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Human Population Genetics and Genomics Alan R. Templeton Charles Rebstock Professor Emeritus & Department of Biology Division of Statistical Genomics Washington University, St. Louis, MO, United States AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1650,SanDiego,CA92101,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom Copyright©2019ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicor mechanical,includingphotocopying,recording,oranyinformationstorageandretrievalsystem,without permissioninwritingfromthepublisher.Detailsonhowtoseekpermission,furtherinformationaboutthe Publisher’spermissionspoliciesandourarrangementswithorganizationssuchastheCopyrightClearance CenterandtheCopyrightLicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions. 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LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN:978-0-12-386025-5 ForinformationonallAcademicPressPublicationsvisitourwebsiteat https://www.elsevier.com/books-and-journals Publisher:AndreWolff AcquisitionEditor:PeterB.Linsley EditorialProjectManager:CarlosRodriguez ProductionProjectManager:PunithavathyGovindaradjane Designer:MilesHitchen TypesetbyTNQTechnologies To Dr. Charles (Charlie) F. Sing and Dr. Edward (Ed) D. Rothman My mentors, colleagues, and friends Preface Human population genetics has grown tremendously in importance and in centrality to the broader field of human genetics, particularly since the era of genomics. The Human Genome Project began in 1990 and was declared essentially complete in 2003. However, having a genome sequence did notimmediatelyyieldthemedicalandresearchbenefitsthatwereusedtojustifytheproject.Itquickly became apparent that these benefits required the study of variation: variation in the human genome, variation in health status, variation in demographic histories, etc. As a result, additional projects werespawnedtocreatedatabasesthatfocusedonvariation.Oncethefocuswasonvariation,human populationgeneticsbecamecentraltothemedicalandresearchgoalsoftheseprojects.Thereasonis simple: human population genetics is the science of human genetic variation: its past, its current significance, and its evolutionary fate. Population genetics provides the principles and tools used by many human geneticists in at least some aspects of their research programs. Many of these human geneticists do not consider themselves population geneticists, but an effective and appropriate use ofthesetoolsandprinciplesrequiressomeknowledgeofpopulationgenetics.Ihavethereforewritten thisbooknotonlyforhumanpopulationgeneticistsandtheirstudentsbutalsoforthebroaderhuman geneticscommunity.Moreover,becauseoftheimmenseamountofknowledgeanddataaboutourown species, humans have become an ideal model organism for population genetic studies. Many of the techniques,bothmolecularandanalytical,whichwerefirstdevelopedforhumanstudiesareportable tootherspecies.Moreover,mostoftheprinciplesofhumanpopulationgeneticsareapplicabletoall speciesandtoageneralunderstandingofevolutionwithinaspecies.Hence,thisbookisrelevanttoall population geneticistsandnotjustthosewho focus mainly onhumans. Besides the advances in genetics and genomics that have propelled population genetics to its increasingly central role in human genetics, there have also been tremendous analytical advances in statistics,bioinformatics,andcomputational biology.Advancesintheseareashavenotonlyallowed us to handle large data sets, but also to make use of principles that have been central to population geneticssinceitsinceptionasafielddofteninwaysunimaginabletotheoriginatorsoftheseprinci- ples.Forexample,thepopulationgeneticprincipleofidentity-by-descenthasplayedinacriticalrole in much population genetic theory since the 1920s, but by coupling this old principle with modern genomic data we can apply it powerfully to identify and localize genetic diseases, map risk factors for common systemic diseases, study inbreeding and its consequences with or without pedigrees, and identify genomic regions under natural selection and important for human adaptationsdjust a few of the applications of this old concept. The pace of these molecular and analytical advances is dizzying, so I have not written a “how to” book that would become almost immediately out-of- date,butrathera“whyandwhen”book.Computerprogramsimplementingtheseoldandestablished principlesofpopulationsgeneticsareconstantlybeingdevelopedinnewandmorepowerfulways,but understandingtheunderlyingpopulationgeneticprincipleswillhelpresearchersanswerthequestions ofwhytheseprogramsdowhattheydoandwhentheyshouldbeuseddandperhapsmoreimportantly, whentheyshouldnotbeused.Thewhyandwhendependsnotonlyonanunderstandingofpopulation genetic principles, but also an understanding offundamental statistical principles such as maximum likelihood (developed in the 1910s) and Bayes theorem (from the 1700s). Despite the widespread use of maximum likelihood and Bayesian statistics in human population genetics, there is still the xi