Human Mitochondrial DNA and the Evolution of Homo sapiens (Nucleic Acids and Molecular Biology, 18) PDF
Preview Human Mitochondrial DNA and the Evolution of Homo sapiens (Nucleic Acids and Molecular Biology, 18)
Nucleic Acids and Molecular Biology 18 Series Editor H. J. Gross Hans-Ju¨rgenBandelt VincentMacaulay MartinRichards (Eds.) Human Mitochondrial DNA and the Evolution of Homo sapiens With31Figures,and10Tables 123 ProfessorHans-Ju¨rgenBandelt Dr.MartinRichards UniversityofHamburg UniversityofLeeds DepartmentofMathematics InstituteofIntegrative Bundestr.55 &ComparativeBiology 20146Hamburg FacultyofBiologicalSciences Germany Leeds,LS29JT UK Dr.VincentMacaulay UniversityofGlasgow DepartmentofStatistics UniversityAvenue Glasgow,G128QQ UK ISSN 0933-1891 ISBN-10 3-540-31788-0 SpringerBerlinHeidelbergNewYork ISBN-13 978-3-540-31788-3 SpringerBerlinHeidelbergNewYork LibraryofCongressControlNumber:2006922802 Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthematerial isconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broad- casting,reproductiononmicrofilmorinanyotherway,andstorageindatabanks.Duplicationof thispublicationorpartsthereofispermittedonlyundertheprovisionsoftheGermanCopyrightLaw ofSeptember9,1965,initscurrentversion,andpermissionforusemustalwaysbeobtainedfrom Springer.ViolationsareliableforprosecutionundertheGermanCopyrightLaw. SpringerisapartofSpringerScience+BusinessMedia springeronline.com ©Springer-VerlagBerlinHeidelberg2006 PrintedinGermany Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublicationdoesnot imply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevantpro- tectivelawsandregulationsandthereforefreeforgeneraluse. Productionandtypesetting:LE-TEXJelonek,Schmidt&VöcklerGbR,04229Leipzig Coverdesign:design&productionGmbH,69126Heidelberg Printedonacid-freepaper 31/3150/YL-543210 Preface MitochondrialDNA (mtDNA) is, compared to our totalgenome, only a tiny molecule.Yetdecipheringitsevolutionhasprofoundlychangedourperception about how modern humans spread across our planet. Analysis of mtDNA variation has matured in the course of the past 20 years and has become a versatile tool in the study of our species for the time horizon of the last 100,000yearsorso,aswellasourrelationshiptootherspecies.Inthistime,it haseffectivelycomeofage,althoughtheprocesshasperhapsbeenrathermore fraught than any growing marker system might have the right to expect. By comparison,theYchromosomehasmaturedinarathermoregenteelfashion. We might say that whereas mtDNA’s youth was more one of wild living and riotousconflict,theYchromosomewasbornmiddle-aged. These two markers together, though, deserve their special role in unrav- ellingtheevolutionaryhistoryofhumanity.Incontrasttotraditionalgenetic markersresidinginthenuclearDNAoftheautosomalchromosomes,mtDNA isnotreshuffledfromgenerationtogeneration,butisinherited purelyalong the maternal line of descent (except in most unusual circumstances). Just as withthenon-recombiningpartoftheYchromosomeinheriteddownthepa- ternal line, we have a uniparental marker at our disposal that evolves along agenealogicaltree,whichcanthenbecomethemajortargetofinvestigation. Although it is impossible to reconstruct the complete mtDNA genealogy of humankindintimeandspace,partsofit—akindofshadow—arefrozeninto themutationalpatternthatisinturnreflectedinthevariationweseeinsam- ples of modern mtDNA sequences. That variation allows the reconstruction of an mtDNA tree (or “phylogeny” as we would say, by a slight abuse of the traditionallanguage),thematernalgenealogyasreflectedinaglassdarkly. When people begantoworkonmtDNAinthe1980s after thepublication ofthe first complete mtDNA genome sequence—the famous Cambridge ref- erence sequence ofAndersonandcolleagues—theyfirstemployed just afew restrictionenzymes,usingthemtoestimateverysimpletrees.Thegenealog- icalresolutionofthesetrees—that is,theamountofgenealogyorcoalescent tree detail they estimated—was so low that they gave quite misleading re- sults,andledtoavarietyof(notparticularly well-publicized)proposalsthat supportedeitheran‘out-of-Asia’originformodernhumans,oreventhemul- tiregionalmodel.Itwasn’tuntilAllanWilson’sgroup,inthelate1980s,began VI Preface to use a higher-resolution restriction analysis system, that mtDNA became both famous and notorious when used as evidence supporting the ‘out-of- Africa’model. Then, in theearly 1990s, PCRandcontrol-regionsequencing, againpioneeredbytheWilsonlab,suddenlymademtDNAstudiestechnically straightforwardandaccessibletoawidercommunityofresearchers. In the control region (especially the first hypervariable segment, HVS-I) a high proportion of mtDNA’s variation is concentrated in a very small and easilysequencedstretch,andforthisreasonithasexertedanenormoushold on the research community ever since. Whilst we would not wish to deny the value of the early work that was done, there are serious limitations in focusing on the control region, even (as is really the bare minimum that is necessary to make anything of the mtDNA data) when supplemented with some important coding-region sites as well. The problems are well known: thehighlevelofvariationinthecontrolregionisaccompaniedbyhighlevels of recurrent mutation, blurring the structure of the tree; and at the same timethereisneverthelessinsufficientvariationtodistinguishmanyimportant ancientbrancheswithinthetree. Whydoesitmatter?Everybranchingevent,andindeedeverymutationthat occurs in mtDNA during the branching genealogical process, is a historical eventthattookplaceatacertaintimeandatacertainplace.Itisthemutational variationthatallowsustostudythebranchingevents,anditisthegeographical variationandtimedepthofthebranchesthathelpustorecoveraspectsofour evolutionarypast,especiallyprocessesofdispersalandcolonization.Fromthe perspective ofthisbook,the mostuseful aspect ofmtDNA isthispossibility ofbeingabletoreconstructwhereandwhenparticularbranchingeventstook place,asthefirststepinthereconstructionofprehistoricdispersals—that is to say, the possibility of being able to draw phylogeographicinferences from mtDNAsequences. Since 2000, though, there has been a new phase of mtDNA studies: the blossoming of complete genome analyses. Of course, sequencing complete mtDNA genomes is much more expensive and requires much more labour. However, the efforts are paying off as the resolution of the mtDNA tree has been improved many-fold. There are now more than 2000 complete mtDNA genomespublishedandthebasalbranchingstructureofmtDNAvariationin many—perhapsmost—partsoftheworldisnowratherwellunderstood. Itisstillnotallplainsailing,however.Recurrentmutationsdooccurinthe codingregionofmtDNA,andtheprecisebranchingorderwillinsomecases neverbefullyresolved.Therearealsoanumberofmultifurcationsinthetree, arising, we believe, froma very rapid series of dispersals and expansions as populations spread out from East Africa in the late Pleistocene. This means thatthereisstillinsufficient variation,eveninthewholemtDNAgenome,to resolvesomeimportantbranchingevents,suchassomeofthebranchingthat wouldreflectboththepartialre-populationofAfricaandthepeoplingofthe rest of the world. Still, we are convinced that a lot can and will be achieved Preface VII with complete mtDNA genome sequences. The shortcomings of the system itself—e.g.,thatitcanonlyhelpustoreconstructthefemalesideofthestory and that it is a molecule of finite length—are no longer the main issue. The majorongoingproblemsaremoreinsidious. Firstly,thereistheproblemofpoorqualitydata.Ithasbecomeapparentthat publishedmtDNAsequences,bothcontrolregionsandcompletegenomes,are oftennotofveryhighquality.Intheearlydaysofmanualsequencingthiswas probablymoreoftenthannotduetotechnicalshortcomingsinthelaboratory process, but in more recent times it seems to be largely due to database- handling steps further down the productionline. It is not clear that mtDNA workers are any worse than other DNA researchers in this respect, but the tendency in population studies to sequence only one strand of the molecule may have exacerbated the problem. Thus, mistakes have emerged, and are indeed often rather common, even when both strands have apparently been sequenced. Unfortunately (and perhaps of even greater concern), even the forensicscommunityhasnotbeenimmunefromthis.Moreover,thesituation is even worse in regard to the now increasingly popular research based on ancientmtDNA,whichregularlyannouncesexcitingnewfindings,butalltoo oftencannotgetpastamerefaithintheauthenticityofthesequencingresults. Thenthereisthequestionofmethodsofanalysis.Analyticalproblemshave besetmtDNAstudiesfromtheearlydaysoftheWilsonlab’sfirstmtDNAtrees to the present. Nowadays, though, the debate centres much less on phyloge- neticreconstruction,inpartbecauseitissomuchmorestraightforwardwith completesequencedata—althoughneighbour-joiningtreesofcontrol-region datacontinue,inexplicably,toseethelightofday—butonmorefundamental questions concerning what approachto take. A number of researchers com- ingfromatraditionalhumanpopulationgeneticsbackgroundstillarguethat mtDNA is best analysed using the battery of statistical tools developed for classicalmarkers,ineffectignoringthegenealogicalinformationinthedata. Theyarethen,iftheyarecautious,troubledthatlittlecanbelearnedfromthese approaches.Iftheyarelesscautious,theymayputforwardinterpretationsof thedatathatarehardtosustain,forexample,seeinghomogeneityofmtDNA variationacrossEuropeorEastAsia. How can we move from mere branching nodes in the tree to dispersal and colonization times? After all, as Guido Barbujani and colleagues have commented, “suppose that some Europeans colonizeMars next year: If they successfully establish a population, the common mitochondrial ancestor of theirdescendantswillbePaleolithic.Butitwouldnotbewiseforapopulation geneticistofthefuturetoinferfromthataPaleolithiccolonizationofMars.”We candiscussthisquestioninthecontextofthesettlementofEurasia,asdescribed in the chapters by Metspalu et al. and Richards et al. Suppose population geneticistsfromMarsweretoevaluate theprosandconsofasouthernroute dispersalofmodernhumansfromAfrica∼65,000yearsagoversuslatermigra- tion(s),say,intheEarthlingNeolithicperiod.Theywouldcorrectlyinferthat VIII Preface thecoalescencetimesofnon-Africansamples(whichcoalesceintheAfrican root of the pan-Afroeurasian haplogroup L3, more than 80,000 years ago), or of the major two or three macro-haplogroup constituents alone, would be ambiguous about this, and most likely compatible with any hypothesis. Indeed they might even erect a First Law of Phylogeography: “The time of colonizationofageographicalregioncannotbeinferredfromthecoalescence timesofgeneticlineagesinthatregion”,withwhichtheirEarthlingcolleagues woulddoubtlessallagree. However, what Martian population genetics would be failing to exploit is the geographical specificity of hierarchical levels of the human mtDNA distribution.EachancestralnodeinthemtDNAphylogenyhadauniquetime and place of origin. The former can be rather well (relying upon a realistic calibration of the mutation rate) estimated from the node’s descendants if sufficiently many (nearly) independent lineages diverged from it. The latter canbeinferredfromthegeographicdistributionofthedescendants(provided that subsequent events have not obscured the pattern too much). When, for example,thethusreconstructedanddatedancestralmtDNAtypesallappearto havegivenrisetoessentiallyautochthonousbranchesofthemtDNAphylogeny withapproximatelyequalcoalescencetimesinseveralsub-continents,thenone couldspeakofcommonfoundertypesinvolvedinonecolonizationevent,as seemstobethecasewiththethreefoundermtDNAsofEurasia(seethechapter byRichardsetal.). Aweaknessrunningthroughmuchoftheworktakingthetraditionalpopu- lationgeneticsapproach—whichwasneveraweaknessintheclassicalstudies ofthefather ofhumanpopulationgenetics, LucaCavalli-Sforza—isalackof embeddednesswithintheanthropologicalcontext.Thetraditionalpopulation genetics approach is very much both to propose and to test hypotheses in an atheoretical vacuum, without any regard for what is known from other disciplines—archaeology, anthropology, palaeontology or whatever—in the nameofscientific objectivity. Oneadvantageofphylogeographicapproaches tothedataisthattheyhavetendedtomakegooduseofnon-geneticaswellas genetic evidence, whilst attempting tomaintain somelevel ofindependence, soastoavoidcircularity.Soanunderstandingofboththestrengthsandlimi- tationsofmtDNAasamarkersystem—reflecting,wemustalwaysremember, justasinglelineofdescent—isanunderlyingthemeofthisbook.Inaddition, wehavefounditimportanttoplaceanymtDNAinferencesaboutthehuman pastinthecontextofasolidfoundationofknowledgeaboutthemoleculeand thesegregationandevolutionaryprocessesthatareresponsibleforthevaria- tionthatcanbeobserved.Perhaps,havingagreedwithourMartiancolleagues on the First Law of Phylogeography, we might also suggest to them an even morefundamental principle:“Makeuseofasmuchoftheavailableevidence asyoucan.” In this volume we have focused on the evolution and spread of modern humansinthedecisiveperiodfromabout100,000to40,000yearsago,which Preface IX thrust modern humans on to a wider stage outside Africa. In a subsequent volume wewilldiscussthedevelopments thatset inafterwards, whicheven- tually led to the peopling of the entire landmass of the earth (except for the Antarctic and extreme environments on other continents). Another volume willthendealwiththemedicalaspectsofmtDNAanditsroleinpathogenesis andageing. AfterfirstplanningthepresentvolumeinMarch2002,itbecameclearthat moreinformationwasneededfromwholemtDNAgenomesequencingbefore we could set out to fill the book chapters. The picture is now coming much moreintofocus,andsoweareslightlymoreconfidentthatourwordswillnot becomestalebeforetheinkisdry. WearegratefultoProfessorH.J.GrossfromWürzburgwhofirstsuggested abookinaSpringerseriesaboutthehumanmitochondrialgenomeinpatho- genesisandevolution. AntonioTorroni,whowasinfactapproachedbyhim, thenfurtherdelegatedthistasktous,andwearemostgratefultohimforhis encouragement and critical guidance ofthe work. We thank allcontributors andco-authorsfortheirenthusiasmandpatienceincompletingthiscollabo- rativeeffort.WeareverygratefultoAntonioTorroniforcommentingonalate versionofthemanuscript;themistakesthatremainareourown. Hamburg, Hans-JürgenBandelt Glasgow, VincentMacaulay Leeds, MartinRichards March2006 Contents PartI PrerequisitesandCaveats MitochondrialDNAinHomoSapiens P.F.Chinnery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2 Mitochondria—StructureandFunction. . . . . . . . . . . . 3 3 MitochondrialBiogenesis . . . . . . . . . . . . . . . . . . . 5 4 HumanmtDNA . . . . . . . . . . . . . . . . . . . . . . . . . 6 5 mtDNATranscription,Translation,andReplication . . . . . 8 6 PathogenicMutationsofmtDNA,Heteroplasmy, andtheThresholdEffect . . . . . . . . . . . . . . . . . . . . 9 7 TheRoleofHomoplasmicmtDNAMutations inHumanDisease. . . . . . . . . . . . . . . . . . . . . . . . 10 8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 TheTransmissionandSegregationofMitochondrialDNA inHomoSapiens P.F.Chinnery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2 mtDNAMutationsandHumanDisease . . . . . . . . . . . . 17 3 MechanismsThatCanChangetheLevelofHeteroplasmy . . 18 4 TheInheritanceofmtDNA . . . . . . . . . . . . . . . . . . . 19 4.1 MaternalInheritance . . . . . . . . . . . . . . . . . . . . . . 19 4.2 TheMitochondrialGeneticBottleneck . . . . . . . . . . . . 20 5 SegregationDuringEarlyDevelopment . . . . . . . . . . . . 24 6 ConclusionsandFuturePerspectives . . . . . . . . . . . . . 25 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 NumtsRevisited C.M.Bravi,W.Parson,H.-J.Bandelt . . . . . . . . . . . . . . . . . 31 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 31 2 NumtsinHumans . . . . . . . . . . . . . . . . . . . . . . . 33
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