Exploring the extent and impact of genetic mosaicism in African populations

Abstract

Post-zygotic mutations (PZMs) accumulate inevitably over a lifetime across all tissues. When PZMs are maintained in genetically distinct clones, it is known as genetic mosaicism (GM). Recent technological advances have facilitated accurate characterisations of GM in large datasets, revealing a complex relationship with normal aging. However, the contribution of GM across a spectrum of debilitating disorders has also become increasingly clear. GM is chronically under investigated in continental African cohorts and our understanding of the scale and impact of GM in healthy and disease affected Africans remains wholly inadequate. This thesis aimed to address these gaps by implementing state-of-the-art bioinformatics tools to sensitively detect GM in two distinct African cohorts. The first objective was to investigate the contribution of GM to developmental disorders (DD) in South Africans by leveraging 62 whole- exome trios from the Deciphering Developmental Disorders in Africa cohort to screen for candidate pathogenic PZMs. Screening successfully identified 5 proband PZM candidates, 3 germline de novo variants, and 5 parental PZM candidates with evidence of gonadosomatic mosaicism. In total, 12 novel variants were classified as likely pathogenic and recommended for future validation. The second objective was to detect and characterise mosaic chromosomal alterations (MCAs) associated with clonal haematopoiesis in healthy adults from the Africa Wits–INDEPTH Partnership for Genomic Studies (AWI-Gen) study. MCAs were successfully characterised in 10.1% of 9917 AWI-Gen participants, and were more prevalent in the elderly, in males, and in Western Africans. The genomic distributions of distinct MCA loci differed significantly between participants from Eastern, Western, and Southern Africans. Finally, novel genes were identified as candidate drivers of MCA expansion in Africans. This is the largest characterization of MCAs in a diverse cohort of continental Africans to date, and the first study to investigate the contribution of GM to a South African DD cohort. These results significantly contribute to our understanding of GM in Africans.