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 LtdNATURE 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