ARTICLE Received 25 Apr 2014 | Accepted 29 Oct 2014 | Published 4 Dec 2014 Khoisan hunter-gatherers have been the largest population throughout most of modern-human demographic history Hie Lim Kim 1,2 , Aakrosh Ratan 1,3 , George H. Perry 4 , Alvaro Montenegro 5,6 , Webb Miller 1 & Stephan C. Schuster 1,2 The Khoisan people from Southern Africa maintained ancient lifestyles as hunter-gatherers or pastoralists up to modern times, though little else is known about their early history. Here we infer early demographic histories of modern humans using whole-genome sequences of five Khoisan individuals and one Bantu speaker. Comparison with a 420K SNP data set from worldwide individuals demonstrates that two of the Khoisan genomes from the Ju/’hoansi population contain exclusive Khoisan ancestry. Coalescent analysis shows that the Khoisan and their ancestors have been the largest populations since their split with the non-Khoisan population B100–150 kyr ago. In contrast, the ancestors of the non-Khoisan groups, including Bantu-speakers and non-Africans, experienced population declines after the split and lost more than half of their genetic diversity. Paleoclimate records indicate that the precipitation in southern Africa increased B80–100kyr ago while west-central Africa became drier. We hypothesize that these climate differences might be related to the divergent-ancient histories among human populations. DOI: 10.1038/ncomms6692 OPEN 1 Center for ComparativeGenomics and Bioinformatics, Pennsylvania State University, 310 Wartik Lab, University Park, Pennsylvania 16802, USA. 2 Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, 60 Nanyang Drive, SBS-01N-27, Singapore 637551, Singapore. 3 Department of Public Health Sciences and Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA. 4 Departments of Anthropology and Biology, Pennsylvania State University, 513 Carpenter Building, University Park, Pennsylvania 16802, USA. 5 Department of Geography, Ohio State University, 154 North Oval Mall, Columbus, Ohio 43210, USA. 6 Campus do Litoral Paulista, Unesp—Univ Estadual Paulista, Sa ˜o Vicente 11330-900, Brazil. Correspondence and requests for materials should be addressed to H.L.K. (email: HLKIM@ntu.edu.sg) or to S.C.S. (email: scs@bx.psu.edu). NATURE COMMUNICATIONS | 5:5692 | DOI: 10.1038/ncomms6692 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved.