The genetic legacy of the expansion of Bantu-speaking peoples in Africa.

The expansion of people speaking Bantu languages is the most dramatic demographic event in Late Holocene Africa and fundamentally reshaped the linguistic, cultural and biological landscape of the continent1-7. With a comprehensive genomic dataset, including newly generated data of modern-day and ancient DNA from previously unsampled regions in Africa, we contribute insights into this expansion that started 6,000-4,000 years ago in western Africa. We genotyped 1,763 participants, including 1,526 Bantu speakers from 147 populations across 14 African countries, and generated whole-genome sequences from 12 Late Iron Age individuals8. We show that genetic diversity amongst Bantu-speaking populations declines with distance from western Africa, with current-day Zambia and the Democratic Republic of Congo as possible crossroads of interaction. Using spatially explicit methods9 and correlating genetic, linguistic and geographical data, we provide cross-disciplinary support for a serial-founder migration model. We further show that Bantu speakers received significant gene flow from local groups in regions they expanded into. Our genetic dataset provides an exhaustive modern-day African comparative dataset for ancient DNA studies10 and will be important to a wide range of disciplines from science and humanities, as well as to the medical sector studying human genetic variation and health in African and African-descendant populations.

Male-biased migration from East Africa introduced pastoralism into southern Africa.

BACKGROUND: Hunter-gatherer lifestyles dominated the southern African landscape up to ~ 2000 years ago, when herding and farming groups started to arrive in the area. First, herding and livestock, likely of East African origin, appeared in southern Africa, preceding the arrival of the large-scale Bantu-speaking agro-pastoralist expansion that introduced West African-related genetic ancestry into the area. Present-day Khoekhoe-speaking Namaqua (or Nama in short) pastoralists show high proportions of East African admixture, linking the East African ancestry with Khoekhoe herders. Most other historical Khoekhoe populations have, however, disappeared over the last few centuries and their contribution to the genetic structure of present-day populations is not well understood. In our study, we analyzed genome-wide autosomal and full mitochondrial data from a population who trace their ancestry to the Khoekhoe-speaking Hessequa herders from the southern Cape region of what is now South Africa. RESULTS: We generated genome-wide data from 162 individuals and mitochondrial DNA data of a subset of 87 individuals, sampled in the Western Cape Province, South Africa, where the Hessequa population once lived. Using available comparative data from Khoe-speaking and related groups, we aligned genetic date estimates and admixture proportions to the archaeological proposed dates and routes for the arrival of the East African pastoralists in southern Africa. We identified several Afro-Asiatic-speaking pastoralist groups from Ethiopia and Tanzania who share high affinities with the East African ancestry present in southern Africa. We also found that the East African pastoralist expansion was heavily male-biased, akin to a pastoralist migration previously observed on the genetic level in ancient Europe, by which Pontic-Caspian Steppe pastoralist groups represented by the Yamnaya culture spread across the Eurasian continent during the late Neolithic/Bronze Age. CONCLUSION: We propose that pastoralism in southern Africa arrived through male-biased migration of an East African Afro-Asiatic-related group(s) who introduced new subsistence and livestock practices to local southern African hunter-gatherers. Our results add to the understanding of historical human migration and mobility in Africa, connected to the spread of food-producing and livestock practices.

Y-Chromosome Variation in Southern African Khoe-San Populations Based on Whole-Genome Sequences.

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.

Khoe-San Genomes Reveal Unique Variation and Confirm the Deepest Population Divergence in Homo sapiens.

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.

Global Statement on Air Pollution and Health: Opportunities for Africa.

The editorial speaks to the Global Statement on Air Pollution and Health and How it may assist African countries to eliminate air pollution-related health impacts.

Whole-genome sequence analysis of a Pan African set of samples reveals archaic gene flow from an extinct basal population of modern humans into sub-Saharan populations.

BACKGROUND: Population demography and gene flow among African groups, as well as the putative archaic introgression of ancient hominins, have been poorly explored at the genome level. RESULTS: Here, we examine 15 African populations covering all major continental linguistic groups, ecosystems, and lifestyles within Africa through analysis of whole-genome sequence data of 21 individuals sequenced at deep coverage. We observe a remarkable correlation among genetic diversity and geographic distance, with the hunter-gatherer groups being more genetically differentiated and having larger effective population sizes throughout most modern-human history. Admixture signals are found between neighbor populations from both hunter-gatherer and agriculturalists groups, whereas North African individuals are closely related to Eurasian populations. Regarding archaic gene flow, we test six complex demographic models that consider recent admixture as well as archaic introgression. We identify the fingerprint of an archaic introgression event in the sub-Saharan populations included in the models (~ 4.0% in Khoisan, ~ 4.3% in Mbuti Pygmies, and ~ 5.8% in Mandenka) from an early divergent and currently extinct ghost modern human lineage. CONCLUSION: The present study represents an in-depth genomic analysis of a Pan African set of individuals, which emphasizes their complex relationships and demographic history at population level.

Genetic variants in SEC16B are associated with body composition in black South Africans.

OBJECTIVE: The latest genome-wide association studies of obesity-related traits have identified several genetic loci contributing to body composition (BC). These findings have not been robustly replicated in African populations, therefore, this study aimed to assess whether European BC-associated gene loci played a similar role in a South African black population. METHODS: A replication and fine-mapping study was performed in participants from the Birth to Twenty cohort (N = 1,926) using the Metabochip. Measurements included body mass index (BMI), waist and hip circumference, waist-to-hip ratio (WHR), total fat mass, total lean mass and percentage fat mass (PFM). RESULTS: SNPs in several gene loci, including SEC16B (Padj < 9.48 × 10-7), NEGR1 (Padj < 1.64 × 10-6), FTO (Padj < 2.91 × 10-5), TMEM18 (Padj < 2.27 × 10-5), and WARS2 (Padj < 3.25 × 10-5) were similarly associated (albeit not at array-wide signficance (P ≤ 6.7 × 10-7) with various phenotypes including fat mass, PFM, WHR linked to BC in this African cohort, however the associations were driven by different sentinel SNPs. More importantly, DXA-derived BC measures revealed stronger genetic associations than simple anthropometric measures. Association signals generated in this study were shared by European and African populations, as well as unique to this African cohort. Moreover, sophisticated estimates like DXA measures enabled an enhanced characterisation of genetic associations for BC traits. CONCLUSION: Results from this study suggest that in-depth genomic studies in larger African cohorts may reveal novel SNPs for body composition and adiposity, which will provide greater insight into the aetiology of obesity.

Whole-genome sequencing for an enhanced understanding of genetic variation among South Africans.

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 < 10-6) differentiation, and FST analysis identifies regions with high divergence. The Coloured individuals show evidence of varying proportions of admixture with Khoesan, Bantu-speakers, Europeans, and populations from the Indian sub-continent. Whole-genome sequencing data reveal extensive genomic diversity, increasing our understanding of the complex and region-specific history of African populations and highlighting its potential impact on biomedical research and genetic susceptibility to disease.

Southern African ancient genomes estimate modern human divergence to 350,000 to 260,000 years ago.

Southern Africa is consistently placed as a potential region for the evolution of Homo sapiens We present genome sequences, up to 13x coverage, from seven ancient individuals from KwaZulu-Natal, South Africa. The remains of three Stone Age hunter-gatherers (about 2000 years old) were genetically similar to current-day southern San groups, and those of four Iron Age farmers (300 to 500 years old) were genetically similar to present-day Bantu-language speakers. We estimate that all modern-day Khoe-San groups have been influenced by 9 to 30% genetic admixture from East Africans/Eurasians. Using traditional and new approaches, we estimate the first modern human population divergence time to between 350,000 and 260,000 years ago. This estimate increases the deepest divergence among modern humans, coinciding with anatomical developments of archaic humans into modern humans, as represented in the local fossil record.

Adaptation to infectious disease exposure in indigenous Southern African populations.

Genetic analyses can provide information about human evolutionary history that cannot always be gleaned from other sources. We evaluated evidence of selective pressure due to introduced infectious diseases in the genomes of two indigenous southern African San groups-the ‡Khomani who had abundant contact with other people migrating into the region and the more isolated Ju|'hoansi. We used a dual approach to test for increased selection on immune genes compared with the rest of the genome in these groups. First, we calculated summary values of statistics that measure genomic signatures of adaptation to contrast selection signatures in immune genes and all genes. Second, we located regions of the genome with extreme values of three selection statistics and examined these regions for enrichment of immune genes. We found stronger and more abundant signals of selection in immune genes in the ‡Khomani than in the Ju|'hoansi. We confirm this finding within each population to avoid effects of different demographic histories of the two populations. We identified eight immune genes that have potentially been targets of strong selection in the ‡Khomani, whereas in the Ju|'hoansi, no immune genes were found in the genomic regions with the strongest signals of selection. We suggest that the more abundant signatures of selection at immune genes in the ‡Khomani could be explained by their more frequent contact with immigrant groups, which likely led to increased exposure and adaptation to introduced infectious diseases.

The disappearing San of southeastern Africa and their genetic affinities.

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.

Could we offer mitochondrial donation or similar assisted reproductive technology to South African patients with mitochondrial DNA disease?

The decision of the UK House of Commons in 2015 to endorse the use of pioneering in vitro fertilisation techniques to protect future generations from the risk of mitochondrial DNA (mtDNA) disease has sparked worldwide controversy and debate. The availability of such technologies could benefit women at risk of transmitting deleterious mutations. MtDNA disease certainly occurs in South Africa (SA) in all population groups. However, diagnostic strategies and practices for identifying individuals who would benefit from technologies such as IVF have in the past been suboptimal in this country. New developments in the molecular diagnostic services available to SA patients, as well as better education of referring clinicians and the implementation of more structured, population-appropriate diagnostic strategies, may open the floor to this debate in SA.

Implications of direct-to-consumer whole-exome sequencing in South Africa.

This editorial examines a number of vitally important ethical, legal and scientific concerns that have to be addressed to ensure proper and ethical implementation of direct-to-consumer whole-exome sequencing in South Africa. Individuals taking part in this endeavour must be fully informed of the positive and negative sequelae.

A genomic portrait of haplotype diversity and signatures of selection in indigenous southern African populations.

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.

Ethical issues in genomic research on the African continent: experiences and challenges to ethics review committees.

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.

Natural selection for the Duffy-null allele in the recently admixed people of Madagascar.

While gene flow between distantly related populations is increasingly recognized as a potentially important source of adaptive genetic variation for humans, fully characterized examples are rare. In addition, the role that natural selection for resistance to vivax malaria may have played in the extreme distribution of the protective Duffy-null allele, which is nearly completely fixed in mainland sub-Saharan Africa and absent elsewhere, is controversial. We address both these issues by investigating the evolution of the Duffy-null allele in the Malagasy, a recently admixed population with major ancestry components from both East Asia and mainland sub-Saharan Africa. We used genome-wide genetic data and extensive computer simulations to show that the high frequency of the Duffy-null allele in Madagascar can only be explained in the absence of positive natural selection under extreme demographic scenarios involving high genetic drift. However, the observed genomic single nucleotide polymorphism diversity in the Malagasy is incompatible with such extreme demographic scenarios, indicating that positive selection for the Duffy-null allele best explains the high frequency of the allele in Madagascar. We estimate the selection coefficient to be 0.066. Because vivax malaria is endemic to Madagascar, this result supports the hypothesis that malaria resistance drove fixation of the Duffy-null allele in mainland sub-Saharan Africa.

Geographic population structure analysis of worldwide human populations infers their biogeographical origins.

The search for a method that utilizes biological information to predict humans' place of origin has occupied scientists for millennia. Over the past four decades, scientists have employed genetic data in an effort to achieve this goal but with limited success. While biogeographical algorithms using next-generation sequencing data have achieved an accuracy of 700 km in Europe, they were inaccurate elsewhere. Here we describe the Geographic Population Structure (GPS) algorithm and demonstrate its accuracy with three data sets using 40,000-130,000 SNPs. GPS placed 83% of worldwide individuals in their country of origin. Applied to over 200 Sardinians villagers, GPS placed a quarter of them in their villages and most of the rest within 50 km of their villages. GPS's accuracy and power to infer the biogeography of worldwide individuals down to their country or, in some cases, village, of origin, underscores the promise of admixture-based methods for biogeography and has ramifications for genetic ancestry testing.

Lactase persistence alleles reveal partial East African ancestry of southern African Khoe pastoralists.

The ability to digest milk into adulthood, lactase persistence (LP), as well as specific genetic variants associated with LP, is heterogeneously distributed in global populations. These variants were most likely targets of selection when some populations converted from hunter-gatherer to pastoralist or farming lifestyles. Specific LP polymorphisms are associated with particular geographic regions and populations; 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.