Strong Effect of Demographic Changes on Tuberculosis Susceptibility in South Africa.

South Africa is among the world's top eight TB burden countries, and despite a focus on HIV-TB co-infection, most of the population living with TB are not HIV co-infected. The disease is endemic across the country with 80-90% exposure by adulthood. We investigated epidemiological risk factors for tuberculosis (TB) in the Northern Cape Province, South Africa: an understudied TB endemic region with extreme TB incidence (645/100,000) and the lowest provincial population density. We leveraged the population's high TB incidence and community transmission to design a case-control study with population-based controls, reflecting similar mechanisms of exposure between the groups. We recruited 1,126 participants with suspected TB from 12 community health clinics, and generated a cohort of 878 individuals (cases =374, controls =504) after implementing our enrollment criteria. All participants were GeneXpert Ultra tested for active TB by a local clinic. We assessed important risk factors for active TB using logistic regression and random forest modeling. Additionally, a subset of individuals were genotyped to determine genome-wide ancestry components. Male gender had the strongest effect on TB risk (OR: 2.87 [95% CI: 2.1-3.8]); smoking and alcohol consumption did not significantly increase TB risk. We identified two interactions: age by socioeconomic status (SES) and birthplace by residence locality on TB risk (OR = 3.05, p = 0.016) - where rural birthplace but town residence was the highest risk category. Finally, participants had a majority Khoe-San ancestry, typically greater than 50%. Epidemiological risk factors for this cohort differ from other global populations. The significant interaction effects reflect rapid changes in SES and mobility over recent generations and strongly impact TB risk in the Northern Cape of South Africa. Our models show that such risk factors combined explain 16% of the variance (r2) in case/control status.

Transcriptomics and chromatin accessibility in multiple African population samples.

Mapping the functional human genome and impact of genetic variants is often limited to European-descendent population samples. To aid in overcoming this limitation, we measured gene expression using RNA sequencing in lymphoblastoid cell lines (LCLs) from 599 individuals from six African populations to identify novel transcripts including those not represented in the hg38 reference genome. We used whole genomes from the 1000 Genomes Project and 164 Maasai individuals to identify 8,881 expression and 6,949 splicing quantitative trait loci (eQTLs/sQTLs), and 2,611 structural variants associated with gene expression (SV-eQTLs). We further profiled chromatin accessibility using ATAC-Seq in a subset of 100 representative individuals, to identity chromatin accessibility quantitative trait loci (caQTLs) and allele-specific chromatin accessibility, and provide predictions for the functional effect of 78.9 million variants on chromatin accessibility. Using this map of eQTLs and caQTLs we fine-mapped GWAS signals for a range of complex diseases. Combined, this work expands global functional genomic data to identify novel transcripts, functional elements and variants, understand population genetic history of molecular quantitative trait loci, and further resolve the genetic basis of multiple human traits and disease.

Persistence of Matrilocal Postmarital Residence Across Multiple Generations in Southern Africa.

Factors such as subsistence turnover, warfare, or interaction between different groups can be major sources of cultural change in human populations. Global demographic shifts such as the transition to agriculture during the Neolithic and more recently the urbanization and globalization of the twentieth century have been major catalysts for cultural change. Here, we test whether cultural traits such as patri/matrilocality and postmarital migration persist in the face of social upheaval and gene flow during the past 150 years in postcolonial South Africa. The recent history of South Africa has seen major demographic shifts that resulted in the displacement and forced sedentism of indigenous Khoekhoe and San populations. During the expansion of the colonial frontier, the Khoe-San admixed with European colonists and enslaved individuals from West/Central Africa, Indonesia, and South Asia, introducing novel cultural norms. We conducted demographic interviews among Nama and Cederberg communities representing nearly 3,000 individuals across three generations. Despite the history of colonial expansion, and the subsequent incorporation of Khoe-San and Khoe-San-descendant communities into a colonial society with strong patrilocal norms, patrilocality is the least common postmarital residence pattern in our study populations today. Our results suggest that more recent forces of integration into the market economy are likely the primary drivers of change in the cultural traits examined in our study. Birthplace had a strong effect on an individual's odds of migration, distance moved, and postmarital residence form. These effects are at least partially explained by the population size of the birthplace. Our results suggest that market factors local to birthplaces are important drivers of residence decisions, although the frequency of matrilocal residence and a geographic and temporal cline in migration and residence patterns also indicate the persistence of some historic Khoe-San cultural traits in contemporary groups.

Predicting Environmental and Ecological Drivers of Human Population Structure.

Landscape, climate, and culture can all structure human populations, but few existing methods are designed to simultaneously disentangle among a large number of variables in explaining genetic patterns. We developed a machine learning method for identifying the variables which best explain migration rates, as measured by the coalescent-based program MAPS that uses shared identical by descent tracts to infer spatial migration across a region of interest. We applied our method to 30 human populations in eastern Africa with high-density single nucleotide polymorphism array data. The remarkable diversity of ethnicities, languages, and environments in this region offers a unique opportunity to explore the variables that shape migration and genetic structure. We explored more than 20 spatial variables relating to landscape, climate, and presence of tsetse flies. The full model explained ∼40% of the variance in migration rate over the past 56 generations. Precipitation, minimum temperature of the coldest month, and elevation were the variables with the highest impact. Among the three groups of tsetse flies, the most impactful was fusca which transmits livestock trypanosomiasis. We also tested for adaptation to high elevation among Ethiopian populations. We did not identify well-known genes related to high elevation, but we did find signatures of positive selection related to metabolism and disease. We conclude that the environment has influenced the migration and adaptation of human populations in eastern Africa; the remaining variance in structure is likely due in part to cultural or other factors not captured in our model.

A weakly structured stem for human origins in Africa.

Despite broad agreement that Homo sapiens originated in Africa, considerable uncertainty surrounds specific models of divergence and migration across the continent1. Progress is hampered by a shortage of fossil and genomic data, as well as variability in previous estimates of divergence times1. Here we seek to discriminate among such models by considering linkage disequilibrium and diversity-based statistics, optimized for rapid, complex demographic inference2. We infer detailed demographic models for populations across Africa, including eastern and western representatives, and newly sequenced whole genomes from 44 Nama (Khoe-San) individuals from southern Africa. We infer a reticulated African population history in which present-day population structure dates back to Marine Isotope Stage 5. The earliest population divergence among contemporary populations occurred 120,000 to 135,000 years ago and was preceded by links between two or more weakly differentiated ancestral Homo populations connected by gene flow over hundreds of thousands of years. Such weakly structured stem models explain patterns of polymorphism that had previously been attributed to contributions from archaic hominins in Africa2-7. In contrast to models with archaic introgression, we predict that fossil remains from coexisting ancestral populations should be genetically and morphologically similar, and that only an inferred 1-4% of genetic differentiation among contemporary human populations can be attributed to genetic drift between stem populations. We show that model misspecification explains the variation in previous estimates of divergence times, and argue that studying a range of models is key to making robust inferences about deep history.

Impact of cross-ancestry genetic architecture on GWASs in admixed populations.

Genome-wide association studies (GWASs) have identified thousands of variants for disease risk. These studies have predominantly been conducted in individuals of European ancestries, which raises questions about their transferability to individuals of other ancestries. Of particular interest are admixed populations, usually defined as populations with recent ancestry from two or more continental sources. Admixed genomes contain segments of distinct ancestries that vary in composition across individuals in the population, allowing for the same allele to induce risk for disease on different ancestral backgrounds. This mosaicism raises unique challenges for GWASs in admixed populations, such as the need to correctly adjust for population stratification. In this work we quantify the impact of differences in estimated allelic effect sizes for risk variants between ancestry backgrounds on association statistics. Specifically, while the possibility of estimated allelic effect-size heterogeneity by ancestry (HetLanc) can be modeled when performing a GWAS in admixed populations, the extent of HetLanc needed to overcome the penalty from an additional degree of freedom in the association statistic has not been thoroughly quantified. Using extensive simulations of admixed genotypes and phenotypes, we find that controlling for and conditioning effect sizes on local ancestry can reduce statistical power by up to 72%. This finding is especially pronounced in the presence of allele frequency differentiation. We replicate simulation results using 4,327 African-European admixed genomes from the UK Biobank for 12 traits to find that for most significant SNPs, HetLanc is not large enough for GWASs to benefit from modeling heterogeneity in this way.

Epidemiological correlates of overweight and obesity in the Northern Cape Province, South Africa.

Background: In the past several decades, obesity has become a major public health issue worldwide, associated with increased rates of chronic disease and death. Like many developing nations, South Africa is experiencing rapid increases in BMI, and as a result, evidence-based preventive strategies are needed to reduce the increasing burden of overweight and obesity. This study aimed to determine the prevalence and predictors of overweight and obesity among a multi-ethnic cohort from the rural Northern Cape of South Africa. Methods: These data were collected as part of a tuberculosis (TB) case-control study, with 395 healthy control participants included in the final analysis. Overweight and obesity were defined according to WHO classification. Multivariate linear models of BMI were generated using sex, age, education level, smoking, alcohol consumption, and diabetes as predictor variables. We also used multivariable logistic regression analysis to assess the relationship of these factors with overweight and obesity. Results: The average BMI in our study cohort was 25.2. The prevalence of overweight was 18.0% and the prevalence of obesity was 25.0%. We find that female sex, being older, having more years of formal education, having diabetes, and being in a rural area are all positively associated with BMI in our dataset. Women (OR = 5.6, 95% CI [3.3-9.8]), rural individuals (OR = 3.3, 95% CI [1.9-6.0]), older individuals (OR = 1.02, 95% CI [1-1.04]), and those with more years of education (OR = 1.2, 95% CI [1.09-1.32]) were all more likely to be overweight or obese. Alternatively, being a smoker is negatively associated with BMI and decreases one's odds of being overweight or obese (OR = 0.28, 95% CI [0.16-0.46]). Conclusions: We observed a high prevalence of overweight and obesity in this study. The odds of being overweight and obese were higher in women, those living in rural areas, and those with more education, and increases with age. Community-based interventions to control obesity in this region should pay special attention to these groups.

Examination of runs of homozygosity in relation to height in an endogamous Namibian population.

OBJECTIVES: Height is a complex, highly heritable polygenic trait subject to both genetic composition and environmental influences. Recent studies suggest that a large proportion of height heritability is determined by the cumulative effect of many low allele frequency variants across the genome. Previous research has also identified an inverse relationship between height and runs of homozygosity (ROH); however, this has yet to be examined within African populations. We aim to identify this association within the Himba, an endogamous Namibian population who are recently bottlenecked, resulting in elevated haplotype sharing and increased homozygosity. MATERIALS AND METHODS: Here, we calculate the fraction of the genome composed of long runs of homozygosity (FROH) in a sample of 245 adults and use mixed effects models to assess its effect on height. RESULTS: We find that Himba adults exhibit increased homozygosity. However, in contrast to previous studies in other populations, we do not find a significant effect of FROH on height within the Himba. We further estimated heritability of height, noting both an enrichment of distant relatives and greater developmental homogeneity across households; we find that h g 2 = 0.59 (SE ± 0.146), comparable to estimates reported in Europeans. DISCUSSION: Our results may be due to other environmental variables we were not able to include, measurement error, or low statistical power, but may also imply that phenotypic expression resulting from increased homozygosity may vary from population to population.

Impact of cross-ancestry genetic architecture on GWAS in admixed populations.

Genome-wide association studies (GWAS) have identified thousands of variants for disease risk. These studies have predominantly been conducted in individuals of European ancestries, which raises questions about their transferability to individuals of other ancestries. Of particular interest are admixed populations, usually defined as populations with recent ancestry from two or more continental sources. Admixed genomes contain segments of distinct ancestries that vary in composition across individuals in the population, allowing for the same allele to induce risk for disease on different ancestral backgrounds. This mosaicism raises unique challenges for GWAS in admixed populations, such as the need to correctly adjust for population stratification to balance type I error with statistical power. In this work we quantify the impact of differences in estimated allelic effect sizes for risk variants between ancestry backgrounds on association statistics. Specifically, while the possibility of estimated allelic effect-size heterogeneity by ancestry (HetLanc) can be modeled when performing GWAS in admixed populations, the extent of HetLanc needed to overcome the penalty from an additional degree of freedom in the association statistic has not been thoroughly quantified. Using extensive simulations of admixed genotypes and phenotypes we find that modeling HetLanc in its absence reduces statistical power by up to 72%. This finding is especially pronounced in the presence of allele frequency differentiation. We replicate simulation results using 4,327 African-European admixed genomes from the UK Biobank for 12 traits to find that for most significant SNPs HetLanc is not large enough for GWAS to benefit from modeling heterogeneity.

The recombination landscape of the Khoe-San likely represents the upper limits of recombination divergence in humans.

BACKGROUND: Recombination maps are important resources for epidemiological and evolutionary analyses; however, there are currently no recombination maps representing any African population outside of those with West African ancestry. We infer the demographic history for the Nama, an indigenous Khoe-San population of southern Africa, and derive a novel, population-specific recombination map from the whole genome sequencing of 54 Nama individuals. We hypothesise that there are no publicly available recombination maps representative of the Nama, considering the deep population divergence and subsequent isolation of the Khoe-San from other African groups. RESULTS: We show that the recombination landscape of the Nama does not cluster with any continental groups with publicly available representative recombination maps. Finally, we use selection scans as an example of how fine-scale differences between the Nama recombination map and the combined Phase II HapMap recombination map can impact the outcome of selection scans. CONCLUSIONS: Fine-scale differences in recombination can meaningfully alter the results of a selection scan. The recombination map we infer likely represents an upper bound on the extent of divergence we expect to see for a recombination map in humans and would be of interest to any researcher that wants to test the sensitivity of population genetic or GWAS analysis to recombination map input.

Hunter-gatherer genomes reveal diverse demographic trajectories during the rise of farming in Eastern Africa.

The fate of hunting and gathering populations following the rise of agriculture and pastoralism remains a topic of debate in the study of human prehistory. Studies of ancient and modern genomes have found that autochthonous groups were largely replaced by expanding farmer populations with varying levels of gene flow, a characterization that is influenced by the almost universal focus on the European Neolithic.1-5 We sought to understand the demographic impact of an ongoing cultural transition to farming in Southwest Ethiopia, one of the last regions in Africa to experience such shifts.6 Importantly, Southwest Ethiopia is home to several of the world's remaining hunter-gatherer groups, including the Chabu people, who are currently transitioning away from their traditional mode of subsistence.7 We generated genome-wide data from the Chabu and four neighboring populations, the Majang, Shekkacho, Bench, and Sheko, to characterize their genetic ancestry and estimate their effective population sizes over the last 60 generations. We show that the Chabu are a distinct population closely related to ancient people who occupied Southwest Ethiopia >4,500 years ago. Furthermore, the Chabu are undergoing a severe population bottleneck, which began approximately 1,400 years ago. By analyzing eleven Eastern African populations, we find evidence for divergent demographic trajectories among hunter-gatherer-descendant groups. Our results illustrate that although foragers respond to encroaching agriculture and pastoralism with multiple strategies, including cultural adoption of agropastoralism, gene flow, and economic specialization, they often face population decline.

Admixed Populations Improve Power for Variant Discovery and Portability in Genome-Wide Association Studies.

Genome-wide association studies (GWAS) are primarily conducted in single-ancestry settings. The low transferability of results has limited our understanding of human genetic architecture across a range of complex traits. In contrast to homogeneous populations, admixed populations provide an opportunity to capture genetic architecture contributed from multiple source populations and thus improve statistical power. Here, we provide a mechanistic simulation framework to investigate the statistical power and transferability of GWAS under directional polygenic selection or varying divergence. We focus on a two-way admixed population and show that GWAS in admixed populations can be enriched for power in discovery by up to 2-fold compared to the ancestral populations under similar sample size. Moreover, higher accuracy of cross-population polygenic score estimates is also observed if variants and weights are trained in the admixed group rather than in the ancestral groups. Common variant associations are also more likely to replicate if first discovered in the admixed group and then transferred to an ancestral population, than the other way around (across 50 iterations with 1,000 causal SNPs, training on 10,000 individuals, testing on 1,000 in each population, p = 3.78e-6, 6.19e-101, ∼0 for FST = 0.2, 0.5, 0.8, respectively). While some of these FST values may appear extreme, we demonstrate that they are found across the entire phenome in the GWAS catalog. This framework demonstrates that investigation of admixed populations harbors significant advantages over GWAS in single-ancestry cohorts for uncovering the genetic architecture of traits and will improve downstream applications such as personalized medicine across diverse populations.

Inferring archaic introgression from hominin genetic data.

Questions surrounding the timing, extent, and evolutionary consequences of archaic admixture into human populations have a long history in evolutionary anthropology. More recently, advances in human genetics, particularly in the field of ancient DNA, have shed new light on the question of whether or not Homo sapiens interbred with other hominin groups. By the late 1990s, published genetic work had largely concluded that archaic groups made no lasting genetic contribution to modern humans; less than a decade later, this conclusion was reversed following the successful DNA sequencing of an ancient Neanderthal. This reversal of consensus is noteworthy, but the reasoning behind it is not widely understood across all academic communities. There remains a communication gap between population geneticists and paleoanthropologists. In this review, we endeavor to bridge this gap by outlining how technological advancements, new statistical methods, and notable controversies ultimately led to the current consensus.

Inferring recombination patterns in African populations.

Although several high-resolution recombination maps exist for European-descent populations, the recombination landscape of African populations remains relatively understudied. Given that there is high genetic divergence among groups in Africa, it is possible that recombination hotspots also diverge significantly. Both limitations and opportunities exist for developing recombination maps for these populations. In this review, we discuss various recombination inference methods, and the strengths and weaknesses of these methods in analyzing recombination in African-descent populations. Furthermore, we provide a decision tree and recommendations for which inference method to use in various research contexts. Establishing an appropriate methodology for recombination rate inference in a particular study will improve the accuracy of various downstream analyses including but not limited to local ancestry inference, haplotype phasing, fine-mapping of GWAS loci and genome assemblies.

The ethics and logistics of field-based genetic paternity studies.

The rapidly decreasing costs of generating genetic data sequencing and the ease of new DNA collection technologies have opened up new opportunities for anthropologists to conduct field-based genetic studies. An exciting aspect of this work comes from linking genetic data with the kinds of individual-level traits evolutionary anthropologists often rely on, such as those collected in long-term demographic and ethnographic studies. However, combining these two types of data raises a host of ethical questions related to the collection, analysis and reporting of such data. Here we address this conundrum by examining one particular case, the collection and analysis of paternity data. We are particularly interested in the logistics and ethics involved in genetic paternity testing in the localized settings where anthropologists often work. We discuss the particular issues related to paternity testing in these settings, including consent and disclosure, consideration of local identity and beliefs and developing a process of continued community engagement. We then present a case study of our own research in Namibia, where we developed a multi-tiered strategy for consent and community engagement, built around a double-blind procedure for data collection, analysis and reporting.

Diversity of KIR, HLA Class I, and Their Interactions in Seven Populations of Sub-Saharan Africans.

HLA class I and KIR sequences were determined for Dogon, Fulani, and Baka populations of western Africa, Mbuti of central Africa, and Datooga, Iraqw, and Hadza of eastern Africa. Study of 162 individuals identified 134 HLA class I alleles (41 HLA-A, 60 HLA-B, and 33 HLA-C). Common to all populations are three HLA-C alleles (C1+C*07:01, C1+C*07:02, and C2+C*06:02) but no HLA-A or -B Unexpectedly, no novel HLA class I was identified in these previously unstudied and anthropologically distinctive populations. In contrast, of 227 KIR detected, 22 are present in all seven populations and 28 are novel. A high diversity of HLA A-C-B haplotypes was observed. In six populations, most haplotypes are represented just once. But in the Hadza, a majority of haplotypes occur more than once, with 2 having high frequencies and 10 having intermediate frequencies. The centromeric (cen) part of the KIR locus exhibits an even balance between cenA and cenB in all seven populations. The telomeric (tel) part has an even balance of telA to telB in East Africa, but this changes across the continent to where telB is vestigial in West Africa. All four KIR ligands (A3/11, Bw4, C1, and C2) are present in six of the populations. HLA haplotypes of the Iraqw and Hadza encode two KIR ligands, whereas the other populations have an even balance between haplotypes encoding one and two KIR ligands. Individuals in these African populations have a mean of 6.8-8.4 different interactions between KIR and HLA class I, compared with 2.9-6.5 for non-Africans.