African Origin of Polyomavirus JC and Implications for Prehistoric Human Migrations

Abstract The presence of distinctive types of JC virus (JCV) in the main ethnic groups suggests a close coevolution with the human host. However, phylogenetic trees of JCV show a basal clade of European lineages (Types 1/4), whereas trees of human genes are coherent in placing the first split between African and non-African populations. This discrepancy places into question the effectiveness of JCV as a marker of human population history. The present study investigates the evolution of JCV using a large set of fully sequenced strains. Their relationships are first elucidated by principal coordinates analysis. It is suggested that Type 6 from West Africa could represent the ancestral type, while the peculiar phylogeny of Types 1/4 could reflect their direct origin from the ancestral lineage. Further credit to the African origin of JCV is provided by a neighbor-joining analysis based on slow-evolving sites. Sequence analysis of fast-evolving sites reveals that the deep emergence of Types 1/4 in the tree does not reflect a real evolutionary divergence; rather it is the implicit result of a remarkably different G + C content. The hypothesis that Types 1/4 originated directly from Type 6 is confirmed by examining the pattern of variation at a few specific fast-evolving sites. On the basis of this approach, a twofold exit of JCV from Africa is hypothesized: one in the direction of the Eurasian continent and another limited to Europe. These findings suggest that two distinct migrations of individuals played a key role in the peopling of Europe during prehistoric times.     

Evolution of Human Polyomavirus JC: Implications for the Population History of Humans

The polyomavirus JC virus (JCV), the etiological agent of progressive multifocal leukoencephalopathy, is ubiquitous in the human population, infecting children asymptomatically, then persisting in the kidney. The main mode of transmission of JCV is from parents to children through long-term cohabitation. Twelve JCV subtypes that occupy unique domains in Europe, Africa, and Asia have been identified. Here, we attempted to elucidate the evolutionary relationships among JCV strains worldwide using the whole-genome approach with which a highly reliable phylogeny of JCV strains can be reconstructed. Sixty-five complete JCV DNA sequences, derived from various geographical regions and belonging to 11 of the 12 known subtypes, were subjected to phylogenetic analysis using three independent methods: the neighbor-joining, maximum parsimony, and maximum likelihood methods. The trees obtained with these methods consistently indicated that ancestral JCVs were divided into three superclusters, designated as Types A, B, and C. A split in Type A generated two subtypes, EU-a and -b, mainly containing European and Mediterranean strains. The first split in Type B generated Af2 (the major African subtype). Subsequent splits in Type B generated B1-c (a minor European subtype) and all seven Asian subtypes (B1-a, -b, -d, B2, MY, CY, and SC). Type C generated a single subtype (Af1), consisting of strains derived from western Africa. While the present findings provided a basis on which to classify JCV into types or subtypes, they have several implications for the divergence and migration of human populations. Received: 4 April 2001 / Accepted: 31 July 2001     

Polyomavirus JC genotypes in an urban United States population reflect the history of African origin and genetic admixture in modern African Americans

The human polyomavirus JC (JC virus), a small, circular, double-stranded DNA virus, has a worldwide distribution and is excreted harmlessly in urine by 20% to 70% of adults. DNA sequence analysis has identified seven distinct genotypes that likely coevolved with modern humans, although the mode of virus transmission is unknown. Type 1 is European in its distribution. Types 2 and 7 are Asian, while Types 3 and 6 are African. Type 4, closely related to Type 1, is of uncertain origin, having been found in population groups in parts of Europe and in the United States, but not in Africa. Here we have studied the JCV partial genomic DNA sequences amplified by polymerase chain reaction techniques from urines of an urban, mainly African American population cohort from Washington, D.C. The predominant genotype identified was Type 4 (32/78 JCV strains, 41%). Type 1 strain was found in 32% of African Americans, while JCV Type 3 strain was found in 18% of African Americans. These African strains have persisted in modern African Americans after 200 to 400 years of minority existence and genetic admixture in the New World. An ancient West African genotype, Type 6, was absent in this African American cohort. However, one Type 6 strain was found in a patient from Sierra Leone (West Africa), domiciled in the United States for 20 years. Type 2A, the most common subtype in Native Americans, was seen in only two African-Americans (3%). A Type 7 strain, previously reported only in Taiwan and South China, was identified in a Vietnamese immigrant. These data support the history of African origin, migration, and genetic admixture of modern African Americans. Analysis of JCV strains in the present American populations provides a novel tool for reconstructing human migrations and genetic admixture in the New World.     

Reconstructing population history using JC virus: Amerinds, Spanish, and Africans in the ancestry of modern Puerto Ricans.

The roots of the Hispanic populations of the Caribbean Islands and Central and South America go back to three continents of the Old World. In Puerto Rico major genetic contributions have come from (1) Asians in the form of the aboriginal Taino population, an Arawak tribe, present when Columbus arrived on the Island, (2) Europeans, largely Spanish explorers, settlers, government administrators, and soldiers, and (3) Africans who came as part of the slave trade. Since JC virus (JCV) genotypes characteristic of Asia, Europe, and Africa have been identified, and excretion of JCV in urine has been proposed as a marker for human migrations, we sought to characterize the JCV strains present in a Caribbean Hispanic population. We found that the strains of JCV present today in Puerto Rico are those derived from the Old World populations represented there: Types 1B and 4 from Spain, Types 3A, 3B, and 6 from Africa, and Type 2A from Asia. The Type 2A genotype represents the indigenous Taino people. This JCV genotype was represented much more frequently (61%) than would be predicted by the trihybrid model of genetic admixture. This might be attributable to characteristics of JCV Type 2A itself, as well as to the nature of the early relationships between Spanish men and native women. These findings indicate that the JCV strains carried by the Taino Indians can be found in today's Puerto Rican population despite the apparent demise of these people more than two centuries ago. Therefore, molecular characterization of JCV provides a tool to supplement genetic techniques for reconstructing population histories including admixed populations.     

JC virus genotypes in the western Pacific suggest Asian mainland relationships and virus association with early population movements

Distinct genotypes of human polyomavirus JC (JCV) have remained population associated possibly from the time of dispersal of modern humans from Africa. Seven major genotypes with additional subtypes serve as plausible markers for following early and more recent human migrations in all parts of the world. Phylogenetic trees of JCV sequences from the major continental population groups show a trifurcation at the base indicating early division into European, African, and Asian branches. Here, we have explored JCV relationships in the island populations of the western Pacific. Since these islands were settled from the Asian mainland and islands of Southeast Asia, we expected that their virus genotypes might show an Asian connection. We found that Type 2E (Austronesian) and Type 8 (non-Austronesian) are widely distributed in western Pacific populations. A few south China strains were found (Type 7A). A subtype of Type 8, Type 8A, was confined to Papua New Guinea. In keeping with these assignments we find that phylogenetic analysis by neighbor-joining and maximum parsimony methods places Type 2E in a closer relationship to east Asian mainland strains such as Type 2A and Type 7. Our findings support the Asian origins of the western Pacific JCV strains, and suggest three broad movements: an ancient one characterized by Type 8A, and then Type 8B, followed much later by migrations carrying Type 2E, which may correlate with the arrival of Austronesian-language speakers, the bearers of the "Lapita" cultural complex (approximately 3,500 to 5,000 years ago), and relatively recent movements carrying largely Type 7A (south China) strains directly from the West.     

JC virus evolution and its association with human populations

The ubiquitous human polyomavirus JC (JCV) is a small double-stranded DNA virus that establishes a persistent infection, and it is often transmitted from parents to children. There are at least 14 subtypes of the virus associated with different human populations. Because of its presumed codivergence with humans, JCV has been used as a genetic marker for human evolution and migration. Codivergence has also been used as a basis for estimating the rate of nucleotide substitution in JCV. We tested the hypothesis of host-virus codivergence by (i) performing a reconciliation analysis of phylogenetic trees of human and JCV populations and (ii) providing the first estimate of the evolutionary rate of JCV that is independent from the assumption of codivergence. Strikingly, our comparisons of JCV and human phylogenies provided no evidence for codivergence, suggesting that this virus should not be used as a marker for human population history. Further, while the estimated nucleotide substitution rate of JCV has large confidence intervals due to limited sampling, our analysis suggests that this virus may evolve nearly two orders of magnitude faster than predicted under the codivergence hypothesis.     

GM haplotype diversity of 82 populations over the world suggests a centrifugal model of human migrations

This study investigates the GM genetic relationships of 82 human populations, among which 10 represent original data, within and among the main broad geographic areas of the world. Different approaches are used: multidimensional scaling analysis and test for isolation by distance, to assess the correlation between genetic variation and spatial distributions; analysis of variance, to investigate the genetic structure at different hierarchical levels of population subdivision; genetic similarity map (geographic map distorted by available genetic information), to identify regions of high and low genetic variation; and minimal spanning network, to point out possible migration routes across continental areas. The results show that the GM polymorphism is characterized by one of the highest amounts of genetic variation observed so far among populations of different continents (Fct=0.3915, P < 0.0001). GM diversity can be explained by a model of isolation by distance (IBD) at most continental levels, with a particularly significant fit to IBD for the Middle East and Europe. Five peripheral regions of the world (Europe, west and south sub-Saharan Africa, Southeast Asia, and America) exhibit a low level of genetic diversity both within and among populations. By contrast, East and North African, Southwest Asian, and Northeast Asian populations are highly diverse and interconnected genetically by large genetic distances. Therefore, the observed GM variation can be explained by a "centrifugal model" of modern humans peopling history, involving ancient dispersals across a large intercontinental area spanning from East Africa to Northeast Asia, followed by recent migrations in peripheral geographic regions.     

Potential transmission of human polyomaviruses through the gastrointestinal tract after exposure to virions or viral DNA

The mechanism of human-to-human transmission of the polyomaviruses JC virus (JCV) and BK virus (BKV) has not been firmly established with regard to possible human exposure. JCV and BKV have been found in sewage samples from different geographical areas in Europe, Africa, and the United States, with average concentrations of 10(2) to 10(3) JCV particles/ml and 10(1) to 10(2) BKV particles/ml. Selected polyomavirus-positive sewage samples were further characterized. The JCV and BKV present in these samples were identified by sequencing of the intergenic region (the region found between the T antigen and VP coding regions) of JCV and the VP1 region of BKV. The regulatory region of the JCV and BKV strains found in sewage samples presented archetypal or archetype-like genetic structures, as described for urine samples. The stability (the time required for a 90% reduction in the virus concentration) of the viral particles in sewage at 20 degrees C was estimated to be 26.7 days for JCV and 53.6 days for BKV. The presence of JCV in 50% of the shellfish samples analyzed confirmed the stability of these viral particles in the environment. BKV and JCV particles were also found to be stable at pH 5; however, treatment at a pH lower than 3 resulted in the detection of free viral DNA. Since most humans are infected with JCV and BKV, these data indicate that the ingestion of contaminated water or food could represent a possible portal of entrance of these viruses or polyomavirus DNA into the human population.     

Utility of DNA viruses for studying human host history: case study of JC virus

Microbial pathogens, and viruses in particular, can serve as important complements to traditional genetic markers when investigating the population histories of their human host. The range of mutation rates for DNA viruses suggests that DNA viruses can be useful markers of both recent and ancient events in their host histories. Here, we assess the utility of a well known DNA virus, JC virus (JCV), for investigating human history and demography. Using complete coding viral genomes, we confirm the phylogeographic structure of JCV in populations worldwide and provide coalescent estimates of its evolutionary rate under two alternative models of its history. Using these rate estimates, we compare Bayesian skyline plots of population size changes for JCV to those of its human host as estimated with coding mitochondrial genomes of the latter. These comparisons, when combined with other evidence including a log Bayes Factor model test, show that JCV is evolving rapidly and is therefore tracking the recent history of its human host. These results support the hypothesis that post-World War II societal changes are most likely responsible for the recent demographic patterns observed among different regional JCV populations. In sum, fast evolving DNA viruses, such as JCV, can complement RNA viruses to provide novel insights about the recent history and demography of their human host.     

利用HPA-1～3,5和15系统多态性估算中外不同人群遗传距离

依据血小板同种抗原5个系统的遗传多态性, 采用聚合酶链反应序列特异性引物技术, 对1 000名中国汉族无关献血者HPA-1~3, 5和15系统进行基因分型, 计算基因频率。使用DISPAN软件及PHYLIP软件计算不同群体间遗传距离并绘制系统树。系统树显示, 亚洲人群先与欧洲人群相聚, 之后再与非洲人群相聚, 非洲人群位于系统发生树的最顶部; 印度人群处于亚洲人群与欧洲人群之间; 南美洲巴西白人与欧洲人群聚在一起; 大洋洲的波利尼西亚人与亚洲人群聚在一起。此研究从一个侧面证明了人类“非洲起源说”, 印证亚洲人群由南亚向东南亚再向东亚迁徙的路线, 并推断出欧洲人群由南欧向北欧、西欧迁徙的线路。HPA能有效估算不同人群间遗传距离, 分析人类迁徙过程, HPA可作为遗传标记应用于人类进化的研究。     

Ecological niche and geographic distribution of human monkeypox in Africa

Monkeypox virus, a zoonotic member of the genus Orthopoxviridae, can cause a severe, smallpox-like illness in humans. Monkeypox virus is thought to be endemic to forested areas of western and Central Africa. Considerably more is known about human monkeypox disease occurrence than about natural sylvatic cycles of this virus in non-human animal hosts. We use human monkeypox case data from Africa for 1970-2003 in an ecological niche modeling framework to construct predictive models of the ecological requirements and geographic distribution of monkeypox virus across West and Central Africa. Tests of internal predictive ability using different subsets of input data show the model to be highly robust and suggest that the distinct phylogenetic lineages of monkeypox in West Africa and Central Africa occupy similar ecological niches. High mean annual precipitation and low elevations were shown to be highly correlated with human monkeypox disease occurrence. The synthetic picture of the potential geographic distribution of human monkeypox in Africa resulting from this study should support ongoing epidemiologic and ecological studies, as well as help to guide public health intervention strategies to areas at highest risk for human monkeypox.     

Gene Flow between the Korean Peninsula and Its Neighboring Countries

SNP markers provide the primary data for population structure analysis. In this study, we employed whole-genome autosomal SNPs as a marker set (54,836 SNP markers) and tested their possible effects on genetic ancestry using 320 subjects covering 24 regional groups including Northern ( = 16) and Southern ( = 3) Asians, Amerindians ( = 1), and four HapMap populations (YRI, CEU, JPT, and CHB). Additionally, we evaluated the effectiveness and robustness of 50K autosomal SNPs with various clustering methods, along with their dependencies on recombination hotspots (RH), linkage disequilibrium (LD), missing calls and regional specific markers. The RH- and LD-free multi-dimensional scaling (MDS) method showed a broad picture of human migration from Africa to North-East Asia on our genome map, supporting results from previous haploid DNA studies. Of the Asian groups, the East Asian group showed greater differentiation than the Northern and Southern Asian groups with respect to Fst statistics. By extension, the analysis of monomorphic markers implied that nine out of ten historical regions in South Korea, and Tokyo in Japan, showed signs of genetic drift caused by the later settlement of East Asia (South Korea, Japan and China), while Gyeongju in South East Korea showed signs of the earliest settlement in East Asia. In the genome map, the gene flow to the Korean Peninsula from its neighboring countries indicated that some genetic signals from Northern populations such as the Siberians and Mongolians still remain in the South East and West regions, while few signals remain from the early Southern lineages.     

Phylogenetic analysis of major African genotype (Af2) of JC virus: Implications for origin and dispersals of modern Africans

Both mtDNA and the Y chromosome have been used to investigate how modern humans dispersed within and out of Africa. This issue can also be studied using the JC virus (JCV) genotype, a novel marker with which to trace human migrations. Africa is mainly occupied by two genotypes of JCV, designated Af1 and Af2. Af1 is localized to central/western Africa, while Af2 is spread throughout Africa and in neighboring areas of Asia and Europe. It was recently suggested that Af1 represents the ancestral type of JCV, which agrees with the African origin of modern humans. To better understand the origin of modern Africans, we examined the phylogenetic relationships among Af2 isolates worldwide. A neighbor-joining phylogenetic tree was constructed based on the complete JCV DNA sequences of 51 Af2 isolates from Africa and neighboring areas. According to the resultant tree, Af2 isolates diverged into two major clusters, designated Af2-a and -b, with high bootstrap probabilities. Af2-a contained isolates mainly from South Africa, while Af2-b contained those from the other parts of Africa and neighboring regions of Asia and Europe. These findings suggest that Af2-carrying Africans diverged into two groups, one carrying Af2-a and the other carrying Af2-b; and that the former moved to southern Africa, while the latter dispersed throughout Africa and to neighboring regions of Asia and Europe. The present findings are discussed with reference to relevant findings in genetic and linguistic studies.     

Principal component analysis of gene frequencies of Chinese populations

Principal components (PCs) were calculated based on gene frequencies of 130 alleles at 38 loci in Chinese populations, and geographic PC maps were constructed. The first PC map of the Han shows the genetic difference between Southern and Northern Mongoloids, while the second PC indicates the gene flow between Caucasoid and Mongoloids. The first PC map of the Chinese ethnic minorities is similar to that of the second PC map of the Han, while their second PC map is similar to the first PC map of the Han. When calculating PC with the gene frequency data from both the Han and ethnic minorities, the first and second PC maps most resemble those of the ethnic minorities alone. The third and fourth PC maps of Chinese populations may reflect historical events that allowed the expansion of the populations in the highly civilized regions. A clear-cut boundary between Southern and Northern Mongoloids in the synthetic map of the Chinese populations was observed in the zone of the Yangtze River. We suggest that the a     

Principal component analysis of gene frequencies of Chinese populations

Principal components (PCs) were calculated based on gene frequencies of 130 alleles at 38 loci in Chinese populations, and geographic PC maps were constructed. The first PC map of the Han shows the genetic difference between Southern and Northern Mongoloids, while the second PC indicates the gene flow between Caucasoid and Mongoloids. The first PC map of the Chinese ethnic minorities is similar to that of the second PC map of the Han, while their second PC map is similar to the first PC map of the Han. When calculating PC with the gene frequency data from both the Han and ethnic minorities, the first and second PC maps most resemble those of the ethnic minorities alone. The third and fourth PC maps of Chinese populations may reflect historical events that allowed the expansion of the populations in the highly civilized regions. A clear-cut boundary between Southern and Northern Mongoloids in the synthetic map of the Chinese populations was observed in the zone of the Yangtze River. We suggest that the ancestors of Southern and Northern Mongoloids had already separated before reaching Asia. The ancestors of the Southern Mongoloids may result from the initial expansion from Africa or the Middle East, via the south coast of Asia, toward Southeast Asia, and ultimately South China. Upon reaching the Yangtze River, they might even have crossed the river to occupy the nearby regions for a period of time. The ancestors of the Northern Mongoloids probably expanded from Africa via the Northern Pamirs, first went eastward, then towards the south to reach the Yangtze River. The expansion of the Northern Mongoloids toward the south of the Yangtze River happened only in the last 2 or 3 thousand years.     

Regional distribution of two related Northeast Asian genotypes of JC virus, CY-a and -b: implications for the dispersal of Northeast Asians

JC virus (JCV) is a useful marker to trace human dispersal. Two genotypes of JCV (MY and CY) are mainly distributed in Northeast Asia. The population history of people carrying MY has been studied in some detail but that of people carrying CY remains poorly understood. To gain insights into the population history of Northeast Asians carrying CY we analyzed the genetic variation in CY isolates. We constructed a neighbor-joining phylogenetic tree from 28 complete CY DNA sequences: on the resultant tree the CY DNA sequences diverged into two clades, designated CY-a and -b, each clustered with a high bootstrap probability. The split into CY-a and -b was estimated to have occurred about 10 000 years ago, based on K(s) values (synonymous substitutions per synonymous site) and the suggested rate of synonymous nucleotide substitutions. Comparison of the 28 complete CY sequences revealed six nucleotide mismatches between CY-a and -b, one of which showed a restriction fragment length polymorphism (RFLP). We then PCR-amplified a region of the genome containing this polymorphic site from many CY isolates in various Northeast Asian populations and classified the isolates into CY-a or -b according to the RFLP analysis. CY-a was more abundant than CY-b in various Chinese and Japanese populations but CY-b was more abundant than CY-a in South Koreans. On the basis of the present findings we inferred the population history in East Asians carrying CY.     

Association between hMLH1 hypermethylation and JC virus (JCV) infection in human colorectal cancer (CRC)

Incorporation of viral DNA may interfere with the normal sequence of human DNA bases on the genetic level or cause secondary epigenetic changes such as gene promoter methylation or histone acetylation. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the USA. Chromosomal instability (CIN) was established as the key mechanism in cancer development. Later, it was found that CRC results not only from the progressive accumulation of genetic alterations but also from epigenetic changes. JC virus (JCV) is a candidate etiologic factor in sporadic CRC. It may act by stabilizing β-catenin, facilitating its entrance to the cell nucleus, initialing proliferation and cancer development. Diploid CRC cell lines transfected with JCV-containing plasmids developed CIN. This result provides direct experimental evidence for the ability of JCV T-Ag to induce CIN in the genome of colonic epithelial cells. The association of CRC hMLH1 methylation and tumor positivity for JCV was recently documented. JC virus T-Ag DNA sequences were found in 77% of CRCs and are associated with promoter methylation of multiple genes. hMLH1 was methylated in 25 out of 80 CRC patients positive for T-Ag (31%) in comparison with only one out of 11 T-Ag negative cases (9%). Thus, JCV can mediate both CIN and aberrant methylation in CRC. Like other viruses, chronic infection with JCV may induce CRC by different mechanisms which should be further investigated. Thus, gene promoter methylation induced by JCV may be an important process in CRC and the polyp-carcinoma sequence.     

JC virus strains indigenous to northeastern Siberians and Canadian Inuits are unique but evolutionally related to those distributed throughout Europe and Mediterranean areas

Human polyomavirus JC virus (JCV) isolates around the world are classified into more than 10 geographically distinct genotypes (designated as subtypes). Evolutionary relationships among JCV subtypes were recently examined, and the following pattern of JCV evolution was indicated. The ancestral JCV first divided into three superclusters, designated Types A, B, and C. A split in Type A generated two subtypes, EU-a and -b, containing mainly European and Mediterranean isolates. The split in Type B generated Af 2 (the major African subtype), Bl-c (a minor European subtype), and various Asian subtypes. Type C generated a single subtype (Afl), consisting of isolates derived from western Africa. In this study, JCV isolates prevalent among northeastern Siberians and Canadian Inuits were evaluated in the context of the above-described pattern of JCV evolution. The Siberian/Arctic JCV isolates were classified as belonging mainly to Type A, based on the result of a preliminary phylogenetic analysis. We then examined, using the whole-genome approach, the phylogenetic relationships among worldwide Type A isolates. In neighbor-joining and maximum-likelihood analyses, Type A JCVs worldwide consistently diverged into three subtypes, EU-a, -b, and -c, with high bootstrap probabilities. EU-c was constructed only by northeastern Siberian isolates, derived mainly from Nanais living in the lower Amur River region, and was shown to have been generated by the first split in Type A. Most Siberian/Arctic isolates derived from Chukchis, Koryaks, and Canadian Inuits formed a distinct cluster within the EU-a subtype, with a high bootstrap probability. Based on the present findings, we discuss ancient human migrations, accompanied by Type A JCVs, across Asia and to Arctic areas of North America.     

A worldwide population study of the Ag-system haplotypes, a genetic polymorphism of human low-density lipoprotein.

The aim of this investigation is to examine the distribution of the Ag immunological polymorphism in human populations on a worldwide scale and to look for possible explanations of this distribution in the field of modern human peopling history and Ag-system evolution. Extensive Ag-antigene typings were carried out on 13 human population samples, including sub-Saharan African, European, west and east Asiatic, Melanesian, Australian aborigine, and Amerindian groups. Complete Ag-haplotype frequencies were estimated by maximum-likelihood-score procedures, and the data were analyzed by genetic distance computations and principal coordinate projections. With the exception of the Amerindian sample, the Ag polymorphism is shown to be highly polymorphic in all the populations tested. Their genetic relationships appear to be closely correlated to their geographical distribution. This suggests that the Ag system has evolved as a neutral or nearly neutral polymorphism and that it is highly informative for modern human peopling history studies. From the worldwide Ag haplotypic distributions, a model for the Ag molecular structure is derived. According to this model and to the most recent results obtained from molecular data, the establishment of the Ag polymorphism could be explained by several mutations and recombination events between the haplotypes most frequently found in human populations today. As a conclusion, genetic and paleontological data suggest that the genetic structure of caucasoid populations (located from North Africa to India) may be the least differentiated from an ancestral genetic stock. Worldwide genetic differentiations are properly explained as the results of westward and eastward human migrations from a Near East-centered but undefined geographical area where modern humans may have originated. The importance of Ag polymorphism analyses for the reconstruction of human settlement history and origins is discussed in the light of the main conclusions of the most recent genetic polymorphism studies.