Abstract
The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10 g-8 per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.
| Original language | English |
|---|---|
| Pages (from-to) | 1061-1073 |
| Number of pages | 13 |
| Journal | Nature |
| Volume | 467 |
| Issue number | 7319 |
| DOIs | |
| State | Published - Oct 28 2010 |
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In: Nature, Vol. 467, No. 7319, 28.10.2010, p. 1061-1073.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - A map of human genome variation from population-scale sequencing
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AU - Ramenani, Ravi
AU - Riches, David
AU - Song, Wanmin
AU - Turcotte, Cynthia
AU - Wang, Shally
AU - Dooling, David
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AU - Fulton, Robert
AU - Weinstock, George
AU - Burton, John
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AU - Zhou, Yan
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AU - Smith, Richard E.
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AU - Humphray, Illumina Sean
AU - Bauer, Markus
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AU - Eberle, Michael
AU - James, Terena
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AU - Peckham, Heather E.
AU - Sakarya, Onur
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AU - Tsung, Eric F.
AU - Mark, A. Batzer
AU - Konkel, Miriam K.
AU - Walker, Jerilyn A.
AU - Albrecht, Marcus W.
AU - Amstislavskiy, Vyacheslav S.
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AU - Parkhomchuk, Dimitri V.
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AU - Paschall, Justin E.
AU - Phan, Lon D.
AU - Rotmistrovsky, Kirill E.
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AU - Shumway, Martin F.
AU - Xiao, Chunlin
AU - Gil, A. McVean
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AU - Iqbal, Zamin
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AU - Marchini, Jonathan L.
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AU - Myers, Simon
AU - Tumian, Afidalina
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AU - Haussler, David
AU - Hinrichs, Angie S.
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AU - Kern, Andrew
AU - Kuhn, Robert M.
AU - Przeworski, Molly
AU - Hernandez, Ryan D.
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AU - Chen, Wei
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AU - Moffatt, Miriam F.
AU - Scheet, Paul
AU - Sidore, Carlo
AU - Snyder, Matthew
AU - Zhan, Xiaowei
AU - Zöllner, Sebastian
AU - Awadalla, Philip
AU - Casals, Ferran
AU - Idaghdour, Youssef
AU - Keebler, John
AU - Stone, Eric A.
AU - Zilversmit, Martine
AU - Jorde, Lynn
AU - Xing, Jinchuan
AU - Eichler, Evan E.
AU - Aksay, Gozde
AU - Alkan, Can
AU - Hajirasouliha, Iman
AU - Hormozdiari, Fereydoun
AU - Kidd, Jeffrey M.
AU - CenkSahinalp, S.
AU - Sudmant, Peter H.
AU - Chen, Ken
AU - Chinwalla, Asif
AU - Ding, Li
AU - Koboldt, Daniel C.
AU - McLellan, Mike D.
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AU - Wendl, Michael C.
AU - Zhang, Qunyuan
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AU - Chen, Yuan
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AU - Danecek, Petr
AU - Dermitzakis, Emmanouil T.
AU - Hu, Min
AU - Huang, Ni
AU - Matt, E. Hurles
AU - Jin, Hanjun
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AU - Keane, Thomas M.
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AU - Lindsay, Sarah
AU - Long, Quan
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AU - Parts, Leopold
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AU - Zhang, Yujun
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AU - Abyzov, Alexej
AU - Balasubramanian, Suganthi
AU - Bjornson, Robert
AU - Grubert, Fabian
AU - Habegger, Lukas
AU - Haraksingh, Rajini
AU - Khurana, Ekta
AU - Lam, Hugo Y.K.
AU - Leng, Jing
AU - Mu, Xinmeng Jasmine
AU - Urban, Alexander E.
AU - Zhang, Zhengdong
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AU - Coafra, Cristian
AU - Dinh, Huyen
AU - Kovar, Christie
AU - Lee, Sandy
AU - Nazareth, Lynne
AU - Wilkinson, Jane
AU - Coffey, Allison
AU - Scott, Carol
AU - Tyler-Smith, Chris
AU - Gharani, Neda
AU - Kaye, Jane S.
AU - Kent, Alastair
AU - Li, Taosha
AU - McGuire, Amy L.
AU - Ossorio, Pilar N.
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AU - Toji, Lorraine H.
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AU - McEwen, Jean E.
AU - Abdallah, Assya
AU - Juenger, Christopher R.
AU - Clemm, Nicholas C.
AU - Duncanson, Audrey
AU - Green, Eric D.
AU - Guyer, Mark S.
AU - Peterson, Jane L.
N1 - Funding Information: Acknowledgements We thank many people who contributed to this project: K. Beal, S. Fitzgerald, G. Cochrane, V. Silventoinen, P. Jokinen, E. Birney and J. Ahringer for comments on the manuscript; T. Hunkapiller and Q. Doan for their advice and coordination; N. Kälin, F. Laplace, J. Wilde, S. Paturej, I. Kühndahl, J. Knight, C. Kodira and M. Boehnke for valuable discussions; Z. Cheng, S. Sajjadian and F. Hormozdiari for assistance in managing data sets; and D. Leja for help with the figures. We thank the Yoruba in Ibadan, Nigeria, the Han Chinese in Beijing, China, the Japanese in Tokyo, Japan, the Utah CEPH community, the Luhya in Webuye, Kenya, the Toscani in Italia, and the Chinese in Denver, Colorado, for contributing samples for research. This research was supported in part by Wellcome Trust grants WT089088/Z/09/Z to R.M.D.; WT085532AIA to P.F.; WT086084/Z/08/Z to G.A.M.; WT081407/Z/06/Z to J.S.K.; WT075491/Z/04 to G.L.; WT077009 to C.T.-S.; Medical Research Council grant G0801823 to J.L.M.; British Heart Foundation grant RG/09/012/28096 to C.A.; The Leverhulme Trust and EPSRC studentships to L.M. and A.T.; the Louis-Jeantet Foundation and Swiss National Science Foundation in support of E.T.D. and S.B.M.; NGI/EBI fellowship 050-72-436 to K.Y.; a National Basic Research Program of China (973 program no. 2011CB809200); the National Natural Science Foundation of China (30725008, 30890032, 30811130531, 30221004); the Chinese 863 program (2006AA02Z177, 2006AA02Z334, 2006AA02A302, 2009AA022707); the Shenzhen Municipal Government of China (grants JC200903190767A, JC200903190772A, ZYC200903240076A, CXB200903110066A, ZYC200903240077A, ZYC200903240076A and ZYC200903240080A); the Ole Rømer grant from the DanishNaturalScienceResearchCouncil; anEmmyNoether Fellowship ofthe German Research Foundation (Deutsche Forschungsgemeinschaft) to J.O.K.; BMBF grant 01GS08201; BMBF grant PREDICT 0315428A to R.H.; BMBF NGFN PLUS and EU 6th framework READNA to S.S.; EU 7th framework 242257 to A.V.S.; the Max Planck Society; a grant from Genome Quebec and the Ministry of Economic Development, Innovation and Trade, PSR-SIIRI-195 to P.A.; the Intramural Research Program of the NIH; the National Library of Medicine; the National Institute of Environmental Health Sciences; and NIH grants P41HG4221 and U01HG5209 to C.L.; P41HG4222 to J.S.; R01GM59290 to L.B.J. and M.A.B.; R01GM72861 to M.P.; R01HG2651 and R01MH84698 to G.R.A.; U01HG5214 to G.R.A. and A.C.; P01HG4120 to E.E.E.; U54HG2750 to D.A.; U54HG2757 to A.C.; U01HG5210 to D.C.; U01HG5208 to M.J.D.; U01HG5211 to R.A.G.; R01HG3698, R01HG4719 and RC2HG5552 to G.T.M.; R01HG3229 to C.D.B. and A.G.C.; P50HG2357 to M.S.; R01HG4960 to B.L.B; P41HG2371 and U41HG4568 to D.H.; R01HG4333 to A.M.L.; U54HG3273 to R.A.G.; U54HG3067 to E.S.L.; U54HG3079 to R.K.W.; N01HG62088 to the Coriell Institute; S10RR025056 to the Translational Genomics Research Institute; Al Williams Professorship funds for M.B.G.; the BWF and Packard Foundation support for P.C.S.; the Pew Charitable Trusts support for G.R.A.; and an NSF Minority Postdoctoral Fellowship in support of R.D.H. E.E.E. is an HHMI investigator, M.P. is an HHMI Early Career Scientist, and D.M.A. is Distinguished Clinical Scholar of the Doris Duke Charitable Foundation.
PY - 2010/10/28
Y1 - 2010/10/28
N2 - The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10 g-8 per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.
AB - The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10 g-8 per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.
UR - http://www.scopus.com/inward/record.url?scp=84975742565&partnerID=8YFLogxK
U2 - 10.1038/nature09534
DO - 10.1038/nature09534
M3 - Article
C2 - 20981092
AN - SCOPUS:84975742565
SN - 0028-0836
VL - 467
SP - 1061
EP - 1073
JO - Nature
JF - Nature
IS - 7319
ER -