Shamil R. Sunyaev, Ph.D. - Department of Medicine

Shamil R. Sunyaev, Ph.D.

Associate Geneticist, Brigham and Women's Hospital
Professor of Biomedical Informatics, Harvard Medical School

Brigham and Women's Hospital
Department of Medicine
Genetics
75 Francis Street
Boston, MA 02115

Research Narrative: We are a computational biology laboratory. We develop and apply computational methods to pursue various problems in fields of genetics, genomics and proteomics. We develop novel computational techniques for proteomics and for comparative analysis of protein sequences and structures. Our main interest is to analyze genetic variation and genome divergence between species with focus on protein coding regions. By predicting the effects of amino acid substitutions on protein structure and function and by using large scale statistical and computational approaches, we can learn more about the evolutionary process of natural selection and the evolution of proteins. We use a translational approach in that we use our methods to investigate the contribution of human genetic polymorphisms to complex disease traits, for example we have been investigating the genetic contribution to high density lipoprotein (HDL) levels in humans. Other efforts are directed towards developing methods to best use available population genetic variation data to investigate potential mechanisms of function and evolution. For example, we are investigating potential epistatic interactions between allelic variants as a mechanism for how genetic variation gives rise to certain phenotypes. As we are interested in the development of computational approaches to protein sequence and structure analysis, we offer web based programs and software that we have developed. Projects include the development of techniques to search for homologous proteins based on data generated by mass spectrometry (MS-BLAST), a program to predict the functional effect of missense mutations (PolyPhen ), and a program for analysis of complex protein mixtures (Eagle Eye).

Education:	Moscow Institute of Physics & Technology , 1997, Ph.D. Moscow Institute of Physics and Technology , 1994, MS

Publications (Pulled from Harvard Catalyst Profiles): 1. Chandonia JM, Adhikari A, Carraro M, Chhibber A, Cutting GR, Fu Y, Gasparini A, Jones DT, Kramer A, Kundu K, Lam HYK, Leonardi E, Moult J, Pal LR, Searls DB, Shah S, Sunyaev S, Tosatto SCE, Yin Y, Buckley BA. Lessons from the CAGI-4 Hopkins clinical panel challenge. Hum Mutat. 2017 Apr 11. 2. Cassa CA, Weghorn D, Balick DJ, Jordan DM, Nusinow D, Samocha KE, O'Donnell-Luria A, MacArthur DG, Daly MJ, Beier DR, Sunyaev SR. Estimating the selective effects of heterozygous protein-truncating variants from human exome data. Nat Genet. 2017 May; 49(5):806-810. 3. Chun S, Casparino A, Patsopoulos NA, Croteau-Chonka DC, Raby BA, De Jager PL, Sunyaev SR, Cotsapas C. Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types. Nat Genet. 2017 Apr; 49(4):600-605. 4. Wang H, Cade BE, Chen H, Gleason KJ, Saxena R, Feng T, Larkin EK, Vasan RS, Lin H, Patel SR, Tracy RP, Liu Y, Gottlieb DJ, Below JE, Hanis CL, Petty LE, Sunyaev SR, Frazier-Wood AC, Rotter JI, Post W, Lin X, Redline S, Zhu X. Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level. Hum Mol Genet. 2016 Dec 01; 25(23):5244-5253. 5. Zou J, Valiant G, Valiant P, Karczewski K, Chan SO, Samocha K, Lek M, Sunyaev S, Daly M, MacArthur DG. Quantifying unobserved protein-coding variants in human populations provides a roadmap for large-scale sequencing projects. Nat Commun. 2016 Oct 31; 7:13293. 6. Cade BE, Chen H, Stilp AM, Gleason KJ, Sofer T, Ancoli-Israel S, Arens R, Bell GI, Below JE, Bjonnes AC, Chun S, Conomos MP, Evans DS, Johnson WC, Frazier-Wood AC, Lane JM, Larkin EK, Loredo JS, Post WS, Ramos AR, Rice K, Rotter JI, Shah NA, Stone KL, Taylor KD, Thornton TA, Tranah GJ, Wang C, Zee PC, Hanis CL, Sunyaev SR, Patel SR, Laurie CC, Zhu X, Saxena R, Lin X, Redline S. Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans. Am J Respir Crit Care Med. 2016 Oct 01; 194(7):886-897. 7. Sul JH, Cade BE, Cho MH, Qiao D, Silverman EK, Redline S, Sunyaev S. Increasing Generality and Power of Rare-Variant Tests by Utilizing Extended Pedigrees. Am J Hum Genet. 2016 Oct 06; 99(4):846-859. 8. Lenz TL, Spirin V, Jordan DM, Sunyaev SR. Excess of Deleterious Mutations around HLA Genes Reveals Evolutionary Cost of Balancing Selection. Mol Biol Evol. 2016 Oct; 33(10):2555-64. 9. Oetting WS, Brenner SE, Brookes AJ, Greenblatt MS, Hart RK, Karchin R, Sunyaev SR, Taschner PE. Pathogenicity Interpretation in the Age of Precision Medicine: The 2015 Annual Scientific Meeting of the Human Genome Variation Society. Hum Mutat. 2016 Apr; 37(4):406-11. 10. Savova V, Chun S, Sohail M, McCole RB, Witwicki R, Gai L, Lenz TL, Wu CT, Sunyaev SR, Gimelbrant AA. Genes with monoallelic expression contribute disproportionately to genetic diversity in humans. Nat Genet. 2016 Mar; 48(3):231-7. show all 11. Palamara PF, Francioli LC, Wilton PR, Genovese G, Gusev A, Finucane HK, Sankararaman S, Sunyaev SR, de Bakker PI, Wakeley J, Pe'er I, Price AL. Leveraging Distant Relatedness to Quantify Human Mutation and Gene-Conversion Rates. Am J Hum Genet. 2015 Dec 03; 97(6):775-89. 12. Kazanov MD, Roberts SA, Polak P, Stamatoyannopoulos J, Klimczak LJ, Gordenin DA, Sunyaev SR. APOBEC-Induced Cancer Mutations Are Uniquely Enriched in Early-Replicating, Gene-Dense, and Active Chromatin Regions. Cell Rep. 2015 Nov 10; 13(6):1103-9. 13. Cassa CA, Smith SE, Docken W, Hoffman E, McLaughlin H, Chun S, Leshchiner I, Miraoui H, Raychaudhuri S, Frank NY, Wilson BJ, Sunyaev SR, Maas RL, Vuzman D. An argument for early genomic sequencing in atypical cases: a WISP3 variant leads to diagnosis of progressive pseudorheumatoid arthropathy of childhood. Rheumatology (Oxford). 2016 Mar; 55(3):586-9. 14. Balick DJ, Do R, Cassa CA, Reich D, Sunyaev SR. Dominance of Deleterious Alleles Controls the Response to a Population Bottleneck. PLoS Genet. 2015 Aug; 11(8):e1005436. 15. Lenz TL, Deutsch AJ, Han B, Hu X, Okada Y, Eyre S, Knapp M, Zhernakova A, Huizinga TW, Abecasis G, Becker J, Boeckxstaens GE, Chen WM, Franke A, Gladman DD, Gockel I, Gutierrez-Achury J, Martin J, Nair RP, Nöthen MM, Onengut-Gumuscu S, Rahman P, Rantapää-Dahlqvist S, Stuart PE, Tsoi LC, van Heel DA, Worthington J, Wouters MM, Klareskog L, Elder JT, Gregersen PK, Schumacher J, Rich SS, Wijmenga C, Sunyaev SR, de Bakker PI, Raychaudhuri S. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases. Nat Genet. 2015 Sep; 47(9):1085-90. 16. Jordan DM, Frangakis SG, Golzio C, Cassa CA, Kurtzberg J, Davis EE, Sunyaev SR, Katsanis N. Identification of cis-suppression of human disease mutations by comparative genomics. Nature. 2015 Aug 13; 524(7564):225-9. 17. Francioli LC, Polak PP, Koren A, Menelaou A, Chun S, Renkens I, van Duijn CM, Swertz M, Wijmenga C, van Ommen G, Slagboom PE, Boomsma DI, Ye K, Guryev V, Arndt PF, Kloosterman WP, de Bakker PI, Sunyaev SR. Genome-wide patterns and properties of de novo mutations in humans. Nat Genet. 2015 Jul; 47(7):822-6. 18. Chopra SS, Leshchiner I, Duzkale H, McLaughlin H, Giovanni M, Zhang C, Stitziel N, Fingeroth J, Joyce RM, Lebo M, Rehm H, Vuzman D, Maas R, Sunyaev SR, Murray M, Cassa CA. Inherited CHST11/MIR3922 deletion is associated with a novel recessive syndrome presenting with skeletal malformation and malignant lymphoproliferative disease. Mol Genet Genomic Med. 2015 Sep; 3(5):413-23. 19. Sahni N, Yi S, Taipale M, Fuxman Bass JI, Coulombe-Huntington J, Yang F, Peng J, Weile J, Karras GI, Wang Y, Kovács IA, Kamburov A, Krykbaeva I, Lam MH, Tucker G, Khurana V, Sharma A, Liu YY, Yachie N, Zhong Q, Shen Y, Palagi A, San-Miguel A, Fan C, Balcha D, Dricot A, Jordan DM, Walsh JM, Shah AA, Yang X, Stoyanova AK, Leighton A, Calderwood MA, Jacob Y, Cusick ME, Salehi-Ashtiani K, Whitesell LJ, Sunyaev S, Berger B, Barabási AL, Charloteaux B, Hill DE, Hao T, Roth FP, Xia Y, Walhout AJ, Lindquist S, Vidal M. Widespread macromolecular interaction perturbations in human genetic disorders. Cell. 2015 Apr 23; 161(3):647-60. 20. Polak P, Karlic R, Koren A, Thurman R, Sandstrom R, Lawrence MS, Reynolds A, Rynes E, Vlahovicek K, Stamatoyannopoulos JA, Sunyaev SR. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature. 2015 Feb 19; 518(7539):360-4. 21. Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, Amin V, Whitaker JW, Schultz MD, Ward LD, Sarkar A, Quon G, Sandstrom RS, Eaton ML, Wu YC, Pfenning AR, Wang X, Claussnitzer M, Liu Y, Coarfa C, Harris RA, Shoresh N, Epstein CB, Gjoneska E, Leung D, Xie W, Hawkins RD, Lister R, Hong C, Gascard P, Mungall AJ, Moore R, Chuah E, Tam A, Canfield TK, Hansen RS, Kaul R, Sabo PJ, Bansal MS, Carles A, Dixon JR, Farh KH, Feizi S, Karlic R, Kim AR, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer TR, Neph SJ, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari RC, Siebenthall KT, Sinnott-Armstrong NA, Stevens M, Thurman RE, Wu J, Zhang B, Zhou X, Beaudet AE, Boyer LA, De Jager PL, Farnham PJ, Fisher SJ, Haussler D, Jones SJ, Li W, Marra MA, McManus MT, Sunyaev S, Thomson JA, Tlsty TD, Tsai LH, Wang W, Waterland RA, Zhang MQ, Chadwick LH, Bernstein BE, Costello JF, Ecker JR, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos JA, Wang T, Kellis M. Integrative analysis of 111 reference human epigenomes. Nature. 2015 Feb 19; 518(7539):317-30. 22. Do R, Balick D, Li H, Adzhubei I, Sunyaev S, Reich D. No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans. Nat Genet. 2015 Feb; 47(2):126-31. 23. Do R, Stitziel NO, Won HH, Jørgensen AB, Duga S, Angelica Merlini P, Kiezun A, Farrall M, Goel A, Zuk O, Guella I, Asselta R, Lange LA, Peloso GM, Auer PL, Girelli D, Martinelli N, Farlow DN, DePristo MA, Roberts R, Stewart AF, Saleheen D, Danesh J, Epstein SE, Sivapalaratnam S, Hovingh GK, Kastelein JJ, Samani NJ, Schunkert H, Erdmann J, Shah SH, Kraus WE, Davies R, Nikpay M, Johansen CT, Wang J, Hegele RA, Hechter E, Marz W, Kleber ME, Huang J, Johnson AD, Li M, Burke GL, Gross M, Liu Y, Assimes TL, Heiss G, Lange EM, Folsom AR, Taylor HA, Olivieri O, Hamsten A, Clarke R, Reilly DF, Yin W, Rivas MA, Donnelly P, Rossouw JE, Psaty BM, Herrington DM, Wilson JG, Rich SS, Bamshad MJ, Tracy RP, Cupples LA, Rader DJ, Reilly MP, Spertus JA, Cresci S, Hartiala J, Tang WH, Hazen SL, Allayee H, Reiner AP, Carlson CS, Kooperberg C, Jackson RD, Boerwinkle E, Lander ES, Schwartz SM, Siscovick DS, McPherson R, Tybjaerg-Hansen A, Abecasis GR, Watkins H, Nickerson DA, Ardissino D, Sunyaev SR, O'Donnell CJ, Altshuler D, Gabriel S, Kathiresan S. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015 Feb 05; 518(7537):102-6. 24. Stitziel NO, Won HH, Morrison AC, Peloso GM, Do R, Lange LA, Fontanillas P, Gupta N, Duga S, Goel A, Farrall M, Saleheen D, Ferrario P, König I, Asselta R, Merlini PA, Marziliano N, Notarangelo MF, Schick U, Auer P, Assimes TL, Reilly M, Wilensky R, Rader DJ, Hovingh GK, Meitinger T, Kessler T, Kastrati A, Laugwitz KL, Siscovick D, Rotter JI, Hazen SL, Tracy R, Cresci S, Spertus J, Jackson R, Schwartz SM, Natarajan P, Crosby J, Muzny D, Ballantyne C, Rich SS, O'Donnell CJ, Abecasis G, Sunaev S, Nickerson DA, Buring JE, Ridker PM, Chasman DI, Austin E, Kullo IJ, Weeke PE, Shaffer CM, Bastarache LA, Denny JC, Roden DM, Palmer C, Deloukas P, Lin DY, Tang ZZ, Erdmann J, Schunkert H, Danesh J, Marrugat J, Elosua R, Ardissino D, McPherson R, Watkins H, Reiner AP, Wilson JG, Altshuler D, Gibbs RA, Lander ES, Boerwinkle E, Gabriel S, Kathiresan S. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med. 2014 Nov 27; 371(22):2072-82. 25. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, Adams DR, Altman RB, Antonarakis SE, Ashley EA, Barrett JC, Biesecker LG, Conrad DF, Cooper GM, Cox NJ, Daly MJ, Gerstein MB, Goldstein DB, Hirschhorn JN, Leal SM, Pennacchio LA, Stamatoyannopoulos JA, Sunyaev SR, Valle D, Voight BF, Winckler W, Gunter C. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014 Apr 24; 508(7497):469-76. 26. Stanley CM, Sunyaev SR, Greenblatt MS, Oetting WS. Clinically relevant variants - identifying, collecting, interpreting, and disseminating: the 2013 annual scientific meeting of the Human Genome Variation Society. Hum Mutat. 2014 Apr; 35(4):505-10. 27. Zuk O, Schaffner SF, Samocha K, Do R, Hechter E, Kathiresan S, Daly MJ, Neale BM, Sunyaev SR, Lander ES. Searching for missing heritability: designing rare variant association studies. Proc Natl Acad Sci U S A. 2014 Jan 28; 111(4):E455-64. 28. Polak P, Lawrence MS, Haugen E, Stoletzki N, Stojanov P, Thurman RE, Garraway LA, Mirkin S, Getz G, Stamatoyannopoulos JA, Sunyaev SR. Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair. Nat Biotechnol. 2014 Jan; 32(1):71-5. 29. Sunyaev SR, Roth FP. Systems biology and the analysis of genetic variation. Curr Opin Genet Dev. 2013 Dec; 23(6):599-601. 30. Agarwala V, Flannick J, Sunyaev S, Altshuler D. Evaluating empirical bounds on complex disease genetic architecture. Nat Genet. 2013 Dec; 45(12):1418-27. 31. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortés ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Lee RS, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CW, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013 Jul 11; 499(7457):214-8. 32. Goldstein DB, Allen A, Keebler J, Margulies EH, Petrou S, Petrovski S, Sunyaev S. Sequencing studies in human genetics: design and interpretation. Nat Rev Genet. 2013 Jul; 14(7):460-70. 33. Gokcumen O, Zhu Q, Mulder LC, Iskow RC, Austermann C, Scharer CD, Raj T, Boss JM, Sunyaev S, Price A, Stranger B, Simon V, Lee C. Balancing selection on a regulatory region exhibiting ancient variation that predates human-neandertal divergence. PLoS Genet. 2013 Apr; 9(4):e1003404. 34. Coste B, Houge G, Murray MF, Stitziel N, Bandell M, Giovanni MA, Philippakis A, Hoischen A, Riemer G, Steen U, Steen VM, Mathur J, Cox J, Lebo M, Rehm H, Weiss ST, Wood JN, Maas RL, Sunyaev SR, Patapoutian A. Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis. Proc Natl Acad Sci U S A. 2013 Mar 19; 110(12):4667-72. 35. Kiezun A, Pulit SL, Francioli LC, van Dijk F, Swertz M, Boomsma DI, van Duijn CM, Slagboom PE, van Ommen GJ, Wijmenga C, de Bakker PI, Sunyaev SR. Deleterious alleles in the human genome are on average younger than neutral alleles of the same frequency. PLoS Genet. 2013; 9(2):e1003301. 36. McFarland CD, Korolev KS, Kryukov GV, Sunyaev SR, Mirny LA. Impact of deleterious passenger mutations on cancer progression. Proc Natl Acad Sci U S A. 2013 Feb 19; 110(8):2910-5. 37. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013 Jan; Chapter 7:Unit7.20. 38. Seim I, Fang X, Xiong Z, Lobanov AV, Huang Z, Ma S, Feng Y, Turanov AA, Zhu Y, Lenz TL, Gerashchenko MV, Fan D, Hee Yim S, Yao X, Jordan D, Xiong Y, Ma Y, Lyapunov AN, Chen G, Kulakova OI, Sun Y, Lee SG, Bronson RT, Moskalev AA, Sunyaev SR, Zhang G, Krogh A, Wang J, Gladyshev VN. Genome analysis reveals insights into physiology and longevity of the Brandt's bat Myotis brandtii. Nat Commun. 2013; 4:2212. 39. Diogo D, Kurreeman F, Stahl EA, Liao KP, Gupta N, Greenberg JD, Rivas MA, Hickey B, Flannick J, Thomson B, Guiducci C, Ripke S, Adzhubey I, Barton A, Kremer JM, Alfredsson L, Sunyaev S, Martin J, Zhernakova A, Bowes J, Eyre S, Siminovitch KA, Gregersen PK, Worthington J, Klareskog L, Padyukov L, Raychaudhuri S, Plenge RM. Rare, low-frequency, and common variants in the protein-coding sequence of biological candidate genes from GWASs contribute to risk of rheumatoid arthritis. Am J Hum Genet. 2013 Jan 10; 92(1):15-27. 40. Schloissnig S, Arumugam M, Sunagawa S, Mitreva M, Tap J, Zhu A, Waller A, Mende DR, Kultima JR, Martin J, Kota K, Sunyaev SR, Weinstock GM, Bork P. Genomic variation landscape of the human gut microbiome. Nature. 2013 Jan 03; 493(7430):45-50. 41. Koren A, Polak P, Nemesh J, Michaelson JJ, Sebat J, Sunyaev SR, McCarroll SA. Differential relationship of DNA replication timing to different forms of human mutation and variation. Am J Hum Genet. 2012 Dec 07; 91(6):1033-40. 42. Thompson BA, Greenblatt MS, Vallee MP, Herkert JC, Tessereau C, Young EL, Adzhubey IA, Li B, Bell R, Feng B, Mooney SD, Radivojac P, Sunyaev SR, Frebourg T, Hofstra RM, Sijmons RH, Boucher K, Thomas A, Goldgar DE, Spurdle AB, Tavtigian SV. Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. Hum Mutat. 2013 Jan; 34(1):255-65. 43. Nusinow DP, Kiezun A, O'Connell DJ, Chick JM, Yue Y, Maas RL, Gygi SP, Sunyaev SR. Network-based inference from complex proteomic mixtures using SNIPE. Bioinformatics. 2012 Dec 01; 28(23):3115-22. 44. Sunyaev SR. Inferring causality and functional significance of human coding DNA variants. Hum Mol Genet. 2012 Oct 15; 21(R1):R10-7. 45. Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, Sheffield NC, Stergachis AB, Wang H, Vernot B, Garg K, John S, Sandstrom R, Bates D, Boatman L, Canfield TK, Diegel M, Dunn D, Ebersol AK, Frum T, Giste E, Johnson AK, Johnson EM, Kutyavin T, Lajoie B, Lee BK, Lee K, London D, Lotakis D, Neph S, Neri F, Nguyen ED, Qu H, Reynolds AP, Roach V, Safi A, Sanchez ME, Sanyal A, Shafer A, Simon JM, Song L, Vong S, Weaver M, Yan Y, Zhang Z, Zhang Z, Lenhard B, Tewari M, Dorschner MO, Hansen RS, Navas PA, Stamatoyannopoulos G, Iyer VR, Lieb JD, Sunyaev SR, Akey JM, Sabo PJ, Kaul R, Furey TS, Dekker J, Crawford GE, Stamatoyannopoulos JA. The accessible chromatin landscape of the human genome. Nature. 2012 Sep 06; 489(7414):75-82. 46. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J, Shafer A, Neri F, Lee K, Kutyavin T, Stehling-Sun S, Johnson AK, Canfield TK, Giste E, Diegel M, Bates D, Hansen RS, Neph S, Sabo PJ, Heimfeld S, Raubitschek A, Ziegler S, Cotsapas C, Sotoodehnia N, Glass I, Sunyaev SR, Kaul R, Stamatoyannopoulos JA. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012 Sep 07; 337(6099):1190-5. 47. Kiezun A, Garimella K, Do R, Stitziel NO, Neale BM, McLaren PJ, Gupta N, Sklar P, Sullivan PF, Moran JL, Hultman CM, Lichtenstein P, Magnusson P, Lehner T, Shugart YY, Price AL, de Bakker PI, Purcell SM, Sunyaev SR. Exome sequencing and the genetic basis of complex traits. Nat Genet. 2012 May 29; 44(6):623-30. 48. Pasaniuc B, Rohland N, McLaren PJ, Garimella K, Zaitlen N, Li H, Gupta N, Neale BM, Daly MJ, Sklar P, Sullivan PF, Bergen S, Moran JL, Hultman CM, Lichtenstein P, Magnusson P, Purcell SM, Haas DW, Liang L, Sunyaev S, Patterson N, de Bakker PI, Reich D, Price AL. Extremely low-coverage sequencing and imputation increases power for genome-wide association studies. Nat Genet. 2012 May 20; 44(6):631-5. 49. Tennessen JA, Bigham AW, O'Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G, Kang HM, Jordan D, Leal SM, Gabriel S, Rieder MJ, Abecasis G, Altshuler D, Nickerson DA, Boerwinkle E, Sunyaev S, Bustamante CD, Bamshad MJ, Akey JM. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012 Jul 06; 337(6090):64-9. 50. Leshchiner I, Alexa K, Kelsey P, Adzhubei I, Austin-Tse CA, Cooney JD, Anderson H, King MJ, Stottmann RW, Garnaas MK, Ha S, Drummond IA, Paw BH, North TE, Beier DR, Goessling W, Sunyaev SR. Mutation mapping and identification by whole-genome sequencing. Genome Res. 2012 Aug; 22(8):1541-8. 51. Liberles DA, Teichmann SA, Bahar I, Bastolla U, Bloom J, Bornberg-Bauer E, Colwell LJ, de Koning AP, Dokholyan NV, Echave J, Elofsson A, Gerloff DL, Goldstein RA, Grahnen JA, Holder MT, Lakner C, Lartillot N, Lovell SC, Naylor G, Perica T, Pollock DD, Pupko T, Regan L, Roger A, Rubinstein N, Shakhnovich E, Sjölander K, Sunyaev S, Teufel AI, Thorne JL, Thornton JW, Weinreich DM, Whelan S. The interface of protein structure, protein biophysics, and molecular evolution. Protein Sci. 2012 Jun; 21(6):769-85. 52. Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012 Apr 04; 485(7397):242-5. 53. Zuk O, Hechter E, Sunyaev SR, Lander ES. The mystery of missing heritability: Genetic interactions create phantom heritability. Proc Natl Acad Sci U S A. 2012 Jan 24; 109(4):1193-8. 54. Du R, Litonjua AA, Tantisira KG, Lasky-Su J, Sunyaev SR, Klanderman BJ, Celedón JC, Avila L, Soto-Quiros ME, Weiss ST. Genome-wide association study reveals class I MHC-restricted T cell-associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations. J Allergy Clin Immunol. 2012 Feb; 129(2):368-73, 373.e1-5. 55. Kim EB, Fang X, Fushan AA, Huang Z, Lobanov AV, Han L, Marino SM, Sun X, Turanov AA, Yang P, Yim SH, Zhao X, Kasaikina MV, Stoletzki N, Peng C, Polak P, Xiong Z, Kiezun A, Zhu Y, Chen Y, Kryukov GV, Zhang Q, Peshkin L, Yang L, Bronson RT, Buffenstein R, Wang B, Han C, Li Q, Chen L, Zhao W, Sunyaev SR, Park TJ, Zhang G, Wang J, Gladyshev VN. Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature. 2011 Oct 12; 479(7372):223-7. 56. Stitziel NO, Kiezun A, Sunyaev S. Computational and statistical approaches to analyzing variants identified by exome sequencing. Genome Biol. 2011 Sep 14; 12(9):227. 57. Gorelik L, Reid C, Testa M, Brickelmaier M, Bossolasco S, Pazzi A, Bestetti A, Carmillo P, Wilson E, McAuliffe M, Tonkin C, Carulli JP, Lugovskoy A, Lazzarin A, Sunyaev S, Simon K, Cinque P. Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity. J Infect Dis. 2011 Jul 01; 204(1):103-14. 58. Spirin V, Shpunt A, Seebacher J, Gentzel M, Shevchenko A, Gygi S, Sunyaev S. Assigning spectrum-specific P-values to protein identifications by mass spectrometry. Bioinformatics. 2011 Apr 15; 27(8):1128-34. 59. Jordan DM, Kiezun A, Baxter SM, Agarwala V, Green RC, Murray MF, Pugh T, Lebo MS, Rehm HL, Funke BH, Sunyaev SR. Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. Am J Hum Genet. 2011 Feb 11; 88(2):183-92. 60. Jordan DM, Ramensky VE, Sunyaev SR. Human allelic variation: perspective from protein function, structure, and evolution. Curr Opin Struct Biol. 2010 Jun; 20(3):342-50. 61. Price AL, Kryukov GV, de Bakker PI, Purcell SM, Staples J, Wei LJ, Sunyaev SR. Pooled association tests for rare variants in exon-resequencing studies. Am J Hum Genet. 2010 Jun 11; 86(6):832-8. 62. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods. 2010 Apr; 7(4):248-9. 63. Molla M, Delcher A, Sunyaev S, Cantor C, Kasif S. Triplet repeat length bias and variation in the human transcriptome. Proc Natl Acad Sci U S A. 2009 Oct 06; 106(40):17095-100. 64. Li JB, Gao Y, Aach J, Zhang K, Kryukov GV, Xie B, Ahlford A, Yoon JK, Rosenbaum AM, Zaranek AW, LeProust E, Sunyaev SR, Church GM. Multiplex padlock targeted sequencing reveals human hypermutable CpG variations. Genome Res. 2009 Sep; 19(9):1606-15. 65. Stamatoyannopoulos JA, Adzhubei I, Thurman RE, Kryukov GV, Mirkin SM, Sunyaev SR. Human mutation rate associated with DNA replication timing. Nat Genet. 2009 Apr; 41(4):393-5. 66. Kryukov GV, Shpunt A, Stamatoyannopoulos JA, Sunyaev SR. Power of deep, all-exon resequencing for discovery of human trait genes. Proc Natl Acad Sci U S A. 2009 Mar 10; 106(10):3871-6. 67. Sunyaev SR, Lugovskoy A, Simon K, Gorelik L. Adaptive mutations in the JC virus protein capsid are associated with progressive multifocal leukoencephalopathy (PML). PLoS Genet. 2009 Feb; 5(2):e1000368. 68. Schmidt S, Gerasimova A, Kondrashov FA, Adzhubei IA, Kondrashov AS, Sunyaev S. Erratum. PLoS Genet. 2008 Dec; 4(12). 69. Schmidt S, Gerasimova A, Kondrashov FA, Adzhubei IA, Adzuhbei IA, Kondrashov AS, Sunyaev S. Hypermutable non-synonymous sites are under stronger negative selection. PLoS Genet. 2008 Nov; 4(11):e1000281. 70. Beckstead WA, Bjork BC, Stottmann RW, Sunyaev S, Beier DR. SNP2RFLP: a computational tool to facilitate genetic mapping using benchtop analysis of SNPs. Mamm Genome. 2008 Oct-Dec; 19(10-12):687-90. 71. Junqueira M, Spirin V, Balbuena TS, Thomas H, Adzhubei I, Sunyaev S, Shevchenko A. Protein identification pipeline for the homology-driven proteomics. J Proteomics. 2008 Aug 21; 71(3):346-56. 72. Junqueira M, Spirin V, Santana Balbuena T, Waridel P, Surendranath V, Kryukov G, Adzhubei I, Thomas H, Sunyaev S, Shevchenko A. Separating the wheat from the chaff: unbiased filtering of background tandem mass spectra improves protein identification. J Proteome Res. 2008 Aug; 7(8):3382-95. 73. Boyko AR, Williamson SH, Indap AR, Degenhardt JD, Hernandez RD, Lohmueller KE, Adams MD, Schmidt S, Sninsky JJ, Sunyaev SR, White TJ, Nielsen R, Clark AG, Bustamante CD. Assessing the evolutionary impact of amino acid mutations in the human genome. PLoS Genet. 2008 May 30; 4(5):e1000083. 74. Lohmueller KE, Indap AR, Schmidt S, Boyko AR, Hernandez RD, Hubisz MJ, Sninsky JJ, White TJ, Sunyaev SR, Nielsen R, Clark AG, Bustamante CD. Proportionally more deleterious genetic variation in European than in African populations. Nature. 2008 Feb 21; 451(7181):994-7. 75. Gorlov IP, Gorlova OY, Sunyaev SR, Spitz MR, Amos CI. Shifting paradigm of association studies: value of rare single-nucleotide polymorphisms. Am J Hum Genet. 2008 Jan; 82(1):100-12. 76. Spirin V, Schmidt S, Pertsemlidis A, Cooper RS, Cohen JC, Sunyaev SR. Common single-nucleotide polymorphisms act in concert to affect plasma levels of high-density lipoprotein cholesterol. Am J Hum Genet. 2007 Dec; 81(6):1298-303. 77. Ballif BA, Carey GR, Sunyaev SR, Gygi SP. Large-scale identification and evolution indexing of tyrosine phosphorylation sites from murine brain. J Proteome Res. 2008 Jan; 7(1):311-8. 78. Asthana S, Roytberg M, Stamatoyannopoulos J, Sunyaev S. Analysis of sequence conservation at nucleotide resolution. PLoS Comput Biol. 2007 Dec; 3(12):e254. 79. Asthana S, Noble WS, Kryukov G, Grant CE, Sunyaev S, Stamatoyannopoulos JA. Widely distributed noncoding purifying selection in the human genome. Proc Natl Acad Sci U S A. 2007 Jul 24; 104(30):12410-5. 80. Waridel P, Frank A, Thomas H, Surendranath V, Sunyaev S, Pevzner P, Shevchenko A. Sequence similarity-driven proteomics in organisms with unknown genomes by LC-MS/MS and automated de novo sequencing. Proteomics. 2007 Jul; 7(14):2318-29. 81. Ilyinskii PO, Gabai VL, Sunyaev SR, Thoidis G, Shneider AM. Toxicity of influenza A virus matrix protein 2 for mammalian cells is associated with its intrinsic proton-channeling activity. Cell Cycle. 2007 Aug 15; 6(16):2043-7. 82. Kryukov GV, Pennacchio LA, Sunyaev SR. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am J Hum Genet. 2007 Apr; 80(4):727-39. 83. Ahituv N, Kavaslar N, Schackwitz W, Ustaszewska A, Martin J, Hebert S, Doelle H, Ersoy B, Kryukov G, Schmidt S, Yosef N, Ruppin E, Sharan R, Vaisse C, Sunyaev S, Dent R, Cohen J, McPherson R, Pennacchio LA. Medical sequencing at the extremes of human body mass. Am J Hum Genet. 2007 Apr; 80(4):779-91. 84. Liska AJ, Sunyaev S, Shilov IN, Schaeffer DA, Shevchenko A. Error-tolerant EST database searches by tandem mass spectrometry and multiTag software. Proteomics. 2005 Nov; 5(16):4118-22. 85. Keightley PD, Kryukov GV, Sunyaev S, Halligan DL, Gaffney DJ. Evolutionary constraints in conserved nongenic sequences of mammals. Genome Res. 2005 Oct; 15(10):1373-8. 86. Kryukov GV, Schmidt S, Sunyaev S. Small fitness effect of mutations in highly conserved non-coding regions. Hum Mol Genet. 2005 Aug 01; 14(15):2221-9. 87. Sunyaev S. Biocomputing enters its adolescence. Genome Biol. 2005; 6(6):325. 88. Jordan IK, Kondrashov FA, Adzhubei IA, Wolf YI, Koonin EV, Kondrashov AS, Sunyaev S. A universal trend of amino acid gain and loss in protein evolution. Nature. 2005 Feb 10; 433(7026):633-8. 89. Dimmic MW, Sunyaev S, Bustamante CD. Inferring SNP function using evolutionary, structural, and computational methods. Pac Symp Biocomput. 2005; 382-4. 90. Asthana S, Schmidt S, Sunyaev S. A limited role for balancing selection. Trends Genet. 2005 Jan; 21(1):30-2. 91. Liska AJ, Popov AV, Sunyaev S, Coughlin P, Habermann B, Shevchenko A, Bork P, Karsenti E, Shevchenko A. Homology-based functional proteomics by mass spectrometry: application to the Xenopus microtubule-associated proteome. Proteomics. 2004 Sep; 4(9):2707-21. 92. Ogurtsov AY, Sunyaev S, Kondrashov AS. Indel-based evolutionary distance and mouse-human divergence. Genome Res. 2004 Aug; 14(8):1610-6. 93. Bazykin GA, Kondrashov FA, Ogurtsov AY, Sunyaev S, Kondrashov AS. Positive selection at sites of multiple amino acid replacements since rat-mouse divergence. Nature. 2004 Jun 03; 429(6991):558-62. 94. Sunyaev SR, Bogopolsky GA, Oleynikova NV, Vlasov PK, Finkelstein AV, Roytberg MA. From analysis of protein structural alignments toward a novel approach to align protein sequences. Proteins. 2004 Feb 15; 54(3):569-82. 95. Habermann B, Oegema J, Sunyaev S, Shevchenko A. The power and the limitations of cross-species protein identification by mass spectrometry-driven sequence similarity searches. Mol Cell Proteomics. 2004 Mar; 3(3):238-49. 96. Sunyaev S, Kondrashov FA, Bork P, Ramensky V. Impact of selection, mutation rate and genetic drift on human genetic variation. Hum Mol Genet. 2003 Dec 15; 12(24):3325-30. 97. Schmidt S, Sunyaev S, Bork P, Dandekar T. Metabolites: a helping hand for pathway evolution? Trends Biochem Sci. 2003 Jun; 28(6):336-41. 98. Sunyaev S, Liska AJ, Golod A, Shevchenko A, Shevchenko A. MultiTag: multiple error-tolerant sequence tag search for the sequence-similarity identification of proteins by mass spectrometry. Anal Chem. 2003 Mar 15; 75(6):1307-15. 99. Stark A, Sunyaev S, Russell RB. A model for statistical significance of local similarities in structure. J Mol Biol. 2003 Mar 07; 326(5):1307-16. 100. Kriventseva EV, Koch I, Apweiler R, Vingron M, Bork P, Gelfand MS, Sunyaev S. Increase of functional diversity by alternative splicing. Trends Genet. 2003 Mar; 19(3):124-8. 101. Shevchenko A, Sunyaev S, Liska A, Bork P, Shevchenko A. Nanoelectrospray tandem mass spectrometry and sequence similarity searching for identification of proteins from organisms with unknown genomes. Methods Mol Biol. 2003; 211:221-34. 102. Kondrashov AS, Sunyaev S, Kondrashov FA. Dobzhansky-Muller incompatibilities in protein evolution. Proc Natl Acad Sci U S A. 2002 Nov 12; 99(23):14878-83. 103. Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 2002 Sep 01; 30(17):3894-900. 104. Shevchenko A, Sunyaev S, Loboda A, Shevchenko A, Bork P, Ens W, Standing KG. Charting the proteomes of organisms with unsequenced genomes by MALDI-quadrupole time-of-flight mass spectrometry and BLAST homology searching. Anal Chem. 2001 May 01; 73(9):1917-26. 105. Sunyaev S, Ramensky V, Koch I, Lathe W, Kondrashov AS, Bork P. Prediction of deleterious human alleles. Hum Mol Genet. 2001 Mar 15; 10(6):591-7. 106. Sunyaev S, Lathe W, Bork P. Integration of genome data and protein structures: prediction of protein folds, protein interactions and "molecular phenotypes" of single nucleotide polymorphisms. Curr Opin Struct Biol. 2001 Feb; 11(1):125-30. 107. Sunyaev SR, Lathe WC, Ramensky VE, Bork P. SNP frequencies in human genes an excess of rare alleles and differing modes of selection. Trends Genet. 2000 Aug; 16(8):335-7. 108. Sunyaev S, Ramensky V, Bork P. Towards a structural basis of human non-synonymous single nucleotide polymorphisms. Trends Genet. 2000 May; 16(5):198-200. 109. Sunyaev S, Hanke J, Brett D, Aydin A, Zastrow I, Lathe W, Bork P, Reich J. Individual variation in protein-coding sequences of human genome. Adv Protein Chem. 2000; 54:409-37. 110. Sunyaev S, Hanke J, Aydin A, Wirkner U, Zastrow I, Reich J, Bork P. Prediction of nonsynonymous single nucleotide polymorphisms in human disease-associated genes. J Mol Med (Berl). 1999 Nov; 77(11):754-60. 111. Sunyaev SR, Eisenhaber F, Rodchenkov IV, Eisenhaber B, Tumanyan VG, Kuznetsov EN. PSIC: profile extraction from sequence alignments with position-specific counts of independent observations. Protein Eng. 1999 May; 12(5):387-94. 112. Huynen M, Doerks T, Eisenhaber F, Orengo C, Sunyaev S, Yuan Y, Bork P. Homology-based fold predictions for Mycoplasma genitalium proteins. J Mol Biol. 1998 Jul 17; 280(3):323-6. 113. Sunyaev SR, Eisenhaber F, Argos P, Kuznetsov EN, Tumanyan VG. Are knowledge-based potentials derived from protein structure sets discriminative with respect to amino acid types? Proteins. 1998 May 15; 31(3):225-46. 114. Sunyaev S, Kuznetsov E, Rodchenkov I, Tumanyan V. Protein sequence-structure compatibility criteria in terms of statistical hypothesis testing. Protein Eng. 1997 Jun; 10(6):635-46.

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