Although many human diseases have a genetic component involving many loci, the majority of studies are statistically underpowered to isolate the many contributing variants, raising the question of the existence of alternate processes to identify disease mutations. To address this question, we collect ancestral transcription factor binding sites disrupted by an individual’s variants and then look for their most significant congregation next to a group of functionally related genes. Strikingly, when the method is applied to five different full human genomes, the top enriched function for each is invariably reflective of their very different medical histories. For example, our method implicates “abnormal cardiac output” for a patient with a longstanding family history of heart disease, “decreased circulating sodium level” for an individual with hypertension, and other biologically appealing links for medical histories spanning narcolepsy to axonal neuropathy. Our results suggest that erosion of gene regulation by mutation load significantly contributes to observed heritable phenotypes that manifest in the medical history. The test we developed exposes a hitherto hidden layer of personal variants that promise to shed new light on human disease penetrance, expressivity and the sensitivity with which we can detect them.
References
[1]
Paul DS, Soranzo N, Beck S. Functional interpretation of non-coding sequence variation: concepts and challenges. Bioessays. 2014;36: 191–199. doi: 10.1002/bies.201300126. pmid:24311363
[2]
Veltman JA, Brunner HG. De novo mutations in human genetic disease. Nat Rev Genet. 2012;13: 565–575. doi: 10.1038/nrg3241. pmid:22805709
[3]
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461: 747–753. doi: 10.1038/nature08494. pmid:19812666
[4]
Gonzaga-Jauregui C, Lupski JR, Gibbs RA. Human genome sequencing in health and disease. Annu Rev Med. 2012;63: 35–61. doi: 10.1146/annurev-med-051010-162644. pmid:22248320
[5]
Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012;337: 1190–1195. doi: 10.1126/science.1222794. pmid:22955828
[6]
Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489: 57–74. doi: 10.1038/nature11247. pmid:22955616
[7]
Gibson G. Rare and common variants: twenty arguments. Nat Rev Genet. 2011;13: 135–145. doi: 10.1038/nrg3118
[8]
Zuk O, Hechter E, Sunyaev SR, Lander ES. The mystery of missing heritability: Genetic interactions create phantom heritability. Proc Natl Acad Sci USA. 2012;109: 1193–1198. doi: 10.1073/pnas.1119675109. pmid:22223662
[9]
McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, et al. GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol. 2010;28: 495–501. doi: 10.1038/nbt.1630. pmid:20436461
[10]
Cantor RM, Lange K, Sinsheimer JS. Prioritizing GWAS results: A review of statistical methods and recommendations for their application. Am J Hum Genet. 2010;86: 6–22. doi: 10.1016/j.ajhg.2009.11.017. pmid:20074509
[11]
Gulko B, Hubisz MJ, Gronau I, Siepel A. A method for calculating probabilities of fitness consequences for point mutations across the human genome. Nat Genet. 2015;47: 276–283. doi: 10.1038/ng.3196. pmid:25599402
[12]
Hume MA, Barrera LA, Gisselbrecht SS, Bulyk ML. UniPROBE, update 2015: new tools and content for the online database of protein-binding microarray data on protein-DNA interactions. Nucleic Acids Res. 2015;43: D117–122. doi: 10.1093/nar/gku1045. pmid:25378322
[13]
Jolma A, Yan J, Whitington T, Toivonen J, Nitta KR, Rastas P, et al. DNA-binding specificities of human transcription factors. Cell. 2013;152: 327–339. doi: 10.1016/j.cell.2012.12.009. pmid:23332764
[14]
Wenger AM, Clarke SL, Guturu H, Chen J, Schaar BT, McLean CY, et al. PRISM offers a comprehensive genomic approach to transcription factor function prediction. Genome Res. 2013;23: 889–904. doi: 10.1101/gr.139071.112. pmid:23382538
[15]
Daily K, Patel VR, Rigor P, Xie X, Baldi P. MotifMap: integrative genome-wide maps of regulatory motif sites for model species. BMC Bioinformatics. 2011;12: 495. doi: 10.1186/1471-2105-12-495. pmid:22208852
[16]
Guturu H, Doxey AC, Wenger AM, Bejerano G. Structure-aided prediction of mammalian transcription factor complexes in conserved non-coding elements. Philos Trans R Soc Lond, B, Biol Sci. 2013;368: 20130029. doi: 10.1098/rstb.2013.0029. pmid:24218641
[17]
Huang Q, Whitington T, Gao P, Lindberg JF, Yang Y, Sun J, et al. A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nat Genet. 2014;46: 126–135. doi: 10.1038/ng.2862. pmid:24390282
[18]
Ashley EA, Butte AJ, Wheeler MT, Chen R, Klein TE, Dewey FE, et al. Clinical assessment incorporating a personal genome. Lancet. 2010;375: 1525–1535. doi: 10.1016/S0140-6736(10)60452-7. pmid:20435227
[19]
Ball MP, Thakuria JV, Zaranek AW, Clegg T, Rosenbaum AM, Wu X, et al. A public resource facilitating clinical use of genomes. Proc Natl Acad Sci USA. 2012;109: 11920–11927. doi: 10.1073/pnas.1201904109. pmid:22797899
[20]
Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DCY, Nazareth L, et al. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med. 2010;362: 1181–1191. doi: 10.1056/NEJMoa0908094. pmid:20220177
[21]
Awad MM, Calkins H, Judge DP. Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med. 2008;5: 258–267. doi: 10.1038/ncpcardio1182. pmid:18382419
[22]
Plazzi G, Moghadam KK, Maggi LS, Donadio V, Vetrugno R, Liguori R, et al. Autonomic disturbances in narcolepsy. Sleep Med Rev. 2011;15: 187–196. doi: 10.1016/j.smrv.2010.05.002. pmid:20634114
[23]
Hwang S, Schwartz RA. Keratosis pilaris: a common follicular hyperkeratosis. Cutis. 2008;82: 177–180. pmid:18856156
[24]
Arnett DK, Claas SA. Preventing and controlling hypertension in the era of genomic innovation and environmental transformation. JAMA. 2012;308: 1745–1746. doi: 10.1001/jama.2012.28747. pmid:23117772
[25]
Fünfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature. 2012;485: 517–521. doi: 10.1038/nature11007. pmid:22622581
[26]
Emery B. Regulation of oligodendrocyte differentiation and myelination. Science. 2010;330: 779–782. doi: 10.1126/science.1190927. pmid:21051629
[27]
1000 Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467: 1061–1073. doi: 10.1038/nature09534. pmid:20981092
[28]
Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014;133: 1–9. doi: 10.1007/s00439-013-1358-4. pmid:24077912
[29]
Parsa A, Chang Y-PC, Kelly RJ, Corretti MC, Ryan KA, Robinson SW, et al. Hypertrophy-associated polymorphisms ascertained in a founder cohort applied to heart failure risk and mortality. Clin Transl Sci. 2011;4: 17–23. doi: 10.1111/j.1752-8062.2010.00251.x. pmid:21348951
[30]
De Jager PL, Jia X, Wang J, de Bakker PIW, Ottoboni L, Aggarwal NT, et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet. 2009;41: 776–782. doi: 10.1038/ng.401. pmid:19525953
[31]
Nishino S, Mignot E. Narcolepsy and cataplexy. Handb Clin Neurol. 2011;99: 783–814. doi: 10.1016/B978-0-444-52007-4.00007–2. pmid:21056228
[32]
Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31: 3812–3814. pmid:12824425 doi: 10.1093/nar/gkg509
[33]
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7: 248–249. doi: 10.1038/nmeth0410-248. pmid:20354512
[34]
Hu H, Huff CD, Moore B, Flygare S, Reese MG, Yandell M. VAAST 2.0: improved variant classification and disease-gene identification using a conservation-controlled amino acid substitution matrix. Genet Epidemiol. 2013;37: 622–634. doi: 10.1002/gepi.21743. pmid:23836555
[35]
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46: 310–315. doi: 10.1038/ng.2892. pmid:24487276
[36]
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD). Online Mendelian Inheritance in Man, OMIM？ [Internet]. [cited 7 Dec 2015].
[37]
Spitz F, Furlong EEM. Transcription factors: from enhancer binding to developmental control. Nat Rev Genet. 2012;13: 613–626. doi: 10.1038/nrg3207. pmid:22868264
[38]
Hunter DJ. Gene-environment interactions in human diseases. Nat Rev Genet. 2005;6: 287–298. doi: 10.1038/nrg1578. pmid:15803198
[39]
Newburger DE, Bulyk ML. UniPROBE: an online database of protein binding microarray data on protein-DNA interactions. Nucleic Acids Res. 2009;37: D77–82. doi: 10.1093/nar/gkn660. pmid:18842628
[40]
Bryne JC, Valen E, Tang M-HE, Marstrand T, Winther O, da Piedade I, et al. JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update. Nucleic Acids Res. 2008;36: D102–106. doi: 10.1093/nar/gkm955. pmid:18006571
[41]
Matys V, Kel-Margoulis OV, Fricke E, Liebich I, Land S, Barre-Dirrie A, et al. TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res. 2006;34: D108–110. doi: 10.1093/nar/gkj143. pmid:16381825
[42]
Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. Genome Res. 2002;12: 996–1006. doi: 10.1101/gr.229102. Article published online before print in May 2002 pmid:12045153
[43]
Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29: 308–311. pmid:11125122 doi: 10.1093/nar/29.1.308
[44]
Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005;15: 1034–1050. doi: 10.1101/gr.3715005. pmid:16024819
[45]
Kel AE, G？ssling E, Reuter I, Cheremushkin E, Kel-Margoulis OV, Wingender E. MATCH: A tool for searching transcription factor binding sites in DNA sequences. Nucleic Acids Res. 2003;31: 3576–3579. pmid:12824369 doi: 10.1093/nar/gkg585
[46]
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. pmid:Nat Genet. 2000;25: 25–29. doi: 10.1038/75556.
Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA. 2009;106: 9362–9367. doi: 10.1073/pnas.0903103106. pmid:19474294
[49]
Imboden M, Bouzigon E, Curjuric I, Ramasamy A, Kumar A, Hancock DB, et al. Genome-wide association study of lung function decline in adults with and without asthma. J Allergy Clin Immunol. 2012;129: 1218–1228. doi: 10.1016/j.jaci.2012.01.074. pmid:22424883
[50]
Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007;449: 851–861. doi: 10.1038/nature06258. pmid:17943122
[51]
Siebold C, Hansen BE, Wyer JR, Harlos K, Esnouf RE, Svejgaard A, et al. Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy. Proc Natl Acad Sci USA. 2004;101: 1999–2004. doi: 10.1073/pnas.0308458100. pmid:14769912
Hor H, Kutalik Z, Dauvilliers Y, Valsesia A, Lammers GJ, Donjacour CEHM, et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat Genet. 2010;42: 786–789. doi: 10.1038/ng.647. pmid:20711174
