Am. J. Hum. Genet. 40:453-463,1987

Polynesian Origins and Affinities:Globin Gene Variants in Eastern Polynesia

A. V. S. HILL,* B. GENTILE,t J. M. BONNARDOT,t J. Roux,tD. J. WEATHERALL,* AND J. B. CLEGG*

*M.R.C. Molecular Haematology Unit, Nuffield Department of Clinical Medicine, Universityof Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU; tInstitut de Recherches

Medicales Louis Malarde, Tahiti, French Polynesia; and fCentre Hospitalier Territorial,Tahiti, French Polynesia

SUMMARY

Analysis of copy number variants of the duplicated a-, t-, and -y-globingenes in eastern Polynesians revealed a high frequency of both trip-licated-(-gene chromosomes and a specific ac thalassemia deletion.This deletion and a novel restriction-enzyme-site polymorphism asso-ciated with a ttt chromosome are found only in Melanesians andPolynesians. Analysis of ao-globin restriction-enzyme haplotypes indi-cated further similarities to Melanesians but suggested an additionalnon-Melanesian genetic component in eastern Polynesia. Several glo-bin gene alleles showed evidence of marked frequency fluctuationsdue to genetic drift.

INTRODUCTION

The origin of the Polynesians, who inhabit a vast area of the Pacific stretchingfrom Hawaii to New Zealand and Easter Island, has been the subject of wildspeculation, bitter controversy, and, more recently, extensive research inmany disciplines (Bellwood 1978; Brockway 1983). Modern reconstructionsbased mainly on linguistic and archeological evidence trace the movement of abasically mongoloid people through island Melanesia to Fiji and then Tongasome 3,500 years B.P. (fig. 1). Samoa was colonized soon afterward, and fromthere a founder population set out to reach the Marquesas Islands in eastern

Received June 13, 1986.Address for correspondence and reprints: Dr. J. B. Clegg, M.R.C. Molecular Haematology Unit,

Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Heading-ton, Oxford OX3 9DU, England.© 1987 by the American Society of Human Genetics. All rights reserved. 0002-9297/87/4005-0007$02.00

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HILL ET AL.

Q.

FIG. 1.-Map of the Pacific showing Polynesia, Melanesia, and Micronesia. T = Tahiti; M =Marquesas Islands; E = Easter Island; H = Hawaii; C = Cook Islands; S = Samoa; Tn = Tonga;NZ = New Zealand; F = Fiji; V = Vanuatu; NC = New Caledonia; PNG = Papua New Guinea;and A = Australia.

Polynesia around A.D. 300. Subsequent migrations from the Marquesas andSociety Islands over the next 1,000 years led to the colonization of Hawaii,Easter Island, and New Zealand.Although this outline is now generally accepted, several questions remain.

The point of origin of the ancestral Polynesians in island or mainland SoutheastAsia is unknown. There is evidence of Polynesian contact with South America,but the existence of gene flow from the Americas into Polynesia is controver-sial. Although a Micronesian route for the colonization of Polynesia (Howells1973) now seems unlikely (Craib 1983), it is unclear whether Polynesians sweptthrough Melanesia without significant intermingling with local Melanesians or,instead, as linguistic analysis suggests, underwent a period of evolution ineastern Melanesia.

Until recently, genetic studies have played a relatively minor role in recon-structing migration pathways and analyzing population affinities in Polynesia.This is partly because of the substantial confounding effect of genetic drift insmall island populations that have been subject to numerous founder effects(Kirk 1980). However, recent analysis of HLA polymorphisms and haplotypeshas supported the general outline presented above (Serjeantson 1984). With theadvent of techniques of rapid DNA analysis and the discovery of manypopulation-specific polymorphisms, DNA studies promise to make a majorcontribution to genetic anthropology. We have described previously a deletionin the a-globin gene complex (- ot 7II1, which produces ax+ thalassemia) thatwas found in Melanesia and western Polynesia but not in numerous otherpopulations (Hill et al. 1985). From analysis of restriction-enzyme haplotypes,

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POLYNESIAN ORIGINS AND AFFINITIES

this appears to have had a single origin and may therefore serve as a marker forPolynesian migration. We report here the results of globin gene analysis ineastern Polynesia, an area that has been subject to very few previous popula-tion surveys. As well as the specific at+ thalassemia deletion, population-specific markers in the 4- and y-globin gene regions were identified and a--globinhaplotypes defined. This haplotype is highly polymorphic and has been studiedin numerous widely dispersed populations (Higgs et al. 1986). The results pro-vide evidence of considerable genetic drift and founder effects during the col-onization of Polynesia and indicate substantial genetic affinity between Polyne-sians and island Melanesians with a suggestion of an earlier non-Melanesian-possibly mongoloid-genetic component in Polynesians.

MATERIAL AND METHODS

Blood samples were collected from 102 unrelated individuals on the island ofTahiti. Although most persons originated from the Society Islands, all fiveisland groups in eastern (French) Polynesia were represented. All individualshad Polynesian parents; in 23 cases, however, one grandparent was of eitherChinese or European origin, representing at least a 6% admixture; admixture inearlier generations is unknown.DNA was extracted and Southern blot analysis performed as described pre-

viously (Old and Higgs 1983; Hill et al. 1985). The probes used for (x and 4genotype determination were (1) a 2.85-kb EcoRI1BamHI C fragment containingthe entire C2 gene, (2) a 1.5-kb PstI fragment containing the entire al gene, and(3) a 1.8-kb Sacl fragment containing the 5' part of the C1 gene. An inter-Chypervariable-region AluI fragment containing 32 copies of a tandemly re-peated 36-bp sequence (Goodbourn et al. 1983) was used for analysis of trip-licated-4-gene chromosomes. A 3.3-kb HindIII A- fragment probe was used fordetermination of y-globin genotypes. Additional probes employed to analyzepolymorphic restriction sites in the at-globin cluster and define ax-globin hap-lotypes were (1) a 0.6-kb BamHhIEcoRI fragment from pJW5, used to detectthe XbaI polymorphism, and (2) a 0.8-kb BamHI fragment from pDH12, usedto detect the PstI-site polymorphism 3' to the al gene (Higgs et al. 1986).

All samples were initially digested with BglII and hybridized with the 2.8-kbC probe. With this digest a -(X37 deletion chromosome is detetAed by thepresence of a 16-kb band and a - a4.2 deletion chromosome (Embury et al.1980) by the presence of an 8.4-kb band. All samples with a 3.7-kb deletionwere subtyped using either ApaI or RsaI and the Pst at probe as previouslydescribed (Higgs et al. 1984). Triplicated-oa-gene chromosomes (Goossens et al.1980; Higgs et al. 1980) were detected by rehybridizing the BglII filters with thePst a probe; a new 3.7-kb band indicated the aaatot arrangement.

Triplicated- and single-C chromosomes were detected by means of the 2.85-kb C probe on BglII- and HindIII-digested samples (Winichagoon et al. 1980).In the presence of HindIII the CCC chromosome produces a new 11-kb band andsingle-C chromosomes produce an 18-kb band. y-Globin genotypes were deter-mined as described previously, by means of BglII and the y probe (Hill et al.1986). Normal (eyy) chromosomes produce a 13-kb band, Syyy chromosomes

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(Trent et al. 1981) an 18-kb band, and single--y-gene chromosomes (Sukumaranet al. 1983) an 8-kb band.

Restriction-enzyme-site and length polymorphisms in the a cluster were ana-lyzed by means of the restriction enzymes XbaI, Bgll, Sacl, AccI, RsaI, andPstI as described elsewhere (Higgs et al. 1986).

RESULTS

a Thalassemia in Eastern PolynesiaSeveral deletions within the a-globin gene cluster that produce the pheno-

type of a thalassemia have been described, as have less common nondeletiondefects (Higgs and Weatherall 1983). Single-a-gene deletions that produce amild a' thalassemia defect are by far the most common and may be dividedinto two types, deleting either 3.7 or 4.2 kb of DNA around the duplicated a-globin genes. The -a37 defect may be divided into three subtypes, one ofwhich, - a3-7111, has been found only in Melanesians and Polynesians (Hill etal. 1985). Gene analysis of 102 individuals from eastern Polynesia (table 1)shows that this is the only deletion form of a thalassemia present in this popula-tion. A gene frequency of .12 for an a thalassemia defect in a population free ofmalaria is surprisingly high. Because restriction-enzyme haplotype data hasshown that the - a3-7111 chromosome in Melanesia and Polynesia probably hada single origin (Hill et al. 1985), it would appear that this chromosome wasbrought from the west by the colonizers of eastern Polynesia and that its

TABLE 1

ALLELE FREQUENCIES OF GLOBIN GENE VARIANTSIN EASTERN POLYNESIA

A. a-GLOBIN GENE ARRANGEMENT

No. aa -ca aca

204. . 875 .12 .005

B. C-GLOBIN GENE ARRANGEMENT

No. tt -t 4rt

204 .835 .835 .005 .16

C. y-GLOBIN GENE ARRANGEMENT

No. y -Y Yy

174. . 965 .0 .035

NOTE.-The number of chromosomes examined and the allele frequency ofeach a-, 4-, and y-globin gene arrangement is shown. All - a deletions were ofthe -ci3aIII subtype. The aca chromosome was of the aca3i7 type. Five of the33 {C; chromosomes were associated with an additional BgIII site polymor-phism (fig. 3), to give an overall frequency for this site polymorphism of .025.

456 HILL ET AL.

POLYNESIAN ORIGINS AND AFFINITIES

,2 +41 *o a2 al_ E1J 0_ _X SB H Z A R P P 3 HVR

1kb

FIG. 2.-Structure of the a-globin gene complex showing polymorphic restriction-enzyme sitesand regions of length variation (Higgs et al. 1986). Indicates length variation. X = XbaI; S =

SacI; B = BglI; A = AccI; R = RsaI; and P = PstI. H = the inter-n HVR. Z = the region oflength variation in IVS-1 of the t1 gene, which is associated with either a pseudo-(- or (-likesequence (Hill et al. 1985b). The region of length variation at the 3' end of the complex-3' HVR-is also indicated.

relatively high present frequency may result from a population bottleneck dur-ing migration.

In contrast to the high frequency of single-a-gene chromosomes, only onetriplicated a gene chromosome was found in this survey. Triplicated a genesare found at gene frequencies of -.05 in present-day Samoa (Lie-Injo et al.1985; Trent et al. 1985, 1986), from where the original colonizers of easternPolynesia are believed to have set out around A.D. 300. It would appear that themuch lower frequency of aaa chromosomes in eastern Polynesia must alsoreflect a founder effect.

t-Globin Gene Variants in Eastern PolynesiaThe duplicated embryonic a-like globin genes, t2 and t1, are situated up-

stream of the a-globin genes on the short arm of chromosome 16 (fig. 2) (Higgsand Weatherall 1983). Both single- and triplicated-c-gene chromosomes havebeen described, but these are rare in most populations (Winichagoon et al.1982). Single-(-gene chromosomes are found at polymorphic frequencies onlyin blacks of African origin, and (C; chromosomes at relatively high frequenciesonly in Southeast Asia (.09) and Melanesia (.02) (Higgs et al. 1986). In view ofthe genetic affinities between Polynesians and both mongoloids and Melane-sians, it was of interest to measure the frequency of variant-c-gene chromo-somes in eastern Polynesia. A remarkably high frequency, 0.16, of the (ttchromosome was found (table 2), including three homozygotes for this hap-lotype, a genotype not previously reported. One single-4-gene chromosomewas found.We have previously noted that the triplicated-4-gene chromosome found in

Southeast Asians and Melanesians has an unusual structure (Hill et al. 1985b),illustrated in figure 3. Between the t2 and *41 genes on normal chromosomeslies a region of length variation-i.e., a hypervariable region (HVR)-thatcommonly produces one of three allele lengths, denoted L, M, and S (large,medium, and small) (Goodbourn et al. 1983, 1984). On the triplicated-C-genechromosome there is an HVR between each pair of the triplicated ; genes, andthese HVRs have different sizes: an M allele is between the 5' pair and an Sallele is between the 3' pair (fig. 3). However, because the first intron of themiddle t gene on this chromosome is larger than that of a C2 gene, the length ofthe allele produced by the 3' gene pair following BglII digestion is not S but

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458 HILL ET AL.

TABLE 2

HAPLOTYPES OF Ma CHROMOSOMES

No. X S B H Z A R P P

17 ....... + - - S PZ + - +/- +/- IVa/Ile14 ....... + + - M PZ + + - - Ia5 ........ - - + M Z - - - - Illa2 ....... - + - L PZ + - - - IaI ....... + + - M Z - - - - IlIgI ....... - + - L Z - - - - Illc

NOTE.-Restriction-enzyme haplotype analysis of 40 normal (Q-aa) chromosomes from eastern Polynesia. Allindividuals were known to have four Polynesian grandparents. The nine polymorphic sites and regions analyzedare shown in fig. 2. The final column indicates the haplotype code used by Higgs et al. (1986). The PstI sites werepolymorphic only on the most common haplotype shown. Because of lack of family studies the linkage arrange-ment of these two sites could not be determined in all cases. A plus sign (+) = the presence of a restriction-enzyme site; a minus sign (-) = its absence. L, M, and S = large-, medium-, and small-length alleles, respec-tively, of the inter-; HVR; PZ and Z = xp1 and (I genes, respectively; X - XbaI; S = SacI; B = BglI; H =inter-C HVR; Z = 4-pseudo-; polymorphism; A = AccI; R = RsaI; and P = PstI.

rather intermediate in size (11 kb) between S (10.5 kb) and M (1 1.3 kb). This 1 1-kb band was useful in identifying triplicated-4-gene chromosomes by means ofa BglII digest.

A BgIlI Polymorphism Associated with the'tt ChromosomeSome of the t4t chromosomes identified by means of HindIII showed a novel

5.5-kb band when BglII was used and lacked the 11-kb band described above.Multiple-enzyme digests showed that this was due to a restriction-enzymepolymorphism for BglI1 between the 3' pair of t genes on the tt; chromosome.Hence, a mutation on this chromosome has produced a new, readily detectablegenetic marker. Fortunately, BglII has been used widely for population screen-ing for a thalassemia, and this 5.5-kb band has only been found previously intwo Melanesians, one from Vanuatu and one from New Caledonia (Higgs et al.1986); it is apparently absent from Southeast Asia and Papua New Guinea.Hence, this BglII polymorphism, which also has been found in the Cook Is-lands and among the Maoris in New Zealand (Trent et al. 1986), represents

S S

B M B +B_ S B

FIG. 3.-Structure of the triplicated-c-gene chromosome found in eastern Polynesia, Melanesia,and Southeast Asia. Between each pair of C-like genes lies a region of length variation that is ofmedium size (M) between the 5' pair of genes and of small size (S) between the 3' pair; 5' to thisHVR lies the polymorphic Sacl site (S, above the complex), which is present between the 5' pair ofgenes and absent between the 3' pair (Hill et al. 1985b). There is a Bg1II site (B) in the 5' region ofeach (-like gene. In addition, in Polynesia and Melanesia a new BgIII site polymorphism is foundbetween the 3' pair of C-like genes on some CtC chromosomes. The inactivating mutations in thepseudo-; genes are indicated by black dots.

POLYNESIAN ORIGINS AND AFFINITIES

another DNA marker that, like the - &3.7III deletion, emphasizes the geneticaffinity between Polynesians and island Melanesians.

-y-Globin Gene Variants in Eastern PolynesiaExtensive analysis of the P-globin gene cluster of normal and variant

chromosomes in many world populations has led to the definition of numerousDNA variants (Antonarakis et al. 1985). Restriction enzyme-haplotype analy-sis of Polynesians has revealed that they have clustered more closely withMelanesians than with other racial groups (Wainscoat et al. 1986). However,the remarkable similarity in haplotype frequencies-at least in the 5' region ofthe ,B-globin gene cluster-between all non-African populations studied to datemakes this region a relatively insensitive one for population comparisons(Wainscoat et al. 1986). However, like the a- and t-globin genes, the duplicated-y-globin genes also display copy-number variants (Trent et al. 1981; Sukuma-ran et al. 1983). Recently, we have found frequencies of single- and triplicated--y-gene chromosomes of as much as .125 in island Melanesia, although thesevariants appear to be less common in other populations (Hill et al. 1986).Analysis of y-gene numbers in eastern Polynesia (table 1) revealed a significantprevalence (.04) of triplicated y genes but no single--y-gene chromosomes. Thisabsence of the - y chromosome accords with surveys conducted elsewhere inPolynesia (Trent et al. 1986) and suggests that this variant was lost by the earlyfounder population of western Polynesia, perhaps in Tonga. The minimalphenotypic difference between y genotypes (Hill et al. 1986) suggests that thishappened by genetic drift rather than by selection.

a-Globin Restriction-Enzyme HaplotypesAn extensive restriction-enzyme haplotype has recently been defined for the

a-globin gene cluster, comprising seven site and two length polymorphisms.These haplotypes have been analyzed in eight populations and have shownremarkable diversity (Higgs et al. 1986). In addition, the region of length varia-tion at the 3' end of the gene cluster (3' HVR) may be used with the haplotypeto generate an extremely informative genetic marker. Despite this diversity afew common haplotypes are found in most populations. Melanesians from bothisland Melanesia and Papua New Guinea, however, are unusual in having alimited number of haplotypes at this locus, including two predominant haplo-types (Illa and IVa/Ile) that are less common in other populations (Flint et al.1986; Higgs et al. 1986).We have determined the restriction-enzyme haplotype of 40 tt-aa chromo-

somes from eastern Polynesia and compared these with haplotypes previouslyreported for other populations (table 2). Limited diversity is observed withthree predominant haplotypes. Interestingly, two of these, representing 55% ofthe chromosomes, are the two common haplotypes found in Melanesians (Flintet al. 1986). However, a third haplotype, type Ia, characterized by the presenceof the polymorphic RsaI restriction-enzyme site, was found on 14 of the 40chromosomes. This haplotype is very uncommon in Melanesia (Flint et al.1986; Higgs et al. 1986) and would appear to represent genetic admixture from

459

another source in Polynesians. Unfortunately, the Ia haplotype is common inmost Eurasian populations, a condition that provides little clue as to its originin Polynesia. Because of its relatively high frequency in individuals denyingany foreign ancestry, it seems very unlikely that this haplotype has simply beenintroduced to eastern Polynesia in the past 200 years. Hence, the a-haplotypedata appear to suggest a substantial genetic similarity with Melanesians whileindicating the presence of another non-Melanesian component, possibly de-rived from the original pre-Polynesian migrants into eastern Melanesia.

DISCUSSION

Studies of genetic markers in eastern Polynesia are of interest for severalreasons. First, eastern Polynesia is culturally distinct from the older popula-tions of Tonga and Samoa, which have been more frequently surveyed (Bell-wood 1978). Eastern Polynesians must have been subject to several populationbottlenecks-in the colonization of Tonga, then of Samoa, and finally of theMarquesas Islands-and their gene frequencies can be expected to reflect this.Finally, proponents of genetic admixture to Polynesia from South America(Heyerdahl 1952) might expect to find the clearest evidence of any such geneflow in the east of Polynesia. Data on several markers in the globin genecomplexes provide clear evidence of founder effects during colonization andprovide substantial evidence of genetic affinity with island Melanesia-andalso, to a lesser extent, with Southeast Asia.The most unequivocal genetic markers found in this survey are the - &37111

deletion and the BglII-site polymorphism associated with a triplicated-4-genechromosome. Both are found in island Melanesians and Polynesians and havenot been found in large surveys of other populations. This a'-thalassemiadeletion is found at high frequency (.17) in island Melanesia, where it is subjectto selection by malaria (Hill et al. 1985) but is much less common in Fiji, Tonga,and Samoa, which are malaria free (Trent et al. 1986; D. K. Bowden, personalcommunication). The intermediate frequency found in eastern Polynesia,which was colonized from Samoa, suggests a founder effect that elevated thefrequency of this deletion in the east. Similarly, the BglII polymorphism, whichis rare in island Melanesia, was probably amplified in frequency by this particu-lar form of genetic drift.

In contrast, other markers in the globin gene clusters are found at muchlower frequencies in eastern Polynesia. The triplicated-a-gene chromosome,which reaches the highest known frequency in present-day Samoans (Lie-Injoet al. 1985; Trent et al. 1986), was found in only one individual in this survey,and the single--y-gene chromosome, like blood group B (Simmons 1962), wouldappear to have been completely lost in the founding population of Polynesia.Likewise, the - a4-2-deletion chromosome, present throughout Melanesia (Hillet al. 1985), has never been found in Polynesia.The remarkably high frequency of triplicated-C-gene chromosomes in eastern

Polynesia again reflects affinity with Melanesia-but also with Southeast Asia,which has the highest previously reported frequencies. The singular structureof this (, resulting from a particular type of interchromosomal unequal cross-

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POLYNESIAN ORIGINS AND AFFINITIES

over event, suggests that it probably had a single origin. Since (C; chromo-somes are relatively uncommon in Papua New Guinea (Higgs et al. 1986), itseems possible that this chromosome may have been brought into easternMelanesia by the original mongoloid pre-Polynesians. There, a further muta-tion, which is detectable as a new BgIII restriction-enzyme-site polymorphism,occurred on this chromosome. Similarly, the a-haplotype data from easternPolynesia, although displaying two haplotypes that are common in Melane-sians, also reveal a third haplotype, type Ia, which may represent an oldermongoloid component.

Analysis of these globin gene polymorphisms in other Polynesian popula-tions should provide valuable indications of the relationships between differentisland populations. In particular, it will be of interest to determine whether theislands believed to have been colonized from eastern Polynesia can be classi-fied as a group genetically distinct from western Polynesia, as is suggested byHLA data (Sejeantson 1984). It is remarkable that the Polynesian "outlier"population of Melanesia, which is believed to be derived by backmigrationfrom Polynesia (Bellwood 1978), have significant frequencies of the _ a4.2 and- y deletions (Flint et al. 1986; Hill et al. 1986), both of which are absent inPolynesia. This is reminiscent of the finding of very high frequencies of bloodgroup B-another variant absent in Polynesia (Simmons 1962)-on the outliersRennell and Bellona (Simmons and Gajdusek 1966), and it presumably resultsfrom admixture with Melanesians. Because of the lack of globin gene data onAmerindians, it is not possible to identify at present any possible gene flow intoPolynesia from the Americas. However, in view of both the accumulatinggenetic data linking Polynesians with islands to the west and extensive linguis-tic and archeological evidence, it is clear that any such admixture must havebeen very limited. In contrast, studies of DNA polymorphism promise to bevery useful in identifying the precise origin of the pre-Polynesians who mi-grated into eastern Melanesia some 3,000-4,000 years B.P. Surveys for Polyne-sian markers in different parts of island Southeast Asia should be informative.

ACKNOWLEDGMENTS

We are grateful to the staffs of the Institut de Recherches Medicales Louis Malardeand the Centre de Transfusion Territorial, Papeete-particularly to M. Gay-for assis-tance in collecting blood samples; to R. J. Trent for communicating his data beforepublication and for discussions; to D. R. Higgs for the gift of probes; to Linda Robertsfor preparing the typescript; and to the Rockefeller Foundation for financial support.A.V.S.H. is an M.R.C. Training Fellow.

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