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.

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