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Genome Biol. 2011 Sep 14;12(9):R84. doi: 10.1186/gb-2011-12-9-r84.

The functional spectrum of low-frequency coding variation.

Collaborators (373)

Durbin RM, Burton J, Carter DM, Churcher C, Coffey A, Cox A, Palotie A, Quail M, Skelly T, Stalker J, Swerdlow HP, Turner D, Ayub Q, Balasubramaniam S, Barrett JC, Chen Y, Conrad DF, Danecek P, Hu M, Huang N, Hurles ME, Jostins L, Keane TM, Le SQ, Lindsay S, Long Q, MacArthur DG, Parts L, Tyler-Smith C, Walter K, Xue Y, Zhang Y, Coffey A, Scott C, Gabriel SB, Lander ES, Lander ES, Altshuler D, Ambrogio L, Bloom T, Cibulskis K, Fennell TJ, Gabriel SB, Jaffe DB, Shefler E, Sougnez CL, Daly MJ, DePristo MA, Ball AD, Banks E, Garimella KV, Grossman SR, Handsaker RE, Hanna M, Hartl C, Kernytsky AM, Korn JM, Li H, Maguire JR, McCarroll SA, McKenna A, Nemesh JC, Philippakis AA, Poplin RE, Rivas MA, Sabeti PC, Schaffner SF, Shlyakhter IA, DePristo MA, Wilkinson J, Altshuler D, Altshuler D, McCarroll SA, Li Y, Anderson P, Blackwell T, Chen W, Ding J, Kang HM, Sidore C, Snyder M, Zhan X, Zllner S, Abecasis GR, Bentley DR, Gormley N, Humphray S, Kingsbury Z, Kokko-Gonzales P, Stone J, Cheetham R, Cox T, Eberle M, James T, Kahn S, Murray L, Chakravarti A, Clark AG, Degenhardt J, Collins FS, De la Vega FM, Hyland FC, Sakarya O, Sun YA, Donnelly P, McVean GA, Auton A, Iqbal Z, Lunter G, Marchini JL, Myers S, Egholm M, Flicek P, Clarke L, Cunningham F, Herrero J, Keenen S, Kulesha E, Leinonen R, McLaren WM, Radhakrishnan R, Smith RE, Zalunin V, Zheng-Bradley X, Gibbs RA, Deiros D, Metzker M, Muzny D, Reid J, Wheeler D, Bainbridge M, Challis D, Sabo A, Yu F, Yu J, Coafra C, Dinh H, Kovar C, Lee S, Nazareth L, Knoppers BM, Lehrach H, Sudbrak R, Borodina TA, Davydov AN, Marquardt P, Mertes F, Nietfeld W, Soldatov AV, Timmermann B, Tolzmann M, Albrecht MW, Amstislavskiy VS, Herwig R, Parkhomchuk DV, Mardis ER, Wilson RK, Dooling D, Fulton L, Fulton R, Weinstock G, Chen K, Chinwalla A, Ding L, Koboldt DC, McLellan MD, Wallis JW, Wendl MC, Zhang Q, Marchini JL, Moutsianas L, Myers S, Tumian A, McVean GA, Nickerson DA, Aksay G, Kidd JM, Schafer AJ, Duncanson A, Sherry ST, Agarwala R, Khouri HM, Morgulis AO, Paschall JE, Phan LD, Rotmistrovsky KE, Sanders RD, Shumway MF, Xiao C, Wang J, Jian M, Li G, Li R, Liang H, Tian G, Wang B, Wang J, Wang W, Yang H, Zhang X, Zheng H, Wang J, Fang X, Guo X, Li Y, Luo R, Tai S, Wu H, Zheng H, Zheng X, Zhou Y, Li T, Su Y, Wang J, Li R, McKernan KJ, Costa GL, Ichikawa JK, Lee CC, Fu Y, Manning JM, McLaughlin SF, Peckham HE, Tsung EF, Dahl A, Rosenstiel P, Schreiber S, Affourtit J, Ashworth D, Attiya S, Bachorski M, Buglione E, Burke A, Caprio A, Celone C, Clark S, Conners D, Desany B, Gu L, Guccione L, Kao K, Kebbel A, Knowlton J, Labrecque M, McDade L, Mealmaker C, Minderman M, Nawrocki A, Niazi F, Pareja K, Ramenani R, Riches D, Song W, Turcotte C, Wang S, Knight J, Winer R, Palotie A, De Witte A, Giles S, Marth GT, Garrison EP, Indap A, Kural D, Lee WP, Leong WF, Stewart C, Ward AN, Wu J, Huang W, Quinlan AR, Stromberg MP, Lee C, Mills RE, Shi X, Altshuler D, Browning BL, Grossman SR, Sabeti PC, Shlyakhter IA, Price A, Cooper DN, Ball EV, Mort M, Phillips AD, Stenson PD, Sebat J, Makarov V, Yoon SC, Ye K, Bustamante CD, Snyder M, Grubert F, Lam HY, Urban AE, Kaganovich M, Kidd JM, Gravel S, Sttz AM, Korbel JO, Ye K, Batzer MA, Konkel MK, Walker JA, Craig DW, Beckstrom-Sternberg SM, Christoforides A, Kurdoglu AA, Pearson JV, Sinari SA, Tembe WD, Haussler D, Hinrichs AS, Katzman SJ, Kern A, Kuhn RM, Przeworski M, Hernandez RD, Howie B, Kelley JL, Melton S, Cookson WO, Moffatt MF, Lathrop M, Liang L, Scheet P, Awadalla P, Casals F, Idaghdour Y, Keebler J, Stone EA, Zilversmit M, Xing J, Jorde L, Eichler EE, Alkan C, Hajirasouliha I, Hormozdiari F, Albers CA, Dermitzakis ET, Montgomery SB, Jin H, Gerstein MB, Abyzov A, Habegger L, Haraksingh R, Jee J, Leng J, Mu XJ, Bjornson R, Du J, Gerstein MB, Balasubramanian S, Khurana E, Zhang Z, Urban AE, Gharani N, Toji LH, Kaye JS, Kent A, McGuire AL, Ossorio PN, Rotimi CN, Brooks LD, Felsenfeld AL, McEwen JE, Clemm NC, Guyer MS, Peterson JL, Abdallah A, Juenger CR, Green ED, Cartwright RA.

Abstract

BACKGROUND:

Rare coding variants constitute an important class of human genetic variation, but are underrepresented in current databases that are based on small population samples. Recent studies show that variants altering amino acid sequence and protein function are enriched at low variant allele frequency, 2 to 5%, but because of insufficient sample size it is not clear if the same trend holds for rare variants below 1% allele frequency.

RESULTS:

The 1000 Genomes Exon Pilot Project has collected deep-coverage exon-capture data in roughly 1,000 human genes, for nearly 700 samples. Although medical whole-exome projects are currently afoot, this is still the deepest reported sampling of a large number of human genes with next-generation technologies. According to the goals of the 1000 Genomes Project, we created effective informatics pipelines to process and analyze the data, and discovered 12,758 exonic SNPs, 70% of them novel, and 74% below 1% allele frequency in the seven population samples we examined. Our analysis confirms that coding variants below 1% allele frequency show increased population-specificity and are enriched for functional variants.

CONCLUSIONS:

This study represents a large step toward detecting and interpreting low frequency coding variation, clearly lays out technical steps for effective analysis of DNA capture data, and articulates functional and population properties of this important class of genetic variation.

PMID:
21917140
[PubMed - indexed for MEDLINE]
PMCID:
PMC3308047
Free PMC Article
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