Demographic history and rare allele sharing among human populations
Authors: Gravel Simon , Henn Brenna M. , Gutenkunst Ryan N. , Indap Amit R. , Marth Gabor T. , Clark Andrew G. , Yu Fuli , Gibbs Richard A. ,   The 1000 Genomes Project, Bustamante Carlos D. , Altshuler David L. , Durbin Richard M. , Abecasis Gonçalo R. , Bentley David R. , Chakravarti Aravinda , Clark Andrew G. , Collins Francis S. , De La Vega Francisco M. , Donnelly Peter , Egholm Michael , Flicek Paul , Gabriel Stacey B. , Gibbs Richard A. , Knoppers Bartha M. , Lander Eric S. , Lehrach Hans , Mardis Elaine R. , McVean Gil A. , Nickerson Debbie A. , Peltonen Leena , Schafer Alan J. , Sherry Stephen T. , Wang Jun , Wilson Richard K. , Gibbs Richard A. , Deiros David , Metzker Mike , Muzny Donna , Reid Jeff , Wheeler David , Wang Jun , Li Jingxiang , Jian Min , Li Guoqing , Li Ruiqiang , Liang Huiqing , Tian Geng , Wang Bo , Wang Jian , Wang Wei , Yang Huanming , Zhang Xiuqing , Zheng Huisong , Lander Eric S. , Altshuler David L. , Ambrogio Lauren , Bloom Toby , Cibulskis Kristian , Fennell Tim J. , Gabriel Stacey B. , Jaffe David B. , Shefler Erica , Sougnez Carrie L. , Bentley David R. , Gormley Niall , Humphray Sean , Kingsbury Zoya , Koko-Gonzales Paula , Stone Jennifer , McKernan Kevin J. , Costa Gina L. , Ichikawa Jeffry K. , Lee Clarence C. , Sudbrak Ralf , Lehrach Hans , Borodina Tatiana A. , Dahl Andreas , Davydov Alexey N. , Marquardt Peter , Mertes Florian , Nietfeld Wilfiried , Rosenstiel Philip , Schreiber Stefan , Soldatov Aleksey V. , Timmermann Bernd , Tolzmann Marius , Egholm Michael , Affourtit Jason , Ashworth Dana , Attiya Said , Bachorski Melissa , Buglione Eli , Burke Adam , Caprio Amanda , Celone Christopher , Clark Shauna , Conners David , Desany Brian , Gu Lisa , Guccione Lorri , Kao Kalvin , Kebbel Andrew , Knowlton Jennifer , Labrecque Matthew , McDade Louise , Mealmaker Craig , Minderman Melissa , Nawrocki Anne , Niazi Faheem , Pareja Kristen , Ramenani Ravi , Riches David , Song Wanmin , Turcotte Cynthia , Wang Shally , Mardis Elaine R. , Wilson Richard K. , Dooling David , Fulton Lucinda , Fulton Robert , Weinstock George , Durbin Richard M. , Burton John , Carter David M. , Churcher Carol , Coffey Alison , Cox Anthony , Palotie Aarno , Quail Michael , Skelly Tom , Stalker James , Swerdlow Harold P. , Turner Daniel , De Witte Anniek , Giles Shane , Gibbs Richard A. , Wheeler David , Bainbridge Matthew , Challis Danny , Sabo Aniko , Yu Fuli , Yu Jin , Wang Jun , Fang Xiaodong , Guo Xiaosen , Li Ruiqiang , Li Yingrui , Luo Ruibang , Tai Shuaishuai , Wu Honglong , Zheng Hancheng , Zheng Xiaole , Zhou Yan , Li Guoqing , Wang Jian , Yang Huanming , Marth Gabor T. , Garrison Erik P. , Huang Weichun , Indap Amit , Kural Deniz , Lee Wan-Ping , Leong Wen Fung , Quinlan Aaron R. , Stewart Chip , Stromberg Michael P. , Ward Alistair N. , Wu Jiantao , Lee Charles , Mills Ryan E. , Shi Xinghua , Daly Mark J. , DePristo Mark A. , Altshuler David L. , Ball Aaron D. , Banks Eric , Bloom Toby , Browning Brian L. , Cibulskis Kristian , Fennell Tim J. , Garimella Kiran V. , Grossman Sharon R. , Handsaker Robert E. , Hanna Matt , Hartl Chris , Jaffe David B. , Kernytsky Andrew M. , Korn Joshua M. , Li Heng , Maguire Jared R. , McCarroll Steven A. , McKenna Aaron , Nemesh James C. , Philippakis Anthony A. , Poplin Ryan E. , Price Alkes , Rivas Manuel A. , Sabeti Pardis C. , Schaffner Stephen F. , Shefler Erica , Shlyakhter Ilya A. , Cooper David N. , Ball Edward V. , Mort Matthew , Phillips Andrew D. , Stenson Peter D. , Sebat Jonathan , Makarov Vladimir , Ye Kenny , Yoon Seungtai C. , Bustamante Carlos D. , Clark Andrew G. , Boyko Adam , Degenhardt Jeremiah , Gravel Simon , Gutenkunst Ryan N. , Kaganovich Mark , Keinan Alon , Lacroute Phil , Ma Xin , Reynolds Andy , Clarke Laura , Flicek Paul , Cunningham Fiona , Herrero Javier , Keenen Stephen , Kulesha Eugene , Leinonen Rasko , McLaren William M. , Radhakrishnan Rajesh , Smith Richard E. , Zalunin Vadim , Zheng-Bradley Xiangqun , Korbel Jan O. , Stütz Adrian M. , Humphray Sean , Bauer Markus , Cheetham R. Keira , Cox Tony , Eberle Michael , James Terena , Kahn Scott , Murray Lisa , Chakravarti Aravinda , Ye Kai , De La Vega Francisco M. , Fu Yutao , Hyland Fiona C. L. , Manning Jonathan M. , McLaughlin Stephen F. , Peckham Heather E. , Sakarya Onur , Sun Yongming A. , Tsung Eric F. , Batzer Mark A. , Konkel Miriam K. , Walker Jerilyn A. , Sudbrak Ralf , Albrecht Marcus W. , Amstislavskiy Vyacheslav S. , Herwig Ralf , Parkhomchuk Dimitri V. , Sherry Stephen T. , Agarwala Richa , Khouri Hoda M. , Morgulis Aleksandr O. , Paschall Justin E. , Phan Lon D. , Rotmistrovsky Kirill E. , Sanders Robert D. , Shumway Martin F. , Xiao Chunlin , McVean Gil A. , Auton Adam , Iqbal Zamin , Lunter Gerton , Marchini Jonathan L. , Moutsianas Loukas , Myers Simon , Tumian Afidalina , Desany Brian , Knight James , Winer Roger , Craig David W. , Beckstrom-Sternberg Steve M. , Christoforides Alexis , Kurdoglu Ahmet A. , Pearson John V. , Sinari Shripad A. , Tembe Waibhav D. , Haussler David , Hinrichs Angie S. , Katzman Sol J. , Kern Andrew , Kuhn Robert M. , Przeworski Molly , Hernandez Ryan D. , Howie Bryan , Kelley Joanna L. , Melton S. Cord , Abecasis Gonçalo R. , Li Yun , Anderson Paul , Blackwell Tom , Chen Wei , Cookson William O. , Ding Jun , Kang Hyun Min , Lathrop Mark , Liang Liming , Moffatt Miriam F. , Scheet Paul , Sidore Carlo , Snyder Matthew , Zhan Xiaowei , Zöllner Sebastian , Awadalla Philip , Casals Ferran , Idaghdour Youssef , Keebler John , Stone Eric A. , Zilversmit Martine , Jorde Lynn , Xing Jinchuan , Eichler Evan E. , Aksay Gozde , Alkan Can , Hajirasouliha Iman , Hormozdiari Fereydoun , Kidd Jeffrey M. , Sahinalp S. Cenk , Sudmant Peter H. , Mardis Elaine R. , Chen Ken , Chinwalla Asif , Ding Li , Koboldt Daniel C. , McLellan Mike D. , Dooling David , Weinstock George , Wallis John W. , Wendl Michael C. , Zhang Qunyuan , Durbin Richard M. , Albers Cornelis A. , Ayub Qasim , Balasubramaniam Senduran , Barrett Jeffrey C. , Carter David M. , Chen Yuan , Conrad Donald F. , Danecek Petr , Dermitzakis Emmanouil T. , Hu Min , Huang Ni , Hurles Matt E. , Jin Hanjun , Jostins Luke , Keane Thomas M. , Le Si Quang , Lindsay Sarah , Long Quan , MacArthur Daniel G. , Montgomery Stephen B. , Parts Leopold , Stalker James , Tyler-Smith Chris , Walter Klaudia , Zhang Yujun , Gerstein Mark B. , Snyder Michael , Abyzov Alexej , Balasubramanian Suganthi , Bjornson Robert , Du Jiang , Grubert Fabian , Habegger Lukas , Haraksingh Rajini , Jee Justin , Khurana Ekta , Lam Hugo Y. K. , Leng Jing , Mu Xinmeng Jasmine , Urban Alexander E. , Zhang Zhengdong , Li Yingrui , Luo Ruibang , Marth Gabor T. , Garrison Erik P. , Kural Deniz , Quinlan Aaron R. , Stewart Chip , Stromberg Michael P. , Ward Alistair N. , Wu Jiantao , Lee Charles , Mills Ryan E. , Shi Xinghua , McCarroll Steven A. , Banks Eric , DePristo Mark A. , Handsaker Robert E. , Hartl Chris , Korn Joshua M. , Li Heng , Nemesh James C. , Sebat Jonathan , Makarov Vladimir , Ye Kenny , Yoon Seungtai C. , Degenhardt Jeremiah , Kaganovich Mark , Clarke Laura , Smith Richard E. , Zheng-Bradley Xiangqun , Korbel Jan O. , Humphray Sean , Cheetham R. Keira , Eberle Michael , Kahn Scott , Murray Lisa , Ye Kai , De La Vega Francisco M. , Fu Yutao , Peckham Heather E. , Sun Yongming A. , Batzer Mark A. , Konkel Miriam K. , Walker Jerilyn A. , Xiao Chunlin , Iqbal Zamin , Desany Brian , Blackwell Tom , Snyder Matthew , Xing Jinchuan , Eichler Evan E. , Aksay Gozde , Alkan Can , Hajirasouliha Iman , Hormozdiari Fereydoun , Kidd Jeffrey M. , Chen Ken , Chinwalla Asif , Ding Li , McLellan Mike D. , Wallis John W. , Hurles Matt E. , Conrad Donald F. , Walter Klaudia , Zhang Yujun , Gerstein Mark B. , Snyder Michael , Abyzov Alexej , Du Jiang , Grubert Fabian , Haraksingh Rajini , Jee Justin , Khurana Ekta , Lam Hugo Y. K. , Leng Jing , Mu Xinmeng Jasmine , Urban Alexander E. , Zhang Zhengdong , Gibbs Richard A. , Bainbridge Matthew , Challis Danny , Coafra Cristian , Dinh Huyen , Kovar Christie , Lee Sandy , Muzny Donna , Nazareth Lynne , Reid Jeff , Sabo Aniko , Yu Fuli , Yu Jin , Marth Gabor T. , Garrison Erik P. , Indap Amit , Leong Wen Fung , Quinlan Aaron R. , Stewart Chip , Ward Alistair N. , Wu Jiantao , Cibulskis Kristian , Fennell Tim J. , Gabriel Stacey B. , Garimella Kiran V. , Hartl Chris , Shefler Erica , Sougnez Carrie L. , Wilkinson Jane , Clark Andrew G. , Gravel Simon , Grubert Fabian , Clarke Laura , Flicek Paul , Smith Richard E. , Zheng-Bradley Xiangqun , Sherry Stephen T. , Khouri Hoda M. , Paschall Justin E. , Shumway Martin F. , Xiao Chunlin , McVean Gil A. , Katzman Sol J. , Abecasis Gonçalo R. , Blackwell Tom , Mardis Elaine R. , Dooling David , Fulton Lucinda , Fulton Robert , Koboldt Daniel C. , Durbin Richard M. , Balasubramaniam Senduran , Coffey Allison , Keane Thomas M. , MacArthur Daniel G. , Palotie Aarno , Scott Carol , Stalker James , Tyler-Smith Chris , Gerstein Mark B. , Balasubramanian Suganthi , Chakravarti Aravinda , Knoppers Bartha M. , Abecasis Gonçalo R. , Bustamante Carlos D. , Gharani Neda , Gibbs Richard A. , Jorde Lynn , Kaye Jane S. , Kent Alastair , Li Taosha , McGuire Amy L. , McVean Gil A. , Ossorio Pilar N. , Rotimi Charles N. , Su Yeyang , Toji Lorraine H. , TylerSmith Chris , Brooks Lisa D. , Felsenfeld Adam L. , McEwen Jean E. , Abdallah Assya , Juenger Christopher R. , Clemm Nicholas C. , Collins Francis S. , Duncanson Audrey , Green Eric D. , Guyer Mark S. , Peterson Jane L. , Schafer Alan J. , Abecasis Gonçalo R. , Altshuler David L. , Auton Adam , Brooks Lisa D. , Durbin Richard M. , Gibbs Richard A. , Hurles Matt E. , McVean Gil A. 
Published: July 2011

High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2–4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ∼1,000 sequenced chromosomes per population, whereas ∼2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence.