Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana.

Large-scale, population-based genomic studies have provided a context for modern medical genetics. Among such studies, however, African populations have remained relatively underrepresented. The breadth of genetic diversity across the African continent argues for an exploration of local genomic context to facilitate burgeoning disease mapping studies in Africa. We sought to characterize genetic variation and to assess population substructure within a cohort of HIV-positive children from Botswana-a Southern African country that is regionally underrepresented in genomic databases. Using whole-exome sequencing data from 164 Batswana and comparisons with 150 similarly sequenced HIV-positive Ugandan children, we found that 13%-25% of variation observed among Batswana was not captured by public databases. Uncaptured variants were significantly enriched (p = 2.2 × 10-16) for coding variants with minor allele frequencies between 1% and 5% and included predicted-damaging non-synonymous variants. Among variants found in public databases, corresponding allele frequencies varied widely, with Botswana having significantly higher allele frequencies among rare (<1%) pathogenic and damaging variants. Batswana clustered with other Southern African populations, but distinctly from 1000 Genomes African populations, and had limited evidence for admixture with extra-continental ancestries. We also observed a surprising lack of genetic substructure in Botswana, despite multiple tribal ethnicities and language groups, alongside a higher degree of relatedness than purported founder populations from the 1000 Genomes project. Our observations reveal a complex, but distinct, ancestral history and genomic architecture among Batswana and suggest that disease mapping within similar Southern African populations will require a deeper repository of genetic variation and allelic dependencies than presently exists.

The Collaborative African Genomics Network (CAfGEN): Applying Genomic technologies to probe host factors important to the progression of HIV and HIV-tuberculosis infection in sub-Saharan Africa.

Background: Here, we describe how the Collaborative African Genomics Network ( CAfGEN) of the Human Heredity and Health in Africa (H3Africa) consortium is using genomics to probe host genetic factors important to the progression of HIV and HIV-tuberculosis (TB) coinfection in sub-Saharan Africa.   The H3Africa was conceived to facilitate the application of genomics technologies to improve health across Africa..          Methods: CAfGEN is an H3Africa collaborative centre comprising expertise from the University of Botswana; Makerere University; Baylor College of Medicine Children's Clinical Centers of Excellence (COEs) in Botswana, Uganda, and Swaziland; as well as Baylor College of Medicine, Texas. The COEs provide clinical expertise for community engagement, participant recruitment and sample collection while the three University settings facilitate processing and management of genomic samples and provide infrastructure and training opportunities to sustain genomics research. Results: The project has focused on utilizing whole-exome sequencing to identify genetic variants contributing to extreme HIV disease progression phenotypes in children, as well as RNA sequencing and integrated genomics to identify host genetic factors associated with TB disease progression among HIV-positive children. These cohorts, developed using the COEs' electronic medical records, are exceptionally well-phenotyped and present an unprecedented opportunity to assess genetic factors in individuals whose HIV was acquired by a different route than their adult counterparts in the context of a unique clinical course and disease pathophysiology. Conclusions: Our approach offers the prospect of developing a critical mass of well-trained, highly-skilled, continent-based African genomic scientists. To ensure long term genomics research sustainability in Africa, CAfGEN contributes to a wide range of genomics capacity and infrastructure development on the continent, has laid a foundation for genomics graduate programs at its institutions, and continues to actively promote genomics research through innovative forms of community engagement brokered by partnerships with governments and academia to support genomics policy formulation.