Haplotypes reveal ancestry, demographic history and variant origins
Year: 2024
Type: dissertation
Abstract: Investigating genetic relationships between individuals offers valuable insights into population genetic diversity, providing critical context for understanding ancestries and demographic histories. These insights, in turn, help elucidate variant frequencies within populations, enabling a better understanding of disease risk. The primary objective of this thesis is to leverage patterns of haplotype sharing to study the population structure and demographic histories of the Irish and British populations and to explore their implications for disease risk.Through analysis of haplotype-sharing patterns, this work reveals subtle genetic structure within Ireland. Irish genetic communities share relatively more short haplotype segments compared to British groups, indicating closer genetic relationships. Evidence of varying degrees of genetic isolation was observed in peripheral Irish and British genetic communities, with recent population bottlenecks identified in the Orcadian and Welsh groups. Additionally, the study uncovered a stable migration corridor between northeast Ireland and southwest Scotland, alongside a recent migration barrier between southeast and western Ireland. Genealogical analysis of surnames in Ireland reflected historical events, such as the enrichment of Anglo-Norman surnames in the Wexford community and Scottish and Gallowglass surnames in the Ulster community.By examining clusters of shared haplotypes over clinically significant variant loci associated with autosomal dominant polycystic kidney disease (ADPKD), this thesis contributed to increasing the sequencing diagnostic yield for an Irish ADPKD dataset by 1.3%. It identified fifteen Irish-like founder variant haplotypes, accurately predicted five out of six putative carriers of ADPKD variants within the unsolved subset of the cohort, and reclassified one variant of unknown significance (VUS) as likely pathogenic (LP).Haplotype-sharing analysis also demonstrated that the Scottish Travellers are genetically similar to the settled Scottish population. Within the Scottish Traveller community, two distinct genetic subgroups were identified, each exhibiting subtly different ancestry profiles. High levels of autozygosity within the community suggested a small effective population size in the recent past. Moreover, enriched clinically significant variants, including putative founder variants rare in other populations, were identified within the Scottish Travellers.In summary, this thesis highlights the importance of understanding the genetic history of populations and its implications for rare variant detection and disease risk. The findings underscore the value of leveraging haplotype-sharing patterns to elucidate population structure, trace demographic histories, and identify clinically significant genetic variation. These insights advance both our understanding of population genetics and the ability to improve diagnostic outcomes for genetic disorders.
Author: Ashwini Shanmugam
Institution: Royal College of Surgeons in Ireland
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6930397326
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