PopulationGeneticsofHumans.pdf

Population Genetics ofModern Human EvolutionJohn H Relethford, State University of New York College at Oneonta, Oneonta, New York, USA

Rosalind M Harding, University of Oxford, Oxford, UK

The aim of studies in human population genetics is to determine how mutation, genetic

drift, gene flow and natural selection have generated patterns of genetic diversity within

and between populations. One application of these studies is to questions about how

modern humans evolved and the meaning of human racial variation.

Introduction

Population genetics tackles questions about geneticdiversity. Approximately 0.08% of the nucleotide basepairs (bp) in human DNA vary among individuals. Whythese and not others? One explanation is that selectionfavours functionally dierent DNA alleles in dierentcircumstances. Another is that DNA variation is toleratedwhen the alleles of a gene are functionally equivalent. Theformer explanation clearly applies to some variation, butthe latter explanation, formalized as neutral theory, isinvoked most often. Either way, the aim of populationgenetics is to model the dynamics of evolutionary changewithin and between populations.There are four basic evolutionary forces: mutation,

natural selection, genetic drift and gene ow. Mutationsare copying errors during DNA replication and transcrip-tion, which introduce new alleles into the population.Natural selection is the dierential transmission of allelesinto the next generation due to the consequences offunctional dierences on an individuals survival andreproductive success. Genetic drift is the dierentialtransmission of alleles into the next generation as a resultof random sampling, and has the greatest potential impactin small populations. Gene ow spreads alleles from onepopulation into another via migration, making themmoregenetically similar to each other, and countering geneticdierentiation by drift. These four evolutionary forces arereected in patterns of diversity, measured by the numbersof dierent alleles at a gene locus, the frequencies of eachallele, and the interrelatedness of each allele to the otherspresent at the same time. To understand why geneticdiversity accumulates to a particular level, why it has itsobserved distribution, and how its turnover occurs, weinvestigate the interactions of these four evolutionaryforces using population genetic models.Population genetic models are mathematical objects

that allow us to interpret genetic diversity when theassumptions on which these models rest are acceptable.To capture the idea of a basicmodel, the following analogymay be helpful. Think of a population as a leaky bucket

where the level of water in the bucket reects the balancebetween the drip from the tap and the size of a leak. Wemight ask how big the bucket has to be to hold a givenmeasure of water and how long the water has beenstanding. The equivalent population genetic questionsconcern the evolutionary size of a population expected fora given measure of genetic diversity and the age of thisdiversity. Mutation is analogous to the inow fromdripping water. Genetic drift is analogous to the waterleaking away. Natural selection is a control mechanism onthe leak that can either act to slow down or speed up theloss. When populations are connected to each other, anadditional force to consider is gene ow, which would beanalogous towater owing between several buckets.Whenone of the four evolutionary forces is stronger than theothers, it is easy to predict the outcome, but when they arein a balance the consequences for patterns of geneticvariation are much more dicult to evaluate.The study of human population genetics (also known as

anthropological genetics) is concerned with explaining thecauses of human diversity in the world today and theevolutionary history that has generated this diversity.Studies of anthropological genetics include eorts todescribe population structure, to reconstruct populationhistory, and to understand adaptation to local environ-ments. Many studies of anthropological genetics havefocused on local populations, but more attention hasrecently been directed toward understanding the evolu-tionary history of the human species.Anthropological genetic investigation of global human

diversity leads to several related questions:

1. What is themagnitude and pattern of genetic variationwithin and among populations in our species today?

2. What are the relative roles of population history,adaptation, and cultural behaviours on structuringdiversity?

3. How well do patterns of genetic variation t atraditional model of racial divergence?

Article Contents

Introductory article

. Introduction

. Race

. Genetic Variation

. Human Evolution

. Mitochondrial Eve

. Y-chromosome Adam

. Neanderthal Enigma

. Summary

1ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net

4. What canwe say about the recent evolutionary historyof our species based on analyses of genetic variation inliving humans?

This nal question is of particular interest to anthropol-ogists grappling with the question of modern humanorigins did modern humans arise as a new species inAfrica within the past 200 000 years, or did our modernform evolve within a population that was subdividedbetween the Old World continents of Africa and Eurasiabut united as a single species by gene ow? To answer thisand related questions, anthropological geneticists rely onmaking inferences about the past based on the present. Inthis sense, our genes reect our history.

Race

Humans commonly and typically classify themselves andtheir neighbours into a number of races. However, theeveryday use of the word race implies a legitimacy that isactually at odds with much of the genetic evidence. Theunderlying concept of race is that there are discrete andeasily identiable genetic subgroups within a species.Racial groups are expected as a consequence of an ongoingprocess of evolutionary divergence eventually expected tocreate new species. At an intermediate stage there is aprediction that the majority of variation occurs betweenraces, andmuch less within races. There are problems withapplying this concept of race to modern humans. The rstproblem is with the expectation of discrete subgroups andthe second problem is with the apportionment of geneticvariance.Historically, there has been little agreement about the

number or denitions of human races, with manyquestions on where to place human populations thatotherwise do not appear to t simplistic models of racialclassication. Even skin colour, one of the most highlyvariable traits in the human species, eludes easy classica-tion, though virtually every racial classication schemerelies heavily on it. Skin colour does not actually appear indiscrete shades such as white or black, but instead showsa continuous distribution across the species. Any decisionto delineate between light medium and dark isarbitrary. Nor does similarity in skin colour necessarilyreect common genetic ancestry; the worldwide distribu-tion of skin colour shows a very strong latitudinalcorrelation, with the darkest indigenous people living ator near the equator, and people being increasingly lighterwith increasing north or south latitude. Ultravioletradiation (UVR) also shows a correlation with latitude(greatest near the equator), suggesting that skin colour hasbeen selected in response to dieringUVR intensity. Thus,dierent populations often have similar skin colourbecause of adaptation to the same environmental factorand not because of close recent ancestry.

Attempts to develop schemes of racial classicationbasedonadditional traits, both genetic and anatomic, havemet with little success. Dierent traits often lead tocompletely dierent classications. Thus, a racial classi-cation based on lactose intolerance will be dierent fromone based on skin colour, which will be dierent from onebased on cranial shape or ABO blood group frequencies.An alternative approach is to dene races by their

geographic location, and to use these geographic units ofanalysis for measuring genetic variation attributed to race.We do expect neighbouring populations to share moregenes than distant populations because geographic dis-tance tends to limit gene ow. One dierence between anisolation by distance model for genetic diversity comparedwith a racial model is that it predicts gradients rather thandistinct boundaries between populations.Gradients ratherthan boundaries are typically observed. A further problemwith geographic classication is the arbitrariness ofdecisions regarding the number of races, and where todraw the line separating one from the next. Should theentire continent of Africa be considered a single race? If so,then we have the problem of dealing with some of thehighest levels of population diversity observed in humanssubsumed under a single label. Where does one draw theline separating dierent regions of Eurasia? Should thepeoples of the subcontinent of India be classied withAfricans based on skin colour, Europeans based on facialcharacteristics, or in a separate race?Geographic analyses of race also illustrate the second

problem regarding the expectation for greater variationbetween racial groups than within. No study of humangenetic diversity has been able to dene groups that showthis pattern. Only about 10% of the total global variationin most genetic markers and craniofacial measures occursbetween continental groups of populations. The remaining90% of the variation occurs within these groups, of whichmost variation (85%) occurs within local populations. Thepartitioning of variation in the human species is exactly theopposite of that implied by the race concept.Anthropologists criticisms of the race concept have

frequently been mistaken as a denial of human diversity.This is not the case there is a lot of diversity within andbetween human populations. The race concept is rejectedas a means to describe this variation because the mainapportionment of variation does not occur betweendiscrete population clusters. While continental regions(e.g. subSaharan Africa, Europe) are often used as units ofanalysis, we realize that these are arbitrary units imposedon reality for the purpose of rough analysis. An analogy ishuman height; while height is continuous in nature,ranging from the shortest person to the tallest person, weoften resort to the use of classicatory groups such asshort, medium and tall, even though we realize that, inreality, there are not three distinct types of height. Whilethe denition of populations and population groups arehelpful for the description of patterns of diversity, the

Population Genetics of Modern Human Evolution

2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net

evidence of genetic data denies the validity of the biologicalrace concept for the human species.

Genetic Variation

Anthropological geneticists do not trace human geneticvariation back to racial origins, but instead ask questionsabout how genetic diversity has evolved within a popula-tion genetic framework. Some of these questions are:

1. What does the level of genetic diversity imply about theevolutionary size of the human population and howold is this diversity? (This question is addressed usingtotal global variation.)

2. Do levels of genetic variation within local populationsvary, and if so, where is the greatest genetic diversityfound? (The average level of total global variationwithin local populations is 85% and within regions is90%.)

3. Do genetic distances between populations vary, and ifso, what does this imply for the evolution of diversityamong continental regions? (The average level ofvariation between populations is 5%within continentsand 10% between continents.)

Polymorphic variation when evaluated in globally repre-sentative samples occurs in about 0.08% of DNA basepairs in the nuclear genome, giving an estimate of about10 000 for the evolutionary population size of humans,assuming a simple population genetic model. (Rememberthe leaky bucket and dripping tap.) This estimate for theevolutionary population size seems small compared withthe number of people living on the planet now, but itreects only a rough estimate of numbers of potentialancestors living in past generations.Our ancestors have theremarkable attribute of an unbroken line of descent intothe current generation, in at least one gene. They lived inpopulations with many other individuals whose lines ofdescent died out before the present generation. Manyselective and random reasons contribute to this variabilityin long-term reproductive success and account for whyestimates of evolutionary population size from geneticdiversity, for all species, are small compared with censussizes.Population genetic models have also been used to

estimate the time depth of typical diversity in the humannuclear genome, and it is suggested to be approximately800 000 years. This is an estimate for the nonfunctional(neutral) diversity at an average gene locus. The time depthof diversity found in any particular locus may be muchmore or much less than this expectation for the average,not only because of selection, but also because of thestochastic nature of genetic drift, whichmay generate hugevariability in persistence times. For most loci, theconsequences of adaptation and genetic drift are a high

rate of turnover, so that typical genetic diversity preservesinformation only about our recent Pleistocene history. Forsome loci, diversity is very recent. The global diversityfound on the Y-chromosome, for example, may have allbeen generated within the last 60 000 years. Outside of thenuclear genome is a special locus, of which there are manycopies in each cell, one in each mitochondrion. Globaldiversity in the human mitochondrial genome (mtDNA)appears to trace back to a glacial maximum at 130 000years ago. A little more explanation of these very recentestimates is given below.Studies of how genetic diversity is distributed geogra-

phically show that common polymorphisms are oftenfound globally and it is usually only polymorphisms with aminor allele frequency less than about 15%that are specicto populations. Population dierences are mainly due tothe presence of low-frequency alleles that have not diusedfar from their geographic place of origin. Most low-frequency alleles are young and are destined to be lost bygenetic drift before ever becoming common. However,common polymorphisms also succumb to drift, and it maybe the old ancestral allele that eventually is reduced to lowfrequency. One way to determine which allele at a locus islikely to be the ancestral variant is to make a comparisonwith a chimpanzee sequence. There will be many humanchimpanzee dierences at sites not polymorphic in hu-mans, but typically, the polymorphic sites will include abase pair variant present in the chimp, allowing theancestral sequence to be reconstructed. Interestingly, whenthese ancestral allelic sequences are low in frequency, theyare more often found within subSaharan African popula-tions than in Europe or Asia.A variety of dierent traits, including craniometric

measures, blood groups and microsatellites (loci withvariable numbers of repeated 25 bp motifs) as well asDNA sequence polymorphisms, have been studied tocompare levels of genetic diversity between Africanpopulations with the populations of other geographicregions.When these studies focus on common polymorph-isms they do not nd signicantly greater diversity insubSaharan Africa, but when they incorporate informa-tion from low-frequency alleles, these contribute more todiversity in populations of sub-Saharan Africa than inEurope or Asia. The most likely explanation for higherAfrican diversity is that there has been less genetic driftover evolutionary time in subSaharan Africa than else-where.Many traits also show a pattern where the largest

interpopulation genetic distances are between subSaharanAfrican populations and a variety of either European orAsian populations. This pattern reects two aspects ofhuman demographic history. First, accumulation ofdiversity within subSaharan Africa contributes a largercomponent to population dierences than dierentiationby drift among European and Asian populations. Second,patterns of both diversity accumulation and low levels of



population dierentiation reect high rates of gene owwithin continental regions and between Europe and Asia.There has been comparatively less gene ow betweenAfrica andEurasia, probably because of isolation imposedby the SaharaDesert during the greater part of Pleistoceneinterglacials.

Human Evolution

Questions about human evolution are addressed throughanalysis of the fossil and archaeological records, combinedwith analyses of diversity in living humanpopulations. Thestudy of recent human evolution focuses on the transitionbetween fossils referred to as archaic humans, with brainsize similar to our own but with some morphologicaldierences, and the fossils of anatomically modernhumans. A variety of archaic fossils with dates between200 000 and 30 000 years are found throughout the OldWorld. These fossils are related within a taxonomic groupthat rst spread from subSaharan Africa into the OldWorld close to 2 million years ago. The oldest fossilsshowingmodern human characteristics have been found inAfrica and date to about 130 000 years ago. The oldestrelated modern human fossils outside of Africa appear intheMiddle East, dating from about 90 000 years ago. Theyturn up in Europe, East Asia and Australia, with datesfrom about 30 000 to 50 000 years ago. How did modernhumans evolve from their archaic form?Two models polarize a debate about the origin of

modern humans. One model focuses on African replace-ment, proposing that modern humans evolved sometimebetween 100 000 and 200 000 years ago in Africa as a newand separate species, and that this species subsequentlydispersed and replaced coexisting archaic human groupselsewhere in the Old World. This out of Africa modelsuggests that all of our ancestors from before 100 000 yearsago lived in subSaharan Africa and that no living humansdescend from archaic human populations such as theNeanderthals of Europe and the Middle East. Analternative view is that humans have been evolving withina single evolutionary population, which, though struc-tured, has been prevented from divergence into a newspecies within the last million years by gene ow. Thismultiregional model suggests that the ancestors of livinghumans trace back to a widely dispersed archaic popula-tion living not only in Africa several hundred thousandyears ago, but perhaps across the entire Old World.Patterns of human genetic variation are most often

interpreted as supporting the African replacement model,but they are also compatible with a multiregional transi-tion. For example, the small estimated evolutionarypopulation size has been argued as incompatible with amultiregionalmodel because 10 000 individuals are too fewto spread between three continents at a density that would

maintain gene ow. But, this number is an estimate of thepotential number of ancestors, and is not an estimate of thecensus size. There is no widely accepted population geneticmodel available for estimating census size from geneticdiversity. Recent ancestry, in particular for mtDNA, hasbeen taken as evidence of a recent speciation origin, butother loci have very dierent time-depths. Higher geneticdiversity in Africa has been said to indicate an origin inAfrica, but in fact, the characteristic pattern of thisdiversity indicates only a larger number of ancestors, notgreater time-depth, within Africa. Larger genetic distancesbetween populations in subSaharan Africa and those inEurope or Asia generate phylogenetic trees of populationswith a characteristic primary split that has been interpretedas evidence of the migration of modern humans out ofAfrica. However, variable rates of genetic drift and geneow between continental regions are a more likelyexplanation for observed geographic patterns of diversity.The main point is that genetic diversity data can beinterpreted to t either model for modern human origins,and therefore have not resolved the debate.

Mitochondrial Eve

Perhaps the most controversial genetic research pertainingto modern human origins has resulted from the use ofmitochondrial DNA (mtDNA). Most human DNA existsin the chromosome pairs within the nucleus of the cell andis inherited through the process discovered by GregorMendel both parents contribute half of their DNA totheir ospring. But the small mtDNA genome is inheritedexclusively from the mother. Without the opportunity forrecombination that occurs during meiosis for nuclearDNA, the simpler uniparenta1 mode of inheritance formtDNA makes genealogies relatively easy to reconstruct.However, because mtDNA traces only through thematernal line, mtDNA variants are subject to greatergenetic drift than diversity in the nuclear genome.Any two people share a single mtDNA ancestor at some

point in the past. A less-related third person also shares asingle ancestor with the rst two, but further back in time.For any piece of DNA that does not recombine, a singlecommon ancestral sequence exists fromwhich theDNAofeveryone now living descends. In 1987, Rebecca Cann andcolleagues looked at mtDNA variations in people fromaround the world and estimated that the most recentcommon ancestor appeared to have lived about 200 000years ago in Africa (referred to as Eve by the press andsome scientists). The implication was that mtDNAevidence supported a recent African origin for modernhumans and that the multiregional hypothesis wasrejected. Subsequent studies of the pattern of diversity inmtDNA suggested an expansion of the modern humanpopulation from a small speciation bottleneck about



130 000 years ago, leading to a prediction that other loci inthe genome would show the same signal. However, it hasbecome clear frommany genetic studies since that themostrecent common ancestral sequences for diversity in otherloci trace to dierent ancestors in dierent generations.Furthermore, it seems unlikely that the number ofancestors in any single generation have ever been fewerthan several thousand. Eve does not necessarily tell usanything about the origin of modern humans.

Y-chromosome Adam

Given the interest in tracing female ancestors back to Eve,it was inevitable that scientistswould turn their attention totracing a genetic Adam by using polymorphisms on theY-chromosome. The sex chromosomes come in two forms,X and Y, with a usual pattern where females have two X-chromosomes, and males have one X- and one Y-chromosome. Because the Y-chromosome is inheritedexclusively through the father, and for the greater part doesnot recombine, it is not too dicult to reconstruct its mostrecent common ancestor. LikemtDNA, the nonrecombin-ing part of the Y-chromosome is also subject to greaterdrift than other loci in the nuclear genome. Whenpopulations are in expansion phases there is less opportu-nity for drift, but at other times, mtDNA and Y-chromosome diversity is expected to leak out faster thandiversity in the recombining nuclear genome.Y-chromosome variations show relatively low levels of

global diversity with a relatively high proportion dieringbetween populations. The low global diversity is consistentwith either a selective sweep or substantial genetic drift.There have been several estimates for the age of the mostrecent common ancestor, and the latest work suggests adate in the neighbourhood of 60 000 years ago. As withanalyses of mtDNA, such results do not tell us aboutmodern human origins but probably do imply uctuationsin ancestral population sizes. Patterns of Y-chromosomediversity are also compatible with gene ow in bothdirections, in and out, of subSaharan Africa. Y-chromo-some data have also been taken to indicate that males arethe sex who stay close to home and contribute less to geneow than their partners. However, DNA variants withestimated ages less than 20 000 years, are typicallypopulation-specic at all loci. The question that remainsis what combination of gene ow, genetic drift, andpossibly selection, accounts for the success and globaldistribution of this recent ancestral Y-chromosome.

Neanderthal Enigma

The studies discussed so far all attempt to make inferencesabout the past based on genetic variation in living humans.

Until recently, there was no way of assessing geneticvariation in prehistory except for inferences obtained fromanalyses of the fossil record. This situation changed in 1997whenmtDNAwas successfully extracted from the originalNeanderthal specimen discovered at Feldhofer Cave in theNeander Valley, Germany. This fossil is undated but isprobably from an individual who lived about 35 000 yearsago. In early 2000, anmtDNAsequencewas obtained froma second Neanderthal specimen, this time from Mezmais-kaya Cave in the northern Caucasus, and dating to 29 000years ago.Many anthropologists have long argued over the

distinctiveness and evolutionary status of the Nean-derthals. Some favour classifying the Neanderthals as asubspecies ofHomo sapiens (H. sapiens neanderthalensis asopposed to modern humans, who are often referred to asH. sapiens sapiens), and others argue for separate speciesstatus (Homo neanderthalensis). The fate of the Nean-derthals has also been ercely debated, with views rangingfrom a multiregional perspective of Neanderthals beingpart of our ancestry, and others arguing for completereplacement in Europe.Sequence analysis of Neanderthal mtDNA allows direct

assessment of prehistoric genetic variation, although thesmall sample size of two specimens with data taken fromonly one gene locusmust be kept inmind.When comparedwith the human reference standard, the Feldhofer Cavespecimen diers at 27 mtDNA sites and the MezmaiskayaCave specimendiers at 23mtDNAsites. These dierencesare larger thanare typically foundbetween randompairs ofliving humans (who average about eight site dierences). Itis not clear, however, exactly what this dierence implies.Are Neanderthals dierent because they belonged to adierent species, or because they lived thousands of yearsago? No mtDNA sequence data of a modern human fromthe same time period is yet available. For comparison,global mtDNA diversity within modern humans has asimilarmagnitude to levels within geographic subspecies ofchimpanzees. So it seems thatNeanderthals are not relatedwithin the same subspecies as living humans. However, thedierence between Neanderthals and living humans is notgreater than variation between chimpanzee subspecies.This comparison suggests that human populations mayhave been more greatly structured in the past and thatNeanderthals may have been a race ofHomo sapiens. If so,there was no species barrier to prevent admixture betweenmodern and Neanderthal groups, but we still do not knowif any people living now carry genetic diversity thatdescends from Neanderthal ancestry.

Summary

Population genetics provides models for investigating thebalance of evolutionary forces acting on genetic diversity.



Studies that use thesemodels have found that the evolutionof contemporary human genetic diversity has occurredover the past several hundred thousand years or longer.Our species is geographically widespread, but shows lowlevels of dierences among population groups suggestingpersistent levels of gene ow as well as dispersal. It isdicult to classify humans into groups by their DNAproles, and impossible to successfully apply a biologicalconcept of race to diversity within living human popula-tions.The origin of modern human genetic diversity is still

widely debated. Genetic data indicates the importance ofAfrica in modern human evolution, in line with theobservations from the fossil record of the rst appearanceof modern anatomical form in Africa. Whether Africa isthe only region that we can trace our ancestors to, orwhether it is the primary region remains to be seen. Somegenetic evidence does suggest ancient contributions insouthern Asia, a region where the fossil evidence forreplacement is equivocal. Itmaybe the case that ouroriginsare best described as mostly (but not exclusively) out ofAfrica.

Further Reading

Foley R (1998) The context of human evolution. Genome Research 8:

339347.

Hawks J, Hunley K, Lee S-H and Wolpo M (2000) Population

bottlenecks and Pleistocene human evolution.Molecular Biology and

Evolution 17: 222.

Jorde LB, BamshadM and Rogers AR (1998) Using mitochondrial and

nuclear DNAmarkers to reconstruct human evolution. BioEssays 20:

126136.

Ovchinnikov IV,GotherstromA,RomanovaGP et al. (2000)Molecular

analysis of Neanderthal DNA from the northern Caucasus. Nature

404: 490493.

Przeworski M, Hudson RR andDi Rienzo A (2000) Adjusting the focus

on human variation. Trends in Genetics 16: 296302.

Relethford JH (1998) Genetics of modern human origins and diversity.

Annual Review of Anthropology 27: l23.

Relethford JH (2001) Genetics and the Search for Modern Human

Origins. New York: John Wiley & Sons.

Templeton AR (1999) Human races: a genetic and evolutionary

perspective. American Anthropologist 100: 632650.



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