Summary Approximately 15 genes have been directly associated with skin pigmentation variation in humans, leading to its characterization as a relatively simple trait. However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed with genetic architecture varying by latitude. We investigate polygenicity in the KhoeSan, populations indigenous to southern Africa, who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but known pigmentation loci explain only a small fraction of the variance. Rather, baseline skin pigmentation is a complex, polygenic trait in the KhoeSan. Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13 using a genome-wide association approach complemented by targeted resequencing. By considering diverse, under-studied African populations, we show how the architecture of skin pigmentation can vary across humans subject to different local evolutionary pressures.

The functions of human NK cells in defense against pathogens and placental development during reproduction are modulated by interactions of killer cell Ig-like receptors (KIRs) with HLA-A, -B and -C class I ligands. Both receptors and ligands are highly polymorphic and exhibit extensive differences between human populations. Indigenous to southern Africa are the KhoeSan, the most ancient group of modern human populations, who have highest genomic diversity worldwide. We studied two KhoeSan populations, the Nama pastoralists and the ≠Khomani San hunter-gatherers. Comprehensive next-generation sequence analysis of ,, and and all genes identified 248 different and 137, which assort into ∼200 haplotypes for each gene family. All 74 Nama and 78 ≠Khomani San studied have different genotypes. Numerous novel alleles were identified, including three arising by intergenic recombination. On average, KhoeSan individuals have seven to eight pairs of interacting KIR and HLA class I ligands, the highest diversity and divergence of polymorphic NK cell receptors and ligands observed to date. In this context of high genetic diversity, both the Nama and the ≠Khomani San have an unusually conserved, centromeric haplotype that has arisen to high frequency and is different in the two KhoeSan populations. Distinguishing these haplotypes are independent mutations in , which both prevent KIR2DL1 from functioning as an inhibitory receptor for C2 HLA-C. The relatively high frequency of C2 HLA-C in the Nama and the ≠Khomani San appears to have led to natural selection against strong inhibitory C2-specific KIR.

Aging is associated with widespread changes in genome-wide patterns of DNA methylation. Thousands of CpG sites whose tissue-specific methylation levels are strongly correlated with chronological age have been previously identified. However, the majority of these studies have focused primarily on cosmopolitan populations living in the developed world; it is not known if age-related patterns of DNA methylation at these loci are similar across a broad range of human genetic and ecological diversity. We investigated genome-wide methylation patterns using saliva- and whole blood-derived DNA from two traditionally hunting and gathering African populations: the Baka of the western Central African rain forest and the ≠Khomani San of the South African Kalahari Desert. We identified hundreds of CpG sites whose methylation levels are significantly associated with age, thousands that are significant in a meta-analysis, and replicate trends previously reported in populations of non-African descent. We confirmed that an age-associated site in the promoter of the gene shows a remarkably congruent relationship with aging in humans, despite extensive genetic and environmental variation across populations. We also demonstrate that genotype state at methylation quantitative trait loci (meQTLs) can affect methylation trends at some age-associated CpG sites. Our study explores the relationship between CpG methylation and chronological age in populations of African hunter-gatherers, who rely on different diets across diverse ecologies. While many age-related CpG sites replicate across populations, we show that considering common genetic variation at meQTLs further improves our ability to detect previously identified age associations.

Fewer than 15 genes have been directly associated with skin pigmentation variation in humans, leading to its characterization as a relatively simple trait. However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed with genetic architecture varying by latitude. We investigate polygenicity in the Khoe and the San, populations indigenous to southern Africa, who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but that known pigmentation loci explain only a small fraction of the variance. Rather, baseline skin pigmentation is a complex, polygenic trait in the KhoeSan. Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13 using a genome-wide association approach complemented by targeted resequencing. By considering diverse, under-studied African populations, we show how the architecture of skin pigmentation can vary across humans subject to different local evolutionary pressures.

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30Aging is associated with widespread changes in genome-wide patterns of DNA methylation. 31Thousands of CpG sites whose tissue-specific methylation levels are strongly correlated with 32 chronological age have been previously identified. However, the majority of these studies have 33 focused primarily on cosmopolitan populations living in the developed world; it is not known if 34 age-related patterns of DNA methylation at these loci are similar across a broad range of human 35 genetic and ecological diversity. We investigated genome-wide methylation patterns using 36 saliva and whole blood derived DNA from two traditionally hunting and gathering African 37 populations: the Baka of the western Central African rainforest and the ≠Khomani San of the 38 South African Kalahari Desert. We identify hundreds of CpG sites whose methylation levels are 39 significantly associated with age, thousands that are significant in a meta-analysis, and replicate 40 trends previously reported in populations of non-African descent. We confirm that an age-41 associated site in the gene ELOVL2 shows a remarkably congruent relationship with aging in 42 humans, despite extensive genetic and environmental variation across populations. We also 43 demonstrate that genotype state at methylation quantitative trait loci (meQTLs) can affect 44 methylation trends at some known age-associated CpG sites. Our study explores the 45 relationship between CpG methylation and chronological age in populations of African hunter-46 gatherers, who rely on different diets across diverse ecologies. While many age-related CpG Introduction 51Aging is a degenerative process that is associated with changes in many molecular, cellular and 52 physiological factors. Identifying biomarkers associated with these changes is of great interest 53 to researchers for generating accurate predictions of both chronological and biological age in 54 humans for health care and forensic applications. Recent epigenomic studies have shown that 55 patterns of DNA methylation change substantially with chronological age: genome-wide 56 methylation levels decrease with increasing age, while particular genomic regions, such as CpG 57 islands, become more methylated with increasing age 1-5 . An epigenome-wide study examining 58 over 475,000 CpG sites found significant age-associated changes in DNA methylation at almost 59 one-third of sites 2 , demonstrating the extensive and stereotypic effect of aging on the human 60 epigenome. Many previously proposed molecular biomarkers for aging, including leukocyte 61 telomere length 6 , aspartic acid racemization 7 and expression levels of certain genes 8-10 , can be 62 challenging to apply for age estimation, due to lack of precision, instability over time, or difficulty 63 in measuring the quantity of interest 11 . In contrast, DNA methylation values measured from 64 relatively few (from three to up to a few hundred) age-associated CpG sites (a-CpGs) have 65 been shown to yield highly precise and accurate estimates of chronological age [12][13...

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.

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 20th century have been major catalysts for cultural change. Here, we test whether cultural traits such as patri/matrilocality and post-natal migration distance persist in the face of social upheaval and gene flow during the past 150 years in post-colonial 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 colonial society with strong patrilocal norms during the historic period, patrilocality is the least common post-marital 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 in our study. An individual’s birthplace had a strong effect on their odds of migration, distance moved, and post-marital 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.