Supplementary Online Material for

Supplementary Online Material for Long Homopurine•homopyrimidine Sequences Are Characteristic of Genes Expressed in Brain and the Pseudoautosomal Region Albino Bacolla, Jack R. Collins, Bert Gold, Nadia Chuzhanova, Ming Yi, Robert M. Stephens, Stefan Stefanov, Adam Olsh, John P. Jakupciak, Michael Dean, Richard A. Lempicki, David N. Cooper, and Robert D. Wells* *To whom correspondence should be addressed. Email: [email protected]

This PDF file includes: Supplementary Text Supplementary Figs. 1 to 9 Supplementary Tables 1 to 8 References

Supplementary Text R•Y Tract-containing Genes and Susceptibility Genes for Schizophrenia. The comparison of ≥250 bp and ≥100 bp R•Y tract-containing genes with the proteomic databases indicated that such tracts were enriched in genes associated with disease, particularly with mental disorders including schizophrenia (Supplementary Tables 2I and 3I). An increasing number of studies point to the altered regulation of brain-specific gene expression mostly at synapses, as a common heritable cause of risk/susceptibility in schizophrenia (1-8). Therefore, the enrichment of R•Y tract-containing genes encoding receptors and ion transporters at synapses (Tables 1, and Supplementary Tables 2 and 3), where they perform signal transduction functions, suggested that some overlap might exist with schizophrenia susceptibility genes, prompting an extensive survey of the literature. All the genes depicted in Supplementary Fig. 1 contain at least one pure R•Y tract ≥100 bp and up to 22 pure R•Y tracts ≥50 bp (Supplementary Table 4), and were displayed according to their interacting properties at synaptic structures (1,8-93). Particularly for glutamate receptor-expressing excitatory neurons, the representation of R•Y tract-containing genes was extensive, and included most of the receptor subunits and several of their anchoring and clustering partners, which together constitute the postsynaptic density (PSD) structure. In addition, key regulatory molecules at signaling pathway crossroads, such as the family of peptides encoded by the NRG1 gene and reelin-activated Fyn kinase (FYN) were represented. Indeed, 5 of these genes (RELN, NTRK2, NRG1, SLC6A4, and DISC1) comprised at least half of all the genes currently regarded as being strongly associated with schizophrenia susceptibility (2-7,16). The DISC1 gene was also found to contain a ~637 bp tandem repeat tract composed of imperfect GCAGTGCAGTACTCAGTAAG motifs in the 3’-UTR, Supplementary Fig. 2). However, the role of this repeat in susceptibility to the disease has yet to be addressed. Nineteen other genes (marked with red asterisks), two thirds of which encoded glutamate receptor assembly complexes, have also been associated with schizophrenia, and together they constitute at least 30-40% of all genes considered as candidates for involvement in this disorder (2-8,10,16,24,30,45,53,56,60,72,87,90,92,93). Hence, a significant portion of schizophrenia susceptibility genes comprises R•Y tract-containing genes implicated in coordinated signal transduction functions at synapses. Gene Terms Enriched Uniquely in the ≥100 R•Y Tract-containing Gene Set. Of the first 16 terms in GO_MF for the ≥100 bp R•Y tract-containing genes (Supplementary Table 3A), 8 (2-4, 6, 8-9, 14, and 16) with P-values of 4x102 for the corresponding terms in the ≥250 bp R•Y tract-containing genes (not shown). Similarly, analysis of the first 16 terms of the GO_BP database (Supplementary Table 3B) revealed that 8 (4-5, 8-10, 14-16) terms with P-values of 2x10-2 for the ≥250 bp R•Y tract-containing genes (not shown). Repeat Sequences in the Pseudoautosomal Region. There were 11 (all numbers indicate pairs of repeats; no mismatches were allowed) MR within PAR1 and 15 in the following 4.4 Mb (After-PAR) ranging from 62 to 132 bp in length. The search for DR yielded 108 repeats ≥250 bp in PAR1 (range 250-1643 bp, median of 412 bp) and 9

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repeats in After-PAR (range 250-498 bp), and 970 and 264 repeats in the 62 – 249 bp range in PAR1 and After-PAR, respectively. With respect to IR, 3 with length ≥250 bp were found both in PAR1 and After-PAR (range 257-450 and 262-307 bp, respectively), whereas 157 and 154 with lengths varying from 49 to 249 bp were identified in PAR1 and After-PAR, respectively. Human-Chimpanzee Orthologous R•Y Tract Comparisons. Of the 814 human R•Y tract, 436 sequence pairs (142 intragenic and 294 intergenic) yielded an informative and unambiguous match with the chimpanzee sequence. The search for all pure R•Y tracts ≥250 bp in the chimpanzee genome yielded a total of 177 (Supplementary Table 6). Of these, 167 contained no sequencing gaps and these were therefore compared directly with the orthologous sites in the human genome. Comparative Analyses of the R•Y Tracts in the Primate PRKCB1 and ADAM18 Genes. The human PRKCB1 gene contained a 416 bp pure R•Y tract which was present as a 620 bp interrupted tract in macaque (Supplementary Fig. 8). A 3.5 kb fragment containing this tract was however absent in chimpanzee; hence we may infer that a deletion must have taken place in the chimpanzee lineage. An AG dinucleotide at the deletion breakpoint existed as an AG…AG homologous pair in human and as an AG…GG pair in macaque; the proximal pair was located within the first of two directly repeated Alu sequences, whereas the distal pair was located between two of three Alu sequences in reverse orientation with respect to the proximal sequences. All five Alu elements shared extensive homologies indicative of their potential to form large hairpin structures (Mfold) with locally mispaired regions, placing the R and Y bases in the loop. Within the global hairpin, the common (proximal) AG dinucleotide localized to the tip of a local hairpin stem, at the junction with an unpaired branch. The stability of the stem increased in the human sequence relative to macaque, owing to a single nt change (several other nt changes also existed between macaque and human/chimpanzee), and was additionally stabilized in chimpanzee as a consequence of the deletion. These observations are consistent with a DNA-strand break occurring at the AG-junction site in the chimpanzee lineage, which was then repaired by the distally homologous AG site, as being a likely cause for the deletion. A similar example of an R•Y tract undergoing evolutionary change is a 252 bp R•Y tract in the ADAM18 gene in the chimpanzee, which was absent from both the human and macaque genomes. Sequence comparisons revealed that a 48-bp tract that is absent from the macaque sequence has been replaced by a 6.8 kb insertion in chimpanzee (Supplementary Fig. 9). In human, the first 93-bp of the chimpanzee insertion is followed by an ~8 kb deletion which has removed part of the downstream sequence common to macaque and chimpanzee. Hence, the R•Y tract-containing insertion must have preceded the divergence of the human and chimpanzee lineages, whilst the deletion occurred later in the human lineage. Small cruciform structures may have formed at the distal breakpoint which could have then served to facilitate the insertion/deletion events. Allelic R•Y Length Polymorphisms in Mammals. Although limited in number, R•Y length-tract polymorphisms have been described, including the D8S210 locus in the telomeric region of the short arm of the human chromosome 8 (94), the 5’ upstream

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promoter region of the human NOS2A (95,96) and HLA-F (97) genes, and the 5’ UTR of the porcine androgen receptor (Ar) gene (98).

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Legends to Supplementary Tables Supplementary Table 4. R•Y Tracts of Human Genes Epistatic in Schizophrenia. The search was conducted for all tracts ≥50 uninterrupted R•Y in genes that contained at least 1 tract with ≥100 uninterrupted R•Y. * When more than 1 pure repeat comprised the total repeat length, only the longest pure repeat tract was reported. ** Introns were identified by the Human Genome Browser Gateway (http://genome.ucsc.edu/cgi-bin/hgGateway) and numbered uning the following criteria: intron 1 = first intron after encoding exon 1; intron -1 = last intron of all 5'-UTR composing exons preceding intron 1.

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Legends to Supplementary Figures Supplementary Figure 1. R•Y Tract-containing Genes in Intersecting Signal Transduction Pathways at Synapses and Their Association with Schizophrenia. The genes all contain at least one pure R•Y tract of ≥100 bp. Large ovals (domains) indicate specific receptor-expressing neuronal cells. The signaling pathways may take place between different cell types, such as the inhibitory inputs of GABAergic Cajal-Retzius cells to the distal dendrites of pyramidal neurons in the dorsolateral prefrontal cortex, or within single cells. NMDA, AMPA, and Kainate comprise the ionotropic glutamate receptor family, whereas Metabotropic includes the metabotropic glutamate receptors: Group I comprises GRM1 and GRM5, which activate phospholipase C; Group II comprises GRM2 and GRM3 (these genes do not contain R•Y tracts); Group III comprises GRM4, GRM6, GRM7, and GRM8. Groups II and III are involved in the inhibition of the cyclic AMP cascade. Blue arrows, epistatic interactions involving the protein products of R•Y tract-containing genes; red arrows, interactions involving pathways not shown in the Figure. GABA, γ-aminobutyric acid; NMDA, N-methyl-Daspartate; AMPA, amino-3-hydroxy-5-methyl-4-isoxazole propionate; PSD, post-synaptic density. Red, genes with strong evidence of association with schizophrenia; red stars, genes with weaker evidence of an association with schizophrenia. Supplementary Figure 2. Repeating Motif Present in the 3’-UTR of the DISC1 Gene. The imperfect repeating motifs were aligned according to complexity analysis criteria. Underline, tandem repeats; yellow highlight, single inverted repeat; other highlights, inverted repeats. Supplementary Figure 3. Gene-Term Association Subnetwork for GO_Biological Process With the Most Enriched Categories Unique to Genes Harboring ≥100 bp of Pure R•Y. Left side, genes containing ≥250 bp pure R•Y tracts; right side, genes containing ≥100 bp pure R•Y tracts; green, “protein amino acid phosphorylation” category; blue, “enzyme linked receptor protein signaling pathway” category; orange, “phosphate metabolism” category; yellow, “development” category. Genes associated with categories are indicated by the rectangles of the radiating lines. Pvalues are indicated. Supplementary Figure 4. Clustering of the R•Y Tracts. Chromosomal locations of the 814 pure R•Y tracts of length ≥250 bp. Thick filled horizontal rectangles, pericentromeric regions whose sequences are not available from the hg17 human genome assembly; orange boxes, significantly clustered R•Y tracts. Note that, because closely spaced vertical bars (which represent the R•Y tracts) collapse into a single bar at this resolution, the figure cannot accurately represent the clustering results from order statistics. Also, each individual chromsome was analyzed independently, and therefore the distances between the tracts were compared only within chromosomes, not between chromosomes.

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Supplementary Figure 5. Micro- and Mini-satellites in the Human Genome. The total number of microsatellite and minisatellite sequences composed of pure monoto 29-mer repeats with total length ≥30 bp is reported. Supplementary Figure 6. Example of a TRB Sequence. This sequence starts at position 127,915 (hg17) on the X and Y chromosomes and comprises 3709 nt of repeat blocks with no intervening sequences with composition ded25(d23e)2a, where d=a+b and e=a+c and a= GAGGAAGGGCCRGGCCYYRTGACC, b= ACAGTCCACATCACACCAGGACACR, and c= TCYGGTCCTCATGACYCTGGGGCACAGCGG. Yellow, block c; green, C→G mismatch in block b; black, missing nts in block b.; red, mismatch at the end of TRB. Supplementary Figure 7. Comparative Analysis of the R•Y Tract in the Mammalian TIAM1 Gene. The 332 bp R•Y tract in the human TIAM1 gene and 5-kb of flanking DNA was used in a BLAT search to identify orthologous sites in the chimpanzee, macaque and dog genomes. R•Y tracts of 158, 20 and 20 bp were found in the chimpanzee, macaque and dog genomes, respectively. Complexity analysis was then performed to identify conserved motifs and to align the tracts relative to the putative ancestral sequences. Except for a C to G transition, the R•Y tracts were identical between dog and macaque and had the composition GGAA(GAAA)3GGGG. The most upstream GGAA(GAAA) motif was retained in the chimpanzee and human, but the following sequence was replaced by more complex and higher copy-number motifs. The R•Y tract diverged to a common GAAA-A-(GAAA)2G (first yellow highlight) sequence in the hominids, a motif that was fully duplicated at the end of the R•Y tract in chimpanzee but which was only partially duplicated in the human lineage (second yellow highlight). By contrast, a GAAA(GAAG)3GGA motif that was present in two copies in the human sequence, was present in only one copy in the chimpanzee (green highlight). Variable numbers of (GA)n, (AAGG)n, (A)n, (GAAA)n repeats also served to distinguish the two species. Finally, the R•Y tract was interrupted by a conserved T residue at a (GA)8/5TAGGG sequence in both species (end of first yellow highlight), whereas a C residue (underlined) was found in the chimpanzee. These data therefore support the conclusion that a combination of replication slippage (variable number of repeats), recombination-based duplications and insertions, and single-nt substitutions were involved in the evolution of this R•Y tract. Supplementary Figure 8. The R•Y Tract in the PRKCB1 Gene. Top left, the last common ancestor (LCA) of humans and chimpanzees lived ~5-8 million years ago (Mya), whereas the LCA of humans and macaque lived ~25 Mya. The R•Y tract in the PRKCB1 gene is present (yes, in red circle) in macaque but not in chimpanzee (no, in blue circle), indicating that this tract was lost during primate evolution (yellow symbol). Top middle, the ~3.5 kb deletion containing the R•Y tract is flanked by homologous AG dinucleotides in the human gene, whereas in macaque, AG and GG are found at the proximal and distal breakpoints, respectively. The region contains 5 major interspersed repeats, all of which share extensive homologies and are arranged in opposite orientations. The proximal breakpoint is located within a free right Alu monomer

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(FRAM) element in human and macaque, whereas the distal breakpoint is located between the directly oriented AluY and FRAM elements in the same species. Top right, the repetitive elements on the left side of the R•Y tract pair with those on the right side to form the arms of a cruciform structure (Mfold analysis, http://www.bioinfo.rpi.edu/applications/mfold) in the human and macaque genes with the R or Y tract in the loop. The most stable structures involve different pairs of repeats at the base of the cruciform in human and macaque as a result of sporadic nucleotide changes. Bottom, in cases where the cruciform stem involves FRAM-FRAM pairing, the proximal AG breakpoint is located at the junction between a pair stem and a local branchsite. A single G→T nt change in human extends the stem by 2 bp to place the AG breakpoint at the tip of the stem. After the deletion process in chimpanzee, the stem was lengthened by an additional 2 bp. These changes are associated with a progressive increase in local stem stability from macaque to human to chimpanzee. Supplementary Figure 9. The R•Y Tract in the ADAM18 Gene. A 252 bp uninterrupted R•Y tract in chimpanzee was not found at the analogous location in the orthologous ADAM18 gene in human and macaque. Top, A 6.8 kb insert containing the R•Y tract was found as a de novo insertion in chimpanzee with a corresponding 48 bp deletion with respect to the sequence in macaque. In the human gene, an ~8 kb deletion retained the proximal 93 bp from the chimpanzee insertion but removed the rest of the insertion plus an additional ~1.3 kb of downstream sequence. Bottom, cruciform structures identified at the distal insertion/deletion sites. Green, deletion in the macaque sequence; yellow, insertions; red, R•Y tract; orange, sequence deleted in the human lineage; Arabic numerals, length in bp; GCA, TTG, and GTA, sequences flanking breakpoints; Roman numerals, non-B DNA forming sequences at breakpoints; arrows, breakpoints. Note that the energetic feasibility of the illustrated strand pairings in Figs. 8 and 9 in the context of duplex DNA and local sequence context is unknown.

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Supplementary References 1. 2. 3. 4. 5. 6. 7. 8. 9.

10. 11. 12. 13.

14. 15. 16.

Craddock, N., O'Donovan, M.C. and Owen, M.J. (2005) The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J. Med. Genet., 42, 193204. Harrison, P.J. and Owen, M.J. (2003) Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet, 361, 417-419. Harrison, P.J. and Weinberger, D.R. (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol. Psychiatry, 10, 40-68. Lewis, D.A., Hashimoto, T. and Volk, D.W. (2005) Cortical inhibitory neurons and schizophrenia. Nat. Rev. Neurosci., 6, 312-324. Moghaddam, B. (2003) Bringing order to the glutamate chaos in schizophrenia. Neuron, 40, 881-884. O'Donovan, M.C., Williams, N.M. and Owen, M.J. (2003) Recent advances in the genetics of schizophrenia. Hum. Mol. Genet., 12, R125-133. Winterer, G. and Weinberger, D.R. (2004) Genes, dopamine and cortical signalto-noise ratio in schizophrenia. Trends Neurosci., 27, 683-690. Stefansson, H., Steinthorsdottir, V., Thorgeirsson, T.E., Gulcher, J.R. and Stefansson, K. (2004) Neuregulin 1 and schizophrenia. Ann. Med., 36, 62-71. Sanjuan, J., Rivero, O., Aguilar, E.J., Gonzalez, J.C., Molto, M.D., de Frutos, R., Lesch, K.P. and Najera, C. (2005) Serotonin transporter gene polymorphism (5HTTLPR) and emotional response to auditory hallucinations in schizophrenia. Int. J. Neuropsychopharmacol., 1-3. Dubertret, C., Hanoun, N., Ades, J., Hamon, M. and Gorwood, P. (2005) Familybased association study of the 5-HT transporter gene and schizophrenia. Int. J. Neuropsychopharmacol., 8, 87-92. Lesch, K.P. and Gutknecht, L. (2005) Pharmacogenetics of the serotonin transporter. Prog. Neuropsychopharmacol. Biol. Psychiatry, 29, 1062-1073. Fan, J.B. and Sklar, P. (2005) Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia. Mol. Psychiatry, 10, 891. Boeckers, T.M., Liedtke, T., Spilker, C., Dresbach, T., Bockmann, J., Kreutz, M.R. and Gundelfinger, E.D. (2005) C-terminal synaptic targeting elements for postsynaptic density proteins ProSAP1/Shank2 and ProSAP2/Shank3. J. Neurochem., 92, 519-524. Hwang, J.I., Kim, H.S., Lee, J.R., Kim, E., Ryu, S.H. and Suh, P.G. (2005) The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal. J. Biol. Chem., 280, 12467-12473. Uemura, T., Mori, H. and Mishina, M. (2004) Direct interaction of GluRdelta2 with Shank scaffold proteins in cerebellar Purkinje cells. Mol. Cell. Neurosci., 26, 330-341. Abdolmaleky, H.M., Thiagalingam, S. and Wilcox, M. (2005) Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. Am. J. Pharmacogenomics, 5, 149-160.

9

17. 18. 19.

20.

21. 22.

23. 24. 25.

26.

27.

28. 29.

Fatemi, S.H., Snow, A.V., Stary, J.M., Araghi-Niknam, M., Reutiman, T.J., Lee, S., Brooks, A.I. and Pearce, D.A. (2005) Reelin signaling is impaired in autism. Biol. Psychiatry, 57, 777-787. Bartlett, C.W., Gharani, N., Millonig, J.H. and Brzustowicz, L.M. (2005) Three autism candidate genes: a synthesis of human genetic analysis with other disciplines. Int. J. Dev. Neurosci., 23, 221-234. Abdolmaleky, H.M., Cheng, K.H., Russo, A., Smith, C.L., Faraone, S.V., Wilcox, M., Shafa, R., Glatt, S.J., Nguyen, G., Ponte, J.F. et al. (2005) Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am. J. Med. Genet. B Neuropsychiatr. Genet., 134, 60-66. Fatemi, S.H., Stary, J.M., Earle, J.A., Araghi-Niknam, M. and Eagan, E. (2005) GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum. Schizophr. Res., 72, 109-122. Liu, W., Pappas, G.D. and Carter, C.S. (2005) Oxytocin receptors in brain cortical regions are reduced in haploinsufficient (+/-) reeler mice. Neurol. Res., 27, 339345. Sinagra, M., Verrier, D., Frankova, D., Korwek, K.M., Blahos, J., Weeber, E.J., Manzoni, O.J. and Chavis, P. (2005) Reelin, very-low-density lipoprotein receptor, and apolipoprotein E receptor 2 control somatic NMDA receptor composition during hippocampal maturation in vitro. J. Neurosci., 25, 6127-6136. Grayson, D.R., Jia, X., Chen, Y., Sharma, R.P., Mitchell, C.P., Guidotti, A. and Costa, E. (2005) Reelin promoter hypermethylation in schizophrenia. Proc. Natl. Acad. Sci. U. S. A., 102, 9341-9346. Fatemi, S.H. (2005) Reelin glycoprotein: structure, biology and roles in health and disease. Mol. Psychiatry, 10, 251-257. Weickert, C.S., Ligons, D.L., Romanczyk, T., Ungaro, G., Hyde, T.M., Herman, M.M., Weinberger, D.R. and Kleinman, J.E. (2005) Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. Mol. Psychiatry, 10, 637-650. Hashimoto, T., Bergen, S.E., Nguyen, Q.L., Xu, B., Monteggia, L.M., Pierri, J.N., Sun, Z., Sampson, A.R. and Lewis, D.A. (2005) Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J. Neurosci., 25, 372-383. Iritani, S., Niizato, K., Nawa, H., Ikeda, K. and Emson, P.C. (2003) Immunohistochemical study of brain-derived neurotrophic factor and its receptor, TrkB, in the hippocampal formation of schizophrenic brains. Prog. Neuropsychopharmacol. Biol. Psychiatry, 27, 801-807. Yamada, K. and Nabeshima, T. (2003) Brain-derived neurotrophic factor/TrkB signaling in memory processes. J. Pharmacol. Sci., 91, 267-270. Green, E.K., Raybould, R., Macgregor, S., Gordon-Smith, K., Heron, J., Hyde, S., Grozeva, D., Hamshere, M., Williams, N., Owen, M.J. et al. (2005) Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder. Arch. Gen. Psychiatry, 62, 642648.

10

30.

31. 32. 33.

34.

35. 36. 37. 38. 39. 40.

41.

42.

43.

Petryshen, T.L., Middleton, F.A., Kirby, A., Aldinger, K.A., Purcell, S., Tahl, A.R., Morley, C.P., McGann, L., Gentile, K.L., Rockwell, G.N. et al. (2005) Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Mol. Psychiatry, 10, 366-374, 328. Cameron, J.S., Dryer, L. and Dryer, S.E. (2001) beta -Neuregulin-1 is required for the in vivo development of functional Ca2+-activated K+ channels in parasympathetic neurons. Proc. Natl. Acad. Sci. U. S. A., 98, 2832-2836. Steinthorsdottir, V., Stefansson, H., Ghosh, S., Birgisdottir, B., Bjornsdottir, S., Fasquel, A.C., Olafsson, O., Stefansson, K. and Gulcher, J.R. (2004) Multiple novel transcription initiation sites for NRG1. Gene, 342, 97-105. Schmid, R.S., McGrath, B., Berechid, B.E., Boyles, B., Marchionni, M., Sestan, N. and Anton, E.S. (2003) Neuregulin 1-erbB2 signaling is required for the establishment of radial glia and their transformation into astrocytes in cerebral cortex. Proc. Natl. Acad. Sci. U. S. A., 100, 4251-4256. Pillai-Nair, N., Panicker, A.K., Rodriguiz, R.M., Gilmore, K.L., Demyanenko, G.P., Huang, J.Z., Wetsel, W.C. and Maness, P.F. (2005) Neural cell adhesion molecule-secreting transgenic mice display abnormalities in GABAergic interneurons and alterations in behavior. J. Neurosci., 25, 4659-4671. Laifenfeld, D., Karry, R., Klein, E. and Ben-Shachar, D. (2005) Alterations in cell adhesion molecule L1 and functionally related genes in major depression: a postmortem study. Biol. Psychiatry, 57, 716-725. Ehrengruber, M.U., Kato, A., Inokuchi, K. and Hennou, S. (2004) Homer/Vesl proteins and their roles in CNS neurons. Mol. Neurobiol., 29, 213-227. Fagni, L., Ango, F., Perroy, J. and Bockaert, J. (2004) Identification and functional roles of metabotropic glutamate receptor-interacting proteins. Semin. Cell. Dev. Biol., 15, 289-298. de Bartolomeis, A. and Fiore, G. (2004) Postsynaptic density scaffolding proteins at excitatory synapse and disorders of synaptic plasticity: implications for human behavior pathologies. Int. Rev. Neurobiol., 59, 221-254. Ango, F., Robbe, D., Tu, J.C., Xiao, B., Worley, P.F., Pin, J.P., Bockaert, J. and Fagni, L. (2002) Homer-dependent cell surface expression of metabotropic glutamate receptor type 5 in neurons. Mol. Cell. Neurosci., 20, 323-329. Takaki, H., Kikuta, R., Shibata, H., Ninomiya, H., Tashiro, N. and Fukumaki, Y. (2004) Positive associations of polymorphisms in the metabotropic glutamate receptor type 8 gene (GRM8) with schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet., 128, 6-14. Holscher, C., Schmid, S., Pilz, P.K., Sansig, G., van der Putten, H. and Plappert, C.F. (2004) Lack of the metabotropic glutamate receptor subtype 7 selectively impairs short-term working memory but not long-term memory. Behav. Brain Res., 154, 473-481. Gupta, D.S., McCullumsmith, R.E., Beneyto, M., Haroutunian, V., Davis, K.L. and Meador-Woodruff, J.H. (2005) Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia. Synapse, 57, 123-131. Warwick, H.K., Nahorski, S.R. and Challiss, R.A. (2005) Group I metabotropic glutamate receptors, mGlu1a and mGlu5a, couple to cyclic AMP response

11

44.

45. 46. 47.

48. 49. 50. 51.

52.

53.

54.

55.

56.

element binding protein (CREB) through a common Ca2+ - and protein kinase Cdependent pathway. J. Neurochem., 93, 232-245. Mao, L., Yang, L., Tang, Q., Samdani, S., Zhang, G. and Wang, J.Q. (2005) The scaffold protein Homer1b/c links metabotropic glutamate receptor 5 to extracellular signal-regulated protein kinase cascades in neurons. J. Neurosci., 25, 2741-2752. Kew, J.N. and Kemp, J.A. (2005) Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology, 179, 4-29. Turle-Lorenzo, N., Breysse, N., Baunez, C. and Amalric, M. (2005) Functional interaction between mGlu 5 and NMDA receptors in a rat model of Parkinson's disease. Psychopharmacology, 179, 117-127. Yang, L., Mao, L., Tang, Q., Samdani, S., Liu, Z. and Wang, J.Q. (2004) A novel Ca2+-independent signaling pathway to extracellular signal-regulated protein kinase by coactivation of NMDA receptors and metabotropic glutamate receptor 5 in neurons. J. Neurosci., 24, 10846-10857. Jia, Z., Lu, Y.M., Agopyan, N. and Roder, J. (2001) Gene targeting reveals a role for the glutamate receptors mGluR5 and GluR2 in learning and memory. Physiol. Behav., 73, 793-802. Kubo, Y. and Tateyama, M. (2005) Towards a view of functioning dimeric metabotropic receptors. Curr. Opin. Neurobiol., 15, 289-295. Guhan, N. and Lu, B. (2004) Homer-PIKE complex: a novel link between mGluRI and PI 3-kinase. Trends Neurosci., 27, 645-648. Tabata, T., Araishi, K., Hashimoto, K., Hashimotodani, Y., van der Putten, H., Bettler, B. and Kano, M. (2004) Ca2+ activity at GABAB receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA. Proc. Natl. Acad. Sci. U. S. A., 101, 16952-16957. Qin, S., Zhao, X., Pan, Y., Liu, J., Feng, G., Fu, J., Bao, J., Zhang, Z. and He, L. (2005) An association study of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B) in schizophrenia with universal DNA microarray. Eur. J. Hum. Genet., 13, 807-814. Di Maria, E., Gulli, R., Begni, S., De Luca, A., Bignotti, S., Pasini, A., Bellone, E., Pizzuti, A., Dallapiccola, B., Novelli, G. et al. (2004) Variations in the NMDA receptor subunit 2B gene (GRIN2B) and schizophrenia: a case-control study. Am. J. Med. Genet. B Neuropsychiatr. Genet., 128, 27-29. Iwayama-Shigeno, Y., Yamada, K., Itokawa, M., Toyota, T., Meerabux, J.M., Minabe, Y., Mori, N., Inada, T. and Yoshikawa, T. (2005) Extended analyses support the association of a functional (GT)n polymorphism in the GRIN2A promoter with Japanese schizophrenia. Neurosci. Lett., 378, 102-105. Shuang, M., Liu, J., Jia, M.X., Yang, J.Z., Wu, S.P., Gong, X.H., Ling, Y.S., Ruan, Y., Yang, X.L. and Zhang, D. (2004) Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios. Am. J. Med. Genet. B Neuropsychiatr. Genet., 131, 48-50. Bah, J., Quach, H., Ebstein, R.P., Segman, R.H., Melke, J., Jamain, S., Rietschel, M., Modai, I., Kanas, K., Karni, O. et al. (2004) Maternal transmission disequilibrium of the glutamate receptor GRIK2 in schizophrenia. Neuroreport, 15, 1987-1991.

12

57.

58. 59. 60.

61.

62. 63. 64.

65. 66. 67.

68. 69.

Delorme, R., Krebs, M.O., Chabane, N., Roy, I., Millet, B., Mouren-Simeoni, M.C., Maier, W., Bourgeron, T. and Leboyer, M. (2004) Frequency and transmission of glutamate receptors GRIK2 and GRIK3 polymorphisms in patients with obsessive compulsive disorder. Neuroreport, 15, 699-702. Scarr, E., Beneyto, M., Meador-Woodruff, J.H. and Deans, B. (2005) Cortical glutamatergic markers in schizophrenia. Neuropsychopharmacology, 30, 15211531. Fisahn, A. (2005) Kainate receptors and rhythmic activity in neuronal networks: hippocampal gamma oscillations as a tool. J. Physiol., 562, 65-72. Makino, C., Fujii, Y., Kikuta, R., Hirata, N., Tani, A., Shibata, A., Ninomiya, H., Tashiro, N., Shibata, H. and Fukumaki, Y. (2003) Positive association of the AMPA receptor subunit GluR4 gene (GRIA4) haplotype with schizophrenia: linkage disequilibrium mapping using SNPs evenly distributed across the gene region. Am. J. Med. Genet. B Neuropsychiatr. Genet., 116, 17-22. Guo, S., Shi, Y., Zhao, X., Duan, S., Zhou, J., Meng, J., Yang, Y., Gu, N., Feng, G., Liu, H. et al. (2004) No genetic association between polymorphisms in the AMPA receptor subunit GluR4 gene (GRIA4) and schizophrenia in the Chinese population. Neurosci. Lett., 369, 168-172. Dracheva, S., McGurk, S.R. and Haroutunian, V. (2005) mRNA expression of AMPA receptors and AMPA receptor binding proteins in the cerebral cortex of elderly schizophrenics. J. Neurosci. Res., 79, 868-878. Adriani, W. and Laviola, G. (2004) Windows of vulnerability to psychopathology and therapeutic strategy in the adolescent rodent model. Behav. Pharmacol., 15, 341-352. Ishikawa, M., Mizukami, K., Iwakiri, M. and Asada, T. (2005) Immunohistochemical and immunoblot analysis of gamma-aminobutyric acid B receptor in the prefrontal cortex of subjects with schizophrenia and bipolar disorder. Neurosci. Lett., 383, 272-277. Zai, G., King, N., Wong, G.W., Barr, C.L. and Kennedy, J.L. (2005) Possible association between the gamma-aminobutyric acid type B receptor 1 (GABBR1) gene and schizophrenia. Eur. Neuropsychopharmacol., 15, 347-352. Lo, W.S., Lau, C.F., Xuan, Z., Chan, C.F., Feng, G.Y., He, L., Cao, Z.C., Liu, H., Luan, Q.M. and Xue, H. (2004) Association of SNPs and haplotypes in GABAA receptor beta2 gene with schizophrenia. Mol. Psychiatry, 9, 603-608. Kojima, N., Sakamoto, T., Endo, S. and Niki, H. (2005) Impairment of conditioned freezing to tone, but not to context, in Fyn-transgenic mice: relationship to NMDA receptor subunit 2B function. Eur. J. Neurosci., 21, 13591369. Nada, S., Shima, T., Yanai, H., Husi, H., Grant, S.G., Okada, M. and Akiyama, T. (2003) Identification of PSD-93 as a substrate for the Src family tyrosine kinase Fyn. J. Biol. Chem., 278, 47610-47621. Dunah, A.W., Sirianni, A.C., Fienberg, A.A., Bastia, E., Schwarzschild, M.A. and Standaert, D.G. (2004) Dopamine D1-dependent trafficking of striatal N-methylD-aspartate glutamate receptors requires Fyn protein tyrosine kinase but not DARPP-32. Mol. Pharmacol., 65, 121-129.

13

70.

71.

72.

73. 74.

75.

76.

77. 78. 79.

80. 81.

Ohnuma, T., Kato, H., Arai, H., McKenna, P.J. and Emson, P.C. (2003) Expression of Fyn, a non-receptor tyrosine kinase in prefrontal cortex from patients with schizophrenia and its correlation with clinical onset. Brain Res. Mol. Brain Res., 112, 90-94. Yamada, K., Nakamura, K., Minabe, Y., Iwayama-Shigeno, Y., Takao, H., Toyota, T., Hattori, E., Takei, N., Sekine, Y., Suzuki, K. et al. (2004) Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts. Biol. Psychiatry, 56, 683-690. Honda, A., Miyoshi, K., Baba, K., Taniguchi, M., Koyama, Y., Kuroda, S., Katayama, T. and Tohyama, M. (2004) Expression of fasciculation and elongation protein zeta-1 (FEZ1) in the developing rat brain. Brain Res. Mol. Brain Res., 122, 89-92. Garcia, R.A., Vasudevan, K. and Buonanno, A. (2000) The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses. Proc. Natl. Acad. Sci. U. S. A., 97, 3596-3601. Rybakowski, J.K., Borkowska, A., Czerski, P.M., Kapelski, P., DmitrzakWeglarz, M. and Hauser, J. (2005) An association study of dopamine receptors polymorphisms and the Wisconsin Card Sorting Test in schizophrenia. J. Neural. Transm., 112, 1575-1582. Hoogendoorn, M.L., Bakker, S.C., Schnack, H.G., Selten, J.P., Otten, H.G., Verduijn, W., van der Heijden, F.M., Pearson, P.L., Kahn, R.S. and Sinke, R.J. (2005) No association between 12 dopaminergic genes and schizophrenia in a large Dutch sample. Am. J. Med. Genet. B Neuropsychiatr. Genet., 134, 6-9. Staddon, S., Arranz, M.J., Mancama, D., Perez-Nievas, F., Arrizabalaga, I., Anney, R., Buckland, P., Elkin, A., Osborne, S., Munro, J. et al. (2005) Association between dopamine D3 receptor gene polymorphisms and schizophrenia in an isolate population. Schizophr. Res., 73, 49-54. Vogel, M., Pfeifer, S., Schaub, R.T., Grabe, H.J., Barnow, S., Freyberger, H.J. and Cascorbi, I. (2004) Decreased levels of dopamine D3 receptor mRNA in schizophrenic and bipolar patients. Neuropsychobiology, 50, 305-310. Petralia, R.S., Sans, N., Wang, Y.X. and Wenthold, R.J. (2005) Ontogeny of postsynaptic density proteins at glutamatergic synapses. Mol. Cell. Neurosci., 29, 436-452. Romorini, S., Piccoli, G., Jiang, M., Grossano, P., Tonna, N., Passafaro, M., Zhang, M. and Sala, C. (2004) A functional role of postsynaptic density-95guanylate kinase-associated protein complex in regulating Shank assembly and stability to synapses. J. Neurosci., 24, 9391-9404. Parker, M.J., Zhao, S., Bredt, D.S., Sanes, J.R. and Feng, G. (2004) PSD93 regulates synaptic stability at neuronal cholinergic synapses. J. Neurosci., 24, 378-388. Leonoudakis, D., Conti, L.R., Anderson, S., Radeke, C.M., McGuire, L.M., Adams, M.E., Froehner, S.C., Yates, J.R., 3rd and Vandenberg, C.A. (2004) Protein trafficking and anchoring complexes revealed by proteomic analysis of inward rectifier potassium channel (Kir2.x)-associated proteins. J. Biol. Chem., 279, 22331-22346.

14

82. 83.

84.

85.

86.

87.

88.

89.

90. 91. 92.

93.

Clinton, S.M. and Meador-Woodruff, J.H. (2004) Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder. Neuropsychopharmacology, 29, 1353-1362. Mueller, H.T., Haroutunian, V., Davis, K.L. and Meador-Woodruff, J.H. (2004) Expression of the ionotropic glutamate receptor subunits and NMDA receptorassociated intracellular proteins in the substantia nigra in schizophrenia. Brain Res. Mol. Brain Res., 121, 60-69. Clinton, S.M., Haroutunian, V., Davis, K.L. and Meador-Woodruff, J.H. (2003) Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia. Am. J. Psychiatry, 160, 11001109. Willatt, L., Cox, J., Barber, J., Cabanas, E.D., Collins, A., Donnai, D., FitzPatrick, D.R., Maher, E., Martin, H., Parnau, J. et al. (2005) 3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome. Am. J. Hum. Genet., 77, 154-160. Sachs, N.A., Sawa, A., Holmes, S.E., Ross, C.A., DeLisi, L.E. and Margolis, R.L. (2005) A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol. Psychiatry, 10, 758764. Callicott, J.H., Straub, R.E., Pezawas, L., Egan, M.F., Mattay, V.S., Hariri, A.R., Verchinski, B.A., Meyer-Lindenberg, A., Balkissoon, R., Kolachana, B. et al. (2005) Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc. Natl. Acad. Sci. U. S. A., 102, 8627-8632. Thomson, P.A., Wray, N.R., Millar, J.K., Evans, K.L., Hellard, S.L., Condie, A., Muir, W.J., Blackwood, D.H. and Porteous, D.J. (2005) Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population. Mol. Psychiatry, 10, 657-668. Seeman, P., Weinshenker, D., Quirion, R., Srivastava, L.K., Bhardwaj, S.K., Grandy, D.K., Premont, R.T., Sotnikova, T.D., Boksa, P., El-Ghundi, M. et al. (2005) Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc. Natl. Acad. Sci. U. S. A., 102, 3513-3518. Cubells, J.F. and Zabetian, C.P. (2004) Human genetics of plasma dopamine betahydroxylase activity: applications to research in psychiatry and neurology. Psychopharmacology, 174, 463-476. Chen, G., Dunbar, R.L., Gao, W. and Ebner, T.J. (2001) Role of calcium, glutamate neurotransmission, and nitric oxide in spreading acidification and depression in the cerebellar cortex. J. Neurosci., 21, 9877-9887. Fallin, M.D., Lasseter, V.K., Avramopoulos, D., Nicodemus, K.K., Wolyniec, P.S., McGrath, J.A., Steel, G., Nestadt, G., Liang, K.-Y., Huganir, R.L. et al. (2005) Bipolar I disorder and schizophrenia: A 440 single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am. J. Hum. Genet., 77, 918-936. Millar, J.K., Pickard, B.S., Mackie, S., James, R., Christie, S., Buchanan, S.R., Malloy, M.P., Chubb, J.E., Huston, E., Baillie, G.S. et al. (2005) DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science, 310, 1187-1191.

15

94. 95.

96. 97. 98.

Brereton, H.M., Firgaira, F.A. and Turner, D.R. (1993) Origins of polymorphism at a polypurine hypervariable locus. Nucleic Acids Res., 21, 2563-2569. Warpeha, K.M., Xu, W., Liu, L., Charles, I.G., Patterson, C.C., Ah-Fat, F., Harding, S., Hart, P.M., Chakravarthy, U. and Hughes, A.E. (1999) Genotyping and functional analysis of a polymorphic (CCTTT)(n) repeat of NOS2A in diabetic retinopathy. FASEB J., 13, 1825-1832. Xu, W., Liu, L., Emson, P.C., Harrington, C.R. and Charles, I.G. (1997) Evolution of a homopurine-homopyrimidine pentanucleotide repeat sequence upstream of the human inducible nitric oxide synthase gene. Gene, 204, 165-170. Raha-Chowdhury, R., Bowen, D.J. and Worwood, M. (1996) A new highly polymorphic marker in the 5' untranslated region of HLA-F shows strong allelic association with haemochromatosis. Hum. Genet., 97, 228-231. Trakooljul, N., Ponsuksili, S., Schellander, K. and Wimmers, K. (2000) A highly polymorphic repetitive polypyrimidine/polypurine (CCTTT)n sequence in the 5' untranslated sequence of the porcine androgen receptor gene. Anim. Genet., 31, 288-289.

16

Supplementary Table 1. Human Genes Containing Uninterrupted R•Y Tracts ≥ 250 bp Long

Entry Position

1A 1B 2 3 4A 4B 5 6 7 8 9 10 11 12 13 14A 14B 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

(hg17)

chr16:6998616 chr16:7219728 chr8:56364629 chr7:48227828 chr17:29450279 chr17:29450555 chr17:37313894 chr9:133458833 chr15:82174394 chr16:49077593 chr6:2361393 chr2:12243936 chr5:24181348 chr4:109870417 chr6:43980704 chr2:113193620 chr2:113312468 chr1:153693897 chrX:148315716 chr8:38533242 chr20:61150861 chr8:25509714 chr19:10020222 chr14:31993576 chr2:29965430 chr17:7951854 chr8:108451539 chr4:40825131 chrX:9600762 chr16:25134852 chr3:35764718 chr7:94789107 chr8:87226506 chrX:76698481 chr13:39865754

Supplementary Table 1

Chromosomal Location

Length Pure Repeat

Length Total Repeat

Gene Name

16p13.3 16p13.3 8q12.1 7p12.3 17q11.2-q12 17q11.2-q12 17q12-q21 9q34.2 15q25.2 16q12.1 6p25.2 2p25.1-p24.3 5p14.2 4q25 6p21.1 2q13 2q13 1q23.1 Xq28 8p11.23 20q13.33 8p21.2 19p13.2 14q13.1 2p23 17p13.1 8q22.3-q23 4p14 Xp22.3 16p12-p11.2 3p22.1 7q21-q22 8q21.13 Xq13.1-q21.1 13q14.11

391 295 393 279 275 389 306 337 301 255 265 261 364 344 262 255 251 268 264 259 253 343 331 312 411 266 276 270 268 267 311 291 259 250 357

649 708 393 359 719 719 306 969 319 351 427 369 364 344 349 284 305 279 387 259 270 343 403 366 419 278 276 270 268 307 624 291 259 332 357

A2BP1 A2BP1 AB067476 ABCA13 ACCN1 ACCN1 ACLY ADAMTSL2 ADAMTSL3 AF289584 AJ420566 AK001558 AK092155 AK094992 AK095548 AK096990 AK096990 AK098809 AK124660 AK127997 AK128329 AK130123 AK131489 AKAP6 ALK ALOXE3 ANGPT1 APBB2 APXL AQP8 ARPP-21 ASB4 ATP6V0D2 ATRX AY116215

Protein Name

Ataxin 2-binding protein 1 (SCA2) Ataxin 2-binding protein 1 (SCA2) KIAA1889 protein ATP-binding cassette gene subfamily A (ABC1) member 13 Amiloride-sensitive cation channel neuronal 1 Amiloride-sensitive cation channel neuronal 1 ATP citrate lyase ADAMTS-like 2 ADAMTS-like 3 Hs_EST Hs_EST Hs_EST Hypothetical protein FLJ34836 Hypothetical protein FLJ37673 Hypothetical protein FLJ38229 Hypothetical protein FLJ39671 Hypothetical protein FLJ39671 FLJ00193 protein Hs_EST Hypothetical protein FLJ46115 Hypothetical protein FLJ46471 Hypothetical protein FLJ26613 Hypothetical protein FLJ16677 A-kinase (PRKA) anchor protein 6 Anaplastic lymphoma kinase Arachidonate lipoxygenase 3 Angiopoietin 1 Amyloid β (A4) precursor protein-binding family B member 2 Apical protein-like (Xenopus laevis) Aquaporin 8 cAMP-regulated phosphoprotein 21kDa Ankyrin repeat- and SOCS box-containing protein 4 ATPase H+ transporting lysosomal 38kDa V0 subunit d isoform 2 α-thalassemia/mental retardation syndrome X-linked TTL/TEL fusion protein TTL-B1/2

Page 1 of 6

33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58A 58B 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74

chr16:27898454 chr11:126654751 chr6:25558927 chr5:148958019 chr7:47864472 chr12:11212067 chr2:87380916 chr1:69895462 chr11:364685 chr19:53465534 chr5:167288548 chr10:133836440 chr10:49665818 chr10:23660112 chr21:29171309 chr22:42153036 chr6:39412720 chr9:137673724 chr19:13462423 chr16:24184089 chr7:71118802 chr10:12909208 chr7:115789445 chrX:149663021 chr5:21916299 chr20:44243622 chr20:44285651 chr5:31338572 chr18:61600119 chr7:718235 chr14:94829195 chr17:30526013 chr7:146360473 chr2:125260093 chrX:107575913 chr8:68550476 chr12:37582224 chr8:94030991 chr19:16748856 chr19:4118333 chr17:34908648 chr22:25347809 chr3:123535045

16p11.2 11q24.2 6p22.2 5q32 7p12.3 12p13.2 2p11.2 1p31.1 11p15.5 19q13.32 5q34 10q26.3 10q11.23 10p12.31 21q21.3 22q13.31 6p21.2 9q34.3 19p13.2-p13.1 16p12-p13.1 7q11 10p14 7q31.1 Xq28 5p14-p13 20q13.1 20q13.1 5p15.1-p14 18q22-q23 7p22.3 14q32.2 17q21.1 7q35-q36 2q14.3 Xq22 8q13.2 12q12 8q22.1 19p13.11 19p13.3 17q21.2 22q12.1 3q21


253 272 314 250 357 267 276 255 347 334 260 277 281 282 328 367 302 356 288 262 286 261 252 753 294 267 262 281 286 1303 316 304 273 280 250 261 301 329 410 254 356 270 252

347 296 314 281 357 267 414 447 547 407 384 290 281 853 681 697 473 831 431 290 637 609 252 753 294 267 262 281 438 1315 354 360 291 358 334 346 346 404 1125 274 356 376 252

AY358206 BC030092 BC040903 BC041325 BC045737 BC064553 BC069048 BC080568 Beta4GalNAc-T4 BX645758 BX648178 C10orf39 C10orf64 C10orf67 C21orf127 C22orf1 C6orf102 C9orf111 CACNA1A CACNG3 CALN1 CAMK1D CAV1 CD99L2 CDH12 CDH22 CDH22 CDH6 CDH7 CENTA1 CLMN CMYA4 CNTNAP2 CNTNAP5 COL4A5 CPA6 CPNE8 CR749421 CR749794 CREB3L3 CRK7 CRYBA4 CSTA

KTSR5831 Hs_EST Hypothetical protein FLJ43708 Hs_EST Hypothetical protein LOC136288 Hypothetical protein FLJ41554 Hs_EST Densin-180 like protein β1,4-N-acetylgalactosaminyltransferases IV Hs_EST Odz, odd Oz/ten-m homolog 2 (Drosophila) Chromosome 10 open reading frame 39 Chromosome 10 open reading frame 64 Chromosome 10 open reading frame 67 Chromosome 21 open reading frame 127 (N6-DNA-methyltransferase?) Chromosome 22 open reading frame 1 Chromosome 6 open reading frame 102 Chromosome 9 open reading frame 111 Calcium channel voltage-dependent P/Q type a1A subunit (SCA6) Calcium channel voltage-dependent g subunit 3 Calneuron 1 Calcium/calmodulin-dependent protein kinase ID Caveolin 1 CD99 antigen-like 2 Cadherin 12 type 2 (N-cadherin 2) Cadherin-like 22 Cadherin-like 22 Cadherin 6 type 2, K-cadherin Cadherin 7 type 2 Centaurin α1 Calmin Cardiomyopathy associated 4 Contactin-associated protein-like 2 Contactin associated protein-like 5 Collagen type IV α5 Carboxypeptidase A6 Copine VIII Hypothetical protein DKFZp779L1068 Hypothetical protein LOC284434 cAMP responsive element binding protein 3-like 3 Cell division cycle 2-related protein kinase 7 Crystallin β A4 Cystatin A (stefin A)

Page 2 of 6

75 76 77 78 79A 79B 80 81A 81B 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107A 107B 108 109 110 111 112 113 114

chr2:80181748 chr10:67790353 chr5:11869710 chr7:73209845 chr18:48866321 chr18:48866599 chr7:131705607 chr1:66808506 chr1:66837721 chr11:83890804 chr18:3762092 chr17:69809537 chr19:10729915 chr16:88228435 chr3:115358253 chr21:40913726 chr7:100700397 chr19:14607796 chr1:22671397 chr11:127959943 chr17:64081144 chr2:88319872 chr2:127678072 chr9:28179212 chr4:185949144 chr2:11204082 chr5:36012731 chr1:219303433 chr21:39210474 chr1:200019171 chrX:147401626 chr13:48533495 chr17:30785447 chr5:151208849 chr12:102912877 chr12:102918050 chr2:175144854 chr10:25570060 chr12:12988937 chrX:122322937 chr21:29854471 chr7:126248908 chr7:43148749

2p12-p11.1 10q22.2 5p15.2 7q11.23 18q21.3 18q21.3 7q32.3 1p31.2 1p31.2 11q21 18p11.3 17q25 19p13.2 16q24.3 3q13.3 21q22.2-q22.3 7q22.1 19p13.1 1p36.11 11q23.3 17q24.2 2p11.2 2q14.3 9p21.2-p21.1 4q35.1 2p25.1 5p13.2 1q41 21q22.2 1q32.1 Xq28 13q14.2 17q12 5q33.1 12q23.3 12q23.3 2q31.1 10p12.1 12p13.3 Xq25-q26 21q22.11 7q31.3-q32.1 7p14.1-p13


257 304 868 300 395 277 254 311 254 303 360 335 328 706 348 586 250 259 286 454 290 481 364 511 278 381 289 291 262 271 256 472 267 253 318 256 284 316 292 300 341 384 293

257 374 868 300 673 673 3150 311 354 388 393 335 328 733 348 586 503 259 818 528 290 481 364 511 301 706 316 291 292 271 314 557 280 504 340 292 284 316 292 324 341 415 528

CTNNA2 CTNNA3 CTNND2 CYLN2 DCC DCC DKFZp434G0625 DKFZp761D221 DKFZp761D221 DLG2 DLGAP1 DNAI2 DNM2 DPEP1 DRD3 DSCAM EMID2 EMR3 EPHA8 ETS1 FAM20A FLJ10916 FLJ16008 FLJ31810 FLJ33167 FLJ33534 FLJ34658 FLJ43505 FLJ45139 FMOD FMR2 FNDC3A G36737 GLRA1 GLT8D2 GLT8D2 GPR155 GPR158 GPRC5D GRIA3 GRIK1 GRM8 HECW1

Catenin α2 Catenin α3 Catenin δ2 (neural plakophilin-related arm-repeat protein) Cytoplasmic linker 2 Deleted in colorectal carcinoma Deleted in colorectal carcinoma Hypothetical protein DKFZp434G0625 Hypothetical protein DKFZp761D221 Hypothetical protein DKFZp761D221 Discs large homolog 2 chapsyn-110 (Drosophila) Discs large (Drosophila) homolog-associated protein 1 Dynein axonemal intermediate polypeptide 2 Dynamin 2 Renal dipeptidase Dopamine receptor D3 Down syndrome cell adhesion molecule EMI domain containing 2 EGF-like module containing mucin-like hormone receptor-like 3 Ephrin receptor EphA8 V-ets erythroblastosis virus E26 oncogene homolog 1 (avian) Family with sequence similarity 20, member A Hypothetical protein FLJ10916 FLJ16008 protein Hypothetical protein FLJ31810 Hypothetical protein FLJ33167 Hypothetical protein FLJ33534 Hypothetical protein FLJ34658 FLJ43505 protein FLJ45139 protein Fibromodulin Fragile X mental retardation 2 Hypothetical protein FLJ31509 Hs_EST Glycine receptor α1 Hypothetical protein FLJ31494 (Gycosyltransferase) Hypothetical protein FLJ31494 (Gycosyltransferase) G protein-coupled receptor 155 G protein-coupled receptor 158 G protein-coupled receptor family C group 5 member D Glutamate receptor ionotrophic AMPA 3 Glutamate receptor ionotropic kainate 1 Glutamate receptor metabotropic 8 KIAA0322 protein

Page 3 of 6

115 116 117 118 119 120 121 122 123 124 125 126 127A 127B 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156

chr17:14173336 17p12-p11.2 chr1:24234492 1p36.11 chr3:186865802 3q28 chr15::39110898 15q15.1 chr3:37528451 3p21.3 chr21:34170229 21q22.1-q22.2 chr2:163195246 2q24.3 chr21:38006626 21q22.13-q22.2 chr10:78370725 10q22-q23 chr1:151541010 1q21.3 chr19:53583752 19q13.3 chr4:25468468 4p15.2 chr10:513935 10p15.3 chr10:552359 10p15.3 chrX:63931527 Xq12 chr7:139744621 7q34 chr1:229781676 1q42 chr11:126298192 11q24.2 chr19:56154733 19q13.3 chr18:6061633 18p11.31 chr2:99701289 2q11.2-q12 chr19:59377176 19q13.4 chr1:65665741 1p31 chr15:63030538 15q22.31 chr4:152084019 4q31.23 chr14:41320442 14q21.1 chr1:69959384 1p31.1 chr16:57002807 16p13.3-p13.2 chr4:141348080 4q28 chrX:19229832 Xp22.12 chr2:119460324 2q12-q13 chr4:6218266 4p16.1 chr8:99075434 8q22 chr15:92643042 15q26.2 chr3:170672891 3q26 chr17:75491397 17q25.3 chr4:84857185 4q21.23 chr2:98254611 2q11.2 chr12:118356329 12q24.23 chr11:10658390 11p15 chr19:8545400 19p13.3-p13.2 chr6:142441764 6q21-qter chr12:116222424 12q24.2-q24.31


294 283 316 251 284 327 306 317 267 281 272 263 403 328 281 317 304 376 319 258 279 585 310 279 416 250 304 277 411 390 263 322 265 254 371 285 332 340 260 308 258 303 410

302 283 458 273 284 327 393 386 267 894 272 263 1192 529 281 421 304 376 496 260 279 641 478 3935 546 250 304 277 411 390 299 348 265 315 390 392 466 585 335 308 282 303 978

HS3ST3B1 IL28RA IMP-2 INO80 ITGA9 ITSN1 KCNH7 KCNJ6 KCNMA1 KCNN3 KDELR1 KIAA0746 KIAA0934 KIAA0934 KIAA1166 KIAA1277 KIAA1804 KIRREL3 KLK6 L3MBTL4 LAF4 LENG4 LEPR LOC348094 LRBA LRFN5 LRRC7 M55268 MAML3 MAP3K15 MARCO MARLIN1 MATN2 MCTP2 MDS1 MGC10561 MGC11324 MGC26733 MGC39827 MRVI1 MYO1F NMBR NOS1

Heparan sulfate (glucosamine) 3-O-sulfotransferase 3B1 Interleukin 28 receptor α (interferon l receptor) IGF2 mRNA-binding protein 2 Homolog of yeast INO80 Integrin α9 Intersectin 1 (SH3 domain protein) Potassium voltage-gated channel subfamily H (eag-related) member 7 Potassium inwardly-rectifying channel subfamily J member 6 K+ large conductance Ca-activated channel subfamily M a member 1 K+ intermediate/small conductance Ca-activated channel N3 KDEL endoplasmic reticulum protein retention receptor 1 KIAA0746 protein KIAA0934 protein KIAA0934 protein Hepatocellular carcinoma-associated antigen 127 KIAA1277 protein Mixed lineage kinase 4 Kin of IRRE like 3 (Drosophila) Kallikrein 6 (neurosin, zyme) L(3)mbt-like 4 (Drosophila) Lymphoid nuclear protein related to AF4 Leukocyte receptor cluster member 4 Leptin receptor Hypothetical protein LOC348094 Lipopolysaccharide-responsive, Beige-like anchor Leucine rich repeat and fibronectin type III domain containing 5 LAP1 protein (Densin-180) Casein kinase 2, alpha prime polypeptide Mastermind-like 3 (Drosophila) Hypothetical protein FLJ16645 Macrophage receptor with collagenous structure Multiple coiled-coil GABABR1-binding protein Matrilin 2 Multiple C2-domains with two transmembrane regions 2 Myelodysplasia syndrome 1 Hypothetical protein MGC10561 hypothetical protein MGC11324 Hypothetical protein MGC26733 Hypothetical protein MGC39827 Murine retrovirus integration site 1 homolog Myosin IF Neuromedin B receptor Nitric oxide synthase 1 (neuronal)

Page 4 of 6

157 158 159 160 161A 161B 162 163 164A 164B 165A 165B 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180A 180B 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195

chr16:14929167 chr4:77403946 chr6:20276764 chr6:9903362 chrX:67289920 chrX:67425343 chr1:238096885 chr16:21633014 chrX:1631560 chrX:1677076 chrY:1631560 chrY:1677076 chrX:150492692 chr13:99902058 chrX:91208921 chrX:99394144 chr4:30734257 chr20:17276433 chr12:18347283 chrX:15211361 na chr20:8558426 chr7:131293258 chr20:36957824 chr21:42149061 chr11:56927461 chr16:23900379 chr16:23939791 chr10:53057593 chr12:15557203 chr20:41130001 chr3:29881301 chr8:57385187 chr1:189341919 chr6:72758809 chr8:74187403 chrX:37901641 chr3:72562947 chr6:148750239 chr16:23284112 chr17:68896451 chr12:112296830 chr6:100967133

16p13-p11 4q21.21 6p22.3 6p24.3 Xq12 Xq12 1q43 16p12.2 Xp22.33 Xp22.33 Yp11.3 Yp11.3 Xq28 13q32 Xq21.3 Xq22.1 4p15 20p11.2 12p12 Xp22.31 16p13.3 20p12 7q32.3 20q12 21q22.3 11q12 16p11.2 16p11.2 10q11.2 12p13.3-p13.2 20q12-q13 3p24-p23 8q12.1 1q31.2 6q12-q13 8q13.3 Xp21.1 3p14.2 6q24.3 16p12.2-p12.1 17q25.1-q25.2 12q24.21 6q16.3-q21


296 264 279 256 279 270 277 339 353 520 353 520 336 387 443 255 250 355 273 403 404 306 419 323 430 250 416 402 291 307 254 266 306 263 278 293 329 273 283 342 295 344 252

516 282 359 256 360 404 277 339 472 628 472 628 336 604 471 255 394 355 273 1129 2493 318 498 576 430 250 446 881 374 307 254 331 354 339 314 364 1191 273 344 342 295 344 290

NPIP NUP54 OACT1 OFCC1 OPHN1 OPHN1 OPN3 OTOA P2RY8 P2RY8 P2RY8 P2RY8 PASD1 PCCA PCDH11X PCDH19 PCDH7 PCSK2 PIK3C2G PIR PKD1 PLCB1 PLXNA4 PPP1R16B PRDM15 PRG2 PRKCB1 PRKCB1 PRKG1 PTPRO PTPRT RBMS3 RDH-E2 RGS13 RIMS1 RPESP RPGR RYBP SASH1 SCNN1B SDK2 SDS SIM1

Nuclear pore complex interacting protein Nucleoporin 54kDa O-acyltransferase (membrane bound) domain containing 1 Orofacial cleft 1 candidate 1 Oligophrenin 1 Oligophrenin 1 Opsin 3 (encephalopsin, panopsin) Otoancorin Purinergic receptor P2Y G-protein coupled 8 Purinergic receptor P2Y G-protein coupled 8 Purinergic receptor P2Y G-protein coupled 8 Purinergic receptor P2Y G-protein coupled 8 PAS domain containing protein 1 Propionyl-CoA carboxylase α subunit Protocadherin 11 X-linked Protocadherin 19 BH-protocadherin 7 Proprotein convertase subtilisin/kexin-type 2 Phosphoinositide-3-kinase class 2 γ polypeptide Pirin Polycystin-1 Phospholipase C, beta 1 (phosphoinositide-specific) Plexin A4 Protein phosphatase 1 regulatory (inhibitor) subunit 16B PR domain containing 15 Proteoglycan 2 Protein kinase C β1 Protein kinase C β1 Protein kinase cGMP-dependent regulatory type I Protein tyrosine phosphatase receptor type O Protein tyrosine phosphatase receptor type T RNA-binding motif single strand-interacting protein 3 Retinal short chain dehydrogenase reductase (fragment) Regulator of G protein signaling 13 Regulating synaptic membrane exocytosis 1 RPE-spondin Retinitis pigmentosa GTPase regulator Ring1- and YY1-binding protein Sterile a motifs- and SH3 domain-containing protein 1 Sodium channel nonvoltage-gated 1 β subunit Sidekick homolog 2 (Drosophila) Serine dehydratase Single-minded homolog 1 (Drosophila)

Page 5 of 6

196 197 198A 198B 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 225 224 226 227 228

chr14:36579151 14q11.2 chr12:7870675 12p13.31 chr17:68170004 17q24.3-q25.1 chr17:68407691 17q24.3-q25.1 chr5:168439064 5q35 chr4:7568766 4p16.1 chr11:16110348 11p15.3-p15.2 chr3:174161357 3q26.31 chr7:104405181 7q22-q31.1 chr1:43952284 1p34.1 chr13:32649841 13q12-q13 chr11:3873400 11p15.5 chr2:166348928 2q24.3 chr7:139018548 7q34-q35 chr21:31504709 21q22.11 chr11:69618958 11q13.3 chr11:22247289 11p14.3 chr11:117472712 11q23.3 chr9:114911402 9q33 chr1:171826339 1q23-q24 chr4:154522911 4q31.3 chr9:71265090 9q21.11 chr2:234618352 2q37.2 chr2:4878820 2p25.3 chr2:217267510 2q35 chr16:20264146 16p13.11p12.3 chr5:79869940 5q14.1 chr3:158472721 3q25.31-q25.32 chr7:70590034 7q11.23 chr16:77196053 16q23.3-q24.1 chr3:197425375 3q29 chr19:62340999 19q13.4 chr19:35566342 19q12 chr19:9098869 19p13.2


255 307 574 280 390 424 283 274 261 396 352 329 268 385 294 253 433 284 302 360 286 422 281 290 261 294 251 251 283 267 276 269 382 327

255 317 574 280 514 1006 283 274 414 595 372 329 1417 385 322 253 574 294 302 482 318 538 281 400 261 294 251 251 1057 398 280 374 414 508

SLC25A21 SLC2A14 SLC39A11 SLC39A11 SLIT3 SORCS2 SOX6 SPATA16 SRPK2 ST3GAL3 STARD13 STIM1 TAIP-2 TBXAS1 TIAM1 TMEM16A TMEM16E TMPRSS4 TNC TNN TRIM2 TRPM3 TRPM8 TSSC1 U72209 UMOD UNQ9217 VEPH1 WBSCR17 WWOX ZDHHC19 ZIM3 ZNF536 ZNF560

Solute carrier family 25 member 21 Solute carrier family 2 (facilitated glucose transporter), member 14 Solute carrier family 39 (metal ion transporter), member 11 Solute carrier family 39 (metal ion transporter), member 11 Slit homolog 3 (Drosophila) VPS10 domain receptor 2 SRY (sex determining region Y)-box 6 NYD-SP12 SFRS protein kinase 2 Sialyltransferase 6 (N-acetyllacosaminide α2,3-sialyltransferase) START domain containing 13 Stromal interaction molecule 1 TGFβ induced apoptosis protein 2 Thromboxane A synthase 1 T-cell lymphoma invasion and metastasis 1 Transmembrane protein 16A Transmembrane protein 16E Transmembrane protease serine 4 Tenascin C (hexabrachion) Tenascin N Tripartite motif-containing 2 Transient receptor potential cation channel, subfamily M, member 3 Transient receptor potential cation channel subfamily M member 8 Tumor suppressing subtransferable candidate 1 YY1-associated factor 2 Uromodulin (uromucoid, Tamm-Horsfall glycoprotein) AASA9217 Hypothetical protein WBS chromosome region 17, N-acetylgalactosaminyltransferase WW domain-containing oxidoreductase Zinc finger, DHHC domain containing 19 Zinc finger imprinted 3 Zinc finger protein 536 Zinc finger protein 560

Page 6 of 6

Supplementary Table 2. Functional Category Enrichment Analysis For Human Genes Harboring ≥ 250 bp Pure R•Y A. Gene Ontology (GO) Molecular Function Term Entry

Category - Terms - Pathways

Total 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

cation channel activity amiloride-sensitive sodium channel activity ion channel activity alpha-type channel activity channel or pore class transporter activity sodium channel activity glutamate receptor activity ligand-gated ion channel activity dipeptidase activity metabotropic glutamate/, GABA-B-like receptor activity protein binding potassium channel activity calcium ion binding exopeptidase activity calcium-activated potassium channel activity ATP citrate synthase activity L-serine ammonia-lyase activity thromboxane-A synthase activity sevenless binding N-acetyllactosaminide alpha-2/,3-sialyltransferase activity neurotransmitter receptor activity voltage-gated ion channel activity neurotransmitter binding propionyl-CoA carboxylase activity KDEL sequence binding phosphatidylinositol-4-phosphate 3-kinase activity glycine-inhibited chloride channel activity


R•Y Gene Hits

Population Hits

Fisher Exact P-Values

114 11 3 12 12 12 3 4 5 2 3 26 5 12 4 2 1 1 1 1 1 4 5 4 1 1 1 1

18541 312 9 446 480 494 27 63 119 11 41 2436 164 792 111 19 1 1 1 1 1 128 201 131 2 2 2 3

3.55E-06 1.85E-05 1.95E-05 4.00E-05 5.27E-05 5.95E-04 6.11E-04 8.42E-04 1.99E-03 2.04E-03 3.14E-03 3.45E-03 3.47E-03 4.90E-03 5.98E-03 6.15E-03 6.15E-03 6.15E-03 6.15E-03 6.15E-03 8.06E-03 8.07E-03 8.73E-03 1.23E-02 1.23E-02 1.23E-02 1.83E-02

Page 1 of 9

28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56

inhibitory extracellular ligand-gated ion channel activity ER retention sequence binding voltage-gated calcium channel activity membrane dipeptidase activity bombesin receptor activity G-protein activated inward rectifier potassium channel activity small conductance calcium-activated potassium channel activity ammonia-lyase activity myosin binding tissue kallikrein activity heparin-glucosamine 3-O-sulfotransferase activity glycine-gated chloride channel activity scavenger receptor activity neuropeptide receptor activity transmembrane receptor activity neuropeptide binding carboxypeptidase activity voltage-gated potassium channel activity CoA carboxylase activity glycine-gated ion channel activity excitatory extracellular ligand-gated ion channel activity transferase activity carbon-nitrogen lyase activity ligase activity/, forming carbon-carbon bonds signal transducer activity calcium channel activity kainate selective glutamate receptor activity transferase activity/, transferring acyl groups/, acyl groups converted into alkyl on transfer molecular_function unknown

1 1 2 1 1 1 1 1 1 1 1 1 2 2 17 2 2 3 1 1 2 18 1 1 28 2 1 1

3 3 35 4 4 4 4 4 4 5 5 5 45 45 1712 46 47 115 6 6 51 1901 7 7 3325 57 8 8

1.83E-02 1.83E-02 1.95E-02 2.44E-02 2.44E-02 2.44E-02 2.44E-02 2.44E-02 2.44E-02 3.04E-02 3.04E-02 3.04E-02 3.12E-02 3.12E-02 3.25E-02 3.25E-02 3.38E-02 3.40E-02 3.63E-02 3.63E-02 3.93E-02 4.20E-02 4.23E-02 4.23E-02 4.60E-02 4.80E-02 4.82E-02 4.82E-02

10

898

4.99E-02

102 7 13 8

16763 174 628 259

9.28E-05 1.11E-04 1.83E-04

185 additional terms displayed p values ≥0.05

B. Gene Ontology (GO) Biological Process Term Total 1 2 3

cell-cell adhesion cell adhesion transmission of nerve impulse


Page 2 of 9

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

neuromuscular physiological process cell communication cation transport metal ion transport cellular process organismal movement ion transport homophilic cell adhesion neurogenesis synaptic transmission monovalent inorganic cation transport transport localization synaptic vesicle transport biological_process unknown central nervous system development cell-cell signaling ATP catabolism nucleoside triphosphate catabolism purine nucleoside triphosphate catabolism ribonucleoside triphosphate catabolism purine ribonucleoside triphosphate catabolism protein autoprocessing potassium ion transport purine nucleotide catabolism purine ribonucleotide catabolism citrate metabolism carbohydrate biosynthesis ribonucleotide catabolism heparan sulfate proteoglycan biosynthesis/, enzymatic modification tissue regeneration organogenesis neuronal cell adhesion myelination regulated secretory pathway neuronal cell recognition heparan sulfate proteoglycan biosynthesis synaptic vesicle exocytosis calcium ion-dependent exocytosis


8 42 12 10 67 10 16 5 9 7 8 28 28 2 12 4 9 1 1 1 1 1 1 5 1 1 1 3 1 1 1 11 1 1 1 1 1 1 1

259 4177 589 421 8165 447 1037 118 405 254 355 2615 2621 10 797 107 543 1 1 1 1 1 1 193 2 2 2 88 3 3 3 903 4 4 4 5 5 5 5

1.83E-04 2.19E-04 2.39E-04 2.44E-04 3.88E-04 3.92E-04 5.08E-04 7.68E-04 8.11E-04 9.18E-04 1.46E-03 1.53E-03 1.59E-03 1.60E-03 3.27E-03 4.13E-03 5.84E-03 6.08E-03 6.08E-03 6.08E-03 6.08E-03 6.08E-03 6.08E-03 6.50E-03 1.21E-02 1.21E-02 1.21E-02 1.70E-02 1.81E-02 1.81E-02 1.81E-02 2.13E-02 2.40E-02 2.40E-02 2.40E-02 3.00E-02 3.00E-02 3.00E-02 3.00E-02

Page 3 of 9

43 44 45 46 47 48 49 50 51 52 53 54 55

wound healing visual perception musculoskeletal movement regulation of balance sensory perception of light equilibrioception coenzyme A metabolism neurophysiological process integrin-mediated signaling pathway prostaglandin biosynthesis prostanoid biosynthesis nucleotide catabolism heparan sulfate proteoglycan metabolism

1 4 4 4 4 4 1 10 2 1 1 1 1

5 193 193 193 193 193 6 864 51 7 7 8 8

3.00E-02 3.02E-02 3.02E-02 3.02E-02 3.02E-02 3.02E-02 3.60E-02 3.74E-02 3.85E-02 4.18E-02 4.18E-02 4.77E-02 4.77E-02

96 59 45 20 22 1 2 1 3 1 1 1 1 1 6 6

14827 5646 4104 1210 1660 2 28 3 92 4 5 5 5 6 409 409

2.78E-06 4.50E-05 7.85E-05 7.72E-04 1.29E-02 1.40E-02 1.93E-02 2.18E-02 2.56E-02 3.20E-02 3.20E-02 3.20E-02 3.82E-02 4.96E-02 4.96E-02


C. Gene Ontology (GO) Cellular Component Term Total 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

membrane integral to membrane integral to plasma membrane plasma membrane citrate lyase complex voltage-gated calcium channel complex presynaptic membrane synapse unconventional myosin sarcoplasm sarcoplasmic reticulum caveolar membrane caveola extracellular matrix (sensu Metazoa) extracellular matrix 41 additional terms displayed p values ≥0.05

D. Pfam Family


Page 4 of 9

Total 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

FN3 CADHERIN_C C2 AF-4 7TM_3 PALP VINCULIN CADHERIN FIBRINOGEN_C ASC DUF590 PDZ ANF_RECEPTOR PAS CNMP_BINDING CYTOCHROM_B_C MDH PIRIN AUXIN_EFF PIRIN_C REOVIRUS_M2 COLLAGEN LAMININ_G_1 SAM_1 LIG_CHAN WW SHTK VATP-SYNT_AC39 COA_BINDING STANNIOCALCIN VPS55 MRVI1 DUF1088 NEOGENIN_C SIM_C LAMININ_G_2 F5_F8_TYPE_C EGF_CA


159 10 4 8 2 3 2 2 5 3 2 2 6 3 3 3 1 1 1 1 1 1 4 3 4 2 3 1 1 1 1 1 1 1 1 1 3 2 4

14222 176 21 132 4 21 6 6 79 29 9 9 144 33 34 37 1 1 1 1 1 1 79 45 86 18 53 2 2 2 2 2 2 2 2 2 56 24 106

2.84E-05 7.76E-05 1.17E-04 7.34E-04 1.57E-03 1.81E-03 1.81E-03 1.90E-03 4.05E-03 4.25E-03 4.25E-03 5.58E-03 5.85E-03 6.36E-03 8.06E-03 1.10E-02 1.10E-02 1.10E-02 1.10E-02 1.10E-02 1.10E-02 1.18E-02 1.38E-02 1.57E-02 1.69E-02 2.14E-02 2.22E-02 2.22E-02 2.22E-02 2.22E-02 2.22E-02 2.22E-02 2.22E-02 2.22E-02 2.22E-02 2.47E-02 2.92E-02 3.10E-02

Page 5 of 9

39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57

PAC IG CITRATE_SYNT CAVEOLIN PEPTIDASE_M19 BK_CHANNEL_A DUF1193 SRCR EGF ION_TRANS LIGASE_COA ER_LUMEN_RECEPT RPH3A_EFFECTOR CAMBD NO_SYNTHASE SK_CHANNEL LEP_RECEPTOR_IG DMAP_BINDING SNF2_N

2 10 1 1 1 1 1 2 7 4 1 1 1 1 1 1 1 1 2

25 457 3 3 3 3 3 27 278 115 4 4 4 4 4 4 4 4 31

3.15E-02 3.26E-02 3.32E-02 3.32E-02 3.32E-02 3.32E-02 3.32E-02 3.63E-02 3.70E-02 4.01E-02 4.40E-02 4.40E-02 4.40E-02 4.40E-02 4.40E-02 4.40E-02 4.40E-02 4.40E-02 4.67E-02

51 2 2 1 1 1 1 1 1 1 2 1 1 1 1

4625 3 8 1 1 1 1 1 1 1 19 2 2 2 2

3.55E-04 3.20E-03 1.10E-02 1.10E-02 1.10E-02 1.10E-02 1.10E-02 1.10E-02 1.10E-02 1.81E-02 2.19E-02 2.19E-02 2.19E-02 2.19E-02

123 additional categories displayed p values ≥0.05

E. Protein Information Resource (PIR) Family Total 1 2 3 4 5 6 7 8 9 10 11 12 13 14

ALPHA-CATENIN MANNOSE 6-PHOSPHATE RECEPTOR, CATION-INDEPENDENT PIRIN PROTEIN-TYROSINE-PHOSPHATASE, RECEPTOR TYPE O TENASCIN ATP CITRATE SYNTHASE, FUSED LARGE AND SMALL SUBUNITS UROMODULIN CAVEOLIN FRUIT FLY CALCIUM-ACTIVATED POTASSIUM CHANNEL SLO CADHERIN PROTOZOAN MYOSIN HEAVY CHAIN IB CGMP-DEPENDENT PROTEIN KINASE DISKS LARGE-ASSOCIATED PROTEIN 1 HUMAN PML-1 PROTEIN


Page 6 of 9

15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

INTEGRIN ALPHA-4 CHAIN MEMBRANE GLYCOPROTEIN 2 THREONINE DEHYDRATASE KDEL RECEPTOR NITRIC-OXIDE SYNTHASE CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE TYPE I DISCS-LARGE TUMOR SUPPRESSOR PROTEIN KINASE C, ALPHA/BETA/GAMMA TYPES 1-PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE PHOSPHODIESTERASE I FRUIT FLY SLIT PROTEIN HSC2 PHOSPHATIDYLINOSITOL 3-KINASE HUMAN ACETYL-COA CARBOXYLASE MEMBRANE DIPEPTIDASE CARTILAGE MATRIX PROTEIN MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 10 HUMAN AMILORIDE-SENSITIVE SODIUM CHANNEL PROTEIN PROTEIN-TYROSINE-PHOSPHATASE, RECEPTOR TYPE MU

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

2 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4

2.19E-02 3.27E-02 3.27E-02 3.27E-02 3.27E-02 3.27E-02 3.27E-02 3.27E-02 3.27E-02 3.27E-02 3.27E-02 3.27E-02 3.27E-02 4.34E-02 4.34E-02 4.34E-02 4.34E-02

23 2 7 3 1 3 1 1 1

2816 15 294 61 2 76 3 5 6

6.28E-03 7.06E-03 1.26E-02 1.63E-02 2.30E-02 2.43E-02 4.02E-02 4.80E-02

13 2 2

1431 20 21

1.32E-02 1.45E-02


F. Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Total 1 2 3 4 5 6 7 8

Nitrobenzene degradation Neuroactive ligand-receptor interaction Cholera - Infection Carbazole degradation Phosphatidylinositol signaling system 1,1,1-Trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) degradation 2,4-Dichlorobenzoate degradation Benzoate degradation via hydroxylation 30 additional pathways displayed p values ≥0.05

G. BioCarta Pathway Total 1 2

Aspirin blocks signaling pathway involved in platelet activation Eicosanoid metabolism


Page 7 of 9

3 4 5 6

CCR3 signaling in eosinophils fMLP induced chemokine gene expression in HMC-1 cells Ion channel and phorbol esters signaling pathway Reversal of insulin resistance by leptin

2 2 1 1

23 27 5 5

1.73E-02 2.35E-02 4.47E-02 4.47E-02

29 2 2 2 1 1 1 1 1 2 3 1 1 1 1 1 2 1 1 1 1 1 2 1 1 1 2 1 2 1

4579 7 8 9 1 1 1 1 1 22 67 2 2 2 2 2 29 3 4 4 4 4 43 5 5 6 51 7 54 8

7.98E-04 1.06E-03 1.36E-03 6.33E-03 6.33E-03 6.33E-03 6.33E-03 6.33E-03 8.27E-03 8.34E-03 1.26E-02 1.26E-02 1.26E-02 1.26E-02 1.26E-02 1.41E-02 1.89E-02 2.51E-02 2.51E-02 2.51E-02 2.51E-02 3.00E-02 3.13E-02 3.13E-02 3.74E-02 4.08E-02 4.35E-02 4.52E-02 4.96E-02

25 additional pathways displayed p values ≥0.05

H. Protein Interaction Partners Total 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

DLG4 FPR1 GNA15 KIAA1365 DPEP1 CTSH GRM1 PDZK3 NCK1 RAC1 CSTA DEDD PTGS2 SNTA1 E2F6 GNAI1 TEK BU683081 CTNND2 FREQ ERBB2IP KRAS2 DLG1 NEDD4 STX1A PRKCA LEP BC030956 F2RL3


Page 8 of 9

30 31 32 33 34

ERBB4 ABL2 COL4A3 COL4A4 COL4A6

1 1 1 1 1

8 8 8 8 8

4.96E-02 4.96E-02 4.96E-02 4.96E-02 4.96E-02

7 3 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

1124 64 1 1 1 1 1 1 1 1 1 1 2 2 3 3 4

5.23E-03 6.23E-03 6.23E-03 6.23E-03 6.23E-03 6.23E-03 6.23E-03 6.23E-03 6.23E-03 6.23E-03 6.23E-03 1.24E-02 1.24E-02 1.86E-02 1.86E-02 2.47E-02


I. Disease Association Total 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

schizophrenia opiate dependence polycystic kidney disease 1 serum insulin levels in obese tIgE body mass index and waist circumference Caroli's disease early-onset prostate cancer EO insulin in obese women with impaired glucose tolerance (IGT) late-onset Alport syndrome Tourette syndrome sickle cell disease Retinitis Pigmentosa affective disorder overfeeding 6 additional categories displayed p values ≥0.05


Page 9 of 9

Supplementary Table 3. Functional Category Enrichment Analysis For Human Genes Harboring ≥ 100 bp Pure R•Y A. Gene Ontology (GO) Molecular Function Term Entry

Total 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27


protein binding kinase activity protein kinase activity phosphotransferase activity/, alcohol group as acceptor ligand-gated ion channel activity transferase activity/, transferring phosphorus-containing groups ion channel activity transferase activity transmembrane receptor protein kinase activity channel or pore class transporter activity alpha-type channel activity calcium ion binding glutamate receptor activity protein serine/threonine kinase activity cation channel activity transmembrane receptor protein tyrosine kinase activity ionotropic glutamate receptor activity glutamate-gated ion channel activity monocarboxylate channel activity glutamate channel activity transmembrane receptor protein tyrosine phosphatase activity transmembrane receptor protein phosphatase activity extracellular ligand-gated ion channel activity signal transducer activity excitatory extracellular ligand-gated ion channel activity calmodulin binding catalytic activity


R•Y Gene Hits

Population Hits

Fisher Exact P-Values

1157 244 129 94 104 27 121 61 178 23 64 62 89 17 65 43 18 9 9 9 9 8 8 18 265 13 20 467

18541 2436 1056 766 890 119 1146 446 1901 95 494 480 792 63 558 312 78 22 23 23 23 18 18 87 3325 51 111 6448

6.25E-15 7.46E-14 1.83E-10 3.20E-10 3.48E-09 5.69E-09 5.92E-09 1.28E-08 1.34E-08 2.10E-08 3.92E-08 4.16E-08 1.92E-07 8.42E-07 8.43E-07 1.07E-06 3.30E-06 5.12E-06 5.12E-06 5.12E-06 5.59E-06 5.59E-06 5.68E-06 5.81E-06 1.04E-05 1.58E-05 2.59E-05

Page 1 of 18

28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

sialyltransferase activity protein-tyrosine kinase activity cytoskeletal protein binding heparin-glucosamine 3-O-sulfotransferase activity GTPase regulator activity diacylglycerol binding protein kinase C activity phorbol ester receptor activity adenyl nucleotide binding receptor activity ATP binding enzyme regulator activity receptor signaling protein activity small GTPase regulatory/interacting protein activity calcium channel activity voltage-gated calcium channel activity phosphatidylinositol binding amiloride-sensitive sodium channel activity guanyl-nucleotide exchange factor activity N-methyl-D-aspartate selective glutamate receptor activity transmembrane receptor protein serine/threonine kinase activity transforming growth factor beta receptor activity metabotropic glutamate/, GABA-B-like receptor activity phosphoinositide binding acetate-CoA ligase activity X-Pro aminopeptidase activity phospholipase A1 activity ubiquitin-like-protein ligase activity lipid binding calcium-release channel activity CoA carboxylase activity guanylate kinase activity ephrin receptor activity sodium channel activity GTPase activator activity GABA receptor activity scavenger receptor activity lysophospholipase activity epidermal growth factor receptor activity


8 43 43 4 32 10 5 5 157 184 153 66 25 23 11 8 4 4 15 3 5 5 8 4 2 2 2 2 24 3 3 4 5 6 15 7 8 3 3

22 364 366 5 251 39 10 10 1917 2310 1888 696 194 173 57 35 9 9 105 5 17 17 41 11 2 2 2 2 215 6 6 12 19 27 116 36 45 7 7


Page 2 of 18

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105

ligase activity/, forming carbon-carbon bonds transporter activity exopeptidase activity phospholipase activity opioid receptor activity cytoskeletal adaptor activity kainate selective glutamate receptor activity GABA-A receptor activity atypical protein kinase C activity insulin-like growth factor receptor activity inositol 1/,4/,5-triphosphate-sensitive calcium-release channel activity inositol-1/,4/,5-triphosphate receptor activity N-acetylgalactosamine 4-O-sulfotransferase activity translation repressor activity receptor tyrosine kinase binding neurotrophin binding phosphoric ester hydrolase activity metallopeptidase activity lipase activity sulfotransferase activity nucleotide kinase activity ligand-dependent nuclear receptor activity actin binding phosphoprotein phosphatase activity phosphotransferase activity/, phosphate group as acceptor purine nucleotide binding nucleobase/, nucleoside/, nucleotide kinase activity extracellular matrix structural constituent phospholipid binding metalloexopeptidase activity nucleotide binding dihydropyrimidinase activity dihydropyridine-sensitive calcium channel activity G-protein activated inward rectifier potassium channel activity regulator of G-protein signaling activity ammonia-lyase activity transferase activity/, transferring sulfur-containing groups steroid hormone receptor activity hydrolase activity/, acting on carbon-nitrogen (but not peptide) bonds


3 151 14 11 3 3 3 6 2 2 2 2 2 2 2 2 34 26 12 8 5 10 26 21 7 172 8 16 10 9 173 2 2 2 2 2 8 9 13

7 2012 111 80 8 8 8 31 3 3 3 3 3 3 3 3 362 260 94 52 24 73 265 203 43 2370 54 145 76 66 2400 4 4 4 4 4 56 68 114


Page 3 of 18

106 107 108 109 110 111 112 113 114 115

116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133

carboxypeptidase activity voltage-gated ion channel activity protein kinase regulator activity intracellular ligand-gated ion channel activity calmodulin regulated protein kinase activity tubulin binding deaminase activity enzyme activator activity transmembrane receptor protein tyrosine kinase signaling protein activity oxidoreductase activity/, acting on paired donors/, with incorporation or reduction of molecular oxygen/, reduced ascorbate as one donor/, and incorporation of one atom of oxygen Ras interactor activity non-membrane spanning protein tyrosine kinase activity metallocarboxypeptidase activity 3'/,5'-cyclic-nucleotide phosphodiesterase activity anion transporter activity cyclic-nucleotide phosphodiesterase activity glycerophosphoinositol inositolphosphodiesterase activity protein tyrosine phosphatase activity AMP binding microtubule binding kinase regulator activity SH3/SH2 adaptor protein activity restriction endodeoxyribonuclease activity type III site-specific deoxyribonuclease activity diphosphotransferase activity hydrolase activity/, acting on carbon-nitrogen (but not peptide) bonds/, in cyclic amides acid-thiol ligase activity GTP-dependent protein binding

7 20 8 3 4 5 5 19 7 2

47 201 58 11 19 28 28 191 49 5

2.55E-02 2.64E-02 2.68E-02 2.70E-02 2.75E-02 2.78E-02 2.78E-02 3.00E-02 3.14E-02 3.43E-02

2 3 5 5 9 5 5 12 3 4 8 6 2 2 2 2 2 2

5 12 30 30 74 31 31 110 13 22 65 43 6 6 6 6 6 6

3.43E-02 3.49E-02 3.64E-02 3.64E-02 4.00E-02 4.12E-02 4.12E-02 4.15E-02 4.33E-02 4.49E-02 4.84E-02 4.93E-02 4.93E-02 4.93E-02 4.93E-02 4.93E-02 4.93E-02 4.93E-02

1064 652 375 87

16763 8165 4177 628

1.25E-17 5.24E-15 3.36E-12


B. Gene Ontology (GO) Biological Process Term Total 1 2 3

cellular process cell communication cell adhesion


Page 4 of 18

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

protein amino acid phosphorylation enzyme linked receptor protein signaling pathway organismal movement neurogenesis phosphorus metabolism phosphate metabolism development organogenesis transmission of nerve impulse neuromuscular physiological process morphogenesis transmembrane receptor protein tyrosine kinase signaling pathway protein modification synaptic transmission phosphorylation cellular physiological process glutamate signaling pathway ion transport signal transduction localization neuromuscular junction development intracellular signaling cascade transport muscle development cell-cell signaling central nervous system development cell growth and/or maintenance cell-cell adhesion regulation of cellular process cation transport myogenesis metal ion transport learning and/or memory cell motility regulation of G-protein coupled receptor protein signaling pathway vesicle-mediated transport homophilic cell adhesion neuropeptide signaling pathway cell death


91 32 61 57 113 113 174 99 41 41 118 24 177 40 94 402 7 102 276 217 4 108 215 22 59 19 344 25 80 60 7 45 6 37 7 34 17 15 48

748 159 447 405 1062 1062 1845 903 259 259 1137 109 1905 254 867 5150 13 1037 3465 2621 4 1144 2615 130 543 107 4559 174 834 589 21 421 17 334 26 307 118 102 491


Page 5 of 18

43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81

proteoglycan metabolism muscle contraction cell migration neuronal cell recognition wound healing death cell recognition synaptic vesicle transport humoral immune response fatty acid metabolism calcium ion transport carbohydrate biosynthesis positive regulation of actin filament polymerization regulation of apoptosis collagen catabolism exocytosis signal complex formation regulation of programmed cell death visual perception musculoskeletal movement regulation of balance sensory perception of light equilibrioception lipid metabolism humoral defense mechanism (sensu Vertebrata) lipid biosynthesis apoptosis proteoglycan biosynthesis neurophysiological process programmed cell death detection of chemical substance energy reserve metabolism glycerophospholipid metabolism sodium ion transport negative regulation of cell proliferation positive regulation of apoptosis membrane lipid metabolism axonogenesis positive regulation of programmed cell death


6 19 11 3 3 48 5 4 20 18 13 13 2 29 5 9 3 29 22 22 22 22 22 54 15 23 43 4 73 43 3 7 6 13 16 16 15 7 16

22 145 64 5 5 496 16 10 162 140 88 88 2 271 18 51 6 273 193 193 193 193 193 598 114 206 458 13 864 461 7 37 29 98 132 133 122 39 134


Page 6 of 18

82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120

phospholipid metabolism heparan sulfate proteoglycan metabolism sulfur metabolism membrane lipid biosynthesis mRNA editing RNA interference posttranscriptional gene silencing RNA editing mRNA modification RNA-mediated gene silencing tissue regeneration sphingolipid biosynthesis axon guidance epidermal growth factor receptor signaling pathway regulation of cell proliferation regulation of neurotransmitter levels monovalent inorganic cation transport endocytosis glycosphingolipid biosynthesis ribonucleoside metabolism membrane fusion purine ribonucleoside salvage neuronal cell adhesion myelination purine salvage nucleoside salvage regulated secretory pathway negative regulation of myogenesis cytokine secretion perception of sound antimicrobial humoral response sensory perception of mechanical stimulus neurotransmitter secretion detection of mechanical stimulus complement activation/, classical pathway induction of apoptosis induction of programmed cell death second-messenger-mediated signaling smooth muscle contraction


11 3 8 9 2 2 2 2 2 2 2 4 5 4 26 7 33 16 3 3 5 2 2 2 2 2 2 2 2 11 11 11 4 11 5 14 14 19 5

79 8 49 59 3 3 3 3 3 3 3 15 23 16 263 43 355 142 10 10 26 4 4 4 4 4 4 4 4 88 88 88 18 89 27 126 126 188 29


Page 7 of 18

121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149

actin polymerization and/or depolymerization detection of abiotic stimulus actin filament polymerization transmembrane receptor protein serine/threonine kinase signaling pathway digestion organic acid biosynthesis carboxylic acid biosynthesis negative regulation of catabolism synaptic vesicle exocytosis regulation of myogenesis collagen fibril organization epithelial cell differentiation metabolic compound salvage regulation of protein secretion di-/, tri-valent inorganic cation transport potassium ion transport glycogen metabolism excretion protein lipidation lipoprotein biosynthesis glycoprotein metabolism antimicrobial humoral response (sensu Vertebrata) glucan metabolism striated muscle contraction secretion glycolipid biosynthesis regulation of cell migration protein amino acid glycosylation fatty acid biosynthesis

5 14 4 6 8 8 8 2 2 2 2 2 2 2 15 19 5 6 4 4 15 10 5 5 8 3 3 13 7

29 129 20 39 60 60 60 5 5 5 5 5 5 5 142 193 30 40 21 21 145 85 31 31 63 13 13 122 53


962 478 184 353 132

14827 5646 1660 4104 1210

2.46E-14 5.25E-14 1.89E-10 1.08E-09


C. Gene Ontology (GO) Cellular Component Term Total 1 2 3 4

membrane plasma membrane integral to membrane integral to plasma membrane


Page 8 of 18

5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

extracellular matrix (sensu Metazoa) extracellular matrix synapse cell fraction Golgi apparatus membrane fraction basement membrane postsynaptic membrane axoneme basal lamina collagen type IV axonemal dynein complex extrinsic to membrane sheet-forming collagen voltage-gated calcium channel complex cell projection collagen type V calcineurin complex lipid raft dystrophin-associated glycoprotein complex endomembrane system fibrillar collagen endoplasmic reticulum caveolar membrane coated pit cytoplasmic vesicle

58 58 17 73 42 57 11 11 5 7 3 4 10 3 6 7 2 2 2 4 22 3 38 2 6 15

409 409 92 738 367 554 52 56 14 30 6 12 63 7 28 38 3 3 3 16 213 10 432 5 39 145

1.33E-08 1.33E-08 7.69E-05 1.88E-04 2.39E-04 3.56E-04 4.18E-04 8.12E-04 1.39E-03 2.58E-03 4.69E-03 5.72E-03 6.98E-03 7.82E-03 8.06E-03 1.02E-02 1.21E-02 1.21E-02 1.21E-02 1.71E-02 2.07E-02 2.32E-02 3.44E-02 3.69E-02 3.82E-02 4.93E-02

1583 54 93 62 16 36 17 10

14222 176 471 278 33 144 45 18

1.43E-12 1.92E-08 5.43E-08 9.44E-08 2.10E-06 2.95E-06 5.35E-06


D. Pfam Family Total 1 2 3 4 5 6 7

FN3 PKINASE EGF ANF_RECEPTOR PDZ LAMININ_G_1 LIG_CHAN


Page 9 of 18

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

ION_TRANS PH SH3_1 C1_1 LAMININ_G_2 CADHERIN_C C2 SAM_1 EGF_CA GUANYLATE_KIN RYDR_ITPR GPS 7TM_3 CADHERIN Y_PHOSPHATASE PID WW IG CALX-BETA RHOGEF COLLAGEN VWA PKINASE_C RYR RR_TM4-6 EPHRIN_LBD SRCR C4 ANATO CUB MIR CH GLYCO_TRANSF_29 LAMININ_N DYNEIN_HEAVY PKD MAM CNMP_BINDING PLAT


30 54 44 19 18 10 31 23 26 10 5 13 9 20 13 12 15 74 5 18 19 18 14 3 3 6 9 4 4 14 5 18 7 6 6 5 6 10 7

115 265 208 61 56 21 132 86 106 23 6 39 21 79 42 37 53 457 8 72 79 74 51 3 3 13 27 6 6 55 10 81 19 15 15 11 16 37 21


Page 10 of 18

47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85

LAMININ_EGF ACTIVIN_RECP TROPOMYOSIN AMP-BINDING GUANYLATE_CYC LIPASE PAX DAGK_ACC NA_CA_EX DUF590 FOCAL_AT DUF737 ANT_C SIM_C ABC_MEMBRANE DAGK_CAT UDENN BAND_41 SH2 RCC1 VINCULIN ZF-C2HC UBA IQ TIG COESTERASE DENN DDENN AMIDOHYDRO_1 BNR PDEASE_I DEP CARB_ANHYDRASE FURIN-LIKE RECEP_L_DOMAIN FERRIC_REDUCT A2M_N RPEL PROTAMINE_P1


11 5 7 9 6 4 4 4 4 4 2 2 2 2 7 5 5 11 20 8 3 3 10 16 8 5 5 5 4 4 6 6 5 3 3 3 3 3 2

43 12 22 34 18 9 9 9 9 9 2 2 2 2 24 14 14 48 110 32 6 6 45 85 33 16 16 16 11 11 22 22 17 7 7 7 7 7 3


Page 11 of 18

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107

CU2_MONOOXYGEN CAVEOLIN SYNAPSIN_N NEUREGULIN SYNAPSIN_C PKI PARALEMMIN BK_CHANNEL_A CU2_MONOOX_C PHK_AB 7TM_2 PSI ZF-U1 FIBRINOGEN_C VWD FN2 MYOSIN_HEAD SEA F5_F8_TYPE_C RGS RHOGAP L27

2 2 2 2 2 2 2 2 2 2 12 8 6 7 4 4 8 5 6 8 12 4

3 3 3 3 3 3 3 3 3 3 61 35 23 29 12 12 36 18 24 37 64 13

3.44E-02 3.44E-02 3.44E-02 3.44E-02 3.44E-02 3.44E-02 3.44E-02 3.44E-02 3.44E-02 3.44E-02 3.46E-02 3.52E-02 3.60E-02 3.60E-02 3.64E-02 3.64E-02 4.10E-02 4.22E-02 4.36E-02 4.74E-02 4.79E-02 4.80E-02

492 8 3 3 3 3 3 3 8 6 3 3

4625 19 3 3 3 3 3 3 24 15 4 4

4.04E-04 1.20E-03 1.20E-03 1.20E-03 1.20E-03 1.20E-03 1.20E-03 2.43E-03 3.04E-03 4.41E-03 4.41E-03


E. Protein Information Resource (PIR) Family Total 1 2 3 4 5 6 7 8 9 10 11

CADHERIN ALPHA-CATENIN PROTEIN KINASE C, ALPHA/BETA/GAMMA TYPES RYANODINE RECEPTOR SKELEMIN FIBRILLIN FRUIT FLY SLIT PROTEIN ACETYLCHOLINE RECEPTOR SIALYLTRANSFERASE PROTEIN KINASE C, DELTA/EPSILON/ETA/THETA TYPES PROTEIN-TYROSINE-PHOSPHATASE, RECEPTOR TYPE MU


Page 12 of 18

12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

ALLANTOINASE PROTEIN-TYROSINE KINASE, RECEPTOR TYPE EPH N-METHYL-D-ASPARTATE RECEPTOR 2A PROTOZOAN MYOSIN HEAVY CHAIN IB SACCHAROMYCES HYPOTHETICAL PROTEIN YKL189W TRANSCRIPTION FACTOR ETS TRANSCRIPTION FACTOR OCT-2 DYSTROPHIN INSULIN RECEPTOR TYROSINE-PROTEIN KINASE, PROTO-ONCOGENE SRC TYPE RIBOSOMAL PROTEIN S6 KINASE II COLLAGEN ALPHA 1(IV) CHAIN NEUREXIN SERINE/THREONINE PROTEIN PHOSPHATASE 2B CATALYTIC SUBUNIT CAMP-DEPENDENT PROTEIN KINASE INHIBITOR HUMAN ACETYL-COA CARBOXYLASE HUMAN DIACYLGLYCEROL KINASE HUMAN TRANSCRIPTION FACTOR 3 MANNOSE 6-PHOSPHATE RECEPTOR, CATION-INDEPENDENT

3 4 2 2 2 2 2 2 2 5 3 3 2 2 2 2 2 2 3

4 8 2 2 2 2 2 2 2 15 6 6 3 3 3 3 3 3 8

4.41E-03 6.24E-03 1.10E-02 1.10E-02 1.10E-02 1.10E-02 1.10E-02 1.10E-02 1.10E-02 1.62E-02 1.87E-02 1.87E-02 3.15E-02 3.15E-02 3.15E-02 3.15E-02 3.15E-02 3.15E-02 4.46E-02

296 21 31 46 14 8 5 6 14

2816 76 164 294 61 32 15 25 83

1.87E-05 6.25E-04 2.52E-03 3.39E-03 1.49E-02 1.53E-02 4.10E-02 4.78E-02

179

1431


F. Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Total 1 2 3 4 5 6 7 8

Phosphatidylinositol signaling system Wnt signaling pathway Neuroactive ligand-receptor interaction Cholera - Infection Phospholipid degradation Dentatorubropallidoluysian atrophy (DRPLA) beta-Alanine metabolism Integrin-mediated cell adhesion 97 additional pathways displayed p values ≥0.05

G. BioCarta Pathway Total


Page 13 of 18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Synaptic proteins at the synaptic junction g-Secretase mediated ErbB4 signaling pathway Agrin in postsynaptic differentiation Gamma-aminobutyric acid receptor life cycle CBL mediated ligand-induced downregulation of EGF receptors Nitric oxide signaling pathway Alpha-synuclein and Parkin-mediated proteolysis in Parkinson's disease Ion channel and phorbol esters signaling pathway IL-7 signal transduction Transcription factor CREB and its extracellular signals Eph Kinases and ephrins support platelet aggregation Phospholipase C signaling pathway Apoptotic signaling in response to DNA damage B lymphocyte cell surface molecules Reelin signaling pathway

7 4 9 4 5 4 2 3 5 6 4 3 6 4 3

17 6 28 7 11 8 2 5 14 19 10 6 21 11 7

2.76E-03 2.89E-03 5.03E-03 6.10E-03 7.09E-03 1.10E-02 1.55E-02 1.59E-02 2.24E-02 2.35E-02 2.70E-02 2.88E-02 3.80E-02 3.83E-02 4.59E-02

426 6 5 4 8 10 6 6 6 6 5 5 7 15 20 15 8 11 13

4579 8 8 5 22 33 13 13 13 13 9 9 18 67 103 69 25 43 56


226 additional pathways displayed p values ≥0.05

H. Protein Interaction Partners Total 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

ERBB4 COL4A6 ADAM15 DAG1 FYN GABRA6 GABRA5 GABRA1 GABRA3 COL4A1 COL4A2 DMD RAC1 GRB2 ITGB1 PSEN1 KRAS2 PXN


Page 14 of 18

19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57

SRC SOCS1 DLG4 SERPINE1 NCK1 PPP3CB ITGA1 SOS1 BM803698 COL4A3 COL4A4 COL4A5 IGHG4 PRKAR1A MLC1 AGRN CDC42 GABRA2 WAS GABRA4 AP2A1 PIK3R1 SHC1 RHOA ITGA2B F12 AP2M1 CTTN GIT2 SERPINB2 PTGER1 PRKACG PRKAR2B PRKACB NM_006218 FYB DTNB VLDLR IRS2


16 8 4 6 7 5 12 14 4 4 4 4 10 10 6 6 9 5 5 5 5 17 15 11 4 4 5 5 5 3 3 11 11 11 15 2 2 2 2

77 26 7 16 22 12 54 68 8 8 8 8 42 42 18 18 36 13 13 13 13 95 80 51 9 9 14 14 14 5 5 53 53 53 83 2 2 2 2


Page 15 of 18

58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96

PREI3 DNM1 BIN1 BIN2 PICALM MYLK PRKAR2A VIL2 DAXX RAPSN FSHB GRB10 ITGB3 HCK PAK2 JUND CASK CSK EPN1 LCP2 GNAI1 PTK2 UTRN PRKCA PPP3CC PML CAST BX464768 ANXA2P2 CBL E2F1 CAPNS1 APBA1 BMP2 ADAM9 EFNB2 LRP8 XM_496386 CASP3


2 7 4 4 4 4 11 7 7 5 3 3 3 3 3 3 3 8 4 4 7 12 5 10 4 4 5 3 3 7 8 6 2 2 2 2 2 2 8

2 27 10 10 10 10 55 28 28 16 6 6 6 6 6 6 6 35 11 11 29 65 17 51 12 12 18 7 7 31 38 25 3 3 3 3 3 3 39


Page 16 of 18

97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135

CAPN2 HLA-DRA EPS15 YWHAB CRKL JAK3 LIMK1 ABL2 GPHN NM_005228 ACTA1 MAPK1 APP CASQ1 RAF1 IL2RG SP100 BIRC5 NCKAP1 PTPRC PPARGC1A CD3G CD3E CD3D CD4 EFNA5 EFNA4 EFNA1 RANBP9 SST BU683081 DPF2 DAB1 DRD3 CTNND2 DTNA WASPIP EFNA3 FGB


5 5 5 5 8 6 3 3 3 7 9 10 5 5 6 6 3 3 3 3 3 4 4 4 4 2 2 2 2 2 2 2 2 2 2 2 2 2 2

19 19 19 19 40 26 8 8 8 34 49 57 21 21 28 28 9 9 9 9 9 15 15 15 15 4 4 4 4 4 4 4 4 4 4 4 4 4 4


Page 17 of 18

136 137 138

STAT5B SYNJ1 BCAR1

2 2 6

4 4 29

4.56E-02 4.56E-02 4.70E-02

75 3 4 11 4 3 2 6 3 2 4

1124 3 7 64 12 8 4 36 11 5 21

2.86E-04 5.50E-04 2.33E-03 6.01E-03 1.25E-02 2.41E-02 2.82E-02 3.19E-02 3.85E-02 4.59E-02


I. Disease Association Total 1 2 3 4 5 6 7 8 9 10

affective disorder autism schizophrenia alcoholism systemic sclerosis coronary atherosclerosis hypertension bipolar disorder IgA nephropathy multiple sclerosis 263 additional categories displayed p values ≥0.05


Page 18 of 18

Supplementary Table 4. R•Y Tracts of Human Genes Epistatic in Schizophrenia. Length R•Y Tract Gene/Chromosome

Pure*

Total

Location**

DBH - chr9 133545098 133552075

145 134

145 134

Intron 6 Intron 11

DISC1 - chr1 228204554 228242302 228329214 228345480 228349439 228355221 228394572 228424829 228447349 228473588

184 123 147 53 222 79 50 61 59 154

229 137 147 83 242 190 50 105 309 436

Intron 4 Intron 7 Intron 9 Intron 9 Intron 9 Intron 9 Intron 9 Intron 10 Intron 10 Intron 12

DLG2 - chr11 82864379 82882016 82969560 83035049 83060817 83123025 83135966 83161104 83208161 83262927 83334626 83606882 83702208 83723852 83890804 83916574 83988791 84100021 84103214

66 82 60 71 80 110 55 157 59 109 75 168 183 53 303 53 136 52 152

81 92 194 71 80 136 116 220 59 257 112 262 241 136 388 53 150 52 169

Intron 17 Intron 16 Intron 14 Intron 13 Intron 13 Intron 13 Intron 13 Intron 13 Intron 12 Intron 11 Intron 9 Intron 3 Intron 2 Intron 2 Intron 2 Intron 2 Intron 2 Intron 1 Intron 1

DLG3 - chrX 69467040

120

120

Intron 9

DLGAP1 - chr18 3524652 3526161 3541655 3572817

57 51 140 75

57 79 222 99

Intron 6 Intron 6 Intron 6 Intron 4


Notes

Repeat in 3'-UTR (Fig. S1)

Chapsin-110; PSD-93

Flanking Z-DNA Next to Z-DNA

NE-DLG; SAP102

GKAP; DAP-1

Page 1 of 5

3573183 3582842 3617824 3629353 3633229 3739093 3742532 3762092 3823131

57 99 71 53 60 77 69 360 113

263 99 71 53 60 77 173 393 123

Intron 4 Intron 4 Intron 4 Intron 4 Intron 4 Intron 2 Intron 2 Intron 2 Intron 1

DRD3 - chr3 115358253

348

348

Intron 3

ERBB4 - chr2 212104732 212386202 212416047 212529349 212693331 212878479 213087707

50 141 71 147 107 67 64

50 210 71 156 219 130 71

Intron 25 Intron 12 Intron 5 Intron 3 Intron 2 Intron 1 Intron 1

FEZ1 - chr11 124868441

221

221

Intron -1

FYN - chr6 112192113 112201452

54 129

54 450

Intron -1 Intron -1

GABRB1 - chr4 46935076 46989226 47017789 47126298 47149375

59 55 133 51 72

59 55 394 51 265

Intron 3 Intron 3 Intron 4 Intron 4 Intron 4

GRIA2 - chr4 158509253 158539562

115 69

151 133

Intron 2 Intron 2

GRIA3 - chrX 122116833 122119813 122322937 122345487

67 133 300 86

158 133 341 207


GRIA4 - chr11 105010291 105061053 105270572

201 98 50

201 98 50

Intron 2 Intron 2 Intron 5

GRIK1 - chr21 29854471

341

341

Intron 12


GLUR2

GLUR3 Flanking tetra-repeat

GLUR4

GLUR5; GLR5

Page 2 of 5

29948786 29992045 30001600 30004960 30028536 30044386 30055873 30140618 30162008 30182320

57 124 78 105 81 69 67 91 141 144

57 275 103 160 81 111 87 134 274 150

Intron 5 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1

GRIK2 - chr6 102027686 102134031 102316600 102476644 102518033 102605808 102618802

73 54 124 80 61 74 204

92 126 426 134 61 74 300


GRIN2A - chr16 9808589 9844287 9844393 9878995 10016611 10041120 10056406 10167016

90 74 68 61 65 77 75 130

278 219 222 331 65 77 75 203

Intron 9 Intron 4 Intron 4 Intron 3 Intron 1 Intron 1 Intron 1 Intron 1

GRIN2B - chr12 13690819 13723158

69 119

69 161

Intron 3 Intron 2

GRIN2D - chr19 53597163 53602013 53607440 53621249

88 53 128 64

106 53 128 64


GRM1 - chr6 146485633 146493046 146502920 146536219 146633667 146665665 146785777

61 64 95 73 185 52 96

61 64 313 73 185 103 152


GRM5 - chr11 87896985 87966566 88195581

67 64 62

67 99 69



C21ORF9 C21ORF9

GLUR6

NR2A

NR2B

mGLUR1

Flanking penta-repeat

mGLUR5

Page 3 of 5

88314254

168

237

Intron 2

GRM7 - chr3 6944114 7120407 7194201 7255414 7278573 7293435 7308177 7490171 7567080

112 110 61 128 68 61 65 50 120

112 155 105 294 99 71 65 50 336


GRM8 - chr7 125711564 125717745 125880227 125943402 125972819 126141260 126158578 126244912 126248908 126281460 126391139

83 61 117 65 52 101 71 52 384 64 53

206 61 117 116 74 325 95 73 384 64 173

Intron 8 Intron 8 Intron 6 Intron 6 Intron 6 Intron 2 Intron 2 Intron 2 Intron 2 Intron 2 Intron 1

HOMER1 - chr5 78718481 78724506 78759230

89 68 132

206 68 260


HOMER2 - chr15 81367111

145

212

Intron 1

NCAM1 - chr11 112347053 112387845 112401711 112422714

50 123 57 59

63 123 57 204


NOS1 - chr12 116128593 116162974 116164990 116222424 116243761

52 86 194 410 62

111 134 293 978 80

Intron 21 Intron 12 Intron 11 Intron 1 Intron -1

NRG1 - chr8 31629941 31674898 31690791 31789596 31807351

175 69 57 64 110

233 69 57 170 110

Intron 1 Intron 1 Intron 1 Intron 1 Intron 1


mGLUR7

Flanking Z-DNA

Flanking tetra repeat

Page 4 of 5

31968345 32004459 32031910 32163519 32186747 32244107 32246105 32261548 32289819 32321362 32389429 32421031 32586599 32592898 32672433 32700816 32735636

61 87 55 55 91 164 72 62 50 95 51 137 102 54 60 50 64

126 87 55 55 104 164 72 62 82 95 51 137 142 54 92 162 64

Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 1 Intron 3 Intron 3 Intron 3 Intron 3 Intron 9

NTRK2 - chr9 84519760 84536907 84562457 84677898 84678049 84748144 84768699 84770541 84848445

61 51 97 53 52 54 81 178 143

61 51 121 91 130 118 94 178 174


PDE4B - chr1 66064811 66301199 66342240 66388300 66432694

231 74 64 54 58

332 99 64 54 112

Intron -1 Intron 2 Intron 2 Intron 2 Intron 3

RELN - chr7 103007490 103031274 103063675 103167883

138 50 80 62

400 50 80 90


SHANK2 - chr11 70123615 70124172

114 62

189 62

Intron 2 Intron 2

SLC6A4 - chr17 25566075 25581164

116 155

158 155

Intron 6 Intron -2


HRG-β2 TrkB

GGC-repeat 5'-UTR

Page 5 of 5

Supplementary Table 5. Human genes with at least 1 pure R•Y tract ≥ 100 bp and 20 pure R•Y tracts ≥ 50 bp in length

Number of R•Y Tracts

Gene

pre-mRNA Size (bp)

57 48 40 36 33 33 32 29 29 28 28 28 26 26 26 25 24 24 24 24 23 23 23 22 22 22 22 22 21 21 20 20 20

A2BP1 CNTNAP2 CALN1 WWOX CSMD1 GNG7 DAB1 ASTN2 DMD CNTNAP5 INSR LOC348094 NRXN1 NRXN3 PARK2 ACCN1 BAI3 CACNA2D3 KCNMA1 LPP DLG2 FRMD4A KCNIP4 C20orf17 CAST DPP10 DSCAM NRG1 EMID2 IL1RAPL1 CDH12 FLJ16124 PTPRT

1693368 2304258 495896 1113014 2056947 135061 1252633 989811 2220382 890049 177374 36908 1108116 1460670 1379133 279902 751963 951097 752943 665115 1463760 687172 574486 514866 78850 535119 834697 216321 194497 1369282 1102578 647928 1117165

≥

Supplementary Table 6. Comparative Frequencies of R•Y Tracts

Lengths Thresholds of Pure R•Y Tracts (bp) Species Human Chimpanzee Dog Mouse Rat Chicken

≥ 50

≥ 100

≥ 250

≥ 400

≥ 800

46,977 32,187 54,071 160,041 127,228 7,983

12,809 6,703 20,866 47,606 20,596 2,902

814 177 2,694 4,008 932 552

89 10 257 673 90 115

3 0 0 11 0 0

Supplementary Table 7. Functional Category Enrichment For Mouse Genes Harboring ≥ 250 bp Pure R•Y A. Gene Ontology (GO) Molecular Function Term Entry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28


Protein Binding Cytoskeletal Protein Binding Calcium Ion Binding Ion Channel Activity Channel/Pore class Transporter Activity Ion Binding Metal Ion Binding Actin Binding Alpha Type Channel Activity Hydrolase Activity Transporter Activity Cation Binding Ion Transporter Activity Adenyl Nucleotide Binding Cation Transporter Activity Catalytic Activity ATP Binding GTPase Regulator Activity Phospholipid Binding Hydrolase Activity (Ester Bonds) Nucleotide Binding Peptidase Activity Enzyme Regulator Activity Purine Nucleotide Binding Voltage-gated Ion Channel Activity Protein Tyrosine Kinase Activity Protein Serine/Threonine KA Porter Activity


R•Y Gene Hits Population Hits

146 27 40 28 29 96 96 18 28 95 69 86 37 60 33 201 58 17 8 34 69 37 29 67 12 21 26 14

2739 294 660 387 435 2222 2222 206 423 2273 1531 2017 675 1301 594 5657 1278 228 63 675 1666 765 564 1637 152 1 498 204

Fisher Exact P-Values 3.52E-20 6.60E-07 3.06E-05 3.35E-05 9.86E-05 1.05E-04 1.05E-04 1.33E-04 1.50E-04 3.65E-04 4.08E-04 4.11E-04 4.60E-04 6.08E-04 7.87E-04 1.03E-03 1.14E-03 1.22E-03 2.45E-03 3.21E-03 3.59E-03 3.96E-03 5.23E-03 5.38E-03 5.40E-03 6.74E-03 7.00E-03 7.56E-03

Page 1 of 6

29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53

Electrochemical Potential Driven TA GTPase Activator Activity Ligase Activity Endopeptidase Activity Lipid Binding Binding Guanyl-nucleotide Exchange Factor Act Symporter Activity Protein Kinase Activity GABA-A Receptor Activity GTPase Binding Glutamate Receptor Activity Ubiquitin-protein Ligase Activity GABA Receptor Activity Phosphotransferase Activity (-OH as acceptor) Metalloendopeptidase Activity Enzyme Activator Activity LIGASE ACTIVITY, FORMING CARBON-NITROGEN BONDS CARBOXYLIC ESTER HYDROLASE ACTIVITY CALCIUM-DEPENDENT PHOSPHOLIPID BINDING RHO GTPASE BINDING Voltage-gated Calcium Channel Activity Phosphoric Ester Hydrolase Activity Magnesium Binding Ionotropic Glutamate Receptor Activity

14 9 25 26 12 332 8 8 29 5 4 7 17 5 32 9 10 19 9 4 3 5 16 11 4

205 98 490 528 174 10398 89 89 622 35 20 73 309 37 727 120 143 372 125 24 10 43 312 183 28

7.87E-03 8.33E-03 1.07E-02 1.38E-02 1.42E-02 1.48E-02 1.60E-02 1.60E-02 1.75E-02 1.89E-02 1.99E-02 2.05E-02 2.12E-02 2.28E-02 2.54E-02 2.56E-02 2.58E-02 2.76E-02 3.16E-02 3.25E-02 3.33E-02 3.71E-02 4.38E-02 4.47E-02 4.82E-02

69 68 75 28 22 22 42 365 108

999 993 1171 247 159 180 569 9682 2180

6.81E-09 1.27E-08 3.19E-08 4.50E-08 5.77E-08 4.87E-07 2.09E-06 4.26E-06 8.62E-06


B. Gene Ontology (GO) Biological Process Term 1 2 3 4 5 6 7 8 9

ORGAN DEVELOPMENT ORGANOGENESIS MORPHOGENESIS CELL-CELL SIGNALING SYNAPTIC TRANSMISSION TRANSMISSION OF NERVE IMPULSE CELL ADHESION CELLULAR PHYSIOLOGICAL PROCESS LOCALIZATION


Page 2 of 6

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

ESTABLISHMENT OF LOCALIZATION CELL MIGRATION PROTEIN MODIFICATION CELL MOTILITY ANTERIOR/POSTERIOR PATTERN FORMATION EMBRYONIC DEVELOPMENT REGULATION OF CELL DIFFERENTIATION UROGENITAL SYSTEM DEVELOPMENT REGULATION OF NEUROTRANSMITTER LEVELS CYCLIC-NUCLEOTIDE-MEDIATED SIGNALING PHOSPHATE METABOLISM FRIZZLED-2 SIGNALING PATHWAY TRANSMEMBRANE RECEPTOR PROTEIN TYROSINE PHOSPHATASE SIGNALING PATHWAY ENZYME LINKED RECEPTOR PROTEIN SIGNALING PATHWAY EMBRYONIC DIGIT MORPHOGENESIS MUSCLE DEVELOPMENT EMBRYONIC DEVELOPMENT (SENSU METAZOA) WNT RECEPTOR SIGNALING PATHWAY SMOOTH MUSCLE CONTRACTION NEUROTRANSMITTER SECRETION HEART DEVELOPMENT CELL DIFFERENTIATION PHOSPHOINOSITIDE-MEDIATED SIGNALING INTRACELLULAR SIGNALING CASCADE CELLULAR MACROMOLECULE METABOLISM SECRETION MUSCLE CELL DIFFERENTIATION CELL-CELL ADHESION BEHAVIOR EMBRYONIC APPENDAGE MORPHOGENESIS EMBRYONIC LIMB MORPHOGENESIS LIMB MORPHOGENESIS REGULATION OF ENZYME ACTIVITY PHOSPHORYLATION POSITIVE REGULATION OF ENZYME ACTIVITY CELLULAR PROTEIN CATABOLISM CELLULAR PROTEIN METABOLISM GAMMA-AMINOBUTYRIC ACID SIGNALING PATHWAY


105 15 72 17 7 16 10 6 7 7 41 5

2162 148 1460 190 36 185 87 30 44 46 797 22

2.81E-05 3.74E-04 4.78E-04 5.46E-04 1.03E-03 1.18E-03 2.20E-03 2.71E-03 2.99E-03 3.75E-03 5.21E-03 5.26E-03

5

22

5.26E-03

15 3 10 9 9 4 6 7 23 6 43 123 7 3 13 9 5 5 5 11 33 8 34 114 4

198 4 104 88 88 14 42 59 399 43 897 3093 61 6 180 100 31 31 32 144 672 88 707 2909 21

5.89E-03 6.19E-03 7.23E-03 8.30E-03 8.30E-03 9.80E-03 1.17E-02 1.26E-02 1.27E-02 1.29E-02 1.32E-02 1.35E-02 1.47E-02 1.48E-02 1.59E-02 1.71E-02 1.80E-02 1.80E-02 2.00E-02 2.06E-02 2.29E-02 2.57E-02 2.65E-02 2.66E-02 3.02E-02

Page 3 of 6

48 49 50 51 52 53 54 55 56

EMBRYONIC DEVELOPMENT (SENSU VERTEBRATA) CELLULAR CATABOLISM PROTEIN METABOLISM MACROMOLECULE METABOLISM CELLULAR MACROMOLECULE CATABOLISM CATABOLISM PROTEIN CATABOLISM METANEPHROS DEVELOPMENT KIDNEY DEVELOPMENT

6 41 114 125 36 43 34 4 4

54 900 2937 3260 781 971 733 24 25

3.17E-02 3.25E-02 3.31E-02 3.59E-02 3.89E-02 4.13E-02 4.16E-02 4.28E-02 4.75E-02

39 39 19 97 121 99 23 9 3 7 20 45 8 3 8 242 3 5

360 360 108 1716 2657 2268 341 75 3 47 298 914 72 5 81 6697 7 41


21 28

195 339

7.25E-06 2.28E-05


C. Gene Ontology (GO) Cellular Component Term 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

EXTRACELLULAR MATRIX EXTRACELLULAR MATRIX (SENSU METAZOA) SYNAPSE PLASMA MEMBRANE EXTRACELLULAR REGION EXTRACELLULAR SPACE CELL FRACTION EXTRINSIC TO MEMBRANE SHEET-FORMING COLLAGEN BASEMENT MEMBRANE MEMBRANE FRACTION INTEGRAL TO PLASMA MEMBRANE EXTRINSIC TO PLASMA MEMBRANE COLLAGEN TYPE IV POSTSYNAPTIC MEMBRANE MEMBRANE INTERCELLULAR CANALICULUS COLLAGEN 1 additional term displayed a p value >0.05

D. Pfam Family 1 2

FN3 EGF


Page 4 of 6

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

BAND_41 LDL_RECEPT_A COLLAGEN ION_TRANS SAM_1 BNR LAMININ_G_2 SH3_1 FH2 GKAP EFHAND G-GAMMA LDL_RECEPT_B 4HBT DRF_FH3 DRF_GBD PDZ CNMP_BINDING WW GUANYLATE_CYC WNT RGS KAZAL_1 PKINASE CUB CADHERIN_C RA C4 NA_CA_EX

9 8 10 11 9 4 7 15 4 3 16 4 4 3 3 3 11 5 6 4 4 5 5 26 6 4 5 3 3

58 47 89 116 81 13 55 212 16 6 251 18 18

152 55 22 22 40 525 59 25 42 11



E. Protein Information Resource (PIR) Family 1 2 3

INT-1 TRANSFORMING PROTEIN LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN PROTEIN-TYROSINE KINASE, RECEPTOR TYPE EPH

4 2 3

30 2 15

3.15E-02 4.59E-02 4.61E-02

1 additional category displayed a p value >0.05


Page 5 of 6

F. Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway 1

CALCIUM SIGNALING PATHWAY

14

179

4.70E-02


G. BioCarta Pathway No entries found

H. Protein Interaction Partners 1 2

NOVA1 PRNP

1 1

3.94E-07 2.54E-03

1 additional category displayed a p value >0.05

I. Disease Association No entries found


Page 6 of 6

Supplementary Table 8. Location and Number of ≥ 250 bp Pure R•Y Tracts in Mouse-Human Orthologous Genes

Gene

Intron Location of the R•Y Tracts

Number of R•Y Tracts in the Intron

Total Number of Introns in RefSeq

Mouse

Human

Mouse

Human

Mouse

Human

CDH22

2

3 9

2

1 1

12

CNTNAP2

1 8 19 13 1 7 1 1 3 1 14 1 6 2 14 2 1 1 7 3 4 7 1 2 3

CPNE8 DCC DLGAP1 FMR2 GRIK1 GRM8 KCNMA1 OTOA PPP1R16B PTPRO PTPRT RBMS3 SIM1 SLC25A21


8 1 7 2 1

14 2 22 12 4 7 1 6 9 1

1 1 1 1 2 1 1 1 1 1 1 2 1 1 1 1 1 3 2 1 1 1 2 1 2

RefSeq Mouse

Human

11

NM_174988

NM_021248

24

25

NM_001004357

NM_014141

20 29

20 29

NM_025815 NM_007831

NM_153634 NM_005215

11 20

10 22

NM_027712 NM_008032

NM_001003809 NM_002025

1 1 1 1 1

16

16

NM_146072

NM_175611

1 1

10

10

NM_008174

NM_000845

1 1 1 1 1

29 29 12 27 30

27 28 11 26 32

NM_010610 NM_139310 NM_153089 NM_011216 NM_021464

NM_002247 NM_144672 NM_015568 NM_002848 NM_133170

1

14

14

1 1

11 10

11 10

NM_011376 NM_172577

NM_005068 NM_030631

Page 1 of 2

SLC39A11 SORCS2 SOX6 SRPK2 STIM1 TIAM1 WBSCR17 WWOX Total

7 13 12 1 11 1 3 1 7


5 7 2 6 2 1 11 9 8

1 1 1 1 1 1 1 1 3 45

1 1 1 1 1

12

10

NM_027216

NM_139177

27 15 15

27 16 15

NM_030889 NM_011445 NM_009274

NM_020777 NM_033326 NM_182691

1 1 1 1 26

12 28 12 9

12 31 11 10

NM_009287 NM_009384 NM_145218 NM_019573

NM_003156 NM_003253 NM_022479 NM_018560

Page 2 of 2

*NOS1*

*PDE4B*

Supplementary Fig. 1

Sequence Positions (hg17): Chr1: 228480103-228480746 gCAGTGCAGcAtTtAGgAAa GCAGTGCAGTACTCAGTAAG GCAGTGCAGTACTCAGTAAc Aca-TaCAGTACTCAG---GCAGTGCAGTACTCAGTAAG -----aCAGT---------GCAGTGC-----TCAGTAAG GCAGTGCAaTACTCAGTAAc --AGTGtAGTACTCAGTAAc --AGTGaAGTACTCAGTAA----TaCAGTAC--AGTAt------------TCAGTAAG GCAGTGaAGTACTCAGTAA----TaCAaTA--------------CAGTACTCAGTtAG GCAGTGCAGTACTCAGgAAt GCAGcaCAGTACTCAG---GCAGTGCAaTACTCAG---GCgG-----TACTCAGTAAc aCAGTGCAGTACTCAGTAAc ---GTGCAGTACTCAGTAA-CAGTGCAGTACTCAGTAAG GCAGTGCAGTACTCAGTAAc aCAGTGCAGTACTCAGTAA----TaCAGTAC--AGTA-c ------------TCAGTAAG GCAGTatgGTACTCAGTAAa GCAaTGCAaTgCTCAGTAAc aCAGTGCAGTgCTCAaTAAG GCAGTGCAGTgCTCAGTAAG GCAGTGaAtTGCTtAGTAAc aCAGTGtAGTgCTCAGTAgG aCAGcAtAGTACTCAGTAAc aCAGgGCAG--CT-------------AGTACTCAGTA------------CT-A-TAAG ---------TACTgA------------GTACTtA-TAtag GCAaTGtAGTACTCAGTAAa tCAGTGCAGTACTCAGTAAtg Structure of a single repeat GCAGTGCAGTACTCAGTAAG


0.20

0.17

1.2e-09

2.8e-08

4.6e-09

0.15

>250 RY

3.2e-08

>100 RY


Chromosome 1 2 3 4

P