Inferring Genetic Ancestry

13 Pages·2010·0.52 MB·English

CORE Metadata, citation and similar papers at core.ac.uk
Provided by Elsevier - Publisher Connector
COMMENTARY
Inferring Genetic Ancestry:
Opportunities, Challenges, and Implications
Charmaine D. Royal,1,* John Novembre,2 Stephanie M. Fullerton,3 David B. Goldstein,1
Jeffrey C. Long,4 Michael J. Bamshad,5 and Andrew G. Clark6
Increasingpublicinterestindirect-to-consumer(DTC)geneticancestrytestinghasbeenaccompaniedbygrowingconcernaboutissues
rangingfromthepersonalandsocietalimplicationsofthetestingtothescientificvalidityofancestryinference.Theveryconceptof
‘‘ancestry’’issubjecttomisunderstandinginboththegeneralandscientificcommunities.Whatdowemeanbyancestry?Howexactly
isancestrymeasured?Howfarbackcansuchancestrybedefinedandbywhichgenetictools?Howdowevalidateinferencesabout
ancestryingeneticresearch?Whatarethedatathatdemonstrateourabilitytodothiscorrectly?Whatcanwesayandwhatcanwe
notsayfromourresearchfindingsandthetestresultsthatwegenerate?ThiswhitepaperfromtheAmericanSocietyofHumanGenetics
(ASHG)AncestryandAncestryTestingTaskForcebuildsuponthe2008ASHGAncestryTestingSummaryStatementinprovidingamore
in-depthanalysisofkeyscientificandnon-scientificaspectsofgeneticancestryinferenceinacademiaandindustry.Itculminateswith
recommendationsforadvancingthecurrentdebateandfacilitatingthedevelopmentofscientificallybased,ethicallysound,andsocially
attentiveguidelinesconcerningtheuseofthesecontinuallyevolvingtechnologies.
Introduction white paper, commissioned by the related to one another by varying
In recent years, advances in genetics ASHG, expands discussion of the degrees,9soitisimportanttobeclear
and genomics have brought new issues highlighted in the Society’s aboutwhatframeofreferenceisbeing
dimensionstothecommercialgenetics 2008 Ancestry Testing Summary used indiscussions of ‘‘ancestry’’ and
enterpriseintheformofDTCgenetic Statement8andintroducesadditional relationship (Figure 1). For example,
testing.Withtheclickofamouse,the pertinent issues. The purpose of our because of recombination, each seg-
publicnowhasdirectaccesstopersonal report is twofold: (1) to enlighten mentofthegenomehasitsownances-
genetic and genomic information and engage ASHG members and the tral history, and various segments of
related to health, ancestry, nutrition, broader scientific and general com- anindividual’sgenomemayhavean-
physical traits, athletic ability, dating munities and (2) to assist in deter- cestralhistoriesthattracetodifferent
compatibility,andaseeminglyinfinite mining the appropriate course of populations.
list of other attributes. Although action for the Society in responding One commonly employed concept
health-related DTC genetic testing tothecriticalconcerns. of ancestry is continental ancestry,
appropriately continues to receive a It is important to note that the which assumes the existence of four
substantial amount of attention,1,2 genetic tools employed by ancestry or five major ‘‘parental’’ populations
discourseregardingotherDTCapplica- testing companies, as well as many thatgaverisewithinthelast100,000
tions of genetics, in particular the of the scientists involved in DTC years to existing populations.10 This
echoing of concern about genetic ancestry testing, have their roots in, conception of ancestry is frequently
ancestrytesting,isincreasing.3–6There andarestillapartof,academia.There- equated with that of ‘‘race,’’ and
are approximately 40 companies, fore,inthisreport,asinthesummary thetermsareoftenusedinterchange-
based in various countries, that statement,weevaluateapplicationof ably; however, this is problematic
currently provide genetic ancestry ancestry estimation technologies in because in the history of science
testing to the public (Table 1). The bothenvironmentsbecausethemany there have been many ‘‘racial’’ taxo-
companiesdifferinboththerangeof overlapping scientific and nonscien- nomic schemes.11,12 A related view
genetic testing services and the types tific issues in academic research have of ancestry is biogeographic ancestry,
ofancestryteststhattheyoffer. not, to date, been adequately ad- in which a person’s origin is associ-
The marketing of genetic tests di- dressed. ated with the geographic location(s)
rectly to consumers is a priority area of presumed ancestors inferred by
for the ASHG, asdemonstrated by its Definition(s)ofAncestry comparison with contemporary pop-
statements on DTC health-related Our common origin as a species ulationslivingintheselocations.13,14
testing7 and ancestry testing.8 This impliesthatwe,asindividuals,areall There is also lineage or family history,
1InstituteforGenomeSciences&Policy,DukeUniversity,Durham,NC27708,USA;2DepartmentofEcologyandEvolutionaryBiology,UniversityofCal-
iforniaLosAngeles,LosAngeles,CA90095,USA;3DepartmentofBioethics&Humanities,UniversityofWashingtonSchoolofMedicine,Seattle,WA
98195,USA;4DepartmentofAnthropology,UniversityofNewMexico,Albuquerque,NM87131,USA;5DepartmentofPediatrics,UniversityofWashing-
tonSchoolofMedicine,Seattle,WA98195,USA;6DepartmentofMolecularBiologyandGenetics,CornellUniversity,Ithaca,NY14853,USA
*Correspondence:[email protected]
DOI10.1016/j.ajhg.2010.03.011.ª2010byTheAmericanSocietyofHumanGenetics.Allrightsreserved.
TheAmericanJournalofHumanGenetics86,661–673,May14,2010 661
Table1. CompaniesProvidingDirect-to-ConsumerGeneticAncestryTesting
StartDate,
Companya URL Locationb GeneticTestingServices AncestryTestsOffered
1.AfricanAncestry http://www.africanancestry.com/ 2002 Ancestry mtDNA,Ychromosome
2.AfricanDNA http://www.africandna.com/ 2007 Ancestry mtDNA,Y
3.Ancestry.com http://ancestry.com 2007 Ancestry mtDNA,Y
4.AncestrybyDNA http://ancestrybydna.com 2009 Ancestry mtDNA,Y,admixture
5.ARGUSBiosciences http://www.argusbio.com/ 2003 Ancestry,cancertissuescreening, mtDNA-HV,mtDNA-FL,Y
personalDNAsequencing
6.CambridgeDNA http://www.cambridgedna.com/ 2007 Ancestry mtDNA,Y,admixture
Services UK
7.deCODEme http://www.decodeme.com/ 2007 R&D,completescan,cancerscan, mtDNA,Y,mapofkinship,
Iceland cardioscan geneticatlas
8.Determigene http://www.determigene.com/ 2002 Paternity,immigrationDNA AncestraloriginsDNAancestry
testing,infidelitytesting, map(populationmatches,
twinzygosity,ancestry, nativeregionmatches,
DNAsafeguarding strengthindicators)
9.DNAAncestry http://www.easternbiotech.com 2006 Ancestry mtDNA,Y
Dubai,UAE
10.DNADirect http://www.dnadirect.com/web/ 2003 Screeningtests,geneticdisorders, Y
drugresponse,DNAstorage,
paternityandfamilytests
11.DNAIdentity http://www.800dnaexam.com/ 2006 Paternity,familyrelationship mtDNA,Y
TestingCenter DNAtests,immigration,adoption,
forensic,ancestry,identity
12.DNAHeritage http://www.dnaheritage.com/ 2003 Ancestry mtDNA,Y,surnameprojects
UK
13.DNAReference http://www.dnareferencelab.com 2006 Paternity,immigrationpaternity mtDNA,Y,ethnicityDNA
Laboratory testing,ancestry,forensic, makeup,Europeanancestry
infectious-diseasetesting,R&D DNAtest,NativeAmerican
ethnicityDNAtest
14.DNASolutions http://www.dnasolutions.us/ 2000 R&D,paternity,siblingDNA, mtDNA,Y
grandparent,twinstest,
ancestry,birdsexing
15.DNATestingSystems http://dnaconsultants.com/ 2003 Ancestry,paternity,linkage mtDNA,Y,admixture,Native
disequilibrium American,African,Melungeon
test,Hindusingle&double
formales
16.DNATribes http://www.dnatribes.com/ 2006 Ancestry Autosomalanalysis
17.DNAWorldwide http://www.dna-worldwide.com/ 2005 Paternity,relationship, mtDNA,Y,worldDNAmatch
UK immigration,ancestry,forensic,
DNAstorage,petDNA
18.easyDNA http://www.easy-dna.com/ 2006 Paternity,legalDNAtest, AncestraloriginsDNAancestry
relationship,DNAprofiles, map(populationmatches,
twinzygosity,forensic,ancestry, nativeregionmatches,strength
immigration,maternity indicators),mtDNA,Y
19.EthnoAncestry http://www.ethnoancestry.com/ 2004 Ancestry mtDNA,Y
Scotland&
Ireland
20.FamilyBuilder https://dna.familybuilder.com 2007 Ancestry mtDNA,Y
21.FamilyGenetics http://www.familygenetics.co.uk 2005 Ancestry mtDNA,Y
UK
22.FamilyTreeDNA http://www.familytreedna.com 2000 Ancestry mtDNA,Y,autosomal,X-STR
23.Genebase http://www.genebase.com/ 2005 Ancestry mtDNA,Y,autosomalDNASTR
Canada
24.Genelex http://www.healthanddna.com 2000 Paternity,drugsensitivity, mtDNA,Y,NativeAmerican
ancestry,predictivegenetics DNA,JewishDNA,African
ancestryDNAtesting
662 TheAmericanJournalofHumanGenetics86,661–673,May14,2010
Table1. Continued
StartDate,
Companya URL Locationb GeneticTestingServices AncestryTestsOffered
25.GeneticTesting http://www.gtldna.com/ 2002 Paternity,ancestry,infidelity, mtDNA,Y,ancestralorigins
Laboratories,Inc. DNAmaternity,siblingship, DNAancestrymap(population
twinzygosity,grandparentage, matches,nativeregionmatches,
missingparent,immigration, strengthindicators)
prenatal
26.Genetree http://www.genetree.com/ 2007 Ancestry mtDNA,Y
27.homeDNAdirect http://www.homednadirect.com/ 2006 Paternity,legalDNAtesting, mtDNA,Y,ancestralorigins
relationship,forensic,ancestry DNAancestrymap(population
matches,nativeregionmatches,
strengthindicators)
28.International http://www.ibdna.com 2007 Paternity,ancestry,siblingship mtDNA,Y,ancestralorigins
Biosciences UK DNAancestrymap(population
matches,nativeregionmatches,
strengthindicators)
29.Metaphase http://www.metaphasegenetics. 2002 Paternity,siblingship, Y
PaternityTest com/ grandparentage,twins,prenatal,
forensic,ancestry
30.OxfordAncestors http://www.oxfordancestors.com 2000 Ancestry mtDNA,Y
UK
31.PaternityExperts http://www.paternityexperts.com 2004 Paternity,sibling,ancestry, Admixture
forensicpaternity
32.PathwayGenomics http://www.pathway.com/ 2009 Healthconditions,ancestry, mtDNA,Y
carrierstatus,personaltraits,
monogenicdominants,
drugresponses
33.RootsforReal http://www.rootsforreal.com/ 2002 Ancestry mtDNA,Y,admixture
UK
34.TestCountry http://www.testcountry.com 2001 Healthconditions,substance AncestraloriginsDNAancestry
abuse,health&wellness, map(populationmatches,
pregnancy/fertility,early nativeregionmatches,
diseasedetection,ancestry strengthindicators)
35.TheGenographic https://genographic. 2005 Research,ancestry mtDNA,Y
Project nationalgeographic.com/
36.UniversalGenetics; http://www.dnatestingforpaternity. 2009 Paternity,forensic,ancestry mtDNA,Y
DNATestingLaboratory com/
37.WarriorRoots http://www.warriorroots.com/ 2009 Ancestry,linkingancestry mtDNA,Y
toancientwarriorgroups,
athleticprofile
38.23andMe https://www.23andme.com/ 2006 Completescan mtDNA,Y,globalsimilarity
LastupdatedFebruary23,2010.
a This list does not include companies or sites that only promote genetic ancestry testing services. On November 17, 2009 deCODE genetics (owner of
deCODEme)announcedthatithasfiledavoluntaryChapter11bankruptcypetitionbutwillcontinuetoofferservicesduringitsrestructuringprocess.OnJanuary
21,2010,deCODEgeneticswaspurchasedbySagaInvestmentsLLC,aconsortiumthatincludesPolarisVenturesandARCHVenturePartners.Sincetheinitial
preparationofthistable,twocompanieshavebeenremovedfromthelist–DNAAncestorshasgoneoutofbusiness,andDNADiagnosticsCenterhasbecome
apromotersite.
b Startdateforofferinggeneticancestrytesting.Somecompanieswereinexistencepriortothisdate.Locationsarelistedfornon-U.S.locationsonly.
which typically represents a genera- forakidneytransplantorbloodtrans- however, neither are these rules
tional narrative about one’s relatives fusion. absolute nor have they been consis-
through his or her maternal and In addition to the concepts tently applied.18 This further illus-
paternal lines of descent.15 It is this described above, there are sociopolit- trates that ancestry-related social
notion of ancestry that people often ical rules about ancestry that guide identity—how a society may see or
focusonwhenconsideringtheirgene- membership in certain groups. In define a person or group in relation-
alogy. However, we note that gene- the United States (US) these include ship to real or putative ancestry—is
alogy does not necessarily confer the legal and historic utility of hypo- to be distinguished from personal
genetic similarity in all biological descent (‘‘one-drop’’ rule) for African or group interpretations of such
systems; for example, even one’s Americans and blood quantum laws identityoractualknowledgeofgene-
offspringmaynotbetheidealmatch for Native Americans.16–18 In reality, alogy.
TheAmericanJournalofHumanGenetics86,661–673,May14,2010 663
Figure1. GlobalAncestry
ThearrowssymbolizemigrationofearlyhumanancestorsoutofAfrica.Thecolormosaicdenotesglobalpopulationdiversityresulting
fromvarioussubsequentinter-andintra-continentalandregionalmigrations.Thepedigreerepresentsthecomplexnetworkofinterme-
diateandrecentancestorsthatisthesubjectofindividualgeneticgenealogytesting.
InterestinAncestryEstimation very close ancestors (i.e., parents or to illuminate patterns of past human
Consumers and researchers are inter- grandparents) or our most distant migration and provide background
ested inusinggenetic information to ancestors(i.e.,theearliesthominids), information about human genetic
inferancestryforavarietyofreasons, geneticancestryteststypicallyaddress variation that is essential for distin-
including genealogical, anthropolog- more intermediate levels of ancestry guishing the impact of demographic
ical, and epidemiological. Most con- that are imprecisely defined and processes from the effects of natural
sumers are interested in using identified10,20 (Figure 1). Given this selection.21–23 Unlike commercial
ancestry testing to gain, confirm, or intrinsic imprecision, the power of ancestry testing, such inferences are
extend knowledge about their recent commercial genetic tests to address nearly always made at the level of
family genealogy.3,19 To permit infer- specific genealogical questions is populationsor groups,rather thanat
ences about shared recent ancestry, contingent on several factors that we theindividuallevel.Asaconsequence
commercialtestersofgeneticancestry willdiscusslaterinthispaper. of this plural focus, these ancestry
employ a variety of genetic-marker Population geneticists and anthro- inferences are more robust with
systems to make comparisons be- pologists use genetic markers and respecttotheirfundamentallyproba-
tween a customer’s DNA and genetic comparative datasets similar to those bilistic nature, and the limitations of
databases of individuals sampled used in commercial ancestry testing ancestry estimation for individuals
from diverse populations and geo- to make inferences about population arecomparativelylessapparent.
graphic regions. However, although histories and relationships. Ancestry Genetic epidemiologists with an
the concept of ‘‘ancestry’’ is least estimation has enormous value in interestinidentifyinggeneticassocia-
ambiguous when it refers to either thisregardbecauseithasthepotential tionswithdiseaseemploymethodsof
664 TheAmericanJournalofHumanGenetics86,661–673,May14,2010
ancestry inference for specific analyt- new mutations and genetic profiles. can be inferred even at fine spatial
ical reasons: either to control for Second, as founder populations be- scales (i.e., the scale of several hun-
statisticalbiasesrelatedtopopulation came more widely separated from dreds of kilometers) within Eu-
stratification among cases and con- oneanother,theprobabilitythattwo rope.41–45 There is rapidly escalating
trols24–26 or as a strategy to map randomly chosen individuals would interestinancestralhistoriesofother
susceptibility variants that might be mate with each other became even continents and geographic regions,
differentially distributed with respect lower, and matings were even more and the deeper timescales of popula-
to ancestry within groups whose his- likely to occur between people living tions from Africa46 and India47 have
tories more clearly demonstrate the close to each other, accentuating the identified deep splits among geo-
‘‘mixing’’ of two or more peoples. divergence between geographically graphic regions with complex pat-
Recently admixed groups (such as isolatedpopulations. terns of past migration and admix-
AfricanAmericansorHispanicAmeri- Over the past two decades, geneti- ture. Further studies of human
cans)providetheopportunitytoper- cists have characterized the geo- genetic diversity are clearly needed;
form mapping by admixture linkage graphic pattern of variation in great these will determine whether such
disequilibrium, commonly referred detail by using both haploid and fine-scale geographic patterns can be
to as admixture mapping.27–29 How- diploid genetic markers (described detected in other parts of the world
ever, epidemiological inferences of below).32–37 Because different parts andassigninterpretivevaluestothese
genetic ancestry are typically applied of the genome can have different patterns.
to individuals and are nearly always ancestral histories, different marker It is important to note that the
based on the analysis of large collec- systems often provide somewhat dif- diversity of human social structures,
tions of single nucleotide polymor- ferent information about population intermarriage patterns, and demo-
phisms(SNPs)orancestryinformative historyandindividualancestry. graphic histories makes it likely that
markers(AIMs,describedbelow).Each Currently, we only have partial theresolutionofpopulationstructure
individual’s genome is then mapped knowledgeofhowhumangeneticdi- will be challenging and that the
as a mosaic of segments inferred to versityisdistributedacrosstheglobe, extentoftheresolutionwillvarycon-
be derived from one or the other but initial studies38 are revealing the siderably among populations. The
ancestral population (or both, in the degreeofresolutionpossibleintesting inclusion of individuals with recent
case where maternal and paternal the relationship between genetic migration among ancestors creates
alleles in the individual are each ancestry and geographic origins. the more complex problem of disen-
derivedfromdifferentancestralpopu- Anumberofthesestudieshaveuseda tanglingrecentlymixedancestry.
lations). collection of ~1100 DNA samples
obtained from 51 populations living ToolsforInferringAncestry
HumanHistoryandVariation in different parts of the world; these Estimatesofgeneticancestryarebased
Genetic ancestry estimation is based samples constitute the Human Ge- either on the use of haploid markers
on an understanding of the distribu- neticDiversityPanel(HGDP).39Anal- (mitochondrial DNA [mtDNA] or Y
tionofdiversityamonghumanpopu- ysisof987microsatellitestypedinthe chromosome haplotypes) or on the
lations that reflects the demographic HGDP collection, for example, in- use of multiple unlinked autosomal
and evolutionary history of our ferred six population clusters that markers that are diploid and some-
species. Genetic and archaeological correspond to continental regions timespreselectedtobe‘‘ancestryinfor-
evidenceindicatesthat,overthepast (i.e., Africa, America, Central/South mative.’’ As uniparentally inherited
100,000yearsorso,asthepopulation Asia, East Asia, and Oceania).38,40 haploid markers, mtDNA provides
size of humans increased markedly, Analysisof~642,000autosomalSNPs information about the female-to-
humansdispersedfromEastAfricato inthe HGDPcollectionenabledclus- femaletransmittedlineage(malechil-
populateotherpartsoftheworld30,31 teringofindividualsnotonlytothese dren also inherit mtDNA from their
(Figure 1). The number of migration large geographic regions, but also to mothersbutdonottransmitittotheir
events, their magnitude, and the specific populations within these offspring),whereastheYchromosome
routes that migrants took are still regions.38,40 Although the HGDP is informative about male-to-male
activeareasofresearch.Nevertheless, collection is a useful collection of transmitted lineage. More recently,
it is apparent that the dispersal of widely distributed human popula- autosomal markers, which are inher-
anatomically modern humans af- tions, it is a convenient sample and ited from both parents, have been
fected the geographic distribution of does not sample densely within any used for assessing patterns of genetic
diversity in at least two important one geographic region; hence, there variation in worldwidehuman popu-
ways.First,founderpopulationstypi- are limitations to the accuracy of lations. Commercial genetic ancestry
cally carried with them only a subset ancestryinferencewithinandamong testing primarily utilizes haploid
ofthegeneticvariationfoundintheir regions. Several studies that sampled markers to make ancestry inferences
mostimmediateancestralpopulation populations deeply across Europe (Table 1), whereas estimates of ge-
while simultaneously developing haveshownthatpopulationstructure netic ancestry in epidemiological
TheAmericanJournalofHumanGenetics86,661–673,May14,2010 665
applicationsrelyalmostexclusivelyon that can be inferred with confidence to estimate admixture proportions
theconsiderationofallelefrequencies isthattheyshareacommonancestor. originating from African, European,
ofautosomalSNPs.Populationgeneti- Without more information about Asian, and Native American popula-
cistsandanthropologistsemployboth family history and/or the geographic tions,51 offer increased power for
typesofmarkers;whichtypetheyuse distributionofcloselyrelatedmtDNA ancestry inference in comparison to
depends on the availability of funds haplotypes, it is impossible to say a random set of autosomal markers.
andthequestionsbeingaddressed. whether this match arises via recent Accordingly, a smaller set of markers
mtDNAandYChromosomeMarkers Indonesian ancestors in the North can be used, reducing genotyping
Haploid genetic markers such as American’s family tree, whether both costsandincreasingthroughput.
mtDNA D-loop region sequences or share distant ancestors who lived in The use of AIMs has facilitated
Y chromosome SNP haplotypes per- anentirelydifferentpartoftheworld, efforts to control for admixture and
mitdirectcomparisonofthelineages orwhethertheIndonesianmatchhas population stratification in genetic
of sampled and reference individ- recentNorthAmericanheritage.Simi- associationstudies.Specifically,know-
uals. As such, and unlike probabilis- larly,itisdifficulttoarriveatarobust ing the proportion of an individual’s
tic estimates of population ances- interpretation of an mtDNA haplo- ancestry that originated in different
try, matches among haploid genetic type that exactly matches those populations and to what degree a
markersareintuitivelyeasytounder- sampled from multiple geographic groupisdividedintogeneticsubpopu-
stand: an exact match of a male’s locations, e.g., Indonesia, Thailand, lationscanbeusefulforbothreducing
Y chromosome haplotype to a man andPapuaNewGuinea. false-positiveassociationsanduncov-
living in Australia implies that these AutosomalVariants eringtrueassociations.Wenote,how-
two men share a common paternal IncomparisontomtDNAandYchro- ever,thatnotallpeoplefromagiven
ancestor. mosome markers, autosomal markers populationhavetheAIM(s)identified
An important issue with regard to provide much more comprehensive with that population, and people
lineage-based genetic estimates is information on individual ancestry from different populations can have
that they reflect only a fraction of because cumulatively they represent thesameAIM(s).Genemappingwith
any person’s total genetic ancestry. amuchgreaterproportionofgenome AIMs, or admixture mapping, has
For example, the Parsis have Y chro- history (i.e., multiple biparentally in- alsobeenusedsuccessfullyforidenti-
mosome information that indicates herited loci versus a single locus, as fying genomic regions associated
anorigininIran,consistentwiththe inherited through mtDNA or the Y withdiseasesandhealth-relatedtraits
historicalrecord,whereasthemtDNA chromosome). However, because the such as prostate cancer (MIM
originates in Gujarat, a region in genomeisfinite,onlyasmallfraction #176807), hypertension (EHT [MIM
northwestern India where the Parsis of ancestors are represented by each #145500]), and white blood cell
arrived in approximately 900 AD, given genomic segment in an indi- count.29,52–54 Admixture mapping is
beforemovingeventuallytoMumbai, vidual, and every ancestor does not most effective for identifying genetic
India,andKarachi,Pakistan.48,49This necessarily pass on his or her DNA variantsassociatedwithhealthcondi-
asymmetry of maternal and paternal at any given genomic segment to a tions that differ between recently
ancestryisnotamatteroftestincon- descendant, so one can only ever admixed populations (e.g., tropical
sistency; rather, it reflects the high have limited information on the ori- African and European in the case of
likelihood that nearly everyone will gins of a given individual’s ances- most African Americans; and Native
have ancestors from different geo- tors.10 American,European,andAfricanpop-
graphiclocations. Autosomal variation can be mea- ulationsinthecaseofHispanicAmer-
Anotherproblemrelatedtolineage- sured by whole-genome sequencing icans) and for which this difference
basedcomparisonsinvolvestheinter- approaches,withgenome-widegeno- has not yet been fully explained by
pretation of exact genetic matches typing panels, or via an assessment nongenetic factors. Although most
between individuals. Although it is of AIMs. Whole-genome sequencing, DTC tests for ancestry offer lineage
biologicallyjustifiedtoinferthattwo although ideal and likely to usher in testing that uses mtDNA and Y-chro-
individuals with the same mtDNA arenaissanceingeneticanthropology, mosome markers, DTC testing with
haplotype share a common ancestor, is still prohibitively expensive and so autosomal markers, especially with
moving from this inference of com- isbeyondthereachofmostacademic whole-genomeSNPchips,isbecoming
mon ancestry to the conclusion that researchers or commercial testing morecommon.Theresultsreportedto
the match implies something about companies. Genome-wide genotyp- the consumer typically estimate
the biogeographical ancestry of both ingarrays,thenext-mostcomprehen- admixture proportions from several
individuals can be problematic. For sive approach, include SNPs that are populations, most often Africans,
example, if someone lives in North commoninaselectsubsetofpopula- Europeans,Asians,andNativeAmeri-
AmericaandhisorhermtDNAhaplo- tionsandleadtoascertainmentbiases cans. However, the interpretation of
type exactly matches an individual that can impact ancestry estima- such estimates by both the scientist
living in Indonesia, the only thing tion.50 AIMs, most often developed andtheconsumerisunclear.
666 TheAmericanJournalofHumanGenetics86,661–673,May14,2010
AccuracyofAncestryInferences in colonial-era population move- a discrete-deme admixture model
Ideally,anyquantitativeclaimsabout ments. This creates a bias that might where thereis a set ofdiscrete demes
ancestry should have an easily inter- leadustodefineancestryinreference (usually or always referred to as
preted assessment of confidence or to particular sociopolitical groups. ‘‘ancestral’’ or ‘‘parental’’ popula-
accuracy associated with them. Our Moreover,ourknowledgeofdiversity, tions), and each individual inherits
interest in accuracy is to assess not and hence the genetic contributions proportions of his or her genome
only what the accuracy estimate is to ancestry, of populations in many from each of these demes. The goal
butalsohowwellwecandescribeour other parts of the world (e.g., East of the method is to estimate this list
confidenceintheinferences.Wealso Africa,SouthAsia,ArabianPeninsula, ofadmixture proportions for each indi-
stressthedifferencebetweenaccuracy andSoutheastAsia)islimited. vidual. Strictly speaking, a deme is a
of a particular individual’s ancestry Lineage Identification with Uniparental breeding population, defined on the
versus the inference of ancestry of a Markers basis of population genetic inference
population sample. The former is While it is now possible to identify of intermixed genetic variation, and
particularly important in the case of related groups of Y-chromosome and it is unlike classical anthropology’s
DTC ancestry testing, whereas most mtDNA lineages with high accuracy, ‘‘races,’’ which are defined by mor-
scientific research on ancestry infer- population-level inferences that have phology.11Nonetheless,theemphasis
encedealswiththelatter.Theaccuracy been made from these uniparental of admixture estimation on differ-
of ancestry inference methods is a systemsaresubstantiallylessaccurate. ences over similarities can be mis-
function of (1) how the underlying Twosimpleexampleshelptoillustrate leading about the overall genetic
patterns of human genetic variation this point. A large number of single- structureofthehumanspecies.
are distributed across the geographic site changes have served as the basis Admixture estimation has greatly
range of human habitation, (2) how for breaking Y chromosomes into advanced the field of ancestry infer-
that diversity is surveyed (i.e., the different ‘‘haplogroups,’’ and it is ence; however, there are caveats to
type and number of genetic markers accurate to say that Y chromosomes the interpretation of its results. First,
used)andwhowassampled,(3)which within, say, haplogroup C are more the ‘‘ancestral populations’’ are not
populationsareusedasreferences,and closely related to one another than directlyobserved—althoughinmany
(4) the statistical methods used for toaYchromosomefromhaplogroup applications, samples from related
interpretingpatternsofvariation. J. Thus, if two men both carry hap- populations are used as a proxy. For
DistributionofGeneticVariation logroup C Y chromosomes, they are example, present-day Yoruba are
Accuracy is limited by the fact that morelikelytoshareapaternallineage the most frequently used proxy for
every person has hundreds of ances- than if they had different haplo- inferring African American ancestry,
tors going back even a few centuries groups. Even so, this relationship despite the fact that most African
and thousands of ancestors in just does not mean that they are more Americans derive their ancestry from
a millennium. There is enormous geneticallysimilaroverall. diverse West African (and other
stochastic variation to the portion of Ontheotherhand,inthescientific African) populations that existed
the genome retained ina descendant literaturetherehasbeenaconnection over a span of several centuries and
from a given ancestor, and there is drawn between one subset of hap- thatmightnotallbewellrepresented
a rough expectation that it halves logroup C and Ghengis Khan on the by present-day proxy popula-
every generation. Genetic ancestry basis of the commonness of that tions.46,56,57Second,ifsomeancestral
tests can access only a fraction of branch of the Y chromosome gene- populations are missing altogether
theseancestralcontributions.Further- alogyin partsoftheworldconquered from the analyses, programs such as
more,thegenomicsegmentscontrib- by Ghengis Khan.55 Although such a STRUCTURE58 and FRAPPE59 will
uted by a particular ancestor are far connectionisbynomeansimpossible, force the results into a composite of
from all being uniquely identifiable, wecurrentlyhavenowayofassessing thereferencesamplesused;therefore,
so even if one’s genome has those howmuchconfidencetoplaceinsuch the results will be skewed simply
specific contributions, identification aconnection.Weemphasize,however, becauseofhowthealgorithmswork.
ofparticularancestryisalwaysuncer- thatwheneverformalinferencesabout Ifapoorproxyisusedforoneances-
tainandstatistical. populationhistoryhavebeenattemp- tral population, the method might
Geneticists also make specific tedwithuniparentalsystems,thestatis- compensate by adding admixture
choicesaboutwhichlevelsofancestry ticalpowerisgenerallylow.Claimsof from other ancestral populations.
to examine. For example, many esti- connections, therefore, between spe- Considergeneticancestrytestingper-
mations of genetic ancestry are de- cificuniparentallineagesandhistorical formed on an individual we will call
signed to distinguish contributions figures or historical migrations of Joe, whose eight great-grandparents
from reference populations that live peoplesaremerelyspeculative. were from southern Europe. The
in particular geographic regions (e.g., AdmixtureEstimation HapMappopulationsareusedasrefer-
West Africa, Europe, East Asia, and Forautosomalmarkers,ancestryinfer- encesfortestingJoe’sgeneticancestry.
the Americas) that were prominent ence is most often performed under The HapMap’s European samples
TheAmericanJournalofHumanGenetics86,661–673,May14,2010 667
consist of ‘‘northern’’ Europeans. In between the source populations, collaborations might be helpful and
regions of Joe’s genome that vary whichisincorrect(e.g.,anindividual commendable, vigilance is needed in
between northern and southern Eu- with an East Asian and European identifying and addressing potential
rope (such regions might include the parent will be indistinguishable from conflicts of interest. The scientific
lactase gene, LCT [MIM #603202]), an individual from Central Asia). claims of companies that choose not
the genetic ancestry test using the This reinforces the need for models to disclose the contents of their pro-
HapMap reference populations is that take these and other limiting prietarydatabasescannotbeassessed;
likelytoincorrectlyassigntheancestry factors into account and recognize therefore, the reliability of the infor-
ofthatportionofthegenometoanon- that in some cases accurate social mation they provide to consumers
European population because that identificationscannotbemade. cannotbeverified.64
genomic region will appear to be ReferenceSamples StatisticalMethods
moresimilartotheHapMap’sYoruba To infer ancestry, researchers rely on Regardless of the methods used or
orHansamplesthantoits(northern) comparinganyindividual’sparticular samples referenced, steps should be
Europeansamples. genetic profile to that of reference taken to adequately convey the
Althoughthediscrete-demeadmix- populations.Researchgeneticistsben- amount of uncertainty in the infer-
ture method is informative about efit from various publicly available ences about ancestry, whether in the
ancestryinsettingswhereindividuals databases such as the HapMap, researchorcommercialsetting.Popu-
have recent admixture from diverse HumanGenomeDiversityPanel,Per- lation genetic inference is ultimately
continental populations, it does not legen Human Genome Resources, a statistical exercise, and rarely can
performwellinsettingswhereindivid- POPRESproject,andSeattleSNPspro- definitive conclusions about ancestry
uals have more ancestors from across jects. However, even the databases be made beyond the assessment of
a continuous gradient of genetic that researchers consider the most whether putative close relatives are
diversity. European populations, for applicable reflect a woefully incom- or are not related. Because ancestry
example, despite revealing genetic plete sampling of human genetic inferences for less simple questions
differences, have been shown (as diversity,andthishasimportantcon- requirerelianceoncomplexstatistical
described above) to exhibit mainly sequencesfortheaccuracyofancestry procedureswithinherentuncertainty,
continuous spatial patterns of varia- inference. One problem is that the both producers and consumers of
tion. When admixture is estimated ‘‘ancestral populations’’ assumed by genetic ancestry estimates need to
for European individuals under the some methods are not explicitly rep- have a fairly sophisticated under-
assumption of two ancestral popula- resented in databases—and indeed standingofprobability.
tions,28 the method chooses admix- cannotberepresentedassuchbecause Therearetwolevelstotheinherent
ture proportions that make individ- we do not have the ability to sample uncertainty of these statistical infer-
uals a mixture of ‘‘northern’’ and ancestral populations. A second ences. First, there is uncertainty in
‘‘southern’’ ancestral populations problem is that populations that are parameter estimates (for instance,
eventhoughthereisnoindependent mixtures of the ‘‘typical’’ reference howlargearetheconfidenceintervals
evidencethattwosuchancestralpop- populations (e.g., Africans, Asians, of admixture coefficients for an indi-
ulationseverexisted. and Europeans) are substantially vidual?). Second, there is uncertainty
Methodsforaddressingcontinuous, under-representedinthesedatabases. in how to interpret these parameters
spatial population structure are still Recent sampling efforts, such as (e.g., what do the admixture coeffi-
under development, but principal- HapMap Phase III samples, are help- cients mean—what does an individ-
components analysis (PCA) has been ingtoremedythisproblem;however, ual’s haplogroup say about his or her
widely applied in this context.60,61 continued attention to diverse sam- past?).Thecontextinwhichancestry
The expected behavior of PCA on pling will be an important aspect of estimation is being used determines
evenly spaced samples from spatially any subsequent surveys of human the importance of these sources of
structured data is to return coordi- geneticvariation. error. In some research contexts (e.g.,
nates that are related to the geo- Some commercial scientists and whenancestryisusedasacovariatein
graphic origin of each individual.62 privategroupshavetheirownunpub- genome-wide association studies), it
Moreover,thereisaclearlyestablished lished databases with the potential might be sufficient to have some
relationshipbetweenthegenealogical to provide more refined information quantitative variable that represents
structureofasampleandtheprincipal than that available from publicly ancestry. In commercial ancestry-
components, grounding PCA in firm available resources. In some cases, testing applications, however, inter-
principles of population genetics.63 the commercial interest in ancestry pretationofteniskeybecausetheinfor-
One caveat of PCA-based approaches testing is indirectly benefiting public mation that is presented might have
is that if individuals are a product of research. For example, the company directpsychosocialandotherpersonal
‘‘recent admixture’’ from disparate 23andMe partially funded the geno- implicationsfortheindividual.
origins, it will assign individuals to a typingfortheHumanGenomeDiver- The statistical methods used to
single origin that is intermediate sityProjectsamples.38Althoughsuch perform ancestry inference vary with
668 TheAmericanJournalofHumanGenetics86,661–673,May14,2010
regardtotheassumptionstheymake, between genetic and environmental prompts a host of psychological,
how much of the information avail- factors.71–73 social,legal,political,andethicalcon-
able in the genetic data is extracted, There are circumstances in which cernsfromtheindividualtotheglobal
andhowtheirstatementsaboutinfer- genetic factors influencing heath- level.Theseactualorpotentialconse-
ence are summarized for the re- related traits are associated with quences have received increasing
searcher or the consumer receiving specific genetic variations that tend attention3,6,81–86andmustbeconsid-
the information. The ease in under- to be more prevalent in a particular eredalongsiderelevanttechnicaland
standing the statistical confidence in racial or ethnic group than in the analyticalissues.
the ancestry inference also varies restofthepopulation.Certaingenetic Knowledge about genetic ancestry,
widely among methods. The most variants associated with hyperten- particularly if undesirable and unex-
important aspect of reporting confi- sion,52 type 2 diabetes mellitus (T2D pected, can lead to the reshaping of
dence in ancestry determinations is [MIM #125853]),74 end-stage renal group, familial, or personal iden-
to accurately convey the level of un- disease (FSGS4 [MIM #612551]),75,76 tity.87–91 Anthropological andpopula-
certainty in the interpretations and prostate cancer,53,77 and some treat- tion-genetics research that postulates
to convey the real meaning of that mentresponses78,79havebeenshown or casts doubt on ancestral relation-
uncertainty. to differ significantly in frequency ships has historically incited varying
amonggroups.Therefore,diseaserisk degrees of identity-related conflict.
AncestryandHealth or treatment response is associated Some of the most notable examples
(Note:unlikeinothersectionsofthis with and, in some situations, influ- includethecaseofKennewickMan,92
report, where we mention ‘‘race’’ to enced by genetic factors that vary researchlinkingtheLembaandcertain
make specific points, in this section among racial or ethnic groups. It is Jews,93,94 and the discovery of family
we use ‘‘race’’ (and ethnicity) as con- notclearhowmuchofthisisactually ties between Thomas Jefferson and
structed by the US Office of Manage- gene expression versus DNA SallyHemings.95Theoccurrenceof,or
ment and Budget (OMB) and as used sequence. potential for, emotional distress in
in US social, government, and bio- Given the complexity and limited people, families, and groups after
medical research parlance. We realize understanding of the relationships receipt of conflicting information
that there are various connotations among genetic variation, ancestry, about their identity through DTC
and limitations of these terms, but race, ethnicity, and health and treat- ancestry testing has also been dis-
ourgoalhereisonlytoprovideabrief ment outcomes, the translation of cussed.3,15,87,89–91 Nonetheless, some
overview of some important issues geneticepidemiologicalresearchfind- research focused on consumers of
pertaining to health outcomes and ings to clinical application requires ancestry testing has revealed that
health differences within and among ample consideration of a variety of althoughancestrytestsmightpromote
the referent ancestry-linked sociopo- factors, including personal, social, genetic thinking about ancestry and
liticalgroups.) and other nongenetic factors. This ‘‘race,’’ test takers also were able to
Researchers still poorly understand issue might be highlighted in the construct meaningful narratives of
the relationship of genetic ancestry contextofDTCgenetictesting,where their identity.5 Clearly, additional
to individual and population health, consumers might share ancestry test empirical research will need to
but this relationship is a potentially results or ancestry-related estimates adequately explore the relationship
important area for investigation in of disease risk with their healthcare between genetic ancestry testing and
that it might have social and politi- providersandexpectthattheinforma- theidentitiesandoverallpsychological
cal consequences.65–68 In the US, it tionbefactoredintotheircare.3,68In well-beingoftesttakers,theirfamilies,
has been commonplace to report view of the ongoing national efforts andtheircommunities.
disease prevalence for each racial or toincreasethepublic’sexplorationof Questions have been raised about
ethnic group separately, and these family(health)history,80itispossible privacyandaboutthesecurityofrefer-
prevalence estimates often vary thatthispracticecouldbecomewide- encedatabasesthatsupportancestry-
amonggroups.69Thishasledtowide- spread as people seek to exhaust the estimation endeavors. For example,
spread speculation that racial or availablesourcesofinformationabout for genetic-ancestry-testing compa-
ethnic differences in individual or their family history and associated niesthataresoldorgobankrupt,there
population health are primarily due health risks. As such, the healthcare are concerns about the future of the
to genetic factors, including genetic community must be recognized as a privacypoliciesandothertermsunder
ancestry.68,70 Yet, racial or ethnic key stakeholder in decision making which data were collected.96 Some
identity could be associated with the concerning genetic ancestry infer- people also fear that commercial
health of an individual or group in ence. ancestry-testing databases might be
several ways. It might co-vary with more vulnerable than other genetics
different environmental or genetic PersonalandSocietalImplications databases to alternate and inappro-
factors that underlie risk or with Ancestry inference—in both its re- priateuses.64,97 The problemof alter-
different interactions within and searchandcommercialapplications— nate uses of data in the context of
TheAmericanJournalofHumanGenetics86,661–673,May14,2010 669
ancestry estimation might also be and discussion about the potentially typing procedures, but it might not
extended to the unauthorized inclu- reifying effects of current ancestry- be very useful to do that and also
sion of population-based genetic estimationpractices.3,16,86,106Beyond claim that the inferences from the
research data or samples in ancestry- ancestryestimationitself,theroutine data are not validated or certified in
related studies6,98 or in commercial treatment, in science, of ancestral, any way. Determination of feasibility
ancestry-testing databases. These ethnic, and so-called racial groups as or of mechanisms for certification
practices bring to the fore consider- bounded biological entities perpetu- and validation, as well as specific
ation about evolving notions of ates an inaccurate concept of human approaches for enhancing consumer
consent, anonymity, respect for variationandincreasesthepossibility understanding of the scientific and
communities, group risk-benefit of stigmatization and discrimination nonscientific issues, will require
assessment, and benefit sharing, and of the groups and the people within thoughtful deliberation beyond the
these issues must also be addressed themonthebasisoftraits,behaviors, scopeofworkofthistaskforce.
within the current broader discourse diseases, and other attributes.64,70,107 The academic research community
on the sharing and secondary use of Scientists and the scientific establish- cannot afford to be exempt from
genetic and genomic data and ment as a whole must attend to this similar efforts to increase scientific
samples.99,100 longstanding and pervasive problem rigor and overall accountability in
Acommonconcernaboutscientific of conveying conflicting messages genetic ancestry estimation. Indeed,
effortstoexplainoriginsisthealleged pertainingtohumanvariation. thepeer-reviewprocessesforfunding
diminished regard for important Although genetic ancestry infer- andjournalpublicationsaredesigned
cultural, religious, social, historical, enceinresearchand themarketplace to assist in such efforts, but their
and political processes that inform isthefocusofthisreport,wearewell effectiveness is compromised by the
origin as well as group membership, awarethatthetechnologiesarebeing inadequacy and inconsistent applica-
identity, and rights.3,16,101 Reports of employed in other arenas. For ex- tion of existing guidelines in this
the use (or intended use) of ancestry ample, since 2003, the forensic use area. Because of the intrinsic uncer-
testresultstomakeclaimsforbenefits ofDNAtomakedeterminationsabout taintiesofthescienceandthepoten-
throughaffirmativeactionorforrights ancestryincriminalcaseshasbecome tial societal ramifications, the field of
perceived to be associated with their more widespread.107–110 More re- population genetics as a whole could
new-found Native American status cently,the‘‘HumanProvenancepilot benefit from improved and enforced
have increased unease over the loss project’’proposedusingDNAancestry standardswithrespecttoterminology
or gain of certain rights or entitle- testing to identify the nationalities and methodologies, as well as inter-
ments.91,102,103 Entitlement could of people seeking asylum in the pretation and communication of
also be viewed in terms of interest UK.111,112Theseandothersuchappli- researchfindings.
amongsomeDTC-ancestry-testtakers cationsofgeneticancestryestimation Recently,Leeandcolleagues6called
in seeking dual citizenship in coun- alsomeritscrutinybecausetheyhave for federal regulation of genetic
triesidentifiedastheirancestralhome- the same technical problems dis- ancestry testing. At this juncture, we
lands.104 This trend is similar to that cussed above and may pose palpable offer an alternate approach, one that
discussedinrelationtosomepopula- threatstohumanwelfare. might itself lead to federal oversight,
tion-geneticsresearchconnectingthe if subsequently deemed appropriate,
Lemba and certain Jews.87,105 It Conclusionsand necessary, or practical. We believe
remains to be seen what tangible Recommendations that effective decision making re-
effects (if any) genetic ancestry infer- Concerns about analytical proce- garding genetic ancestry inference,
ence will have on these pre-existing dures, interpretation, and the per- in particular DTC genetic ancestry
entitlementissues. sonal and social implications of ge- testing, willbe best initiated through
Genetic ancestry inference (in neticancestryinferencemakeitclear cooperative interaction among a va-
particular,theuseofAIMsandadmix- that enormous care is required in riety of stakeholders, including suit-
ture mapping techniques) could theapplicationofancestryestimation able federal agencies. Considering
reveal the nuances of ancestry and in both research and commercial that such collective engagement has
dispel the notion of race in humans settings.Amajorissueregardingcom- not yet occurred, it is premature to
and/or the practice of equating race mercialancestrytestingisthatthereis assume reticence or resistance on the
with ancestry. Paradoxically, it is no quality assurance guarantee. This part of any of the players or that
equally capable of giving credence to gives rise to the question of whether federalregulationistheonlyrecourse.
the idea that humans subdivide into there is a need for lab certification or On the basis of our review of the
distinctbiologicalracesandimplying accreditation.Wetendtoleanagainst state ofthe science and the personal,
that there are the clear-cut connec- anything so formal because it would societal, and health-related implica-
tions between DNA and specific provide a stamp of approval by any tions of genetic ancestry inference in
geographic regions or ethnic groups. designated accrediting body. It isone academia and industry, we make the
There has been substantial anxiety thing tocertifyaccuracyofthegeno- followingrecommendations:
670 TheAmericanJournalofHumanGenetics86,661–673,May14,2010