Cell Modeling recent Human Evolution in Mice by Expression of a selected EDAR Variant Yana G. Kamberov, 1, 2,3,5,6,7, 16 Sijia Wang, 5, 7, 16, 18 Jingze Tan, 9 Pascale Gerbault, 10 Abigail Wark, 1 Longzhi Tan, 5 unhao Mao 8.21 Asa Schachar, 5, 7 Madeline Paymer, 5,7 Elizabeth Hostetter, Elizabeth byrne, Melissa Burnett, 24.S20 Yajun Yang, 9 Shilin Li,Kun Tang, 13 Hua Chen, 14 Adam Powell, 1 Yuval Itan, 10, 19 Dorian Fuller, 12 Jason Lohmueller ndrew P. McMahon 8,22 Mark G. Thomas 10 Daniel E. Lieberman 6,17 Li Jin 9, 13, 17, Clifford J. Tabin 1, 17 Bruce A. Morgan 2,317, and Pardis C. Sabeti5, 7, 15,17,* 1Department of Genetics Harvard Medical School, Boston, MA 02115, USA cUtaneous Biology Research Center 4Department of Dermatology Massachusetts General Hospital, Boston, MA 02114, USA SThe Broad Institute of Harvard and MIT, cambridge, MA 02142, USA 6Department of Human Evolutionary Biology 7Center for Systems Biology, Department of Organismic and Evolutionary Biology aDepartment of Molecular and cellular Biology ity, Cambridge, MA 02138, US 9MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200433, China 10Department of Genetics, Evolution and Environment 11UCL Genetics Institute(UGI ste of University College London, London WC1H OPY, UK 13CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, 14Department of Epidemiology Department of Immunology and Infectious Diseases Harvard School of Public Health, Boston, MA 02115, USA 1 These authors contributed equally to this work 17These authors contributed equally to this work and are cosenior authors 18Present address: Max Planck-CAS Paul Gerson Unna Research Group on Dermatogenomics, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China 19Present address: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA 20Present address: Department of Systems Biology Harvard Medical School, Boston, MA 02115, USA 2Present address: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA 22Present address: Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School Of Medicine University of Southern Califomia, CA 90089, USA Correspondence:lijinfudan@gmail.com(L.J.)bruce.morgan@cbrc2.mgh.harvard.edu(BA.M),pardis@broadinstituteorg(PC..) ttp/ dx. doi. oro/10.1016/ce.2013.01.016 SUMMARY its direct biological significance and potential adaptive role remain unclear. We generated a An adaptive variant of the human Ectodysplasin knockin mouse model and find that, as in humans receptor, EDARV370A, is one of the strongest candi- hair thickness is increased in EDAR370A mice We lates of recent positive selection from genome- identify new biological targets affected by the muta- wide scans. We have modeled EDAR370A in mice tion, including mammary and eccrine glands and characterized its phenotype and evolutionary Building on these results, we find that EDAR370A origins in humans. Our computational analysis is associated with an increased number of active suggests the allele arose in central China approxi- eccrine glands in the Han Chinese. This interdisci mately 30,000 years ago. Although EDAR370A plinary approach yields unique insight into the has been associated with increased scalp hair thick generation of adaptive variation among modern ness and changed tooth morphology in humans, humans Cell 152, 691-702, February 14, 2013@2013 Elsevier Inc. 691Modeling Recent Human Evolution in Mice by Expression of a Selected EDAR Variant Yana G. Kamberov,1,2,3,5,6,7,16 Sijia Wang,5,7,16,18 Jingze Tan,9 Pascale Gerbault,10 Abigail Wark,1 Longzhi Tan,5 Yajun Yang,9 Shilin Li,9 Kun Tang,13 Hua Chen,14 Adam Powell,11 Yuval Itan,10,19 Dorian Fuller,12 Jason Lohmueller,5,20 Junhao Mao,8,21 Asa Schachar,5,7 Madeline Paymer,5,7 Elizabeth Hostetter,5 Elizabeth Byrne,5 Melissa Burnett,2,4 Andrew P. McMahon,8,22 Mark G. Thomas,10 Daniel E. Lieberman,6,17 Li Jin,9,13,17, * Clifford J. Tabin,1,17 Bruce A. Morgan,2,3,17, * and Pardis C. Sabeti5,7,15,17, * 1Department of Genetics 2Department of Dermatology Harvard Medical School, Boston, MA 02115, USA 3Cutaneous Biology Research Center 4Department of Dermatology Massachusetts General Hospital, Boston, MA 02114, USA 5The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA 6Department of Human Evolutionary Biology 7Center for Systems Biology, Department of Organismic and Evolutionary Biology 8Department of Molecular and Cellular Biology Harvard University, Cambridge, MA 02138, USA 9MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200433, China 10Department of Genetics, Evolution and Environment 11UCL Genetics Institute (UGI) 12Institute of Archaeology University College London, London WC1H 0PY, UK 13CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, China 14Department of Epidemiology 15Department of Immunology and Infectious Diseases Harvard School of Public Health, Boston, MA 02115, USA 16These authors contributed equally to this work 17These authors contributed equally to this work and are cosenior authors 18Present address: Max Planck-CAS Paul Gerson Unna Research Group on Dermatogenomics, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China 19Present address: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA 20Present address: Department of Systems Biology Harvard Medical School, Boston, MA 02115, USA 21Present address: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA 22Present address: Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School Of Medicine, University of Southern California, CA 90089, USA *Correspondence: lijin.fudan@gmail.com (L.J.), bruce.morgan@cbrc2.mgh.harvard.edu (B.A.M.), pardis@broadinstitute.org (P.C.S.) http://dx.doi.org/10.1016/j.cell.2013.01.016 SUMMARY An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candi￾dates of recent positive selection from genome￾wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in central China approxi￾mately 30,000 years ago. Although EDAR370A has been associated with increased scalp hair thick￾ness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knockin mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify new biological targets affected by the muta￾tion, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisci￾plinary approach yields unique insight into the generation of adaptive variation among modern humans. Cell 152, 691–702, February 14, 2013 ª2013 Elsevier Inc. 691