复旦大学：《人类进化 Human Evolution》参考文献_分子人类学_NATIVES OR IMMIGRANTS：MODERN HUMAN ORIGIN IN EAST ASIA

REVIEWS NATIVES OR IMMIGRANTS MODERN HUMAN ORIGIN IN EAST ASIA Li Jin and Bing Su East Asia is one of the few regions in the world where a relatively large number of human fossils have been unearthed - a discovery that has been taken as evidence for an independent local origin of modern humans outside of Africa. However, genetic studies conducted in the past ten years, especially using Y chromosomes, have provided unequivocal evidence for an African origin of East Asian populations. The genetic signatures present in diverse East Asian populations mark the footsteps of prehistoric migrations that occurred tens of thousands of years ago The'Out-of-Africa' hypothesis of modern human ori- human origin in East Asia2-. In addition, although the A different electrophoretic gins suggests that local populations outside Africa were expansion of modern humans into Europe, the due to allelic differences completely replaced by modern humans who originat- Americas and Oceania(Australia and New guinea)is ed in Africa. This hypothesis has been widely accepted now relatively well characterized", little is known about since it was first proposed in the late 1980s, and it is the earliest migratory routes that modern humans took supported by extensive genetic evidence and by in spreading from Africa to Asia. So a close examination archaeological findings-(see BOX 1 for the competing of East Asians is essential to resolve the long-standing hypotheses ) However, it has been claimed, mostly controversy over the origin of modern humans. A by archaeologists, that the abundant hominid fossils recent series of genetic studies on East Asian popula- found in China and in other regions of East Asia show tions have been informative. The results have filled the evolutionary continuity, not only in morphological gap in the genetic data of this important region, and characters, but also in spatial and temporal distribu- have cleared the confusion that surrounds the origin tions-4. This observation implies that the evolution and prehistory of humanity in East Asia2122 from Homo erectus to Homo sapiens and then to Homo sapiens sapiens(modern man), took place in East Asia Genetic relationship of East Asian populations s well as in Africa-a theory that has been used The genetic structure of Chinese populations was first repeatedly to challenge the validity of the Out-of- studied using classical genetic markers, such as blood Africa hypothesis. groups, immunoglobins and ALLOZYMEs23-25A distinct University of Texa Genetic data that support the Out-of-Africa model, genetic difference was observed between northern and Houston. Texas 77030 which come mostly from mitochondrial DNa southern populations, despite millennia of common (mtDNA)studies, are often disputed, and the interpre- history and migrations. This raises the question of ation of the genetic evidence has been controversials hether southern and northern populations are Fudan University, China. National Human Genom Furthermore, in most of the genetic studies, the Chinese descendants of the same population or belong to popu- DNA samples derive from Canton, in Southern China, lations that arrived in China from different sources Center at Shanghai,China. which contains many diversified ethnic populations. Several studies of mt DNA variations in a limited nun Therefore, this might not be the representative sample ber of populations indicated that East Asians may u@utsph sph uth mcedu needed to resolve the competing hypotheses of modern descend from a common ancestor25-2 The mtDNA 126 NOVEMBER 2000 VOLUME 1 www.nature.com/reviews/genetics M@ 2000 Macmillan Magazines Ltd

126 | NOVEMBER 2000 | VOLUME 1 www.nature.com/reviews/genetics REVIEWS human origin in East Asia3–6. In addition, although the expansion of modern humans into Europe, the Americas and Oceania (Australia and New Guinea) is now relatively well characterized17, little is known about the earliest migratory routes that modern humans took in spreading from Africa to Asia. So a close examination of East Asians is essential to resolve the long-standing controversy over the origin of modern humans. A recent series of genetic studies on East Asian popula￾tions have been informative. The results have filled the gap in the genetic data of this important region, and have cleared the confusion that surrounds the origin and prehistory of humanity in East Asia7,21,22. Genetic relationship of East Asian populations The genetic structure of Chinese populations was first studied using classical genetic markers, such as blood groups, immunoglobins and ALLOZYMES23–25. A distinct genetic difference was observed between northern and southern populations, despite millennia of common history and migrations. This raises the question of whether southern and northern populations are descendants of the same population or belong to popu￾lations that arrived in China from different sources. Several studies of mtDNA variations in a limited num￾ber of populations indicated that East Asians may descend from a common ancestor26–28. The mtDNA The ‘Out-of-Africa’ hypothesis of modern human ori￾gins suggests that local populations outside Africa were completely replaced by modern humans who originat￾ed in Africa. This hypothesis has been widely accepted since it was first proposed in the late 1980s, and it is supported by extensive genetic evidence and by archaeological findings1–8 (see BOX 1 for the competing hypotheses9,10). However, it has been claimed, mostly by archaeologists, that the abundant hominid fossils found in China and in other regions of East Asia show evolutionary continuity, not only in morphological characters, but also in spatial and temporal distribu￾tions11–14. This observation implies that the evolution from Homo erectus to Homo sapiens and then to Homo sapiens sapiens (modern man), took place in East Asia as well as in Africa — a theory that has been used repeatedly to challenge the validity of the Out-of￾Africa hypothesis13,14. Genetic data that support the Out-of-Africa model, which come mostly from mitochondrial DNA (mtDNA) studies, are often disputed, and the interpre￾tation of the genetic evidence has been controversial15–20. Furthermore, in most of the genetic studies, the Chinese DNA samples derive from Canton, in Southern China, which contains many diversified ethnic populations. Therefore, this might not be the representative sample needed to resolve the competing hypotheses of modern NATIVES OR IMMIGRANTS: MODERN HUMAN ORIGIN IN EAST ASIA Li Jin and Bing Su East Asia is one of the few regions in the world where a relatively large number of human fossils have been unearthed — a discovery that has been taken as evidence for an independent local origin of modern humans outside of Africa. However, genetic studies conducted in the past ten years, especially using Y chromosomes, have provided unequivocal evidence for an African origin of East Asian populations. The genetic signatures present in diverse East Asian populations mark the footsteps of prehistoric migrations that occurred tens of thousands of years ago. Human Genetics Center, University of Texas, Houston, Texas 77030, USA. School of Life Sciences, Fudan University, China. National Human Genome Center at Shanghai, China. e-mails: ljin@sph.uth.tmc.edu; bsu@utsph.sph.uth.tmc.edu ALLOZYME A different electrophoretic form of the same enzyme due to allelic differences. © 2000 Macmillan Magazines Ltd

REVIEWS veral studies using other autosomal and X-chro- Box 1 'Out-of-Africa versus the multiregional hypothesis mosomal markers in worldwide populations are also consistent with the Out-of-Africa hypothesis However, as only a few East Asian populations were 1.000.000H erectus alysed, there is insufficient data to refute the multire- gional hypothesis convincingly, let alone trace the early migrations of modern humans in East Asia. A recent study of the markers on chromosome 21 provided ncouraging evidence by using intact autosomal haplo type data to trace migrations. A 565-base-pair DNA fragment near the MXi gene(which encodes an inter- feron-inducible protein) was found to contain nine polymorphic sites in human populations. No recombi- nation or recurrent mutations(for example, A-G and then back to A)were observed in this genomic region 100,000Hs sapien The results show that Africans have the greatest overal haplotype diversity. The ancestral haplotype( called Htl) has moderate frequency in African populations, but is rare or absent in other world populations, includ- Aca□ Europe[Asia Oceania ing five East Asian populations. This finding is consis- tent with the Out-of-Africa hype Broadly speaking, there are two competing hypotheses on the origin of modern humans: the Out-of-Africa hypothesis and the multiregional hypothesis(reviewed in Y-chromosome haplotypes REFS 9, 10). Both agree that Homo erectus originated in Africa and expanded to Eurasia In 1999, another systematic genetic study on East Asian about one million years ago, but they differ in explaining the origin of modern populations was published by Su and colleagues. A set humans(Homo sapiens sapiens). The first hypothesis proposes that a second of 19 highly informative Y-chromosome biallelic mark- ation out of Africa happened about 100,000 years ago, in which anatomically ers, developed at Stanford University, were used to modern humans of African origin conquered the world by completely replacing reveal the genetic structure of the paternal lineages in archaic human populations (Homo sapiens)(Model A). The multiregional hypothesis East Asia (BOX 2). Owing to the low level of genetic div states that independent multiple origins (Model D)or shared multiregional evolution sity, the use ofY-chromosome markers in reconstruct with continuous gene flows between continental populations(Model C)occurred in ing human history shad been hampered until the intro- the million years since Homo erectus came out of Africa(the trellis theory).A duction of denaturing HIGH-PERFORMANCE LIQUID compromised version of the Out-of-Africa hypothesis emphasizes the African origin f most human populations but allows for the possibility of minor local contribution CHROMATOGRAPHY, an efficient technique for detecting mutations-8. Many Y-chromosome biallelic markers (Model B) have been identified in the past few years.,. Su et al2 data from seven Asian populations are consistent with ing 21 Chinese ethnic populations, 22 provincial Han the hypothesis of a common southern origin of East Chinese populations, three Northeast-Asian popula Asians, which had originally been proposed on the basis tions and five Southeast-Asian populations, as well as 12 dental variations 9 non-Asian populations from Africa, America, Europ ENETIC ARCHITECTURE In 1998, Chu et al. studied the GENETIC ARCHITECTURE of and Oceania. These representative samples and the East Asians using up to 28 East Asian populations and 30 informative Y-chromosome markers led to the conclu- autosomal-microsatellite markers. By using an sion that Southeast-Asian populations are much more HIGH-PERFORMANCELIQUID approach based on the phylogenetic relationships diverse than their northern counterparts, and could CHROMATOGRAPHY between populations, they showed that all East Asian mean that mainland Southeast Asia was the first settle- technique for separating opulations in their study form a single cluster rooted by ment of modern humans in East Asia. On the basis of DNAorprotein molecules by African populations. This observation strongly supports the VARIANCE ofY-chromosome microsatellites, the initial n African origin of East Asian populations. In settlement was estimated to have occurred addition, northern and southern East Asians belong to 18, 000-60,000 years ago. It was hypothesized that a distinct clusters in the phylogenetic tree, confirming that ding with the A measure of the variation they are genetically divergent. The phylogenetic analysis ier of the last ice age, resulted in the peopling of China lso indicated that the peopling of East Asia might have and of northerly regions as far as Siberia.The current uared deviation of the been caused by an entry of modern humans from the genetic difference between northern and southern East observations from their mean south, followed by a northward migration. This was the Asian populations was probably caused by a bottleneck first systematic genetic study on East Asian populations event that occurred during the northward migration and provided the genetic evidence that supports the followed by geographic separation. The original set introduced witha Out-of-Africa origin of modern humans of East Asia. of samples used for screening is highly representative of However, the phylogeny presented in this study has rela- both northern and southern East Asian populations, tively weak statistical support and falls short of providing and excludes possible ASCERTAINMENT BIAS. In addition, the A set of genetic markers present an unequivocal picture of the prehistoric migrations of distribution patterns of the HAPLOTYPES shared by multi modern humans in that region. le populations reveal regional characteristics, thereby NATURE REVIEWS ENETIC VOLUME 1 NOVEMBER 200012 M@ 2000 Macmillan Magazines Ltd

NATURE REVIEWS | GENETICS VOLUME 1 | NOVEMBER 2000 | 127 REVIEWS Several studies using other autosomal and X-chro￾mosomal markers in worldwide populations are also consistent with the Out-of-Africa hypothesis4,6,31–33. However, as only a few East Asian populations were analysed, there is insufficient data to refute the multire￾gional hypothesis convincingly, let alone trace the early migrations of modern humans in East Asia. A recent study of the markers on chromosome 21 provided encouraging evidence by using intact autosomal haplo￾type data to trace migrations34. A 565-base-pair DNA fragment near the MX1 gene (which encodes an inter￾feron-inducible protein) was found to contain nine polymorphic sites in human populations. No recombi￾nation or recurrent mutations (for example, A→G and then back to A) were observed in this genomic region. The results show that Africans have the greatest overall haplotype diversity. The ancestral haplotype (called Ht1) has moderate frequency in African populations, but is rare or absent in other world populations, includ￾ing five East Asian populations. This finding is consis￾tent with the Out-of-Africa hypothesis34. Y-chromosome haplotypes In 1999, another systematic genetic study on East Asian populations was published by Su and colleagues21. A set of 19 highly informative Y-chromosome biallelic mark￾ers, developed at Stanford University, were used to reveal the genetic structure of the paternal lineages in East Asia (BOX 2). Owing to the low level of genetic diver￾sity, the use of Y-chromosome markers in reconstruct￾ing human history35 had been hampered until the intro￾duction of denaturing HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY, an efficient technique for detecting mutations36–38. Many Y-chromosome biallelic markers have been identified in the past few years36,39,40. Su et al.21 studied a large collection of population samples, includ￾ing 21 Chinese ethnic populations, 22 provincial Han Chinese populations, three Northeast-Asian popula￾tions and five Southeast-Asian populations, as well as 12 non-Asian populations from Africa, America, Europe and Oceania. These representative samples and the informative Y-chromosome markers led to the conclu￾sion that Southeast-Asian populations are much more diverse than their northern counterparts, and could mean that mainland Southeast Asia was the first settle￾ment of modern humans in East Asia. On the basis of the VARIANCE of Y-chromosome microsatellites, the initial settlement was estimated to have occurred 18,000–60,000 years ago. It was hypothesized that a northward diaspora, coinciding with the retreating glac￾ier of the last ice age, resulted in the peopling of China and of northerly regions as far as Siberia21. The current genetic difference between northern and southern East Asian populations was probably caused by a bottleneck event that occurred during the northward migration, followed by geographic separation21,41. The original set of samples used for screening is highly representative of both northern and southern East Asian populations, and excludes possible ASCERTAINMENT BIAS. In addition, the distribution patterns of the HAPLOTYPES shared by multi￾ple populations reveal regional characteristics, thereby data from seven Asian populations28 are consistent with the hypothesis of a common southern origin of East Asians, which had originally been proposed on the basis of dental variations29. In 1998, Chu et al.studied the GENETIC ARCHITECTURE of East Asians using up to 28 East Asian populations and 30 autosomal-microsatellite markers7 . By using an approach based on the phylogenetic relationships between populations, they showed that all East Asian populations in their study form a single cluster rooted by African populations. This observation strongly supports a common African origin of East Asian populations. In addition, northern and southern East Asians belong to distinct clusters in the phylogenetic tree, confirming that they are genetically divergent. The phylogenetic analysis also indicated that the peopling of East Asia might have been caused by an entry of modern humans from the south, followed by a northward migration. This was the first systematic genetic study on East Asian populations and provided the genetic evidence that supports the Out-of-Africa origin of modern humans of East Asia30. However, the phylogeny presented in this study has rela￾tively weak statistical support and falls short of providing an unequivocal picture of the prehistoric migrations of modern humans in that region. Box 1 | ‘Out-of-Africa’ versus the multiregional hypothesis Broadly speaking, there are two competing hypotheses on the origin of modern humans: the Out-of-Africa hypothesis and the multiregional hypothesis (reviewed in REFS 9,10). Both agree that Homo erectus originated in Africa and expanded to Eurasia about one million years ago, but they differ in explaining the origin of modern humans (Homo sapiens sapiens). The first hypothesis proposes that a second migration out of Africa happened about 100,000 years ago, in which anatomically modern humans of African origin conquered the world by completely replacing archaic human populations (Homo sapiens) (Model A). The multiregional hypothesis states that independent multiple origins (Model D) or shared multiregional evolution with continuous gene flows between continental populations (Model C) occurred in the million years since Homo erectus came out of Africa (the trellis theory). A compromised version of the Out-of-Africa hypothesis emphasizes the African origin of most human populations but allows for the possibility of minor local contributions (Model B). 1,000,000 years ago 100,000 years ago H. erectus A H. s. sapiens Africa B C D Europe Asia Oceania GENETIC ARCHITECTURE The genetic make-up of a population. HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY A technique for separating DNA or protein molecules by molecular weight and conformation. VARIANCE A measure of the variation around the central class of a distribution (the average squared deviation of the observations from their mean value). ASCERTAINMENT BIAS An error introduced with a biased sampling scheme. HAPLOTYPES A set of genetic markers present on one chromosome. © 2000 Macmillan Magazines Ltd

REVIEWS chromosome Alu polymorphism; MI in FIG. 1)5.Therefore, most East Asian Y chromosomes (H2-H17)can be traced back to an African ancestor. However, as the East Asian individuals that carry H1 (about 10% )are ancestral to all the other haplotypes. and are therefore indistinguishable from those in Africans, these could conceivably be carrying Y-chro M130 M1 mosomal lineages that represent a local origin. Recently, up to 98 new Y-chromosomal simple uence polymorphisms(point mutations and short the flanking non-coding regions of four Y-chromosome ●M122·M119◆M95●M5●M45 genes.0.They reveal an extreme geographic structure, with the oldest clades representing African populations and the younger ones representing some African and all African Y chromosomes seem to be derived from a small number of Africans Thomson et al.39 estimated ●M0●M11 the age of the common ancestor of the y chromosomes to be 59,000 years (95% confidence interval: African ancestors H1 H2 H3 H4 H7 H6 H8 H9 H10 H11 H12 H5 H17 H13 H14 H15 H16 40,000-140,000 years) if based on the assumption of recent population growth, or 84,000 years(95% confi- Figure 1 I The phylogeny of Y-chromosome haplotypes in East Asians(H1-H17) The Y- dence interval: 55,000-149,000 years)if a constant pop- chromosome haplotypes H1-H17 are observed in East Asian populations2. 22.East Asian- ulation size is assumed. The recent common african specific haplotypes(H6-H12)are indicated in red. The genetic loci associated with the ancestry is therefore a strong confirmation of the Out- plotypes are labelled next to the branches, and the polymorphisms at these loci are indicated in brackets. The shaded region represents the work in REFS 21, 22. On the basis of this of-Africa hypothesis In contrast, the clear geographic work, the ancestral haplotype. Hi, is indistinguishable from African haplotypes. Mutations structure was not observed in the mtDNA data owing and 2 are two ancient polymorphisms (point mutations). Mutations 1 and 2 establish that H to frequent recurrence of mutations, which tends to blur the geographic pattern, or possibly because of the larger EFFECTIVEPOPULATION SIZE of mt DNA compared with at of the y chromosome(BOX 2) reducing the bias that might be introduced by sampling Two critical point mutations, defined as mutations 1 errors or from geneticdrift and 2 are believed to be associated with the out-of Of the haplotypes derived from the 19 Y-chromo- Africa migratory event. When the East Asian data are some biallelic markers, 17 are present in more than incorporated into the global tree, all the haplotypes 1,000 East Asian individuals from different ethnic back- found in East Asia(including HI)fall into the younger grounds. No recurrent mutations were observed and the clade unified by mutation 2. This mutation is derived phylogenetic relationships among the haplotypes are from mutation 1(REE. 40), which is only polymorphic in unequivocal owing to the non-recombinant nature ofY Africa"(FIG. 1). Therefore all 1,046 Y chromosomes 122 chromosomes (FIG. 1). Therefore, the geographic distrib- sampled from East Asia are directly derived from the ution(see FIG. 2 for the geographic locations of rican li With these data, the replacement of GENETIC DRIFT tions sampled)of these 17 haplotypes reflects the demo- modern humans of African origin in East Asia is com- hanges in allele frequency that graphic history of the populations under study. HI is plete. This leaves the multiregional hypothesis onlya the ancestral haplotype and H2-H17 are the derived remote possibility (in East Asia, at least), although a appearing in offspring are not a haplotypes. The majority(about 70%)of East AsianY larger sample may be needed to establish this with perfectly representative sample chromosomes(H6-H12)are specific East Asians and stronger confidence example, in small populations). absent in other world populations, indicating a com mon origin of East Asian populations (FIG. 2). Those Genetic and archaeological data ALUSEQUENCE aplotypes specific to East Asians share a C-G muta- The Out-of-Africa hypothesis has been subjected to two tion at locus m9 that is also prevalent in other world main criticisms from the school of multiregionalists opulations, except those in Africa".H5 and H13-H17 The first is the claim that the multiregional hypothesis about 300,000 copies.The also belong to this lineage. H4 was derived from Hl, but has been misinterpreted, by suggesting that it demands sequence is about 300 base pairs is ancestral to the MgG haplotypes(H5-H17)and is that modern populations have strictly independent ori- defined by a C-T mutation at locus M89. This muta- gins. According to the network(trellis)model, frequent (Alud) that cleaves it. tion has a non-trivial contribution (roughly 4% on gene exchanges would have occurred between continen- average)to East Asians, especially to northerners(for tal populations since H erectus came out of Africa abou EFFECTIVE POPULATION SIZE Mongolians the h2 and h3 haplotypes whichare evolution act:图mm)pgw individuals who contribute to predominant in Tibetan and Japanese populations but claimed that the extensive genetic data supporting the the next generation, assuming generally absent in other East Asians, contain an Out-of-Africa hypothesis could also be explained under random mating insertion of a 300-base-pair ALU SEQUENCE, or YAP(Y- this version of the multiregional hypothesis. However, 128 NOVEMBER 2000 VOLUME 1 Nnature. com/reviews/genetics M@ 2000 Macmillan Magazines Ltd

128 | NOVEMBER 2000 | VOLUME 1 www.nature.com/reviews/genetics REVIEWS chromosome Alu polymorphism; M1 in FIG. 1)5 .Therefore, most East Asian Y chromosomes (H2–H17) can be traced back to an African ancestor. However, as the East Asian individuals that carry H1 (about 10%) are ancestral to all the other haplotypes, and are therefore indistinguishable from those in Africans21, these could conceivably be carrying Y-chro￾mosomal lineages that represent a local origin. Recently, up to 98 new Y-chromosomal simple￾sequence polymorphisms (point mutations and short insertions or deletions) were reported in the coding and the flanking non-coding regions of four Y-chromosome genes39,40. They reveal an extreme geographic structure, with the oldest clades representing African populations and the younger ones representing some African and all non-African populations. In other words, the non￾African Y chromosomes seem to be derived from a small number of Africans. Thomson et al.39 estimated the age of the common ancestor of the Y chromosomes to be 59,000 years (95% confidence interval: 40,000–140,000 years) if based on the assumption of recent population growth, or 84,000 years (95% confi￾dence interval: 55,000–149,000 years) if a constant pop￾ulation size is assumed. The recent common African ancestry is therefore a strong confirmation of the Out￾of-Africa hypothesis. In contrast, the clear geographic structure was not observed in the mtDNA data1,3 owing to frequent recurrence of mutations, which tends to blur the geographic pattern, or possibly because of the larger EFFECTIVE POPULATION SIZE of mtDNA compared with that of the Y chromosome (BOX 2). Two critical point mutations, defined as mutations 1 and 2, are believed to be associated with the Out-of￾Africa migratory event. When the East Asian data are incorporated into the global tree, all the haplotypes found in East Asia (including H1) fall into the younger clade unified by mutation 2. This mutation is derived from mutation 1 (REF. 40), which is only polymorphic in Africa40 (FIG. 1). Therefore, all 1,046 Y chromosomes21,22 sampled from East Asia are directly derived from the African lineages. With these data, the replacement of modern humans of African origin in East Asia is com￾plete. This leaves the multiregional hypothesis only a remote possibility (in East Asia, at least), although a larger sample may be needed to establish this with stronger confidence. Genetic and archaeological data The Out-of-Africa hypothesis has been subjected to two main criticisms from the school of multiregionalists. The first is the claim that the multiregional hypothesis has been misinterpreted, by suggesting that it demands that modern populations have strictly independent ori￾gins. According to the network (trellis) model, frequent gene exchanges would have occurred between continen￾tal populations since H. erectus came out of Africa about one million years ago, causing shared multiregional evolution across the human range (BOX 1)42. It was claimed that the extensive genetic data supporting the Out-of-Africa hypothesis could also be explained under this version of the multiregional hypothesis. However, reducing the bias that might be introduced by sampling errors or from GENETIC DRIFT. Of the haplotypes derived from the 19 Y-chromo￾some biallelic markers, 17 are present in more than 1,000 East Asian individuals from different ethnic back￾grounds. No recurrent mutations were observed and the phylogenetic relationships among the haplotypes are unequivocal owing to the non-recombinant nature of Y chromosomes (FIG. 1). Therefore, the geographic distrib￾ution (see FIG. 2 for the geographic locations of popula￾tions sampled) of these 17 haplotypes reflects the demo￾graphic history of the populations under study. H1 is the ancestral haplotype and H2–H17 are the derived haplotypes. The majority (about 70%) of East Asian Y chromosomes (H6–H12) are specific to East Asians and absent in other world populations, indicating a com￾mon origin of East Asian populations (FIG. 2). Those haplotypes specific to East Asians share a C→G muta￾tion at locus M9 that is also prevalent in other world populations, except those in Africa36. H5 and H13–H17 also belong to this lineage. H4 was derived from H1, but is ancestral to the M9G haplotypes (H5–H17) and is defined by a C→T mutation at locus M89. This muta￾tion has a non-trivial contribution (roughly 4% on average) to East Asians, especially to northerners (for example, 20% in Hui, 11% in Manchurians and 8.3% in Mongolians). The H2 and H3 haplotypes, which are predominant in Tibetan and Japanese populations but are generally absent in other East Asians, contain an insertion of a 300-base-pair ALU SEQUENCE, or YAP (Y￾African ancestors H1 1 2 M130 (C→T) M1 (Alu insertion) M89 (C→T) M9 (C→G) M122 M119 M95 M5 M45 M15 M7 M134 M50 M103 M110 M111 M88 M120 M117 M3 H2 H3 H4 H7 H6 H8 H9 H10 H11 H12 H5 H17 H13 H14 H15 H16 Figure 1 | The phylogeny of Y-chromosome haplotypes in East Asians (H1–H17). The Y￾chromosome haplotypes H1–H17 are observed in East Asian populations21,22. East Asian￾specific haplotypes (H6–H12) are indicated in red. The genetic loci associated with the haplotypes are labelled next to the branches, and the polymorphisms at these loci are indicated in brackets. The shaded region represents the work in REFS 21,22. On the basis of this work, the ancestral haplotype, H1, is indistinguishable from African haplotypes. Mutations 1 and 2 are two ancient polymorphisms (point mutations)40. Mutations 1 and 2 establish that H1 is actually derived from African haplotypes. GENETIC DRIFT Changes in allele frequency that result because the genes appearing in offspring are not a perfectly representative sample of the parental genes (for example, in small populations). ALU SEQUENCE A dispersed, intermediately repetitive DNA sequence found in the human genome in about 300,000 copies. The sequence is about 300 base pairs long. The name Alu comes from the restriction endonuclease (AluI) that cleaves it. EFFECTIVE POPULATION SIZE The size of a population determined by the number of individuals who contribute to the next generation, assuming random mating. © 2000 Macmillan Magazines Ltd

REVIEWS OALESCENCE del fails to explain the haplotype data from million year pedigree-like network in Chromosomes. As discussed above, evidence from Y- only reflect the difference in the effective population sampled are united under a e biallelic markers seems to be consister sizes between y chromosome/mtDNA and X chromo- nly under the Out-of-Africa model, as all of the East some/autosome(3-4 times greater in the latter)in bot- Asian haplotypes are regionally specific, are derived tleneck events that were associated with the outbound from a small number of African ancestors and show no migrations from Africa". That is, the coALESCENCE of ancient local contributions. In particular, all the muta autosome and X chromosome DNA sequences may tions found outside Africa are less than 50,000 years old precede the divergence between Africans and non and were derived from Africa. However, if extensive Africans. In other words, the age estimates based on X gene flow had occurred between continental popula- chromosomal and autosomal regions are compatible tions during the past one million years, the ancient Y- with both competing hypotheses; therefore, those chromosome haplotypes seen in African populations, above are not useful statistics to distinguish between or even much older haplotypes, would also be expected the two competing models. in East Asia, which seems not to be the case The second argument raised by multiregionalists The only remaining genetic evidence that seems to comes from archaeological findings in East Asia, espe irreconcilable with the Out-of-Africa hypothesis cially in China. As already mentioned, a continuous comes from several studies on autosomal and X-chro- evolutionary chain has been proposed to connect H. mosomal genes -3.The common ancestor of these erectus to H. sapiensin China, and this was used to sup- genes is estimated to have originated 535,000 to port either an independent origin of modern humans 1,860,000 years ago. This is much older than the age in East Asia or the trellis model 2. However, close estimates for mtdna and y chromosomes and has examination of the collection of hominid fossils in been considered to favour a multiregional origin. a China revealed a non-trivial temporal gap between recent study on a 10-kilobase non-coding region of archaic humans(H sapiens) and modern humans(Hs chromosome 22 gave a similar estimate(about 1. 29 sapiens)(BOX 3). All the H sapiens fossils are at least ①=mc Korean Taiwanese Malaysian -H12 Figure 2 The distribution of the seven East Asian-specific Y-chromosome haplotypes. Northern populations are indicated in red text and southern populations in black text. The Yangtze River divides the northern and southern populations Tibetans are an exception and are classified as northern on the basis of their history. In general, the seven East Asian-specific Y-chromosome haplotypes(H6-H12)represent most East Asian Y chromosomes and support a common African origin(FIG. 1) Mainland Southeast Asia is probably the first settlement of modern humans from Africa, as reflected by the presence of almost NATURE REVIEWS GENETIC VOLUME 1 NOVEMBER 2000129 M@ 2000 Macmillan Magazines Ltd

NATURE REVIEWS | GENETICS VOLUME 1 | NOVEMBER 2000 | 129 REVIEWS million years)43. This difference in age estimates might only reflect the difference in the effective population sizes between Y chromosome/mtDNA and X chromo￾some/autosome (3–4 times greater in the latter) in bot￾tleneck events that were associated with the outbound migrations from Africa44. That is, the COALESCENCE of autosome and X chromosome DNA sequences may precede the divergence between Africans and non￾Africans. In other words, the age estimates based on X￾chromosomal and autosomal regions are compatible with both competing hypotheses; therefore, those above are not useful statistics to distinguish between the two competing models. The second argument raised by multiregionalists comes from archaeological findings in East Asia, espe￾cially in China. As already mentioned, a continuous evolutionary chain has been proposed to connect H. erectus to H. sapiens in China, and this was used to sup￾port either an independent origin of modern humans in East Asia or the trellis model11,12. However, close examination of the collection of hominid fossils in China revealed a non-trivial temporal gap between archaic humans (H. sapiens) and modern humans (H. s. sapiens) (BOX 3). All the H. sapiens fossils are at least the trellis model fails to explain the haplotype data from Y chromosomes. As discussed above, evidence from Y￾chromosome biallelic markers seems to be consistent only under the Out-of-Africa model, as all of the East Asian haplotypes are regionally specific, are derived from a small number of African ancestors and show no ancient local contributions. In particular, all the muta￾tions found outside Africa are less than 50,000 years old and were derived from Africa40. However, if extensive gene flow had occurred between continental popula￾tions during the past one million years, the ancient Y￾chromosome haplotypes seen in African populations, or even much older haplotypes, would also be expected in East Asia, which seems not to be the case. The only remaining genetic evidence that seems to be irreconcilable with the Out-of-Africa hypothesis comes from several studies on autosomal and X-chro￾mosomal genes31–33. The common ancestor of these genes is estimated to have originated 535,000 to 1,860,000 years ago. This is much older than the age estimates for mtDNA and Y chromosomes, and has been considered to favour a multiregional origin. A recent study on a 10-kilobase non-coding region of chromosome 22 gave a similar estimate (about 1.29 Buryat Manchurian Mongolian Korean Japanese Hui Tibetan Tujia Yao Zhuang Dong Lahu Yi She Li Cambodian Dai Tu Sala Northern Han Southern Han Baric Thai Malaysian Taiwanese Indonesian Micronesian Polynesian =H6 =H7 =H8 =H9 =H10 =H11 =H12 =Others Figure 2 | The distribution of the seven East Asian-specific Y-chromosome haplotypes. Northern populations are indicated in red text and southern populations in black text. The Yangtze River divides the northern and southern populations. Tibetans are an exception and are classified as northern on the basis of their history. In general, the seven East Asian-specific Y-chromosome haplotypes (H6–H12) represent most East Asian Y chromosomes and support a common African origin (FIG. 1). Mainland Southeast Asia is probably the first settlement of modern humans from Africa, as reflected by the presence of almost all seven haplotypes in Thai and Cambodian populations. COALESCENCE A pedigree-like network in which all living individuals sampled are united under a most recent common ancestor. © 2000 Macmillan Magazines Ltd

REVIEWS Box 2 Molecular markers used in population studies gests a southern origin and northward migration of East Asians'21. The third model assumes that the ancestors of Genetic variations on Y chromosomes are inherited paternally from father to son. The the northern and southern populations arrived in East effective population size of Y chromosomes is much smaller than that of the autosomes Asia separately From the evidence that has been pre- because of the hemizygous(that is, haploid) nature of the Y chromosome, and mating sented so far, genetic data collected on Y chromosomes structure(for example, polygamy). Because of this, many of the Y-chromosome microsatellite rs support the sec- biallelic markers tend to show restricted regional distribution or, in other words, ond model. According to the distribution of Y-chromo- some haplotypes in East Asian populations, southern Mitochondrial DNA(mtDNA) has been the most frequently studied genetic system,, populations are much more diverse than northern pop- roviding the foundation for genetic tools to delineate human history. One drawback the distribution of polymorphic sites along the mtDNA genome; these are rare i ulations(admittedly, this could be due to a bottleneck of mtDNA is its limited genome size(only 16 kilobases). In addition, there is a bi event that occurred in northern populations). The pro posed admixture between the East Asian and regions. Unfortunately, no systematic study using mtDNA has been done so far on the Australoids(first model) is less likely, as all seven East extant East Asian populations. Asian specific haplotypes are not present in the non- Y chromosomes have all the merits of the extensively studied mt DNA; the absence of Austronesian-speaking populations sampled from New recombination provides unambiguous lineages and a small effective population size Guinea highlanders and from Melanesia Nasioi (pre which tends to generate population-specific markers. Y-chromosome haplotype sumably australoids). In addition, the H17 haplotype, derived from multiple biallelic markers can be considered as alleles from a single locus which is exclusive to non-Austronesians, was not that occurred in an ordered time series, each of which might mark the footprint of a observed in East Asians. z2. Most Y haplotypes found in unique migration event. In addition, with a genome size about 4,000 times that of orthern populations were derived from a subset of the mtDNA(60 megabases, 95%of which is non-recombinant), the Y chromosome uthern populations, which makes the third model contains much more information than mt DNA. Furthermore, the slowly mutating unlikely(although the presence of YAP+ and H4 may biallelic markers and the highly mutable microsatellite markers allow history to be indicate a contribution from a migration originating in dissected on different timescales. There are potential problems in using Y-chromosome Central Asia that arrived in East Asia much later) markers. Selection acting on Y chromosomes will influence estimates of the age of Therefore, the main migratory pattern of modern common ancestors. In addition, the Y chromosome is strongly subject to the effects of humans in mainland East Asia is from south to north. genetic drift and differential male success in producing offspring, which can affect the which is also indicated by mtDNA evidence2 haplotype frequency markedly The East Asian-specific haplotypes show a north ward migration, but the other haplotypes are also story- 100,000 years old, whereas all the H s sapiens fossils are tellers. Our further genetic dissection with a new Y- less than 40,000 years old(with most between 10,000 chromosome marker 7 showed that all the H1 and 30,000 years old). In other words, no hominid fos- haplotypes in East Asians share a C-T mutation at sils that can be dated from 100,000 to 40,000 years ago locus RPS4Y (M130 in FIG. 1). We found that all the ave been found in East Asia. This finding is particularly RPS4YT transitions in East Asia originally entered anomalous given the abundance of either earlier or later East Asia from the south and then expanded to the fossil records that have been found in this area. 12. The northern part of East Asia(LJ and B.S., unpublished long duration of the temporal discontinuity of the fossil observations). The RPS4Y-T transition is also present records in China and the distinctive morphological in North American Indians", suggesting that a group characters of the hominid fossils found before 100,000 of the northward diaspora reached the far north of East years ago and after 40,000 years ago implies that this gap Asia and eventually found their way to the New wo cannot be casually attributed to a'missing link Instead, However, most Y chromosomes found in the America the extinction of local archaic humans and the subse- Indian populations may have come from somewhere quent peopling of modern humans from Africa is other than East Asia. thought to be a more reasonable explanation. To explore the extent of the northward diaspora in Interestingly, this 60,000-year fossil gap coincides with East Asia would require a large study of Y-chromosome the last ice age, during which modern humans of markers in Siberian populations. Interestingly, the den African origin are thought to have arrived in the south- tal evidence showed that the 'Sinodont dentition(a ern regions of East Asia2 series of characteristic dental traits in East Asians. such as shovel-shaped incisors)in northern Asian peoples Ancient migrations of modern humans in Asia occurred about 20,000 years ago, and a similar dentition The validation of the Out-of-Africa hypothesis requires pattern, which is ancestral to the Sinodont pattern, pre an understanding of the migratory routes of modern dominates among all the Southeast Asian populations humans from Africa to East Asia. One interesting obser- Another important feature of Y chromosomes in ation related to the prehistoric population movements East Asia is reflected in the appearance of YAP"and of a is the substantial distinction between northern and further ancient polymorphism(C-Tat locus M89) southern East Asian populations that has been observed The haplotypes associated with these two polymor in the analyses of both genetic markers and of physical phisms are H2/H3(YAP*)and H4(M89T)2. The characteristics23-25, 1. 45,46. Three models have been pro- prevalence of YAP- and M89T in Central and Mid-east posed to interpret this observation. The first model pos- en Asian populations(RS Wells, personal comn ADMIXTURE ulates a north-to-south migratory pattern, which led to cation) implies a genetic influence to the East Asian the ADMIXTURE with Australoids. The second model sug- populations from the northwest, possibly starting in 130 NOVEMBER 2000 VOLUME 1 Nnature. com/reviews/genetics M@ 2000 Macmillan Magazines Ltd

130 | NOVEMBER 2000 | VOLUME 1 www.nature.com/reviews/genetics REVIEWS gests a southern origin and northward migration of East Asians7,21. The third model assumes that the ancestors of the northern and southern populations arrived in East Asia separately. From the evidence that has been pre￾sented so far, genetic data collected on Y chromosomes and autosomal-microsatellite markers support the sec￾ond model. According to the distribution of Y-chromo￾some haplotypes in East Asian populations, southern populations are much more diverse than northern pop￾ulations (admittedly, this could be due to a bottleneck event that occurred in northern populations). The pro￾posed admixture between the East Asian and Australoids (first model) is less likely, as all seven East Asian specific haplotypes are not present in the non￾Austronesian-speaking populations sampled from New Guinea Highlanders and from Melanesia Nasioi (pre￾sumably Australoids). In addition, the H17 haplotype, which is exclusive to non-Austronesians, was not observed in East Asians21,22. Most Y haplotypes found in northern populations were derived from a subset of the southern populations, which makes the third model unlikely (although the presence of YAP+ and H4 may indicate a contribution from a migration originating in Central Asia that arrived in East Asia much later). Therefore, the main migratory pattern of modern humans in mainland East Asia is from south to north, which is also indicated by mtDNA evidence28. The East Asian-specific haplotypes show a north￾ward migration, but the other haplotypes are also story￾tellers. Our further genetic dissection with a new Y￾chromosome marker47 showed that all the H1 haplotypes in East Asians share a C→T mutation at locus RPS4Y (M130 in FIG. 1). We found that all the RPS4Y→T transitions in East Asia originally entered East Asia from the south and then expanded to the northern part of East Asia (L.J. and B.S., unpublished observations). The RPS4Y→T transition is also present in North American Indians47,48, suggesting that a group of the northward diaspora reached the far north of East Asia and eventually found their way to the New World. However, most Y chromosomes found in the American Indian populations may have come from somewhere other than East Asia. To explore the extent of the northward diaspora in East Asia would require a large study of Y-chromosome markers in Siberian populations. Interestingly, the den￾tal evidence showed that the ‘Sinodont dentition’ (a series of characteristic dental traits in East Asians, such as shovel-shaped incisors) in northern Asian peoples occurred about 20,000 years ago, and a similar dentition pattern, which is ancestral to the Sinodont pattern, pre￾dominates among all the Southeast Asian populations29. Another important feature of Y chromosomes in East Asia is reflected in the appearance of YAP+ and of a further ancient polymorphism (C→T at locus M89). The haplotypes associated with these two polymor￾phisms are H2/H3 (YAP+) and H4 (M89T)21. The prevalence of YAP+ and M89T in Central and Mid-east￾ern Asian populations (R. S. Wells, personal communi￾cation) implies a genetic influence to the East Asian populations from the northwest, possibly starting in 100,000 years old, whereas all the H. s. sapiens fossils are less than 40,000 years old (with most between 10,000 and 30,000 years old). In other words, no hominid fos￾sils that can be dated from 100,000 to 40,000 years ago have been found in East Asia. This finding is particularly anomalous given the abundance of either earlier or later fossil records that have been found in this area11,12. The long duration of the temporal discontinuity of the fossil records in China and the distinctive morphological characters of the hominid fossils found before 100,000 years ago and after 40,000 years ago implies that this gap cannot be casually attributed to a ‘missing link’. Instead, the extinction of local archaic humans and the subse￾quent peopling of modern humans from Africa is thought to be a more reasonable explanation21. Interestingly, this 60,000-year fossil gap coincides with the last ice age, during which modern humans of African origin are thought to have arrived in the south￾ern regions of East Asia21. Ancient migrations of modern humans in Asia The validation of the Out-of-Africa hypothesis requires an understanding of the migratory routes of modern humans from Africa to East Asia. One interesting obser￾vation related to the prehistoric population movements is the substantial distinction between northern and southern East Asian populations that has been observed in the analyses of both genetic markers and of physical characteristics23–25,41,45,46. Three models have been pro￾posed to interpret this observation. The first model pos￾tulates a north-to-south migratory pattern, which led to the ADMIXTURE with Australoids41. The second model sug- ADMIXTURE Inter-population gene flow. Box 2 | Molecular markers used in population studies Genetic variations on Y chromosomes are inherited paternally from father to son. The effective population size of Y chromosomes is much smaller than that of the autosomes because of the hemizygous (that is, haploid) nature of the Y chromosome, and mating structure (for example, polygamy). Because of this, many of the Y-chromosome biallelic markers tend to show restricted regional distribution or, in other words, population specificity. Mitochondrial DNA (mtDNA) has been the most frequently studied genetic system, providing the foundation for genetic tools to delineate human history. One drawback of mtDNA is its limited genome size (only 16 kilobases). In addition, there is a bias in the distribution of polymorphic sites along the mtDNA genome; these are rare in coding regions and rich (but with frequent recurrent mutations) in non-coding regions. Unfortunately, no systematic study using mtDNA has been done so far on the extant East Asian populations. Y chromosomes have all the merits of the extensively studied mtDNA; the absence of recombination provides unambiguous lineages and a small effective population size, which tends to generate population-specific markers. Y-chromosome haplotypes derived from multiple biallelic markers can be considered as alleles from a single locus that occurred in an ordered time series, each of which might mark the footprint of a unique migration event. In addition, with a genome size about 4,000 times that of mtDNA (60 megabases, 95% of which is non-recombinant), the Y chromosome contains much more information than mtDNA. Furthermore, the slowly mutating biallelic markers and the highly mutable microsatellite markers allow history to be dissected on different timescales. There are potential problems in using Y-chromosome markers. Selection acting on Y chromosomes will influence estimates of the age of common ancestors. In addition, the Y chromosome is strongly subject to the effects of genetic drift and differential male success in producing offspring, which can affect the haplotype frequency markedly. © 2000 Macmillan Magazines Ltd

REVIEWS Central Asia. The influence of YAP" from Central Asia that of YAP"; it expanded to many populations in the to the East Asian populations is mysterious. In East mainland, with more influence on the northern popula- Asian populations, it was demonstrated that only tions and less on the southern populations, but did not Tibetans(in the west) and the Japanese(in the east) reach island populations such as the Taiwanese and show high frequencies of YAP*, with asporadic occur- Polynesians. Whether YAP"and M89T came to East nce in the other East Asian populations. YAP*is al Asia from Central Asia in the same migratory wave absent from Siberian populations, so forming a huge needs further investigation. geographic gap in its distribution in East Asia After modern humans from Africa settled in Interestingly, besides Tibetans (42.5%)49 and the Southeast Asia, other than the proposed northward Japanese(27.6%), another Chinese ethnic minority expansion to China and Siberia, they also migrated (Yao-Jinxiu), which lives in southern China, shows a southward to explore the new habitats. Y-chromosome high frequency of YAP*(50%)2. This might provide a biallelic markers again were used to trace the origins of although more data is needed to solve the YAP puzzle. was confirmed as the place of the first settlement of The distribution of M89T is easier to understand than modern humans in East Asia, as it holds almost all the Box 3 Fossil records in East Asia gOngwangling, Shaanxi(-1, 150 K)Guojabao, Yunnan(-1,000 K) Yuanmou, Yunnan(600-1, 700 K) Chenjawo, Shaanxi (500-650 K) U Homo sapiens(archaic humans) U Homo sapiens sapiens 400K Zhoukoudian Locality 1, Beijing (230-500 K Dali Shaaxi(209-230)//Jinniushan, Liaoning (160-310K) hangyang, Hubei(174-218 K 200K Hexian, Anhui (150-195 K) Chaoxian, Anhui(160-200 K) Dingcui, Shanxi(160-210 K) Tongzi, Guizhou(113-181 K [ Maba, Guangdong(129-135 K)Zhoukoudian Locality 4, Beijing(122-171 K) I xujiayao, Shanxi(104-125 Hominid fossil gap in China(40-100 K) 40K SAlawusu, Inner Mongolia(33-37 K) shan, Gansu(38-39 K ILongtanshan, Yunnan(-30 K) oukoudian, Upper Cave(29-34 K) SHiyu, Shanxi(27-30 K) 20KLiujiang, Guangxi(10-30 K) IMaomaodong. Guizhou(13-15 K) 10K China is one of the few regions in the world where ancient hominid fossils have been found. The most ancient human Homo erectus at Zhoukoudian in the early 193n .7 million years ago(see figure). Since the sensational finding of ther hominids have been unearthed at more than 60 sites".Archaeologists described a set of morphological traits shared between Homo erectus and Homo sapiens, including shovel-shaped incisors, flat nasal saddle and INCA BONE However, the existence of morphological continuity between Homo sapiens and Homo sapiens sapiens is controversial. NCA BONES The figure shows the hominid fossil records found in China. The age estimates(1 Kbeing 1,000 years)and the at lambda, the corn geographic locations of those fossils are labelled next to the time bars. A non-trivial gap exists between 100,000 and between the two parietal and 40,000 years ago, for which there are no hominid fossils. NATURE REVIEWS GENETIC VOLUME 1 NOVEMBER 2000 131 M@ 2000 Macmillan Magazines Ltd

NATURE REVIEWS | GENETICS VOLUME 1 | NOVEMBER 2000 | 131 REVIEWS that of YAP+; it expanded to many populations in the mainland, with more influence on the northern popula￾tions and less on the southern populations, but did not reach island populations such as the Taiwanese and Polynesians. Whether YAP+ and M89T came to East Asia from Central Asia in the same migratory wave needs further investigation. After modern humans from Africa settled in Southeast Asia, other than the proposed northward expansion to China and Siberia, they also migrated southward to explore the new habitats. Y-chromosome biallelic markers again were used to trace the origins of Polynesians22. In this study, mainland Southeast Asia was confirmed as the place of the first settlement of modern humans in East Asia, as it holds almost all the Central Asia. The influence of YAP+ from Central Asia to the East Asian populations is mysterious. In East Asian populations, it was demonstrated that only Tibetans (in the west) and the Japanese (in the east) show high frequencies of YAP+, with a sporadic occur￾rence in the other East Asian populations5 . YAP+ is also absent from Siberian populations48, so forming a huge geographic gap in its distribution in East Asia. Interestingly, besides Tibetans (42.5%)49 and the Japanese (27.6%), another Chinese ethnic minority (Yao-Jinxiu), which lives in southern China, shows a high frequency of YAP+ (50%)21. This might provide a clue for tracing the dispersion of YAP+ Y chromosomes, although more data is needed to solve the YAP puzzle. The distribution of M89T is easier to understand than INCA BONES Supernumerary bones on the skull at lambda, the corner between the two parietal and the occipital bones. Box 3 | Fossil records in East Asia China is one of the few regions in the world where ancient hominid fossils have been found. The most ancient human fossils in China can be traced back to as early as 1.7 million years ago (see figure). Since the sensational finding of Homo erectus at Zhoukoudian in the early 1930s, originally called the Peking Man (Homo erectus pekinensis), many other hominids have been unearthed at more than 60 sites13. Archaeologists described a set of morphological traits shared between Homo erectus and Homo sapiens, including shovel-shaped incisors, flat nasal saddle and INCA BONES13. However, the existence of morphological continuity between Homo sapiens and Homo sapiens sapiens is controversial. The figure shows the hominid fossil records found in China. The age estimates (1 K being 1,000 years) and the geographic locations of those fossils are labelled next to the time bars. A non-trivial gap exists between 100,000 and 40,000 years ago, for which there are no hominid fossils. 10 K Maomaodong, Guizhou (13–15 K) Liujiang, Guangxi (10–30 K) Gongwangling, Shaanxi (~1,150 K) Guojiabao, Yunnan (~1,000 K) Yuanmou, Yunnan (600–1,700 K) Chenjiawo, Shaanxi (500–650 K) Changyang, Hubei (174–218 K) Dingcui, Shanxi (160–210 K) Zhoukoudian Locality 4, Beijing (122–171 K) Jinniushan, Liaoning (160–310 K) Chaoxian, Anhui (160–200 K) Maba, Guangdong (129–135 K) Zhoukoudian Locality 1, Beijing (230–500 K) Dali, Shaaxi (209–230 K) Hexian, Anhui (150–195 K) Tongzi, Guizhou (113–181 K) Xujiayao, Shanxi (104–125 K) Zhoukoudian, Upper Cave (29–34 K) Wushan, Gansu (38–39 K) Ziyang, Sichuan (35–40 K) Longtanshan, Yunnan (~30 K) Yanjiagang, Heilongjiang (~22 K) Salawusu, Inner Mongolia (33–37 K) Shiyu, Shanxi (27–30 K) 20 K 30 K 40 K Hominid fossil gap in China (40–100 K) 100 K 200 K 300 K 400 K 500 K 600 K Homo erectus Homo sapiens (archaic humans) Homo sapiens sapiens (modern humans) © 2000 Macmillan Magazines Ltd

REVIEWS for two independent migrations, one towards Taiwa and the other towards Polynesia. The latter would have occurred through island Southeast Asia, which was by far the fastest and widest expansion of humans during rehistoric times. The Austronesian languages of the Pacific spread across 10,000 kilometres of coastline and sea within a span of only 1, 500 years Interestingly, a repeated analysis of the published mtdna data by richards et al. is more in line with the hypothesis based on the Y-chromosome data8 The genetic relationship between East Asians (including Austronesian-speaking Pacific Islanders)and Australoids still remains a question. However, data from both y chromosomes and autosomes have indicated eparate migrations from Africa, one to East and the other to oceania 4.36, 0 Conclusions Figure 3 The putative migratory routes of East Asians On the basis of the genetic evidence generated so far of African origin. Migrations that have occurred in the past particularly from Y-chromosome data, modern humans 60,000 years are indicated by the red arrows. The first entry in East Asia have a recent common origin in Africa. It is of modern humans into the southern part of East Asia suggested that the first entry of modern humans into occurred about 18,.000-60,000 years ago, followed by a the southern part of East Asia occurred about northward migration. A southern route also started from 18,000-60,000 years ago, and was followed by a north mainland Southeast Asia, through Malaysia and Indonesia. eventually continuing eastwards to the Pacific lslands. The ward migration that coincided with the receding glaci- blue arrows indicate a contribution from Central Asia that ers in that area. a southern route also started from arrived in East Asia at a later time mainland Southeast Asia, through Malaysia and Indonesia, eventually continuing eastwards to the 6》 Animated online Pacific Islands(FIG 3). It should be noted that the con- clusions made on the East Asian-specific haplotypes. The dominating Y- humans in East Asia are definitely not the end of the A hypothesis that claims a rapid chromosome haplotypes found in the Pacific story. Many questions are unresolved. Future studies slanders, including Polynesians and Micronesians, will be directed towards: revealing any genetic contribu- constitute a small subset of haplotypes found in tion from local populations by studying a larger sample and the associated outheast Asian populations. More interestingly, the of East Asians; delineating the local migratory routes in aplotypes found in Taiwanese aborigines are general- East Asia that led to the diversified languages spoken in Pacific islands about 4,000 to ly absent in Polynesia, whereas a specific type found in this area( six language families and almost 2,000 indi 5,000 years ago. Melanesian populations(H17) is also missing in the vidual languages, see LINKs); evaluating the genetic influ- Polynesian populations. These findings are contrary to ce of Central Asia on East Asian populations, such as the two prevailing hypotheses of Polynesian origins. YAP*and M89T: and reconstructing migratory routes First, it negates the Taiwan-homeland theory of from East Asia to the New World implicated by the Polynesian origin that is based on mtDNA studies -3. CT transitions at the RPS4Y locus. Finally, we should The Y-chromosome data, however, do not entirely assess the relationship between East Asians and refute the EXPRESS TRAIN MODEL, which contends the Australoids. Resolving these questions will lead to a spread of Austronesian language and Lapita culture more complete understanding of the evolutionary his- rom Southeast Asia5. Second, the Y-chromosome tory of our own species. data challenge the Melanesian origin of the Pacific Islanders that is supported by a-globin data.57. Links Interestingly, all of the Y haplotypes found in Taiwan DATABASE LINKS MXI and in Polynesia were detected in the mainland FURTHER INFORMATION The Ethnologue: Languages of Southeast Asian populations. These findings have led the World to an alternative model for the origins of Polynesians, ENCYCLOPEDIA OF LIFE SCIENCEs Human evolution: in which Southeast Asia provided the genetic source Overview 1. Cann, R L, Stoneking. M.& wilson, ochondrial 03-150701991) igrs. Science271.1380-138701996) 2. Stringer, C B. Andrews, P c-e 32 cock, A M. ef a. High resolution of hur evidence lutionary trees with polymorphic microsatellites. China. Proc. Naf Acad. Sci. USA 95.11763-11768 origin of modern humans. Science 239. 263-126801988 try for human Y ntana-Murci, L. et al. Genetic evidence of an early populations and the disequilibrium at the CD4 locus and modern human 32 NOVEMBER 2000 VOLUME 1 Nnature. com/reviews/genetics M@ 2000 Macmillan Magazines Ltd

132 | NOVEMBER 2000 | VOLUME 1 www.nature.com/reviews/genetics REVIEWS for two independent migrations, one towards Taiwan and the other towards Polynesia. The latter would have occurred through island Southeast Asia, which was by far the fastest and widest expansion of humans during prehistoric times. The Austronesian languages of the Pacific spread across 10,000 kilometres of coastline and sea within a span of only 1,500 years51. Interestingly, a repeated analysis of the published mtDNA data by Richards et al. is more in line with the hypothesis based on the Y-chromosome data58. The genetic relationship between East Asians (including Austronesian-speaking Pacific Islanders) and Australoids still remains a question. However, data from both Y chromosomes and autosomes have indicated two separate migrations from Africa, one to East Asia and the other to Oceania34,36,40. Conclusions On the basis of the genetic evidence generated so far, particularly from Y-chromosome data, modern humans in East Asia have a recent common origin in Africa. It is suggested that the first entry of modern humans into the southern part of East Asia occurred about 18,000–60,000 years ago, and was followed by a north￾ward migration that coincided with the receding glaci￾ers in that area. A southern route also started from mainland Southeast Asia, through Malaysia and Indonesia, eventually continuing eastwards to the Pacific Islands (FIG. 3). It should be noted that the con￾clusions made on the origin and migrations of modern humans in East Asia are definitely not the end of the story. Many questions are unresolved. Future studies will be directed towards: revealing any genetic contribu￾tion from local populations by studying a larger sample of East Asians; delineating the local migratory routes in East Asia that led to the diversified languages spoken in this area (six language families and almost 2,000 indi￾vidual languages, see LINKS); evaluating the genetic influ￾ence of Central Asia on East Asian populations, such as YAP+ and M89T; and reconstructing migratory routes from East Asia to the New World implicated by the C→T transitions at the RPS4Y locus. Finally, we should assess the relationship between East Asians and Australoids. Resolving these questions will lead to a more complete understanding of the evolutionary his￾tory of our own species. East Asian-specific haplotypes. The dominating Y￾chromosome haplotypes found in the Pacific Islanders, including Polynesians and Micronesians, constitute a small subset of haplotypes found in Southeast Asian populations. More interestingly, the haplotypes found in Taiwanese aborigines are general￾ly absent in Polynesia, whereas a specific type found in Melanesian populations (H17) is also missing in the Polynesian populations. These findings are contrary to the two prevailing hypotheses of Polynesian origins. First, it negates the Taiwan-homeland theory of Polynesian origin that is based on mtDNA studies50–53. The Y-chromosome data, however, do not entirely refute the EXPRESS TRAIN MODEL, which contends the spread of Austronesian language and Lapita culture from Southeast Asia54,55. Second, the Y-chromosome data challenge the Melanesian origin of the Pacific Islanders that is supported by α-globin data56,57. Interestingly, all of the Y haplotypes found in Taiwan and in Polynesia were detected in the mainland Southeast Asian populations. These findings have led to an alternative model for the origins of Polynesians, in which Southeast Asia provided the genetic source Figure 3 | The putative migratory routes of East Asians of African origin. Migrations that have occurred in the past 60,000 years are indicated by the red arrows. The first entry of modern humans into the southern part of East Asia occurred about 18,000–60,000 years ago, followed by a northward migration. A southern route also started from mainland Southeast Asia, through Malaysia and Indonesia, eventually continuing eastwards to the Pacific Islands. The blue arrows indicate a contribution from Central Asia that arrived in East Asia at a later time. Animated online EXPRESS TRAIN MODEL A hypothesis that claims a rapid eastward migration of humans starting in Southern China, spreading Austronesian language and the associated Lapita culture through the Pacific islands about 4,000 to 5,000 years ago. Links DATABASE LINKS MX1 FURTHER INFORMATION The Ethnologue: Languages of the World ENCYCLOPEDIA OF LIFE SCIENCES Human evolution: Overview 1. Cann, R. L., Stoneking, M. & Wilson, A. C. Mitochondrial DNA and human evolution. Nature 325, 31–36 (1987). 2. Stringer, C. B. & Andrews, P. Genetic and fossil evidence for the origin of modern humans. Science 239, 1263–1268 (1988). 3. Vigilant, L., Stoneking, M., Harpenden, H., Hawkes, K. & Wilson, A. C. African populations and the evolution of human mitochondrial DNA. Science 253, 1503–1507 (1991). 4. Bowcock, A. M. et al. High resolution of human evolutionary trees with polymorphic microsatellites. Nature 368, 455–457 (1994). 5. Hammer, M. F. A recent common ancestry for human Y chromosomes. Nature 378, 376–378 (1995). 6. Tishkoff, S. A. et al. Global patterns of linkage disequilibrium at the CD4 locus and modern human origins. Science 271, 1380–1387 (1996). 7. Chu, J. Y. et al. Genetic relationship of populations in China. Proc. Natl Acad. Sci. USA 95,11763–11768 (1998). 8. Quintana-Murci, L. et al. Genetic evidence of an early exit of Homo sapiens sapiens from Africa through eastern Africa. Nature Genet. 23, 437–441 (1999). 9. Wilson, A. C. & Cann, R. L. The recent African genesis of © 2000 Macmillan Magazines Ltd

REVIEWS on the 'Out-of- hinese. Scientia Sinica. 31, 860-Bymorphism in 43. Wolpoff, M. H, Hawks, J& Caspari, R. ultiple origins. Am. J. Phys. Anthropol. 112, nong five Asian populations. Am J. Hum. Genet. 43, 44. Zhao, Z. on on human chromosome 22 45. Fay. J.C.& Wu, C L A human popuation bottleneck lear DNA variation. Mo. Bi e story. 30. of modern Chinese. Acta Anthropo. Sin. 7 2. Li, T& Etler, D. A New middle Pleistocene hominid 31. Harding, R. 47 ania from yunxian in China. Nature 357 404-407 fifty-two Chinese populations. Acta Anthropol Sin. 7. 789(1997 13 won Haeseler, A. Paabo, S. 48. Berge DNA sequence variation in a non-coding region of lo eage identied by RPS4Y resequencing 4. Euler In combination on the human x chromosome. Nature icrosatellite haplotyping. Ann. Hum. Genet. 63, 63-80 75-301(1996 15. Templet 33. is, E.E.& Hey. J. X chromosome evidence for 9. Karafet, T ef af Y chromosome markers and Trans- chondrial DNA sequences. Science ncient human histories. Proc. Nat/ Acad. Sci USA 96 Bering Strait dispersals. Am. J. Phys. Anthropol. 102 6. Relethford, J H ef al. Ancient differences in population 34. Jin, Lef tion of haplotypes from a 21 region distinguishes multiple prehistoric chromosomes. Hum. Genet. 106, 453-454(2000) umans Cur. Anthropol. 36, 667-674(199 nan migrations. Proc Natl Acad. SCi. USA 96. 51. Melton, T. et al. Polynesian genetic affinities 17. Cavalli-Sforza, L. L. et al. The History and Geography of by mtDNA uman Genes(Princeton Univ Press, Princeton, New 35. Jobling, M. A& Tyler-Smith, C Fathers and sons: the Y analysis. Am J. Hum. Genet. 57. 403-414 omosome and human evolution Trends Genet. 11 rovides a compreh 52. Melton, T. Clifford, s. Martinson, J. Batzer. M.& iew article on f ome markers in the study of human tribes. Am. ges 272.1363-1364 19 liquid chromatography. Genome Res enome. Curr Opin. Gene om the paciic. io. EvoL 12 37. Oefner, P J& Underhill, P Comparative DN concise summary of mtDNA studies on modern 54. A. Low-Beer... Tetzner s.& atography (DHPLC). Am J. Hum. Genet. O. Templeton, A.R. Out of Africa? What do genes tel us? from mitochondrial lineage analysis. Am J. m. Genet.57.1463-1475(1995 21. Su, B. et using denaturing high performance 55. Diamond, J M. Express train to Polynesia. Nature 336, hy(DHPLC). CuT. Protocols Hum. Genet. st ice age. Am J. Hum. Genet. 65, 1718-1724(19991 710.1-7.10.120199 P. The Austronesia al and the origin hromosome. Proc. Natl Acad. Sci. USA 97, 8225-8228 as an entangled T et al The distribution of i Gm roc Nat Acad. Sci USA 97. 7360-734 prehistory in the South Pacific. types in forty Chinese populations. Acta Anthropo. M. ef a. An ancient com m populations: a hypothesis of the origin of the Chinese 41. Du, R et a s supported by a-globin haplotype analysis. cience in China (Series C)40, 613-621(1997) nan populations in China. Acta Anthropol Sin. 8. nch. E. cavall evidence for a higher female migration rate in humans. Hum. Genet.63.1234-12361998 NATURE REVIEWS GENETIC VOLUME 1 NOVEMBER 2000 133 M@ 2000 Macmillan Magazines Ltd

NATURE REVIEWS | GENETICS VOLUME 1 | NOVEMBER 2000 | 133 REVIEWS humans. Sci. Am. 266, 68–73 (1992). This was the first extensive review on the ‘Out-of￾Africa’ hypothesis based on mtDNA evidence, published at a time when there was an extremely hot debate between two schools of hypotheses on modern human origin. 10. Thorne, A. G. & Wolpoff, M. H. The multiregional evolution of humans. Sci. Am. 266, 76–83 (1992). A companion review written by archaeologists who support the multiregional hypothesis, with a systematic description of morphological studies of human fossil records. 11. Brooks, A. S. & Wood, B. The Chinese side of the story. Nature 344, 288–289 (1990). 12. Li, T. & Etler, D. A. New middle Pleistocene hominid crania from Yunxian in China. Nature 357, 404–407 (1992). 13. Wu, X. Z. et al. Human evolution in China (Oxford Univ. Press, Oxford, 1995). 14. Etler, D. A. The fossil evidence for human evolution in Asia. Annu. Rev. Anthropol. 25, 275–301 (1996). 15. Templeton, A. R. Human origins and analysis of mitochondrial DNA sequences. Science 255, 7–37 (1992). 16. Relethford, J. H. et al. Ancient differences in population size can mimic a recent African origin of modern humans. Curr. Anthropol. 36, 667–674 (1995). 17. Cavalli–Sforza, L. L. et al. The History and Geography of Human Genes (Princeton Univ. Press, Princeton, New Jersey, 1994). This book provides a comprehensive summary of genetic data with in-depth description of linguistic and historical background of continental populations. 18. Ayala, F. J. Gene lineages and human evolution. Science 272, 1363–1364 (1996). 19. Stoneking, M. & Soodyal, H. Human evolution and the mitochondrial genome. Curr. Opin. Genet. Dev. 6, 731–736 (1996). A concise summary of mtDNA studies on modern human evolution. 20. Templeton, A. R. Out of Africa? What do genes tell us? Curr. Opin. Genet. Dev. 7, 841–847 (1997). 21. Su, B. et al. Y-chromosome evidence for a northward migration of modern human into East Asia during the last ice age. Am. J. Hum. Genet. 65, 1718–1724 (1999). 22. Su, B. et al. Polynesian origins: insights from the Y chromosome. Proc. Natl Acad. Sci. USA 97, 8225–8228 (2000). 23. Zhao, T. et al. The distribution of immunoglobulin Gm allotypes in forty Chinese populations. Acta Anthropol. Sin. 6, 1–8 (1986). 24. Zhao, T. M. Gm and Km allotypes in 74 Chinese populations: a hypothesis of the origin of the Chinese nation. Hum. Genet. 83, 101–110 (1989). 25. Weng, Z. et al. Analysis of the genetic structure of human populations in China. Acta Anthropol. Sin. 8, 261–268 (1989). 26. Yu, M. et al. Mitochondrial DNA polymorphism in Chinese. Scientia Sinica. 31, 860–872 (1988). 27. Harihara, S. et al. Mitochondrial DNA polymorphism among five Asian populations. Am. J. Hum. Genet. 43, 134–143 (1988). 28. Ballinger, S. W. et al. Southeast Asian mitochondrial DNA analysis reveals genetic continuity of ancient Mongoloid migrations. Genetics 130, 139–152 (1992). 29. Turner, C. G. Late pleistocene and holocene population history of East Asia based on dental variations. Am. J. Phys. Anthropol. 73, 305–321 (1987). 30. Piazza, A. Towards a genetic history of China. Nature 395, 636–639 (1998). 31. Harding, R. M. et al. Archaic African and Asian lineages in the genetic ancestry of modern humans. Am. J. Hum. Genet. 60, 772–789 (1997). 32. Kaessmann, H., Heissig F., von Haeseler, A. & Paabo, S. DNA sequence variation in a non-coding region of low recombination on the human X chromosome. Nature Genet. 22, 78–81 (1999). 33. Harris, E. E. & Hey, J. X chromosome evidence for ancient human histories. Proc. Natl Acad. Sci. USA 96, 3320–3324 (1999). 34. Jin, L. et al. Distribution of haplotypes from a chromosome 21 region distinguishes multiple prehistoric human migrations. Proc. Natl Acad. Sci. USA 96, 3796–3800 (1999). 35. Jobling, M. A. & Tyler-Smith, C. Fathers and sons: the Y chromosome and human evolution. Trends Genet. 11, 449–455 (1995). An elegant review article on the utility of Y￾chromosome markers in the study of human evolution. 36. Underhill, P. A. et al. Detection of numerous Y chromosome biallelic polymorphisms by denaturing high-performance liquid chromatography. Genome Res. 7, 996–1005 (1997). 37. Oefner, P. J. & Underhill, P. Comparative DNA sequencing by denaturing high–performance liquid chromatography (DHPLC). Am. J. Hum. Genet. 57, A266 (1995). 38. Oefner, P. J. & Underhill, P. DNA mutation detection using denaturing high performance liquid chromatography (DHPLC). Curr. Protocols Hum. Genet. 19, 7.10.1–7.10.12 (1998). 39. Thomson, R., Pritchard J. K., Shen, P., Oefner, P. J. & Feldman, M. W. Recent common ancestry of human Y chromosomes: evidence from DNA sequence data. Proc. Natl Acad. Sci. USA 97, 7360–7365 (2000). 40. Shen, P. et al. Population genetic implications from sequence variation in four Y chromosome genes. Proc. Natl Acad. Sci. USA 97, 7354–7359 (2000). 41. Du, R. et al. Genetic distances between Chinese populations calculated on gene frequencies of 38 loci. Science in China (Series C) 40, 613–621 (1997). 42. Seielstad, M. T., Minch, E. & Cavalli-Sforza, L. L. Genetic evidence for a higher female migration rate in humans. Nature Genet. 20, 1–3 (1998). 43. Wolpoff, M. H., Hawks, J. & Caspari, R. Multiregional, not multiple origins. Am. J. Phys. Anthropol. 112, 129–136 (2000). 44. Zhao, Z. et al. Worldwide DNA sequence variation in a 10kb noncoding region on human chromosome 22. Proc. Natl Acad. Sci. USA (in the press). 45. Fay, J. C. & Wu, C. I. A human population bottleneck can account for the discordance between patterns of mitochondrial versus nuclear DNA variation. Mol. Biol. Evol. 16, 1003–1005 (1999). 46. Zhang, Z. B. An analysis of the physical characteristics of modern Chinese. Acta Anthropol. Sin. 7, 314–323 (1988). 47. Zhang, H. Distribution of dermatoglyphic parameters in fifty-two Chinese populations. Acta Anthropol. Sin. 7, 39–45 (1988). 48. Bergen, A. W. et al. An Asian-Native American paternal lineage identified by RPS4Y resequencing and microsatellite haplotyping. Ann. Hum. Genet. 63, 63–80 (1999). 49. Karafet, T. et al. Y chromosome markers and Trans￾Bering Strait dispersals. Am. J. Phys. Anthropol. 102, 301–314 (1997). 50. Qian, Y. P. et al. Multiple origins of Tibetan Y chromosomes. Hum. Genet. 106, 453–454 (2000). 51. Melton, T. et al. Polynesian genetic affinities with Southeast Asian populations as identified by mtDNA analysis. Am. J. Hum. Genet. 57, 403–414 (1995). 52. Melton, T., Clifford, S., Martinson, J., Batzer, M. & Stoneking, M. Genetic evidence for the proto￾Austronesian homeland in Asia: mtDNA and nuclear DNA variation in Taiwanese aboriginal tribes. Am. J. Hum. Genet. 63, 1807–1823 (1998). 53. Redd, A. J. et al. Evolutionary history of the COII/tRNALys intergenic 9 base pair deletion in human mitochondrial DNAs from the Pacific. Mol. Bio. Evol. 12, 604–615 (1995). 54. Sykes, B. Leiboff, A., Low-Beer, J., Tetzner, S. & Richards, M. The origins of the Polynesians: an interpretation from mitochondrial lineage analysis. Am. J. Hum. Genet. 57, 1463–1475 (1995). 55. Diamond, J. M. Express train to Polynesia. Nature 336, 307–308 (1988). 56. Bellwood, P. The Austronesian dispersal and the origin of language. Sci. Am. 266, 88–93 (1991). 57 Terrell, J. History as a family tree, history as an entangled bank: constructing images and interpretations of prehistory in the South Pacific. Antiquity 62, 642–657 (1988). 58 Roberts-Thomson, J. M. et al. An ancient common origin of aboriginal Australians and New Guinea highlanders is supported by α-globin haplotype analysis. Am. J. Hum. Genet. 58, 1017–1024 (1996). 59 Richards, M., Oppenheimer, S. & Sykes, B. mtDNA suggests Polynesian origins in Eastern Indonesia. Am. J. Hum. Genet. 63, 1234–1236 (1998). © 2000 Macmillan Magazines Ltd

Copyright o 2003 EBSCO Publishing