dendrogram (samples #3, #6, #9 and #12) are representing only t14 samples. This means a microarray of the current invention is able to distinguish between de-differentiated, proliferated samples (t0 and t7) and re-differentiated samples in a later stage (t14).

An outlier represents sample #4 located at the most left side of FIG. 7. which represents proliferated chondrocytes (t0) from donor 2 and could not clustered together with the remaining proliferated samples. Interestingly, this sample that it is not similar to all other proliferated samples (#1, #7 and #10) was impaired with its capacity to form cartilage tissue equivalents following expandation in 2D culture. The biochemical analysis revealed a lower amount of total collagen/DNA for this sample and immunohistochemisty with collagen II antibodies resulted in only weak staining for a collagen II.

Example 3
Aortic Fibroblasts vs. Chondrocytes

Example to differentiate between expanded chondrocytes and aortic fibroblasts cultivated over 14 days in 3D settings.

A human aortic fibroblast cell source was proliferated and brought to 3D culture. RNA was isolated after 14 days of culture. Expression data analysis was performed as described in previous Examples 1 and 2 using CART-CHIP™ 300 microarray.

A hierarchical cluster analysis was performed as described in example 2. Samples representing 3D culture after 14 days (t14) were included in said data analysis (samples #3, # 6, # 9 and #12, see Tab V).

The result of the described analysis can be seen in FIG. 8. The upper part of the figure shows a dendrogram as described in example 2. Aortic fibroblasts are not clustered together with human chondrocytes. The cluster shows a significantly different pattern compared to all other cultures.

Obviously a gene expression pattern of an aortic fibroblast cell source can be clearly separated from a gene expression pattern of human chondrocytes. A micorarray of the present invention is therefore not only able to study differences between different chondrocyte culture conditions but also to distinguish between cells isolated from different tissues.

Example 4
Arthritic Conditions vs. Healthy Conditions

Useful to distinguish between normal healthy chondrocyte behavior from cells resembling an arthritic phenotype. Interleukin-1β is known to play a central role in the inflammation and connective tissue destruction observed in both rheumatoid arthritis (RA) and osteoarthitis (OA). Stimulation of in vitro chondrocyte cultures with Interleukin-1β thus represents a simple experimental arthritis model.

The chondrocyte cell source from donor 4 (see Tab V) was proliferated over 3 passages and then cultivated as high-density pellet cultures (0.5*10⁶cells) for 16 hours and 7 days either in the absence or presence of Interleukin-1β (30 ng/mL). RNA was isolated from all samples, hybridized to CART-CHIP™ 300 and expression profiles were generated as described in Example 1.

A hierarchical cluster analysis was performed as described in Example 1 and the dendrogram and a selection of the representative gene clusters are shown in FIG. 9. This clearly shows that already a short stimulus of Interleukin-1β results in alteration of the chondrocyte phenotype with gene expression changes that can be distinguished from untreated normal chondrocyte cultures.

Appendix

TABLE INumber of markerExperiment and correlated genegenes for eachexperimentexpression analysisexperiment (analysis)(analysis)2D marker adult vs. fetal/infant151A2D/3D adult vs. fetal/infant96B3D marker failure165C3D marker adult/fetal/infant350D2D/3D marker adult48ETime dependent failure marker75F3D failure marker41GApoptosis related failure markers30H

TABLE V

Sample Numbers (#)

Proliferation
7 days in 3D culture
14 days in 3D culture

(t0)
(t7)
(t14)

Donor 1
#1
#2
#3

Donor 2
#4
#5
#6

Donor 3
#7
#8
#9

Donor 4
#10
#11
#12

Table IV shows the results of a bioinformatic analysis of gene expression profiles of the 467 cartilage specific marker genes.

Clus-AccesionterSOM DescriptionH4 P2 3Dfailure poolH5 P1 2DH4 P2 2DH4 P1 2DH5 P1 3DAA28369322D/3D0.6201469520.5630126080.5436515670.4674628550.5029629070.971864748AA84515622D/3D1.8228873841.9740625171.7935084072.0562341562.1345027412.109619189R52548222D/3D42.1530528524.9163283636.0320414838.2023447138.1288655536.73272848T6712842D/3D0.1149078970.1652235430.1751438380.2305152320.1115186320.115949318AA84501582D/3D5.1529858985.1633663864.6006176985.4904006185.6131702465.081143315AA93789582D/3D2.8415722932.0356801552.5745300083.5323764132.9042404442.88987266AA844998152D/3D9.59711418213.6392843814.0597626912.9954202410.5659058111.73420854AA844518162D/3D34.9525123932.5663609235.2961204639.3130525238.1095320732.87879549AA894557162D/3D56.2367342443.6103165236.3070495858.4787588159.7004262348.33981986AA872001202D/3D81.8138921256.4445436738.3070495889.1188802682.1202862154.71499842H0959012D/3D0.5387581030.6060288340.9230903710.6109703030.5824461190.488768664AA888278112D/3D failure vs.0.8724354071.5417434811.3208411851.4183312351.440543091.142574932cartilageAA490855112D/3D failure vs.5.2563550423.9829078463.7404730995.0199008555.0728105764.193769533cartilageH0582022D/3D failure vs.0.3267714540.2985680270.7239720510.3734211520.2912281610.42426813cartilageN5776632D/3D failure vs.1.2445806791.4306458931.2371287621.4357608921.6210841111.793426963cartilageAA87388532D/3D failure vs.2.3899777211.4028652741.9603008492.64212618231.1744161442.132327967cartilageAA87888032D/3D failure vs.1.9755164130.7062715342.2352005162.8529095622.3419575962.325462095cartilageR5481862D/3D failure vs.1.4332226171.4087640411.0264670361.6532459591.5552805681.313068482cartilageAA458830232D/3D failure vs.6.2259116467.1311028696.4496910697.1812237427.4355282818.273231774cartilageW37884112D/3D failure vs.3.425428523.4349489232.8228432163.9204083864.0314400512.924316539cartilageN63192112D/3D failure vs.2.0164166981.8803418171.9551284552.6042841122.5559861741.868963757cartilageR55789112D/3D failure vs.3.0507342072.9163593872.4592702843.0861806972.7686816432.87080332cartilageR56871142D/3D failure vs.8.053043566.7632181129.2026025129.3157428039.6568174256.703182113cartilageAA448659152D/3D failure vs.4.0866964727.4047857333.704329594.6242656354.7809515696.12097414cartilageAA235388112D/3D failure vs.4.7939072095.5906162986.4307497196.1194064965.7872157625.448903875cartilageW37769182D/3D failure (adult)9.6661535739.04179720110.480600699.182358879.7790570419.301866835AA421701182D/3D failure (adult)6.398515436.9449778646.7870007177.8057964658.0441485636.091762141NB1029222D/3D failure (adult)11.256126667.5362012059.79182281610.2690977911.0918988511.24056884AA644128222D/3D failure (adult)8.870087868.6342388818.98068068810.6221094511.076343858.151499526N26536232D/3D failure (adult)1.1275889190.9340502121.2768622771.3390906171.7228628871.543708239AA890663232D/3D failure (adult)7.5024665656.5865164488.7071105837.5825244426.2724588656.92700675AA405987172D/3D failure (adult)8.0078489347.3981319917.1800245659.6444840859.3294354897.017060375AA88818242D/3D failure (adult)1.1597093940.9973935081.7618660871.6095583883.0764631381.864862168H09730232D/3D failure (adult)6.0165985614.380979194.5122187065.754674565.7084093034.568792922AA285155222D/3D failure (adult)3.9111639634.3757316944.1034049963.9767016873.5669162484.846020855AA87335112D/3D failure (adult)0.7157167740.4489616881.1430949381.0863057020.66438810.576661574H1232012D/3D failure (adult)0.5619735562.577230080.5165282650.3649690350.4267699581.536698149AA85655812D/3D failure (adult)2.0838750020.7349066880.980567151.173631080.3406926191.146139751R4358122D/3D failure (adult)2.1065344210.6014958312.9985095551.8853491641.785600621.913887067AA63376822D/3D failure (adult)0.6416603490.3948979570.9891615850.803494180.6769319060.471526265AA49688022D/3D failure (adult)0.8190010280.4462446051.0789739380.969467431.0015677050.612915544AA62563242D/3D failure (adult)1.4931447590.5356553072.3200488352.1455851161.4615140481.208574247R4085032D/3D failure (adult)0.6823080840.5950080171.3258817581.1681130390.5766137680.894548353AA48607292D/3D failure (adult)2.0330913316.0093955491.3972417731.3063359171.6675983864.321686833N8012942D/3D failure (adult)0.3515361610.8603819991.0123669320.3364660050.4429151980.530986466T6727052D/3D failure (adult)1.9635298631.2011083713.3143472023.1080113092.1598114031.603756559AA77630462D/3D failure (adult)0.8624628850.4684375741.0001250841.0509634090.8405472060.712318096AA6474362D/3D failure (adult)1.4191350240.9724170851.724672261.5366125871.4418268881.267977482AA66398372D/3D failure (adult)0.9922372460.5621084962.114074741.5057385731.5049370071.363338621AA63400882D/3D failure (adult)1.6333160950.5464448231.6701981382.6681279711.5795451891.258079751AA68305082D/3D failure (adult)1.6043493050.6093058292.8697333562.494299741.6639289361.276592262AA77587432D/3D failure (adult)1.7876344460.6394105481.35601571.2630039941.2347971312.355664777AA029934192D/3D failure (adult)2.3566369431.5588465862.7874204722.7431300892.3302962952.141155369AA872397213D adult vs. fetal19.5023386217.5136955530.149953623.2663050524.5294553517.84127943AA42819533D adult vs. fetal7.0719206145.2679678636.1385570017.235077277.482710815.35099208AA47872433D adult vs. fetal5.2483647163.4703871544.1720403495.0527053185.1685291496.015264941T4054123D adult vs. fetal3.23888994612.314795532.5218700241.4846265732.4632058826.610009772N3321423D adult vs. fetal2.654734482.9611974811.7271136131.5171968641.8636435985.009412045W6939923D adult vs. fetal2.8363345432.4186478352.3848597731.2715570982.2186620354.984390107H8545423D adult vs. fetal2.5806886681.885829911.3886080051.2448440151.5344830513.983108173T7128423D adult vs. fetal1.9868790182.4752585730.7441830470.7683070250.7650854264.427870608N9541823D adult vs. fetal3.215859131.5837151561.5720900761.1524546831.550451454.188689886AA430675183D adult vs. fetal20.4001118713.511577323.3592491319.0355612422.7050449416.6788312AA682851213D adult vs. fetal25.4423622417.1095221833.7668484128.2212921726.8605202324.00871315AA42743333D adult vs. fetal6.6829307274.7374770885.9857361577.068792287.2172232126.130314027AA100296213D adult vs. fetal16.7351846414.1622253825.1751965321.6389847721.1601350817.85039728AA070997203D adult vs. fetal21.1332906416.508022230.6385511426.143858226.2718268619.46457951R27585203D adult vs. fetal18.9599876513.5139625326.8269742321.4504783921.4483263316.96978325N71628203D adult vs. fetal18.6083899416.3339380626.6812052921.611302821.3387784616.98487296AA484566203D adult vs. fetal16.0699279710.8563399818.7056317917.2702628817.7007398414.07448353AA043228203D adult vs. fetal12.813128249.80384982917.9762082914.1933275614.2855905410.85546077AA478273193D adult vs. fetal52.0692919732.1701728736.3070495847.9343210243.9400551645.65265571H0561823D adult vs. fetal2.6329069884.6423003631.2848805250.9739064381.3268802614.570563698AA40556253D adult vs. fetal6.9934413894.7829747495.2195812646.6118432366.4478119845.853372531AA14704353D adult vs. fetal5.267129764.8562654738.4993818825.5614642695.306074015.35955551AA03538453D adult vs. fetal6.4017285394.126660217.5787714816.9048665647.1289812725.672655498R6015053D adult vs. fetal4.2151974744.384426364.8601947244.9735920315.3016138774.146462455N6405153D adult vs. fetal5.4266816364.9280784325.6088705275.6229620255.3712109984.561721051AA40574853D adult vs. fetal5.3686058643.190021514.3533399264.1064427935.4770503154.525369392AA46111053D adult vs. fetal3.5753283162.6046249154.1307148783.9159388434.1313126863.482794563AA84516753D adult vs. fetal3.785784593.6092114344.6180925364.2447501764.7793804053.825719327AA44311853D adult vs. fetal4.3143815126.098760626.2767594925.3038876245.5684481875.169715811N9231933D adult vs. fetal4.5722133223.0335133743.3545059473.0673021053.2437954996.319683552AA18714853D adult vs. fetal5.5118205275.9848339479.5614584517.5387717757.3309183494.996228711AA25341333D adult vs. fetal5.7539539454.7080579235.134091918.2219090986.2162234394.722726065AA04570143D adult vs. fetal7.2447408697.0042005699.559741718.4375523929.2630827196.552005827AA16456243D adult vs. fetal7.6274255075.2164967888.6999867287.9238816999.5082336076.844029007AA48635743D adult vs. fetal6.415758836.97511326110.402297197.967450728.417425836.451127762AA18074243D adult vs. fetal5.521213676.2345525538.1039308476.9831675696.9462382416.26480073AA45474343D adult vs. fetal7.5114883129.36915801211.346967479.5625519629.4569378247.36978659AA43722643D adult vs. fetal7.1127444978.79165326410.805111438.2662897998.5074701887.034847567AA45884933D adult vs. fetal5.4693285443.663731474.9033066944.8270769475.6602065424.514629804AA60489133D adult vs. fetal5.2581780688.2512131266.903220936.3699126345.6765235217.288981598AA609655183D adult vs. fetal21.3342903219.0808178330.0108900223.998220425.3168124820.18144049AA59915863D adult vs. fetal5.739057774.7655854178.3462451196.4236344416.610804945.063695516AA05293223D adult vs. fetal4.1602944872.1838960022.7628997492.0968614012.1922481175.413063915AA76932823D adult vs. fetal3.496641113.7953461473.5432443963.2021554621.6644356534.680897198AA12953763D adult vs. fetal5.4900991484.0335119646.7532246785.2705050526.1045942814.571138177AA48620923D adult vs. fetal2.9511278382.6224581072.3966285521.8767784972.1540385664.999645899H3901623D adult vs. fetal2.8158249781.8269666891.6719447711.2539708391.6432793534.632563322AA46421723D adult vs. fetal2.2702650162.1316317111.5206590081.0646185181.3294002454.21418601T9505323D adult vs. fetal2.6887076925.333824981.7946832321.5317652421.7158147555.3630072AA45464023D adult vs. fetal2.1028862481.5375703731.3467796991.1278491411.2141747544.183264486AA44840023D adult vs. fetal3.3062421372.2350062021.7476240630.6312261141.5680828348.474436694H13691193D adult vs. fetal54.0005294538.0602739536.3070495853.0147492949.8679462150.27373427AA13208623D adult vs. fetal3.3370977433.2575503592.2931253811.5675144081.6047518285.862999872AA48807323D adult vs. fetal4.3510330234.041949441.4526928623.5113346644.1188862075.708773871N4094523D adult vs. fetal3.4470968422.1545880972.5016832812.520851832.2973851714.762374759R5570523D adult vs. fetal2.9093086131.8513416211.4326889681.2127493841.6381050544.556458468H5011423D adult vs. fetal3.3017365691.9083879221.7058409381.4074144651.7810486684.589212608AA45284123D adult vs. fetal3.9819436111.2313737731.02481980.9639834321.6208341534.505595396W7379023D adult vs. fetal3.9148885371.7139277351.6792587311.6087153722.2530848094.790266687N30302173D adult vs. fetal16.23642614.3382550320.1773345716.7288297218.6038598415.82011639AA29155623D adult vs. fetal2.8583891186.1644310672.3129411111.6249683191.9590016875.460005926AA59851023D adult vs. fetal2.6983236732.6533830751.7091970681.4487456871.8522747655.166038663AA45378723D adult vs. fetal2.7025894251.6205969671.7173365061.4990793291.5226160024.378038549H0565523D adult vs. fetal3.1075153982.5218928451.3118055731.3141996791.6337792526.087070828AA419177183D adult vs. fetal23.8974296215.4548558925.8821758524.4779011428.2082541220.47309058AA458807183D adult vs. fetal22.0291622116.6544335725.4587448522.4348537525.6718292718.88009347AA293218183D adult vs. fetal19.7966862415.4044301527.2312895322.1320952321.0750456718.14351405W44860173D adult vs. fetal12.734095110.68967718.0730704313.8942718715.9291708712.73205002AA629862173D adult vs. fetal14.5967919311.5337689517.2122922315.5998960816.6454175814.01615062AA44767423D adult vs. fetal2.5342641272.1501543931.4277892521.0003282711.4234422294.137781882T5248423D adult vs. fetal3.2363984073.0265111811.8389209991.6170021061.7597104234.94920807AA49681023D adult vs. fetal2.8034224631.5959897351.7289213731.4550200121.727321324.877833042AA48623323D adult vs. fetal1.1052945283.6126295662.0165141631.4070573531.1460127654.325105426AA07977523D adult vs. fetal3.604129572.705671373.0090552652.1261825682.5173226185.903186938W7388923D adult vs. fetal3.1747041744.2283123053.5835009443.6327041493.2331527346.073296967R5033723D adult vs. fetal2.2523891811.3011177711.6960680831.2468813051.591507463.84378734R5504623D adult vs. fetal4.8040680013.9144207594.4793345885.3104312475.1552235664.292901695R4682123D adult vs. fetal4.4817815033.605171073.1943158633.7367303284.0598315283.62674894R8776323D adult vs. fetal4.3493712891.7389580852.0165763531.5642462552.1671571054.929744779H8958323D adult vs. fetal3.4720101083.1681230653.0707588331.8763350352.5297082875.529732134R5604023D adult vs. fetal2.87503403912.021989373.6360429263.1342955662.8625008765.657443535AA92270523D adult vs. fetal2.4679009125.7538486962.3642249431.8262355641.9909350845.56199203AA48757123D adult vs. fetal2.3920957412.0300468741.89821671.1673801721.4452412793.891969777AA40244023D adult vs. fetal3.040184434.5375744392.8166672782.3134361272.5678719276.461198799H2952123D adult vs. fetal3.4580795612.0890884681.7228772581.4564455291.9296681925.361928045AA490911153D adult vs. fetal42.6703039226.5285998536.2825042240.3946660241.6081196934.97057694AA486082133D adult vs. fetal10.417276098.93788432715.0504014210.8205637211.952820188.842288293AA678065173D adult vs. fetal14.1209313811.5407006220.8616820818.07570817.8384938413.73636722R43509163D adult vs. fetal11.025635989.50959594916.7413373314.1391827813.4852049410.63815358N57653163D adult vs. fetal10.412320610.4434677914.6780588411.7418167611.7450065411.69858601AA670955163D adult vs. fetal9.1216101768.54764067216.3794585812.2534516212.216401639.258251347R1469223D adult vs. fetal0.7571985590.5880638990.7528116990.8526555021.4471797280.869563322AA488979153D adult vs. fetal33.6664051523.4078535936.2268495635.8378007136.119953929.2581877AA44363023D adult vs. fetal3.1793669121.1417473641.7668104521.1189067271.6318391034.49413229AA027840143D adult vs. fetal30.7758403823.5875253832.6281540733.0594410333.6020565525.63272733AA458830143D adult vs. fetal25.5837920826.3984868328.1572278825.8740841627.4098783824.06147297AA459015133D adult vs. fetal10.031768848.70900637116.0356301513.1017471514.030431149.884872553AA074446133D adult vs. fetal11.858079439.62004641513.8272611312.8756943414.0425634511.73842466AA027042133D adult vs. fetal12.734910059.45989614416.5198387813.4999494714.9322452412.43468402AA629923133D adult vs. fetal11.094276396.09683584711.6373540210.2000494710.489612549.430135362AA460830153D adult vs. fetal43.4676302625.8958554936.2332173837.9574235639.8790588737.77709716AA45421803D adult vs. fetal4.4702936843.0932394244.9375297564.6881226665.0724194863.72227458AA04652363D adult vs. fetal6.1558052634.3888373556.9345322295.9492547536.8833219675.158132106R5134603D adult vs. fetal3.2305112453.0624181613.7875200433.7832850323.8260035632.512202334AA02996403D adult vs. fetal3.8558471354.0141231915.7588885724.6133620374.0072808553.687657081AA48921903D adult vs. fetal3.2749981572.3617176843.9180529743.2430681033.4690993893.176498463AA04313303D adult vs. fetal3.0398427453.4711213895.2035293534.2213520794.2590921853.419382811AA812973173D adult vs. fetal15.7724819710.7454912818.8539467918.8666315716.7733314112.70379222AA45347103D adult vs. fetal3.9571682943.0389267992.879378114.1886925114.4538348953.457945931AA284693173D adult vs. fetal14.41273649.49783989813.9671751812.7558513613.6355452714.18625183N9028103D adult vs. fetal2.8891088983.0650730213.8250434243.7727224463.8978979172.916608408AA62954203D adult vs. fetal3.3391245053.202781434.0202900224.3678481384.2033430713.045430554AA67934503D adult vs. fetal4.0419145653.401891775.3345805354.7673471845.0520521683.629044952H3777423D adult vs. fetal2.5821360515.7514095440.8261304310.7491986530.9503960524.924705249T9718123D adult vs. fetal2.8481449461.7623042591.7809318171.6629772371.9304894834.429079742AA45487923D adult vs. fetal2.5888148181.8958229680.7886229970.6839395220.8684268644.58445785AA14764003D adult vs. fetal3.1111741823.6891393093.7815242964.0968607993.9590117742.732271995AA76742993D adult vs. fetal7.0540935915.3635801527.9881055676.8396045087.3706922627.981701609AA49099193D adult vs. fetal10.987573177.79072953812.357102479.88568191611.004355778.898305631AA422058173D adult vs. fetal14.7140852514.8468556524.4917606219.9463204819.2929138514.68049409N6620893D adult vs. fetal8.1237977416.17796255610.331881197.8947259178.5808982976.881934203AA63077693D adult vs. fetal9.1381192735.8323329811.419539399.0032090989.5900939698.070647196AA82728793D adult vs. fetal8.4826493487.4822703078.8917469699.199842689.9767257928.422494842AA48808493D adult vs. fetal7.64913415214.9795571613.4176671310.420938819.0717033888.874743158R89715133D adult vs. fetal9.75009975117.870550218.0361641613.8209133412.9973534314.90421282AA49050193D adult vs. fetal7.9444154447.8597581911.060331989.2840974898.9924684347.63431741N3219993D adult vs. fetal9.678286567.8933297239.9163110999.83723627911.239875639.150031823AA43440493D adult vs. fetal6.867304598.4266744729.5772633228.0372366748.0968675756.953180054N9368883D adult vs. fetal5.03827407610.941876249.0368238397.3584562377.1552506576.336977302AA29267673D adult vs. fetal11.094204239.8678443969.54886042211.5285540912.532749719.824831453AA46441773D adult vs. fetal10.409786629.639874911.9576262912.7765155112.876747910.07601153AA44209273D adult vs. fetal9.9659871227.3702891488.8837016139.4416917999.6676880438.214697052AA44209273D adult vs. fetal9.9659871227.3702891488.8837016139.4416917999.6676880438.214697052AA02664473D adult vs. fetal7.7696023836.6382145925.1371190183.5720830724.08691540115.10517784AA48146493D adult vs. fetal7.3566160499.39472763111.968715239.6244887899.6978190227.196159079T68859123D adult vs. fetal7.1022392876.06301127310.143429778.3161214378.907191987.165656319AA699560133D adult vs. fetal9.9784214719.3729577814.7586328616.4268922714.2647165112.73562928AA705069133D adult vs. fetal8.51274942710.5159537813.199830179.99900030110.133971759.694546633AA457739133D adult vs. fetal13.7629668810.2763570815.406212312.7665295714.099349810.82804945H99843133D adult vs. fetal11.425453669.86048960411.0835809110.096311629.90220466710.73353077AA399410133D adult vs. fetal11.492689139.86830484816.5098841414.4967271213.2365899510.91245055AA44303993D adult vs. fetal8.6616156815.47355357210.75920738.2683475799.7710736917.541136242AA164440113D adult vs. fetal17.8298923311.8787762820.3539582118.4826771119.4681564414.70024382AA446453113D adult vs. fetal16.5539613813.8111699416.5029465119.5404856321.2277512416.02767268AA280692113D adult vs. fetal17.4075022516.1866970419.0493581719.7134708520.167305716.35083848AA031514113D adult vs. fetal20.5863575717.5016200921.0384417922.3994119321.4147095518.33395551R33154113D adult vs. fetal15.8092905313.2369693913.3719107614.5281382614.9531260716.05415087AA487452113D adult vs. fetal13.7132719319.4186653412.6183166312.07734912.7449843718.11228999AA40032993D adult vs. fetal9.4714103258.1390992249.94549624610.1383760911.0744297.250594994AA454668133D adult vs. fetal9.0473500147.525411512.6065292510.8193226110.343138918.424799177AA486393233D adult vs. failure0.6820300676.7244405650.8006208680.5622992760.6033813681.639697615R62541233D adult vs. failure0.4020991162.0472329430.4765348180.4197460760.3647906010.848514165AA171613233D adult vs. failure0.8339163046.4280130191.0494895330.8316181441.0615439982.831110499AA23570603D adult vs. failure103.286214545.1845903336.3070495866.2209646176.1933609853.68696068AA668527233D adult vs. failure1.3601339456.8050321541.0712150780.975296831.063106683.121521767T64144233D adult vs. failure0.4769157257.4177821020.7462626220.4559357760.5889076161.573719963R14080233D adult vs. failure0.4428126417.9061103840.6279508070.4986149460.3724661791.218619609AA609599233D adult vs. failure0.3593524617.1433691520.5693051770.3662818570.3414884031.345297086AA489201233D adult vs. failure0.7462476737.7612670380.5692305120.5680393980.514457571.823393758R08876233D adult vs. failure0.8813001086.2044384871.3465941921.1273749451.3035117481.365140688H46425233D adult vs. failure0.4461191297.5495502630.424236280.3841257050.3042565791.948954368R56149203D adult vs. failure3.9467394852.2218895352.6873967482.293497912.9944361376.00466275AA454619203D adult vs. failure4.6700539672.368993683.2856026992.8115680953.5305448236.168078813H15445203D adult vs. failure3.6381470662.7064470871.4588852771.4572651292.0212837146.315381377AA705225233D adult vs. failure1.3868367866.4295768971.837113771.344835131.1505001042.597429853AA19148823D adult vs. failure2.17422405245.101443442.0690088381.6318705161.7765358216.32613468N64862143D adult vs. failure0.65059609512.108380171.0653065040.6656829470.6145172483.167265877R4541373D adult vs. failure0.71657841326.619523551.0650460510.9177799850.7738917666.012284228R7729373D adult vs. failure4.17327001418.877878696.0980814596.1584633315.1924893996.808820493AA43618763D adult vs. failure7.7308455834.644386099.7403013867.5825200528.23360474918.4559413AA67647053D adult vs. failure23.0946175912.7974988219.6726119218.8319537425.3128319219.5015243AA443634233D adult vs. failure0.4836747246.5077666680.8345468010.6022371790.5630616291.705323839AA66418043D adult vs. failure77.2884280543.6641894336.3070495868.2665995973.0139747154.50243711W58658203D adult vs. failure3.7389570431.1576474861.6252986070.5670456341.3622637585.290498458H5402323D adult vs. failure2.51842566676.647641281.4557672771.895583912.24404381523.68020326H73724113D adult vs. failure0.79456527215.904876261.1247425320.6602428570.6888145954.296719254T7003123D adult vs. failure2.00615554848.924723692.7897401032.014774141.74667180315.29766287AA48175803D adult vs. failure123.621164461.2069391136.3070495892.35920856102.049803754.85301063AA52143103D adult vs. failure125.241390456.7799976636.3070495893.6827224100.836215654.85301063AA446103233D adult vs. failure0.3386243037.6527040120.5710459630.3499893940.4068838511.434663101N9264653D adult vs. failure30.4286591114.8970988829.9017217226.5933908828.5667260526.04183434AA453789183D adult vs. failure2.0441504528.4959580172.3280261542.5721675282.2121597293.457082607AA425299183D adult vs. failure7.8877700783.91896305810.383879947.6600892728.7943045317.329938113AA868929183D adult vs. failure1.980911219.9373685382.0130894651.4710739141.4208287245.418655459R60019183D adult vs. failure2.1160442898.5254642961.0470370180.9280425391.0827275055.235772895AA857343183D adult vs. failure1.6500374186.2978087372.4268714591.7046231261.7419668133.845429741AA481438183D adult vs. failure2.5739334988.3913109092.4456251761.8932173171.763412186.043734557AA399674183D adult vs. failure2.1307834178.1646854363.3889708592.3540399542.2799935424.872785488T98887183D adult vs. failure1.1007401488.7564205090.9361008221.1003179220.8035840443.484794007AA678404183D adult vs. failure1.6015987277.0151974661.9325476651.8209359771.808523633.313612045H15747203D adult vs. failure3.7033687871.8412365611.319837110.4682663551.5791898076.384201738H16958163D adult vs. failure4.9116525742.5057770166.1532386073.2582789889.4218777512.976025283AA936783143D adult vs. failure1.34203102813.570921721.9529741921.3349545681.222401261.341547085AA884709183D adult vs. failure2.2624020267.4675275383.1583798072.6523550752.6630072644.51372877H24688183D adult vs. failure1.3954802637.0593718752.2326698641.9219325651.9637420234.014560107AA884403183D adult vs. failure2.0325268088.5082160032.4088693382.2672180442.2819830034.451591143AA404619193D adult vs. failure0.72199655511.040392280.8490349270.4750836650.6454712182.92914746AA598611193D adult vs. failure0.4733817419.6582268180.4856427180.3827762930.3274975623.321739H72875193D adult vs. failure1.0475286079.9655930161.75147176480.961457310.7181460533.174877726H63361193D adult vs. failure0.4447057018.6085862980.4606179180.3477647670.3275264892.835780951R39221193D adult vs. failure0.0634576238.803694050.9164046880.5884415670.5838329612.21717036R02348193D adult vs. failure0.3809571158.7232845390.6898437440.4306804090.3149078461.628641297R51835193D adult vs. failure0.3198210383.2050919880.4991331480.3418007180.3987729730.702868877R33031193D adult vs. failure0.3091991039.8719013530.8707190130.4989823020.4468159011.737947999AA412053183D adult vs. failure2.1734621598.6587493771.5605259392.3353018651.600011133.312435004AA001897113D adult vs. failure0.70739961918.561991851.2768330430.8393940930.6984452893.44857855W81191183D adult vs. failure2.0351308279.5644976211.4700284381.2784600581.4666815455.442558928AA430552163D adult vs. failure6.7047433633.9127448797.3084276256.1824878356.7156393245.892347254AA594130203D adult vs. failure4.1976845461.9509485443.3997477892.7927992713.3081486086.573561928N92864203D adult vs. failure3.9648890921.120305551.2550474341.0288752071.5976883926.129597747AA457123203D adult vs. failure3.8254350821.3724546841.7375817191.8054118882.2425797765.776097858R43320193D adult vs. failure0.53452418510.133923580.3075403410.3347624090.2971540333.300796986AA670430203D adult vs. failure6.0339655432.4110897816.4904137765.2275075656.004887884.958892131H85068113D adult vs. failure0.93224082519.083053721.0628518621.3235240850.8432083223.42676519AA458785113D adult vs. failure1.02454448114.762207111.6735154651.0163031391.1179239583.660946499AA485871113D adult vs. failure1.24042548516.321240361.8196649781.0514756581.2438323784.885742561T39411143D adult vs. failure0.68341690614.12804820.8277627840.6658951650.7763097263.661139864R00855203D adult vs. failure4.1168687082.5450896832.7682016592.6587618852.7880151216.090967819H98666163D adult vs. failure7.4962610533.4230393883.9173991833.2080477954.0213380117.436138134H72028143D adult vs. failure1.12238724810.877255291.1072692890.8946511850.6930975515.481280912AA679177143D adult vs. failure0.81360198611.39800190.8847298180.7387568430.6244866573.353148409N21578143D adult vs. failure0.49386796112.220187110.6300689880.3322392140.4528744053.48979683AA007419143D adult vs. failure0.64054828210.872907960.5737073730.4265985120.3909732665.000691355T49657143D adult vs. failure1.47843858812.24546221.661727021.0858534581.1581501764.728340076N38959143D adult vs. failure0.9666851812.215217541.2222409190.3902419651.0365873173.877992922R51912143D adult vs. failure0.93168569113.326668320.5540654560.5844709010.5453792334.794685202H90415143D adult vs. failure1.02793373814.409388681.5435608471.0150151980.9134668973.697172386H4148912D/3D adult vs. fetal4.0273897862.0974222391.7263497931.4133624142.2236169837.753646206H1645612D/3D adult vs. fetal4.0153862577.0104560832.9746472282.5124933813.1069409988.704678862W4541512D/3D adult vs. fetal5.6123638271.0652168812.6917032682.0270564212.5689737826.615995267AA44775112D/3D adult vs. fetal3.7073034654.7802410732.2235906872.4379727782.6314581567.623606101AA48748612D/3D adult vs. fetal4.213365964.0457658013.0152832942.2862020192.7689486058.048478397R5660412D/3D adult vs. fetal4.1651863073.8467799082.9738153712.3699299363.15098127.458099126T6577212D/3D adult vs. fetal4.4878639132.5382866052.6430157632.4621407123.00626864480.741762884H1508512D/3D adult vs. fetal4.5320706882.5526062551.8747285761.7979286532.2493235387.10815384R6129512D/3D adult vs. fetal5.75226253.645420132.9451208332.5643637722.8261039447.68061273T6125612D/3D adult vs. fetal5.2603641.6419685891.8195661121.6258567062.4320495656.879367501AA40573102D/3D adult vs. fetal2.09045402234.420336661.6645159981.3042883821.29310533810.6339838T7187912D/3D adult vs. fetal4.1937328894.2102426651.9856668971.9466581192.1956625088.143137484R5992712D/3D adult vs. fetal4.8262080774.3833519711.6023441461.525574342.1922906277.925477266AA49678002D/3D adult vs. fetal1.51470484626.444598431.1351590780.9126926151.00108479310.48006188AA17688802D/3D adult vs. fetal0.88361337516.907089110.9690726450.7593704660.7818785166.758214974AA43616302D/3D adult vs. fetal1.14528648319.390079970.910328680.799087371.0628124927.470804263AA42877802D/3D adult vs. fetal2.70593623723.816042441.6500597641.2918758431.52645549110.05785097AA46322502D/3D adult vs. fetal1.80546783622.976891021.5452261551.4160831911.2895957259.717200851AA48542602D/3D adult vs. fetal1.38932569525.671399541.270392931.0697424780.9984576859.858144828W4748502D/3D adult vs. fetal1.74534195627.399460251.2876684411.3050113861.41649271911.04790889H8498202D/3D adult vs. fetal1.53303272328.301311991.0475898171.5496339711.236864819.828318446AA50461512D/3D adult vs. fetal4.0502571883.6253563012.1997038891.9413848762.751182897.641495993H9448702D/3D adult vs. fetal1.64575044322.479038433.5948200421.0288459361.6816861498.286429124AA44895902D/3D adult vs. fetal3.1249901254.5923558123.8993747353.1737343923.4512639586.793092921AA07035822D/3D adult vs. fetal8.0126674751.5641023791.8835382831.5849967532.6423933899.48000834AA45340112D/3D adult vs. fetal5.6929345921.5285936291.9056523831.9043506962.2064532076.672888766N66737142D/3D adult vs. fetal24.900739080.3933340781.0954207790.5562986380.9237593813.442649218AA66618092D/3D adult vs. fetal2.11574080512.057257532.145704431.4880454731.8707920545.34373246AA85713192D/3D adult vs. fetal0.1520326730.2074607040.2689974710.2106853190.1323671620.357440795AA47910292D/3D adult vs. fetal2.29519738225.016325313.6812146053.4259280263.028510338.49611205AA45607772D/3D adult vs. fetal7.7311702924.5092918854.7616311353.9226052054.87560399511.60167555R8749772D/3D adult vs. fetal7.5538572034.5182976673.0062179171.0677944684.39366135712.60889243AA71891072D/3D adult vs. fetal7.124143183.5484317373.9285524413.5578147264.38310191110.82120865AA40626972D/3D adult vs. fetal5.8877775876.4937000593.3765706132.3590087753.44790057911.90806873N7462342D/3D adult vs. fetal0.7386924110.8856322060.5075691850.4239274960.4058942221.326758097H9936462D/3D adult vs. fetal4.6544468323.9679452223.1731553422.530202582.8260206259.199591084AA44768462D/3D adult vs. fetal3.97640874514.438160724.7637381512.4718822352.7321350778.763139341AA28230162D/3D adult vs. fetal5.7417530462.6389265343.5259555973.1165351423.4425630428.08592064H9958852D/3D adult vs. fetal1.45545970629.421123570.938180730.7056632940.914080749.587415089N5351252D/3D adult vs. fetal1.88589083327.437557491.4378310641.4881932941.48951443411.66412529AA68332152D/3D adult vs. fetal1.13323626527.223451341.3949683860.9683653610.719729128.309498154AA60855752D/3D adult vs. fetal2.57727394329.046464782.8073871592.0292020141.9326897928.478935818AA75776422D/3D adult vs. fetal5.6909141963.3578957653.8811018882.7520798212.9555362289.043391314AA40606422D/3D adult vs. fetal6.9571082193.8550680493.9282749783.8303066155.1435775699.248530935N54598202D/3D adult vs. fetal6.41186447540.4586411412.324761058.7400606418.36142845811.67500348AA48198872D/3D adult vs. fetal6.0297167697.6192818163.8013458733.5970223083.98812421712.08244483N6239432D Marker adult vs. fetal2.4368139793.6878658051.4119116864.0457704910.8441503412.656973499N2014832D Marker adult vs. fetal3.449953412.7599425123.7518065483.900904853.1423789074.04494813AA49667832D Marker adult vs. fetal7.0011008434.035685635.2974095833.7223839235.16064782310.19230959AA40097332D Marker adult vs. fetal2.893468034.470767384.4702102093.1934784913.2570432684.020015252AA49702732D Marker adult vs. fetal1.8022504830.5781621023.9220926622.4070651021.2867628682.157496735N6450832D Marker adult vs. fetal2.1157959843.2768561681.902350475.3142584832.7883313953.540796101AA03356432D Marker adult vs. fetal5.3167886512.7200449473.1338832022.6838715963.5322843268.161295359AA44610832D Marker adult vs. fetal2.0783019352.2110419443.7927599433.3246840953.3754025852.756568814AA15957732D Marker adult vs. fetal4.7460904644.9890706894.2878130073.5937687923.8164252447.786959581R3695832D Marker adult vs. fetal4.7495391443.4005887875.6247938065.2344221925.2863953514.078616944AA82950832D Marker adult vs. fetal1.9201635070.79099063.9232583243.4574913811.131748481.710017559AA48206732D Marker adult vs. fetal6.1946252214.2388819663.2546113873.3153406623.8794010328.171254871AA66931432D Marker adult vs. fetal6.8095386694.1330509125.3297403513.7800768864.4248218898.385883026AA77524132D Marker adult vs. fetal6.0142475824.2226790245.9094339034.6519358934.5297693857.71821785R7358432D Marker adult vs. fetal2.7882206825.7447558014.1741728783.1100310362.8405232853.830886431H2898452D Marker adult vs. fetal2.8926976483.8313277944.3378370944.2897022713.6431144673.029043454R4420232D Marker adult vs. fetal3.8434106642.6363587873.7867349613.4155903843.4734438963.189323952W7005142D Marker adult vs. fetal0.4607436550.4356376110.5991116910.6346479410.6845088610.518398472AA40197252D Marker adult vs. fetal4.6943093295.2372668984.8032643686.39578276.1878098575.273916388AA23616452D Marker adult vs. fetal4.4891903295.9991328566.5332185175.7919853555.2059939275.089326434R2241252D Marker adult vs. fetal3.3223607378.9245892875.2576122644.25286884.4330390784.372991798AA42480452D Marker adult vs. fetal6.723164624.9455973598.8447060587.1003834427.6907369985.712216735AA66944352D Marker adult vs. fetal3.4731412735.6420749495.8041367924.7805134814.8191900273.624913174N6968922D Marker adult vs. fetal1.472684261.5006097471.5777722151.631585121.6735786711.20775425H2431642D Marker adult vs. fetal4.0977598374.5718096866.6705949985.5195593275.3023467464.332423617AA07422432D Marker adult vs. fetal2.91604043742.179085733.9960843213.4212636282.97761414115.7136877R3657142D Marker adult vs. fetal1.220882450.6979792451.2461739411.1060082831.4343400531.173334441AA05846542D Marker adult vs. fetal5.11368367910.127792515.9776206385.1830538065.6569094785.941479667AA63381142D Marker adult vs. fetal5.0475857473.5413299875.8597000354.9175621736.0330893174.6898963101AA45715542D Marker adult vs. fetal4.599191552.6344630515.2077960083.4446002543.8886579774.888009989AA45910442D Marker adult vs. fetal4.7908490262.497177764.8759335594.0526375624.5322774663.791654155R4021242D Marker adult vs. fetal5.6956065236.5366050835.500149254.8783092215.7548232598.404118354AA08647642D Marker adult vs. fetal3.8261883642.3382346194.058451783.5736490923.9428665343.486560771AA68331052D Marker adult vs. fetal4.9888759250.4275359746.8844502047.0595425166.2129110715.167664215AA45564012D Marker adult vs. fetal2.296948252.2465092122.4909409022.654443592.5288897512.024350751AA49687812D Marker adult vs. fetal2.3292066722.4648092112.7089234992.5915261712.8207579062.528269298AA08574912D Marker adult vs. fetal1.1343525761.1452194230.9196949081.2138924331.1919523061.148805945AA42575512D Marker adult vs. fetal1.2560262531.426298561.4561010821.5383761891.5211672660.95599115N5235012D Marker adult vs. fetal2.1595422252.6513545972.4274194752.2560407582.4841513342.217863077AA63010412D Marker adult vs. fetal1.8985906871.8504290132.3231189972.2653402832.5438861711.567701571AA45485412D Marker adult vs. fetal1.855054551.8742190482.2890798472.0768822041.7755274871.600396337W7340622D Marker adult vs. fetal1.1458618171.6886941221.3947201581.51500591.3482661151.257230067R1280212D Marker adult vs. fetal0.7540363840.4587561912.0512384681.1238799390.7416727036.651716983AA46535522D Marker adult vs. fetal2.4273189671.2344973821.3829752982.8207066271.7580253332.561266549AA82938312D Marker adult vs. fetal0.6278741180.3616002070.6374472620.6082217180.5139083430.712979229AA62918912D Marker adult vs. fetal3.3844603233.9071655253.9333431914.238369013.4687460443.982435808AA43051202D Marker adult vs. fetal2.2394794452.6377567363.818761713.369431293.4045405352.413395122AA45643902D Marker adult vs. fetal3.8382217272.7794391394.3969472894.3258714814.4457036123.414286314H2786402D Marker adult vs. fetal4.0830673992.5882601933.2471677313.6829894944.0528354613.076145132AA64465702D Marker adult vs. fetal2.7495657531.9495299533.2827185752.772404422.8353863952.393138312R4046002D Marker adult vs. fetal2.6177412852.770449952.3457688872.5303489372.6391320342.129569504W9605812D Marker adult vs. fetal0.5517930530.7199357680.8231729550.7169488840.6470542850.511406835T7220222D Marker adult vs. fetal1.3721332290.6547777581.3544965651.3358283191.2991485371.132910683AA59879432D Marker adult vs. fetal0.8573142710.387601244.809290414.4490909193.26754150.950844105AA59917832D Marker adult vs. fetal1.9875008421.0762386973.6165328313.4704981292.4059451181.70047288R8824732D Marker adult vs. fetal9.2955594764.1456590513.8070365173.2476959124.81155695918.08933692T9881232D Marker adult vs. fetal3.2060075780.455826997.360085663.7623881774.6293937622.262352025AA45485832D Marker adult vs. fetal7.6875301643.1303742763.7702301813.3572680943.9084029511.3903899N6704822D Marker adult vs. fetal0.1829010120.367693940.2979747860.308071280.275640650.333601513AA77687522D Marker adult vs. fetal1.0887833090.8506502791.0340765311.1675616550.9983641630.903409454H5111722D Marker adult vs. fetal0.5379325420.6873681020.5740220430.7302995710.6835260330.743361636N3617452D Marker adult vs. fetal6.0890611654.4814158575.5401915895.6233205996.5884294574.496005766AA77718722D Marker adult vs. fetal1.5231557041.0779768012.0605249631.9463273522.2994715541.87592009R0958182D Marker adult vs. fetal5.8905195533.7840339555.7862617074.7335796924.5244896625.169772778R1684922D Marker adult vs. fetal1.239793051.317395381.9899665060.6637510341.5945001531.415959831AA88416722D Marker adult vs. fetal1.2174201370.768776890.8481430071.0702649721.1026697251.097445419AA13698322D Marker adult vs. fetal1.9882988132.6386817892.5406758322.6509690742.5176269881.836297875AA48862222D Marker adult vs. fetal1.8343687142.6646994162.9162003922.7161784442.2806362911.670136989AA69942722D Marker adult vs. fetal1.743939142.6426516342.7057348032.7908512592.3616294531.978094745AA49045932D Marker adult vs. fetal6.368330465.6719794563.6803742444.9367686054.8847317099.255585154AA62678722D Marker adult vs. fetal1.6882594042.1642127052.1159462851.7951976312.3528503192.121107168N62179152D Marker adult vs. fetal35.5082634619.1116059133.526972327.5793893135.3246830829.21398971N27190162D Marker adult vs. fetal9.7509932257.53089157612.7591895711.0591622512.035352198.653835849AA441895162D Marker adult vs. fetal7.1772825645.2357196137.3854394827.0140869538.1265156436.246092446AA463924162D Marker adult vs. fetal10.419706087.96461685812.5507262811.4266537112.312902399.520621452N78843162D Marker adult vs. fetal7.664641545.435696937.613477187.6083679588.8836007155.827918931AA629719162D Marker adult vs. fetal14.071138818.0715828215.0702968813.1884212413.8947992212.78716552AA404755162D Marker adult vs. fetal10.907926719.0158774712.2739380610.0367106511.2043816112.29601389AA45935172D Marker adult vs. fetal3.307388165.3136938767.1226688513.5298839533.6710313654.776266565AA488346162D Marker adult vs. fetal9.4886919267.54295044711.216932059.80533776610.464545339.180810589AA427899172D Marker adult vs. fetal13.33651699.04185112816.9794616612.4420604515.1682003911.53880939AA453813152D Marker adult vs. fetal23.5301466218.5505137326.1323255224.0775444427.0570211419.41686645AA397824152D Marker adult vs. fetal28.0835196220.6264896827.0278726626.2925730330.8506713119.80045327AA633901152D Marker adult vs. fetal34.7798491823.7844288736.1225076235.6148843441.6670368430.60345109AA181334152D Marker adult vs. fetal27.2807527718.9816048931.1843798827.2312908529.8986819924.05531978AA292410152D Marker adult vs. fetal31.3095984329.1382109233.6079600835.9837859938.081089727.93817331AA253434152D Marker adult vs. fetal27.2883674624.4875187226.02107229.5137739331.8189776124.38068282AA455058162D Marker adult vs. fetal12.5476244410.9029949912.0419297813.9613355814.9351835210.87358414R55188212D Marker adult vs. fetal31.1287496512.8190488226.2960439518.7293530827.1618963419.64403686AA46572302D Marker adult vs. fetal0.6260999050.5198298530.9650563450.8018344910.7230635920.645073541N49856232D Marker adult vs. fetal58.2549612343.8120692736.3070495858.8810781563.7354541151.53609212AA455272232D Marker adult vs. fetal78.722654557.9574528836.3070495870.8338612384.6013683354.29877782AA459292232D Marker adult vs. fetal84.9801390754.5523752838.3070495878.8103129185.9454599854.78113735AA878561232D Marker adult vs. fetal91.8902348970.2473383636.3070495885.95771786103.455624654.83812392AA772068232D Marker adult vs. fetal100.702276760.9138633236.3070495895.803451785.6315468754.85301063N78821172D Marker adult vs. fetal18.182601138.90096933117.9596811814.8822388316.8155028814.041252AA291490212D Marker adult vs. fetal16.1520001912.258977119.6408566416.9896540318.8813471113.99432924N46828172D Marker adult vs. fetal16.540968869.83078421217.5335127613.8676389716.83867472615.02548971AA150487212D Marker adult vs. fetal15.1951241213.8004219117.9560927714.509467517.5505627515.10253571AA282537212D Marker adult vs. fetal17.2424409913.6487038621.8292302718.5390260218.3443304217.95537212AA707922212D Marker adult vs. fetal29.5242348119.1724810230.4281424229.0943966827.85417625.96068749AA443638202D Marker adult vs. fetal15.100059415.1534878217.8855885315.769711218.9415190714.61633105W73892192D Marker adult vs. fetal53.6200201339.0238065536.3070495856.6767482653.8292161146.25990911N70734192D Marker adult vs. fetal50.139552837.0198634136.3070495848.4833530447.5755142945.25023946H57136132D Marker adult vs. fetal10.271996469.12448778812.52381089.8058514811.1253217910.90999216AA700414292D Marker adult vs. fetal72.8127183437.6154646236.3070495868.6734399162.2529265954.4411949W6546172D Marker adult vs. fetal5.4768392395.0674429815.4268877256.0791261186.40146343485.626362584AAA36584152D Marker adult vs. fetal23.0294131315.2475403825.7374051522.6155695422.798115919.91483801AA02904292D Marker adult vs. fetal8.0222346447.3115960058.8956622779.4792177399.6054859347.544837461AA42772592D Marker adult vs. fetal12.692948647.65553614213.673268124.26115533412.429097112.81248352N5128092D Marker adult vs. fetal6.6323338155.8745950417.3851662727.5206081067.7857485065.963530521AA28134782D Marker adult vs. fetal5.0897806134.6404875924.94155943445.452510256.2882045124.490066004AA40296082D Marker adult vs. fetal4.9651506214.501829246.5962238212.2420329284.8803565984.839655851N9848592D Marker adult vs. fetal7.1254059276.5441299517.77218647.5567538998.4790668086.411666818AA49020972D Marker adult vs. fetal5.8031947295.0249034.5467054126.0463216556.5006092144.920009122W6136192D Marker adult vs. fetal7.3847509127.33529892511.109355188.81000279.4217617766.881790584N5101872D Marker adult vs. fetal5.48810080238.5926231210.69983086.0325845865.21684924217.32422488AA45528172D Marker adult vs. fetal6.9980827829.3174338768.4954600117.3529590687.9385711078.110370507W6947172D Marker adult vs. fetal7.2150227978.1485654598.1976569115.320008854.95685901713.55485747AA48632172D Marker adult vs. fetal6.6168434063.68842166710.11482245.5389223615.4047767736.062776617AA45898272D Marker adult vs. fetal6.9612869586.2809752666.4414697747.0729224757.6465980096.402438243AA44209572D Marker adult vs. fetal10.533688676.9692518289.0351043148.5307320528.7159248757.353607298N9900372D Marker adult vs. fetal7.7773465275.1234065977.2713608357.6940762998.0150565246.947984869AA60928472D Marker adult vs. fetal5.2035276316.7252287275.9622528165.3928726925.4869840166.647332466AA195036122D Marker adult vs. fetal4.7390318125.6302234896.1684193273.9521371256.2991839564.511434885AA47826852D Marker adult vs. fetal4.5876230854.3196685216.074467365.3210948195.7057838994.273131909AA608583132D Marker adult vs. fetal8.7102134196.63363191410.892670069.89780320410.764056117.594364628AA480435132D Marker adult vs. fetal10.666031076.87839339811.707023219.86286046610.6292080710.9035389AA505046132D Marker adult vs. fetal6.1759089697.77474045210.846325817.6575846137.6323284685.432221512AA487893132D Marker adult vs. fetal6.289133917.08662981910.383170338.1866379198.6777816396.646527414AA292226122D Marker adult vs. fetal6.9783117659.4983791679.9997577538.2451734088.455332717.944255354H8710692D Marker adult vs. fetal8.5117731668.3067660688.6397284118.6882707479.8172682927.409517924W96450122D Marker adult vs. fetal6.3333046046.1145487410.938548168.2950255368.5018486856.781838425N33331132D Marker adult vs. fetal12.011977589.75328304514.058316210.9245679413.4554004419.89513482AA405800122D Marker adult vs. fetal6.1213964795.2233205887.7215005487.7181066586.4625475985.753462094T51539122D Marker adult vs. fetal6.4899001466.5705582519.4690299978.8202642889.1944191145.883142749N59764122D Marker adult vs. fetal7.6005406594.7567248228.391915387.2799064258.1352046556.251234677AA521346112D Marker adult vs. fetal18.018746311.9881399120.0453914717.6643728519.7279358215.44668566AA428551112D Marker adult vs. fetal11.813798389.13234451413.5770354512.53677114.2611507811.3197892AA489383112D Marker adult vs. fetal10.071964536.4071018510.636545389.1152673499.3458068828.56845107AA490172112D Marker adult vs. fetal8.3747661471.41529748517.3871325612.090499188.2903468936.184780432AA504477122D Marker adult vs. fetal5.4178912163.859722356.0903534315.2092473215.8290420514.969815506AccesionH1 V2 t0H1 V2 t2dH1 V2 t4dH2 P1 3DH2 P1 2DH3 F P4 t0dH3 F P4 t2dH3 F P4 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Identification of tissue/cell specific marker genes and use thereof

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Date Filed

Date Published

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CPC

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Abstract

Description

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CROSS REFERENCES TO RELATED APPLICATIONS

PCT Information

Provisional Applications (1)