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 Ltd130 | 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