UC Davis

Africa harbours the most deeply divergent human lineages among living populations and is exceptionally rich in phenotypic and genetic diversity. The first lineages to have split are uniquely found among southern African Khoe and San. Traditionally, Khoe and San peoples spoke click-consonant Khoisan languages and practiced pastoralism and hunter-gatherer subsistence strategies, respectively. Though culturally distinct, geneticists often refer to them collectively as “Khoe-San” because of their high genetic affinity. The ancestral signature we refer to as Khoe-San is unique in its genetic diversity, retaining high levels of heterozygosity and ancestral alleles relative to other populations.Today, there are few communities in southern Africa that still identify ethnically as Khoe or San. Inter- and intra-continental migrations over the past 3,000 years have profoundly shaped the region’s present ethnic mosaic, including signatures from a small East African pastoralist migration and the Bantu expansion. More recently over the last 400 years, European colonial impact has also given rise to highly heterogeneous Coloured communities, who constitute a sizable proportion of present-day South Africans (~42%). As a result of these multi-faceted migrations, it is not uncommon to find Khoe-San, European, South and Southeast Asian, and equatorial African ancestry among South African Coloured (SAC) communities (i.e. SAC are 5-way admixed). In this dissertation, I explore questions surrounding the contemporary phenotypic and genetic diversity of South Africa, with a focus on the SAC, one pastoral Khoekhoe-speaking group (Nama) and three San populations from South Africa (≠Khomani San) and Botswana (!Xoo and Ju|’hoansi).Chapter 1, Genetic Divergence within Southern Africa During the Later Stone Age, sets our understanding of Khoe-San genetics by providing a comprehensive review focused on uniparental lineage and genome-wide autosomal data divergence patterns within and between indigenous southern African Khoe and San groups. This chapter aims to contextualize the genetic diversity present in southern Africa during the Later Stone Age, a period when the 36,000-year-old Hofmeyr skull dates back to. This skull is impressively intact and might be one of the only anatomically modern humans remains in Sub-Saharan Africa that date to this time period, when modern humans were likely moving across the landscape. I conceptualize the effects that climatic changes may have on population migration. Additionally, I discuss the relationship between linguistics and genetics and also clarify differences in dating between the archaeological record and genetic evidence (i.e. population divergence vs. genetic divergence).Khoe and San groups from South Africa, Namibia, and Botswana have been well described in previously published studies, but we know little regarding the Coloured populations in southern Africa. Few SAC individuals have been extensively sampled in South Africa’s Western and Northern Cape provinces, with most published studies either focusing primarily on the Eastern Cape and Cape Town or relying on small Northern Cape sample sizes. While Cape Town lies in the Western Cape, it has been a focal point of recent migrations, and individuals sampled there may not be representative of SAC populations elsewhere. Chapter 2, Recovering the Pre‑Colonial Population Structure of Khoe‑San Descendant Populations, begins by characterizing the ancestral components present in the largest SAC cohort collected outside of Cape Town to date (n = 620). I put effort to distinguish which ancestral populations contributed these components into the population, while considering which populations are implicated by the historical record and previously published genetic research. For instance, the historical record surrounding the Dutch East Indian slave trade implicates Indonesia as a source of the Southeast Asian component found among the SAC, although we lack genetic evidence to support this. In this chapter, I estimate SAC global ancestry proportions using ADMIXTURE, characterize their genetic composition with principal component analysis (PCA), infer local ancestry across the genome, and plot ancestry‑specific multidimensional scaling to assess putative reference populations for each of the 5 ancestries. Khoe-San ancestry predominates across all SAC participants (>48%), indicating that these communities are primarily Khoe-San descendants.After grasping the genetic diversity that exists among the Khoe, San, and SAC participants in this study, I move on to characterizing the phenotypic diversity among the populations. Most pigmentation studies have focused on Eurasian populations, with only a handful having turned to describe skin and eye color genetic variation among continental Africans. Chapter 3, Assessing the effect of rs2470102 (SLC24A5) on iris pigmentation in southern Africa, reports a candidate gene study of the intronic variant rs2470102 in SLC24A5, a strong-effect and well-characterized pigmentation gene whose lightening allele rs2470102*A has been associated with lightening brown eye color among Cape Verdeans. I assess the locus’s putative influence on iris pigmentation among 262 individuals with high Khoe San ancestry and find the analysis largely underpowered due to fieldwork challenges in image collection and quality control, but the lessons learned inform recommendations for future iris image collection in remote regions.Lastly, I build on previously published skin pigmentation studies which focused on continental Africans, including the Khoe and San. These studies report the genetic architecture of skin pigmentation among continental Africans to be far more complex than in admixed populations or populations adapted at higher latitudes (such as Europeans or East Asians). In Chapter 4, Partitioned heritability estimates highlight genomic regions omitted by GWAS, I merge previously published Khoe and San data with newly collected SAC samples to run the largest Khoe-San focused skin pigmentation study (n = 1119). I begin by characterizing the heritability distribution across the genome by partitioning by chromosome. Partitioned heritability reveals enrichments on chromosomes 15, 5, 6 and 9, yet standard genome-wide association study (GWAS) reproduces only a previously known hit on chromosome 15, SLC24A5. Functional knockouts in zebrafish fail to validate any additional loci implicated in skin pigmentation. Moreover, I demonstrate how strong phenotype‑ancestry correlation reduces power to detect pigmentation variants and breaks assumptions used in polygenic scores (PGS) development and transferability. Finally, I argue for the development of novel approaches capable of identifying other contributors to the genetic architecture of skin pigmentation.Together, these studies illustrate how deep and recent demographic processes have molded genetic and phenotypic diversity in southern Africa and underscore the importance of population history and evolutionary forces in shaping the genetic architecture of skin pigmentation among Khoe-San and Khoe-San descendant communities.