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.

本研究报道了针对南部非洲原住民的全基因组高密度单核苷酸多态性（Single Nucleotide Polymorphism, SNP，约90万个位点）与拷贝数多态性（Copy Number Polymorphism, CNP）数据。本研究阐明了南部与东部非洲人群的遗传组成，其遗传来源涉及本土桑族（San）、使用尼日尔-刚果语系的族群以及欧亚血统人群之间的血统混合。该发现表明，开展全基因组关联研究（Genome-Wide Association Studies, GWAS）时需考虑群体分层问题，且混合映射定位（Admixture Mapping）或许可在这类人群中取得良好应用效果。本研究开发了一种策略，用于检测推定的群体混合事件发生前后的自然选择信号。多个基因组区域呈现出尼日尔-科尔多凡语系族群血统的异常富集，以及桑族与欧亚血统的异常缺失，这类区域被视作群体混合后自然选择的遗留信号。在混血的南部非洲原住民人群与其欧亚血统祖先人群之间，观测到多个等位基因频率差异显著的SNP位点。值得注意的是，在呈现选择信号的基因组区域内鉴定出的诸多候选基因，与南部非洲特有的高风险传染病密切相关，例如疟疾、流感、结核病以及人类免疫缺陷病毒/艾滋病（Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome, HIV/AIDS）。该结果提示，这类基因或许在该人群适应本土环境的过程中发挥了关键作用。此外，我们针对单倍型（Haplotype）结构、连锁不平衡（Linkage Disequilibrium, LD）、重组、拷贝数变异以及全基因组血统混合的分析，证实并支持了桑族相较于非洲及非非洲人群均具有独特的遗传地位。本研究有助于增进人们对东南非人群的血统起源与自然选择的理解；本研究获得的数据与结果，将为该区域传染病与非传染病的遗传易感性相关研究提供支撑。