Search

The southern African indigenous Khoe-San populations harbor the most divergent lineages of all living peoples. Exploring their genomes is key to understanding deep human history. We sequenced 25 full genomes from five Khoe-San populations, revealing many novel variants, that 25% of variants are unique to the Khoe-San, and that the Khoe-San group harbors the greatest level of diversity across the globe. In line with previous studies, we found several gene regions with extreme values in genome-wide scans for selection, potentially caused by natural selection in the lineage leading to Homo sapiens and more recent in time. These gene regions included immunity-, sperm-, brain-, diet-, and muscle-related genes. When accounting for recent admixture, all Khoe-San groups display genetic diversity approaching the levels in other African groups and a reduction in effective population size starting around 100,000 years ago. Hence, all human groups show a reduction in effective population size commencing around the time of the Out-of-Africa migrations, which coincides with changes in the paleoclimate records, changes that potentially impacted all humans at the time.

The Southern African Human Genome Programme is a national initiative that aspires to unlock the unique genetic character of southern African populations for a better understanding of human genetic diversity. In this pilot study the Southern African Human Genome Programme characterizes the genomes of 24 individuals (8 Coloured and 16 black southeastern Bantu-speakers) using deep whole-genome sequencing. A total of ~16 million unique variants are identified. Despite the shallow time depth since divergence between the two main southeastern Bantu-speaking groups (Nguni and Sotho-Tswana), principal component analysis and structure analysis reveal significant (p, African populations show a high level of genetic diversity and extensive regional admixture. Here, the authors sequence the whole genomes of 24 South African individuals of different ethnolinguistic origin and find substantive genomic divergence between two southeastern Bantu-speaking groups.

A significant portion of the current human adaptive and demographic traits is believed to have originated in north-east Africa, the putative scene of early human evolution. However interesting such assumption might be, the genetic structure and phenotypic traits of populations in this part of the globe remains poorly studied, including the widely analyzed genome of the mitochondria. Mitochondrial hypervariable region and whole mitogenomes of Sudanese and South Sudanese were compared to regional and global sequences. Haplotypes, mismatch distribution, PCAs, FST, Ne, and phylogenetic trees were constructed and analyzed. The HVRI in particular and whole mitogenomes produced robust phylogenies that were greatly concordant. Observed haplotypes were found to belong mainly to the major mitochondrial macrohapolgroups L0, L1, L2, L4, L5, L3, M and N. Expectedly the L0 was confined to populations previously shown to occupy the deepest and most ancestral lineages in the human evolutionary tree. The observed regional variation and diversity, depicted in various metrics imply that the female lineages in this part of Africa are likely to have been shaped by a longer history of in-situ evolution.

Multiple questions relating to contributions of cultural and demographical factors in the process of human geographical dispersal remain largely unanswered. India, a land of early human settlement and the resulting diversity is a good place to look for some of the answers. In this study, we explored the genetic structure of India using a diverse panel of 78 males genotyped using the GenoChip. Their genome-wide single-nucleotide polymorphism (SNP) diversity was examined in the context of various covariates that influence Indian gene pool. Admixture analysis of genome-wide SNP data showed high proportion of the Southwest Asian component in all of the Indian samples. Hierarchical clustering based on admixture proportions revealed seven distinct clusters correlating to geographical and linguistic affiliations. Convex hull overlay of Y-chromosomal haplogroups on the genome-wide SNP principal component analysis brought out distinct non-overlapping polygons of F*-M89, H*-M69, L1-M27, O2a-M95 and O3a3c1-M117, suggesting a male-mediated migration and expansion of the Indian gene pool. Lack of similar correlation with mitochondrial DNA clades indicated a shared genetic ancestry of females. We suggest that ancient male-mediated migratory events and settlement in various regional niches led to the present day scenario and peopling of India.

Southern Africa is consistently placed as one of the potential regions for the evolution of Homo sapiens. To examine the region’s human prehistory prior to the arrival of migrants from East and West Africa or Eurasia in the last 1,700 years, we generated and analyzed genome sequence data from seven ancient individuals from KwaZulu-Natal, South Africa. Three Stone Age hunter-gatherers date to ~2,000 years ago, and we show that they were related to current-day southern San groups such as the Karretjie People. Four Iron Age farmers (300–500 years old) have genetic signatures similar to present day Bantu-speakers. The genome sequence (13x coverage) of a juvenile boy from Ballito Bay, who lived ~2,000 years ago, demonstrates that southern African Stone Age hunter-gatherers were not impacted by recent admixture; however, we estimate that all modern-day Khoekhoe and San groups have been influenced by 9–22% genetic admixture from East African/Eurasian pastoralist groups arriving >1,000 years ago, including the Ju|‘hoansi San, previously thought to have very low levels of admixture. Using traditional and new approaches, we estimate the population divergence time between the Ballito Bay boy and other groups to beyond 260,000 years ago. These estimates dramatically increases the deepest divergence amongst modern humans, coincide with the onset of the Middle Stone Age in sub-Saharan Africa, and coincide with anatomical developments of archaic humans into modern humans as represented in the local fossil record. Cumulatively, cross-disciplinary records increasingly point to southern Africa as a potential (not necessarily exclusive) ‘hot spot’ for the evolution of our species.

Southern Africa was likely exclusively inhabited by San hunter-gatherers before ~2000 years ago. Around that time, East African groups assimilated with local San groups and gave rise to the Khoekhoe herders. Subsequently, Bantu-speaking farmers, arriving from the north (~1800 years ago), assimilated and displaced San and Khoekhoe groups, a process that intensified with the arrival of European colonists ~350 years ago. In contrast to the western parts of southern Africa, where several Khoe-San groups still live today, the eastern parts are largely populated by Bantu speakers and individuals of non-African descent. Only a few scattered groups with oral traditions of Khoe-San ancestry remain. Advances in genetic research open up new ways to understand the population history of southeastern Africa. We investigate the genomic variation of the remaining individuals from two South African groups with oral histories connecting them to eastern San groups, i.e., the San from Lake Chrissie and the Duma San of the uKhahlamba-Drakensberg. Using ~2.2 million genetic markers, combined with comparative published data sets, we show that the Lake Chrissie San have genetic ancestry from both Khoe-San (likely the ||Xegwi San) and Bantu speakers. Specifically, we found that the Lake Chrissie San are closely related to the current southern San groups (i.e., the Karretjie people). Duma San individuals, on the other hand, were genetically similar to southeastern Bantu speakers from South Africa. This study illustrates how genetic tools can be used to assess hypotheses about the ancestry of people who seemingly lost their historic roots, only recalling a vague oral tradition of their origin. Electronic supplementary material The online version of this article (doi:10.1007/s00439-016-1729-8) contains supplementary material, which is available to authorized users.

Primary congenital glaucoma (PCG) is a genetically heterogeneous autosomal recessive disorder, which is an important cause of blindness in childhood. The first known gene, CYP1B1, accounts for a variable proportion of cases in most populations. A second gene, LTBP2, was recently reported in association with a syndrome, in which glaucoma is secondary to lens dislocation. We report on the molecular and clinical profile of 34 families diagnosed as PCG, all originating from the Roma/Gypsy founder population. Comprehensive sequencing analysis revealed a level of heterogeneity unusual for this population, with five CYP1B1 and one ancestral LTBP2 mutation accounting for ∼70% of patients (25 out of 37) and the remainder still unexplained. Homozygosity for the founder LTBP2 p.R299X mutation resulted in a more severe clinical phenotype and poorer outcome despite a markedly higher number of surgical interventions. The genetically homogeneous group of p.R299X homozygotes showed variable phenotypes (presumably also underlying pathogenetic mechanisms), wherein PCG proper with primary dysgenesis of the trabecular meshwork, and Marfan syndrome-like zonular disease with ectopia lentis and later onset secondary glaucoma are two extremes. The spectrum manifestations may occur in different combinations and have a different evolution even within the same sibship or a single patient. Preliminary observations on compounds with mutations in both CYP1B1-LTBP2 suggest that the observed combinations are of no clinical significance and digenic inheritance is unlikely. We provide a population genetics perspective to explain the allelic heterogeneity, comparing the history and geographic distribution of the two major founder mutations – p.R299X/LTBP2 and p.E387K/CYP1B1.

Africa is the ultimate source of modern humans and as such harbors more genetic variation than any other continent. For this reason, studies of the patterns of genetic variation in African populations are crucial to understanding how genes affect phenotypic variation, including disease predisposition. In addition, the patterns of extant genetic variation in Africa are important for understanding how genetic variation affects infectious diseases that are a major problem in Africa, such as malaria, tuberculosis, schistosomiasis, and HIV/AIDS. Therefore, elucidating the role that genetic susceptibility to infectious diseases plays is critical to improving the health of people in Africa. It is also of note that recent and ongoing social and cultural changes in sub-Saharan Africa have increased the prevalence of non-communicable diseases that will also require genetic analyses to improve disease prevention and treatment. In this review we give special attention to many of the past and ongoing studies, emphasizing those in Sub-Saharan Africans that address the role of genetic variation in human disease.

We report a study of genome-wide, dense SNP (∼900K) and copy number polymorphism data of indigenous southern Africans. We demonstrate the genetic contribution to southern and eastern African populations, which involved admixture between indigenous San, Niger-Congo-speaking and populations of Eurasian ancestry. This finding illustrates the need to account for stratification in genome-wide association studies, and that admixture mapping would likely be a successful approach in these populations. We developed a strategy to detect the signature of selection prior to and following putative admixture events. Several genomic regions show an unusual excess of Niger-Kordofanian, and unusual deficiency of both San and Eurasian ancestry, which were considered the footprints of selection after population admixture. Several SNPs with strong allele frequency differences were observed predominantly between the admixed indigenous southern African populations, and their ancestral Eurasian populations. Interestingly, many candidate genes, which were identified within the genomic regions showing signals for selection, were associated with southern African-specific high-risk, mostly communicable diseases, such as malaria, influenza, tuberculosis, and human immunodeficiency virus/AIDs. This observation suggests a potentially important role that these genes might have played in adapting to the environment. Additionally, our analyses of haplotype structure, linkage disequilibrium, recombination, copy number variation and genome-wide admixture highlight, and support the unique position of San relative to both African and non-African populations. This study contributes to a better understanding of population ancestry and selection in south-eastern African populations; and the data and results obtained will support research into the genetic contributions to infectious as well as non-communicable diseases in the region., Author Summary Genome-wide analysis of human populations is useful in shedding light on the evolutionary history of the human genome, with a wide range of applications from reconstructing past associations between different population histories to disease mapping. In this manuscript we report on the application of genome-wide data to southern African populations and the identification of genome-wide signatures of selection pre- and post-admixture. Several signals of selection, before and after admixture, were identified, some of which involved loci associated with human diseases, including malaria, influenza, tuberculosis and HIV/AIDS. These results may reflect adaptations of southern African populations to infectious diseases. Consistent with previous studies, this study highlights the significance of the San in the genetics of human populations, as they are distinct from the other populations in many respects i.e. haplotype structure, locations of recombination hotspots, copy number and population structure. Furthermore, our study demonstrates the admixture of the San, Bantu-speaking populations and populations of Eurasian ancestry in some of the southern and eastern African populations. It illustrates the value in correcting for this stratification in future genome-wide association studies, and suggests that a future admixture mapping in these populations would likely be warranted and successful.

This report describes the outcomes of a workshop that dealt with the role of mtDNA variation in the health of Black African popula- tions, which was held in November 2014 at Potchefstroom, South Africa, and supported by the National Research Foundation of South Africa and the Royal Society of the United Kingdom. The meeting aimed to review our understanding of mitochondrial variation and disease and considered inherited mitochondrial disorders and the role of mtDNA variants in common disease in Black African popu- lations, particularly in southern Africa. It was hosted by the North- West University, Potchefstroom campus (http://www.nwu.ac.za/) and invitees were based in either a South African or British Univer- sity. Although small in size, with 20 attendees (15 from South Africa and 5 from the UK), the core of the South African mitochondrial community was present along with some of those in the UK with overlapping academic interests. Those interested in mtDNA from a clinical perspective were well represented including clinical geneti- cists, clinical pharmacologists, pediatric and adult neurologists, and diagnostic scientists. Additionally, scientists specializing in genetic susceptibility and pharmacogenomics, as well as scientists involved in fundamental biochemical and molecular research on mitochon- drial function and disease, were present. The meeting considered both the identification of pathogenic mutations causing mitochon- drial disease in patients, and the importance of conducting mtDNA association studies in southern African populations

To investigate associations between genetic, linguistic, and geographic variation in Africa, we type 50 Y chromosome SNPs in 1122 individuals from 40 populations representing African geographic and linguistic diversity. We compare these patterns of variation with those that emerge from a similar analysis of published mtDNA HVS1 sequences from 1918 individuals from 39 African populations. For the Y chromosome, Mantel tests reveal a strong partial correlation between genetic and linguistic distances (r=0.33, P=0.001) and no correlation between genetic and geographic distances (r=-0.08, P>0.10). In contrast, mtDNA variation is weakly correlated with both language (r=0.16, P=0.046) and geography (r=0.17, P=0.035). AMOVA indicates that the amount of paternal among-group variation is much higher when populations are grouped by linguistics (Phi(CT)=0.21) than by geography (Phi(CT)=0.06). Levels of maternal genetic among-group variation are low for both linguistics and geography (Phi(CT)=0.03 and 0.04, respectively). When Bantu speakers are removed from these analyses, the correlation with linguistic variation disappears for the Y chromosome and strengthens for mtDNA. These data suggest that patterns of differentiation and gene flow in Africa have differed for men and women in the recent evolutionary past. We infer that sex-biased rates of admixture and/or language borrowing between expanding Bantu farmers and local hunter-gatherers played an important role in influencing patterns of genetic variation during the spread of African agriculture in the last 4000 years.

The island population of Tristan da Cunha has a well-documented genealogy that dates to its first permanent settlement in 1816. The current population is thought to have descended from only seven females and eight males. Today, there are seven family names in use, corresponding to the number of founding fathers with present-day male descendents. Y chromosome polymorphisms have previously been shown to be reliable tools for tracing patrilineal genealogies. Here, we studied Y chromosome polymorphisms in a sample from Tristan da Cunha together with genealogical records to (i) infer the haplotypes of the seven founders and (ii) test if the Y chromosome transmission is consistent with the documented patrilineal history of the island community. We observed nine Y chromosome haplotypes of which seven could be traced to the known ancestors. Of the two additional lineages, one probably evolved from a founder haplotype due to a single-step microsatellite mutation, while the other had an obvious non-island origin. Its introduction, however, is not reflected in the records. Four more instances of non-paternity were identified, with the "new" chromosomes matching other island haplotypes. The Y chromosome data presented here question the validity of some of the genealogical documentation and emphasise the value of genetic studies in tracing ancestry.

The extent of genetic differentiation between seven South African Bantu-speaking groups (Zulu, Xhosa, Tsonga/Shangaan, Southern Sotho, Pedi, Tswana, and Venda) was assessed from coancestry coefficients (F(ST)) estimated from autosomal serogenetic, DNA, and Y-chromosome DNA haplotypes. The overall F(ST) obtained from the autosomal data was 0.002, and that from the Y chromosome data was 0.014. The genetic relationships between groups examined were inferred from their cluster affinities in phylogenetic trees constructed from the genetic distances between them. Both autosomal and Y-chromosome DNA studies reveal that 6 of the 7 South African Bantu-speaking groups cluster according to their linguistic groupings, the exception being the Tsonga, who do not cluster with other Nguni language speakers, but rather with the Venda who live close to them. This suggests that the invading Shangaan-speakers, whose Nguni language was adopted by the Tsonga, did not have a major effect on the Tsonga gene pool, and that gene flow from the Venda into the Tsonga may have been considerable. Genetic distances were found to correlate with geographic distances between the regions where each group's apparent population density is the highest. Linguistic distances were also found to correlate with genetic distances, but linguistic and geographic distances showed no correlation. Together, these results suggest that linguistic and some genetic differentiation took place before the groups (or their forerunners) reached their present-day locations, and that further genetic change occurred after their arrival.

This is a report on a workshop titled ‘Ethics for genomic research across five African countries: Guidelines, experiences and challenges’, University of the Witwatersrand, Johannesburg, South Africa, 10 and 11 December 2012. The workshop was hosted by the Wits-INDEPTH partnership, AWI-Gen, as part of the H3Africa Consortium.

H3Africa is developing capacity for health-related genomics research in Africa

We examined 43 biallelic polymorphisms on the nonrecombining portion of the Y chromosome (NRY) in 50 human populations encompassing a total of 2,858 males to study the geographic structure of Y-chromosome variation. Patterns of NRY diversity varied according to geographic region and method/level of comparison. For example, populations from Central Asia had the highest levels of heterozygosity, while African populations exhibited a higher level of mean pairwise differences among haplotypes. At the global level, 36% of the total variance of NRY haplotypes was attributable to differences among populations (i.e., Phi(ST) = 0.36). When a series of AMOVA analyses was performed on different groupings of the 50 populations, high levels of among-groups variance (Phi(CT)) were found between Africans, Native Americans, and a single group containing all 36 remaining populations. The same three population groupings formed distinct clusters in multidimensional scaling plots. A nested cladistic analysis (NCA) demonstrated that both population structure processes (recurrent gene flow restricted by isolation by distance and long-distance dispersals) and population history events (contiguous range expansions and long-distance colonizations) were instrumental in explaining this tripartite division of global NRY diversity. As in our previous analyses of smaller NRY data sets, the NCA detected a global contiguous range expansion out of Africa at the level of the total cladogram. Our new results support a general scenario in which, after an early out-of-Africa range expansion, global-scale patterns of NRY variation were mainly influenced by migrations out of Asia. Two other notable findings of the NCA were (1) Europe as a "receiver" of intercontinental signals primarily from Asia, and (2) the large number of intracontinental signals within Africa. Our AMOVA analyses also supported the hypothesis that patrilocality effects are evident at local and regional scales, rather than at intercontinental and global levels. Finally, our results underscore the importance of subdivision of the human paternal gene pool and imply that caution should be exercised when using models and experimental strategies based on the assumption of panmixia.

Genealogical histories show that the inhabitants of Tristan da Cunha are derived from a known number of founders. Using the transmission of mitochondrial DNA (mtDNA) from mother to offspring pairs, we traced the mtDNA types found in 161 extant individuals to five female founders. Although the historical data claimed that two pairs of sisters were among the founding females, mtDNA data showed support for only one pair of sisters. We also studied the fidelity of mtDNA transmission in conjunction with the genealogical data. We did not detect any mutations from 698 base pairs of sequence data from 75 individuals, which together accounted for 108 independent transmissions of mtDNA from mother to offspring. Based on this observation, we estimate that the mtDNA mutation rate is no more than one new mutation every 36 transmissions. These results indicate a high fidelity of maternal mtDNA transmission and support the utility of mtDNA in evolutionary and forensic studies. Am J Phys Anthropol 104:157–166, 1997. © 1997 Wiley-Liss, Inc.

International audience

The populations of Africa harbour the greatest human genetic diversity following an evolutionary history tracing its beginnings on the continent to time before the emergence of Homo sapiens. Signatures of selection are detectable as responses to ancient environments and cultural practices, modulated by more recent events including infectious epidemics, migrations, admixture and, of course, chance. The age of high-throughput biology is not passing Africa by. African-based cohort studies and networks with an African footprint are ideal springboards for disease-related genetic and genomic studies. Initiatives like HapMap, the 1000 Genomes Project, MalariaGEN, the INDEPTH network and Human Heredity and Health in Africa are catalysts to exploring African genetic diversity and its role in the spectrum from health to disease. The challenges are abundant in dissecting biological questions in the light of linguistic, cultural, geographic and political boundaries and their respective roles in shaping health-related profiles. Will studies based on African populations lead to a new wave of discovery of genetic contributors to disease?

Sub-Saharan Africa has consistently been shown to be the most genetically diverse region in the world. Despite the fact that a substantial portion of this variation is partitioned between groups practicing a variety of subsistence strategies and speaking diverse languages, there is currently no consensus on the genetic relationships of sub-Saharan African populations. San (a subgroup of KhoeSan) and many Pygmy groups maintain hunter-gatherer lifestyles and cluster together in autosomal-based analysis, whereas non-Pygmy Niger-Kordofanian speakers (non-Pygmy NKs) predominantly practice agriculture and show substantial genetic homogeneity despite their wide geographic range throughout subSaharan Africa. However, KhoeSan, who speak a set of relatively unique click-based languages, have long been thought to be an early branch of anatomically modern humans based on phylogenetic analysis. To formally test models of divergence among the ancestors of modern African populations, we resequenced a sample of San, Eastern, and Western Pygmies and non-Pygmy NKs individuals at 40 nongenic (;2 kb) regions and then analyzed these data within an Approximate Bayesian Computation (ABC) framework. We find substantial support for a model of an early divergence of KhoeSan ancestors from a proto-Pygmynon-Pygmy NKs group ;110 thousand years ago over a model incorporating a proto-KhoeSan–Pygmy hunter-gatherer divergence from the ancestors of non-Pygmy NKs. The results of our analyses are consistent with previously identified signals of a strong bottleneck in Mbuti Pygmies and a relatively recent expansion of non-Pygmy NKs. We also develop a number of methodologies that utilize ‘‘pseudo-observed’’ data sets to optimize our ABC-based inference. This approach is likely to prove to be an invaluable tool for demographic inference using genome-wide resequencing data.

The Karretjie people of the South African Great Karoo are itinerants who subsist by sheep shearing. Although officially classified 'Coloured', they are aware of their Khoe and San roots. To investigate the maternal and paternal ancestries of the Karretjie people we analyzed their mitochondrial and Y-chromosome DNA variation. Their genetic ancestry was compared with a neighboring group of 'Coloured' individuals. We found that the mitochondrial DNA (mtDNA) haplogroup L0d was present in all the Karretjie people examined, suggesting a maternal contribution, exclusively from the Khoe and San, whereas the paternal ancestry in males was more heterogeneous. The Coloured sample, on the other hand, were found to have a lower frequency of L0d (64.5%), but did harbor other African (27.6%) and non-African (7.9%) mtDNA haplogroups. Similar to the Karretjie people, the Y-chromosome lineages identified in the Coloured group had heterogeneous origins. This study also enabled an assessment of mtDNA variation within L0d sub-haplogroups. All seven of the L0d sub-clades were identified in the combined sample and were used to construct an L0d network.

Y-chromosome Haplogroup O is the dominant lineage of East Asians, comprising more than a quarter of all males on the world; however, its internal phylogeny remains insufficiently investigated. In this study, we determined the phylogenetic position of recently defined markers (L127, KL1, KL2, P164, and PK4) in the background of Haplogroup O. In the revised tree, subgroup O3a-M324 is divided into two main subclades, O3a1-L127 and O3a2-P201, covering about 20 and 35% of Han Chinese people, respectively. The marker P164 is corrected from a downstream site of M7 to upstream of M134 and parallel to M7 and M159. The marker PK4 is also relocated from downstream of M88 to upstream of M95, separating the former O2(*) into two parts. This revision evidently improved the resolving power of Y-chromosome phylogeny in East Asia.

African mitochondrial DNA (mtDNA) haplogroups are divided into seven macro-haplogroups (L0'1'2'3'4'5'6), while the rest of the world's lineages are classified as subgroups of macro-haplogroups M, N and R. The most common approach to characterizing mtDNA variation is the sequencing of hypervariable segments I and II of the non-coding control region of the molecule. Given the higher mutation rate within the control region compared with the coding regions of the molecule, recurrent mutations in the former can sometimes hide possible phylogenetic structure. The incorporation of haplogroup-defining coding region mutations has helped in overcoming this limitation. By judiciously selecting 14 coding region SNPs and incorporating them into a multiplex minisequencing assay we were able to resolve mtDNA sequences from some sub-Saharan African populations into ten macro-haplogroups (L0-L6, M, N and R). We tested the efficacy of the panel by screening 699 individuals, consisting mostly of Khoe-San, Bantu speakers and individuals with mixed ancestries (Coloreds) and found no inconsistencies compared with hypervariable segment sequencing results. The panel provided a fast and efficient means of classifying mtDNA into the ten mitochondrial macro-haplogroups and provided a reliable screening to distinguish African from non-African-derived mtDNA lineages.

A history of Pleistocene population expansion has been inferred from the frequency spectrum of polymorphism in the mitochondrial DNA (mtDNA) of many human populations. Similar patterns are not typically observed for autosomal and X-linked loci. One explanation for this discrepancy is a recent population bottleneck, with different rates of recovery for haploid and autosomal loci as a result of their different effective population sizes. This hypothesis predicts that mitochondrial and Y chromosomal DNA will show a similar skew in the frequency spectrum in populations that have experienced a recent increase in effective population size. We test this hypothesis by resequencing 6.6 kb of noncoding Y chromosomal DNA and 780 basepairs of the mtDNA cytochrome c oxidase subunit III (COIII) gene in 172 males from 5 African populations. Four tests of population expansion are employed for each locus in each population: Fu's F s statistic, the R 2 statistic, coalescent simulations, and the mismatch distribution. Consistent with previous results, patterns of mtDNA polymorphism better fit a model of constant population size for food-gathering populations and a model of population expansion for food-producing populations. In contrast, none of the tests reveal evidence of Y chromosome growth for either food-gatherers or food-producers. The distinct mtDNA and Y chromosome polymorphism patterns most likely reflect sex-biased demographic processes in the recent history of African populations. We hypothesize that males experienced smaller effective population sizes and/or lower rates of migration during the Bantu expansion, which occurred over the last 5,000 years.

The quest to explain demographic history during the early part of human evolution has been limited because of the scarce paleoanthropological record from the Middle Stone Age. To shed light on the structure of the mitochondrial DNA (mtDNA) phylogeny at the dawn of Homo sapiens, we constructed a matrilineal tree composed of 624 complete mtDNA genomes from sub-Saharan Hg L lineages. We paid particular attention to the Khoi and San (Khoisan) people of South Africa because they are considered to be a unique relic of hunter-gatherer lifestyle and to carry paternal and maternal lineages belonging to the deepest clades known among modern humans. Both the tree phylogeny and coalescence calculations suggest that Khoisan matrilineal ancestry diverged from the rest of the human mtDNA pool 90,000-150,000 years before present (ybp) and that at least five additional, currently extant maternal lineages existed during this period in parallel. Furthermore, we estimate that a minimum of 40 other evolutionarily successful lineages flourished in sub-Saharan Africa during the period of modern human dispersal out of Africa approximately 60,000-70,000 ybp. Only much later, at the beginning of the Late Stone Age, about 40,000 ybp, did introgression of additional lineages occur into the Khoisan mtDNA pool. This process was further accelerated during the recent Bantu expansions. Our results suggest that the early settlement of humans in Africa was already matrilineally structured and involved small, separately evolving isolated populations. S.R. is partially supported by European Union grant MIRG-CT-2007-208019. C.T.S. is supported by The Wellcome Trust. Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP) (L.P.) is supported by Programa Operacional Ciência, Tecnologia e Inovação (POCTI) and Quadro Comunitário de Apoio III.

We estimate parameters of a general isolation-with-migration model using resequence data from mitochondrial DNA (mtDNA), the Y chromosome, and two loci on the X chromosome in samples of 25–50 individuals from each of 10 human populations. Application of a coalescent-based Markov chain Monte Carlo technique allows simultaneous inference of divergence times, rates of gene flow, as well as changes in effective population size. Results from comparisons between sub-Saharan African and Eurasian populations estimate that 1500 individuals founded the ancestral Eurasian population ∼40 thousand years ago (KYA). Furthermore, these small Eurasian founding populations appear to have grown much more dramatically than either African or Oceanian populations. Analyses of sub-Saharan African populations provide little evidence for a history of population bottlenecks and suggest that they began diverging from one another upward of 50 KYA. We surmise that ancestral African populations had already been geographically structured prior to the founding of ancestral Eurasian populations. African populations are shown to experience low levels of mitochondrial DNA gene flow, but high levels of Y chromosome gene flow. In particular, Y chromosome gene flow appears to be asymmetric, i.e., from the Bantu-speaking population into other African populations. Conversely, mitochondrial gene flow is more extensive between non-African populations, but appears to be absent between European and Asian populations.

Recent genetic studies, based on Y chromosome polymorphic markers, showed that Ashkenazi Jews are more closely related to other Jewish and Middle Eastern groups than to their host populations in Europe. However, Ashkenazim have an elevated frequency of R-M17, the dominant Y chromosome haplogroup in Eastern Europeans, suggesting possible gene flow. In the present study of 495 Y chromosomes of Ashkenazim, 57 (11.5%) were found to belong to R-M17. Detailed analyses of haplotype structure, diversity and geographic distribution suggest a founder effect for this haplogroup, introduced at an early stage into the evolving Ashkenazi community in Europe. R-M17 chromosomes in Ashkenazim may represent vestiges of the mysterious Khazars.

The recent insertion of mobile elements, of the Alu and L1 families, in the human genome provides a distinct class of polymorphism in the human genome. Because the insertion of these elements in the genome is so rare and once they are inserted they are stable; they represent a unique group of markers that are identical by descent. This type of marker is among the most informative in ascertaining relationships between individuals and populations. The assays for these markers are extremely robust, easy to perform, and readily adaptable to mass analysis and automation. In addition, as the insertion alleles are all newly arisen, the ancestral allele is always the allele missing the insertion. This information allows estimations of the roots of trees, which are not possible with all types of markers. The greatest potential for these markers is with upcoming developments that will allow the identification of new insertions in many different genomes simultaneously. These procedures will allow investigators to isolate markers that are particularly informative for specific populations and allow development of panels of markers tailored for particular populations.

Alu insertion polymorphisms (polymorphisms consisting of the presence/absence of an Alu element at a particular chromosomal location) offer several advantages over other nuclear DNA polymorphisms for human evolution studies. First, they are typed by rapid, simple, PCR-based assays; second, they are stable polymorphisms—newly inserted Alu elements rarely undergo deletion; third, the presence of an Alu element represents identity by descent—the probability that different Aluelements would independently insert into the exact same chromosomal location is negligible; and fourth, the ancestral state is known with certainty to be the absence of an Alu element. We report here a study of 8 loci in 1500 individuals from 34 worldwide populations. African populations exhibit the most between-population differentiation, and the population tree is rooted in Africa; moreover, the estimated effective time of separation of African versus non-African populations is 137,000 ± 15,000 years ago, in accordance with other genetic data. However, a principal coordinates analysis indicates that populations from Sahul (Australia and New Guinea) are nearly as close to the hypothetical ancestor as are African populations, suggesting that there was an early expansion of tropical populations of our species. An analysis of heterozygosity versus genetic distance suggests that African populations have had a larger effective population size than non-African populations. Overall, these results support the African origin of modern humans in that an earlier expansion of the ancestors of African populations is indicated.

Elucidating the history of Homo sapiens has been a passion shared by many researchers spanning several decades. There are now overwhelming lines of evidence from genetic, archaeological, palaeoanthropological and, to some extent, palaeoenvironmental research, that place Africa as the region of origin of our species. The different fields of study use diverse types of data, and methods are subject to variances introduced by mutation rates, time estimates and/or sampling biases. All of these approaches have their respective shortcomings and error ranges and are accompanied by intense debate. Yet, it is timeous to review the most recent and salient highlights that the different approaches are contributing towards explaining our deep history and ancestry. It is, after all, one history, and consequently, there ought to be several convergent patterns between data sets. Our focus is to present an updated regional synthesis from each discipline for a specific window in time within the southern African context, namely between ~160 ka and 85 ka, and to speculate about possible connections between data sets for this period. Even though our focus is specific in time and space, it is not intended to consider southern Africa in isolation from the rest of Africa or to suggest a singular ‘origins’ locale for modern Homo sapiens. We hope that this integrated approach will stimulate discussions to include broader time periods within Africa and between continents.

The use of mitochondrial DNA (mtDNA) continues to dominate studies of human genetic variation and evolution. Recent work has re-affirmed the strict maternal inheritance of mtDNA, yielded new insights into the extent and nature of intra-individual variation, supported a recent African origin of human mtDNA, and amply demonstrated the utility of mtDNA in tracing population history and in analyses of ancient remains.

Restriction analysis of mitochondrial DNA (mtDNA) of 3065 humans from 62 geographic samples identified 149 haplotypes and 81 polymorphic sites. These data were used to test several aspects of the evolutionary past of the human species. A dendrogram depicting the genetic relatedness of all haplotypes shows that the native African populations have the greatest diversity and, consistent with evidence from a variety of sources, suggests an African origin for our species. The data also indicate that two individuals drawn at random from the entire sample will differ at approximately 0.4% of their mtDNA nucleotide sites, which is somewhat higher than previous estimates. Human mtDNA also exhibits more interpopulation heterogeneity (GST = 0.351 +/- 0.025) than does nuclear DNA (GST = 0.12). Moreover, the virtual absence of intermediate levels of linkage disequilibrium between pairs of sites is consistent with the absence of genetic recombination and places constraints on the rate of mutation. Tests of the selective neutrality of mtDNA variation, including the Ewens-Watterson and Tajima tests, indicate a departure in the direction consistent with purifying selection, but this departure is more likely due to the rapid growth of the human population and the geographic heterogeneity of the variation. The lack of a good fit to neutrality poses problems for the estimation of times of coalescence from human mtDNA data.

To test hypotheses about the origin of modern humans, we analyzed mtDNA sequences, 30 nuclear restriction-site polymorphisms (RSPs), and 30 tetranucleotide short tandem repeat (STR) polymorphisms in 243 Africans, Asians, and Europeans. An evolutionary tree based on mtDNA displays deep African branches, indicating greater genetic diversity for African populations. This finding, which is consistent with previous mtDNA analyses, has been interpreted as evidence for an African origin of modern humans. Both sets of nuclear polymorphisms, as well as a third set of trinucleotide polymorphisms, are highly consistent with one another but fail to show deep branches for African populations. These results, which represent the first direct comparison of mtDNA and nuclear genetic data in major continental populations, undermine the genetic evidence for an African origin of modern humans.

Variation in the mitochondrial DNA (mtDNA) control region as detected by sequence-specific oligonucleotide (SSO) probes is described for 381 individuals from nine sub-Saharan African populations. Population diversity estimates for SSO types ranged from 0.23 to 0.97, while 102 SSO types were detected, none of these types was shared by more than four populations. Eighteen types occurred in ≥ 10% of individuals in some populations; of these, 11 were population-specific. One type occurred in 15% of the total sample, but was shared among only three populations. African SSO types were characterized by high frequencies of blank variants, indicating that there was additional variation present at the nucleotide sequence level in regions where SSO probes hybridize. Analyses of molecular variance (AMOVA) incorporating genetic distances between SSO types showed that 30% of the total variation was due to differences among populations, indicating that there is statistically significant heterogeneity (p

SummaryThe ability to digest milk into adulthood, lactase persistence (LP), as well as specific genetic variants associated with LP, is heterogeneously distributed in global populations [1–4]. These variants were most likely targets of selection when some populations converted from hunter-gatherer to pastoralist or farming lifestyles [5–7]. Specific LP polymorphisms are associated with particular geographic regions and populations [1–4, 8–10]; however, they have not been extensively studied in southern Africa. We investigate the LP-regulatory region in 267 individuals from 13 southern African populations (including descendants of hunter-gatherers, pastoralists, and agropastoralists), providing the first comprehensive study of the LP-regulatory region in a large group of southern Africans. The “East African” LP single-nucleotide polymorphism (SNP) (14010G>C) was found at high frequency (>20%) in a strict pastoralist Khoe population, the Nama of Namibia, suggesting a connection to East Africa, whereas the “European” LP SNP (13910C>T) was found in populations of mixed ancestry. Using genome-wide data from various African populations, we identify admixture (13%) in the Nama, from an Afro-Asiatic group dating to >1,300 years ago, with the remaining fraction of their genomes being from San hunter-gatherers. We also find evidence of selection around the LCT gene among Khoe-speaking groups, and the substantial frequency of the 14010C variant among the Nama is best explained by adaptation to digesting milk. These genome-local and genome-wide results support a model in which an East African group brought pastoralist practices to southern Africa and admixed with local hunter-gatherers to form the ancestors of Khoe people.

Although the human Y chromosome has effectively shown utility in uncovering facets of human evolution and population histories, the ascertainment bias present in early Y-chromosome variant data sets limited the accuracy of diversity and TMRCA estimates obtained from them. The advent of next-generation sequencing, however, has removed this bias and allowed for the discovery of thousands of new variants for use in improving the Y-chromosome phylogeny and computing estimates that are more accurate. Here, we describe the high-coverage sequencing of the whole Y chromosome in a data set of 19 male Khoe-San individuals in comparison with existing whole Y-chromosome sequence data. Due to the increased resolution, we potentially resolve the source of haplogroup B-P70 in the Khoe-San, and reconcile recently published haplogroup A-M51 data with the most recent version of the ISOGG Y-chromosome phylogeny. Our results also improve the positioning of tentatively placed new branches of the ISOGG Y-chromosome phylogeny. The distribution of major Y-chromosome haplogroups in the Khoe-San and other African groups coincide with the emerging picture of African demographic history; with E-M2 linked to the agriculturalist Bantu expansion, E-M35 linked to pastoralist eastern African migrations, B-M112 linked to earlier east-south gene flow, A-M14 linked to shared ancestry with central African rainforest hunter-gatherers, and A-M51 potentially unique to the Khoe-San.

Variants of different Class I alcohol dehydrogenase (ADH) genes have been shown to be associated with an effect that is protective against alcoholism. Previous work from our laboratory has shown that the two sites showing the association are in linkage disequilibrium and has identified the ADH1B Arg47His site as causative, with the ADH1C Ile349Val site showing association only because of the disequilibrium. Here, we describe an initial study of the nature of linkage disequilibrium and genetic variation, in population samples from different regions of the world, in a larger segment of the ADH cluster (including the three Class I ADH genes and ADH7). Linkage disequilibrium across approximately 40 kb of the Class I ADH cluster is moderate to strong in all population samples that we studied. We observed nominally significant pairwise linkage disequilibrium, in some populations, between the ADH7 site and some Class I ADH sites, at moderate values and at a molecular distance as great as 100 kb. Our data indicate (1) that most ADH-alcoholism association studies have failed to consider many sites in the ADH cluster that may harbor etiologically significant alleles and (2) that the relevance of the various ADH sites will be population dependent. Some individual sites in the Class I ADH cluster show Fst values that are among the highest seen among several dozen unlinked sites that were studied in the same subset of populations. The high Fst values can be attributed to the discrepant frequencies of specific alleles in eastern Asia relative to those in other regions of the world. These alleles are part of a single haplotype that exists at high (65%) frequency only in the eastern-Asian samples. It seems unlikely that this haplotype, which is rare or unobserved in other populations, reached such high frequency because of random genetic drift alone.

Background: The current San and Khoe populations are remnant groups of a much larger and widely dispersed population of hunter-gatherers and pastoralists, who had exclusive occupation of southern Africa before the influx of Bantu-speakers from 2 ka (ka = kilo annum [thousand years] old/ago) and sea-borne immigrants within the last 350 years. Here we use mitochondrial DNA (mtDNA) to examine the population structure of various San and Khoe groups, including seven different Khoe-San groups (Ju/'hoansi, !Xun, /Gui+//Gana, Khwe, not equal Khomani, Nama and Karretjie People), three different Coloured groups and seven other comparative groups. MtDNA hyper variable segments I and II (HVS I and HVS II) together with selected mtDNA coding region SNPs were used to assign 538 individuals to 18 haplogroups encompassing 245 unique haplotypes. Data were further analyzed to assess haplogroup histories and the genetic affinities of the various San, Khoe and Coloured populations. Where possible, we tentatively contextualize the genetic trends through time against key trends known from the archaeological record. Results: The most striking observation from this study was the high frequencies of the oldest mtDNA haplogroups (L0d and L0k) that can be traced back in time to similar to 100 ka, found at high frequencies in Khoe-San and sampled Coloured groups. Furthermore, the L0d/k sub-haplogroups were differentially distributed in the different Khoe-San and Coloured groups and had different signals of expansion, which suggested different associated demographic histories. When populations were compared to each other, San groups from the northern parts of southern Africa (Ju speaking: !Xun, Ju/'hoansi and Khoe-speaking: /Gui+//Gana) grouped together and southern groups (historically Tuu speaking: not equal Khomani and Karretjie People and some Coloured groups) grouped together. The Khoe group (Nama) clustered with the southern Khoe-San and Coloured groups. The Khwe mtDNA profile was very different from other Khoe-San groups with high proportions of Bantu-speaking admixture but also unique distributions of other mtDNA lineages. Conclusions: On the whole, the research reported here presented new insights into the multifaceted demographic history that shaped the existing genetic landscape of the Khoe-San and Coloured populations of southern Africa.

Background The ability of the Y chromosome to retain a record of its evolution has seen it become an essential tool of molecular anthropology. In the last few years, however, it has also found use in forensic genetics, providing information on the geographic origin of individuals. This has been aided by the development of efficient screening methods and an increased knowledge of geographic distribution. In this study, we describe the development of single base extension assays used to resolve 61 Y chromosome haplogroups, mainly within haplogroups A, B and E, found in Africa. Results Seven multiplex assays, which incorporated 60 Y chromosome markers, were developed. These resolved Y chromosomes to 61 terminal branches of the major African haplogroups A, B and E, while also including a few Eurasian haplogroups found occasionally in African males. Following its validation, the assays were used to screen 683 individuals from Southern Africa, including south eastern Bantu speakers (BAN), Khoe-San (KS) and South African Whites (SAW). Of the 61 haplogroups that the assays collectively resolved, 26 were found in the 683 samples. While haplogroup sharing was common between the BAN and KS, the frequencies of these haplogroups varied appreciably. Both groups showed low levels of assimilation of Eurasian haplogroups and only two individuals in the SAW clearly had Y chromosomes of African ancestry. Conclusions The use of these single base extension assays in screening increased haplogroup resolution and sampling throughput, while saving time and DNA. Their use, together with the screening of short tandem repeat markers would considerably improve resolution, thus refining the geographic ancestry of individuals.

Behar, Doron M. et al.-- The Genographic Consortium, Different lines of evidence point to the resettlement of much of western and central Europe by populations from the Franco-Cantabrian region during the Late Glacial and Postglacial periods. In this context, the study of the genetic diversity of contemporary Basques, a population located at the epicenter of the Franco-Cantabrian region, is particularly useful because they speak a non-Indo-European language that is considered to be a linguistic isolate. In contrast with genome-wide analysis and Y chromosome data, where the problem of poor time estimates remains, a new timescale has been established for the human mtDNA and makes this genome the most informative marker for studying European prehistory. Here, we aim to increase knowledge of the origins of the Basque people and, more generally, of the role of the Franco-Cantabrian refuge in the postglacial repopulation of Europe. We thus characterize the maternal ancestry of 908 Basque and non-Basque individuals from the Basque Country and immediate adjacent regions and, by sequencing 420 complete mtDNA genomes, we focused on haplogroup H. We identified six mtDNA haplogroups, H1j1, H1t1, H2a5a1, H1av1, H3c2a, and H1e1a1, which are autochthonous to the Franco-Cantabrian region and, more specifically, to Basque-speaking populations. We detected signals of the expansion of these haplogroups at ∼4,000 years before present (YBP) and estimated their separation from the pan-European gene pool at ∼8,000 YBP, antedating the Indo-European arrival to the region. Our results clearly support the hypothesis of a partial genetic continuity of contemporary Basques with the preceding Paleolithic/Mesolithic settlers of their homeland., This work was supported by the Institut Pasteur, National Geographic, and the Histoire des populations et variation linguistique dans les Pyrénées de l'Ouest project, which received funding from the Conseil Régional d'Aquitaine, the Conseil Général des Pyrénées-Atlantiques, the Conseil des Elus du Pays-Basque, and the Centre National de la Recherche Scientifique interdisciplinary program Origine de l'Homme, des Langues et du Langage. This study also benefited from the support of Department of Hematology, Centre Hospitalier de la Côte Basque, in Bayonne, and Association Sang 64.