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Investigating the genomic distribution and potential contribution of retrotransposable elements in relation to their potential impact on genome function and predisposition to human diseases. Randa Aweis Ali Active retrotransposable elements (RTEs) provide a continuous source of genomic diversity in humans. The potential impact of a novel RTE insertion depends on its genomic location. Previous studies investigating the landscape of polymorphic RTEs report their higher fraction in functional regions compared with fixed elements, thereby highlighting the potential impact of RTE activity on genome function (GF). However, studies have only recently begun incorporating RTE variants (RTEV) in association with complex human diseases. This study aimed to investigate the impact of RTEs activity on GF and the potential association of RTEV with disease susceptibility. A comprehensive database of all non-reference L1s, Alus, and SVA insertions reported in the literature to April 2019 was curated (n=39,798 RTEs). The curated database includes numerous singleton and rare RTE insertions. Such insertions potentially faced fewer selection pressures compared with common RTEs, thus are likely more representative of RTEs preferred integration site. The genomic distribution of the curated RTEs was compared with the distribution of ancient RTEs that are fixed in the human genome to hypothesise the likely effect of new RTE insertions. Non-reference insertions were found at higher frequencies in functional regions and had a more even genomic distribution than fixed RTEs, suggesting their ability to impact GF. The positional overlap between RTEs and trait-associated SNPs (TASs) was investigated to determine the potential of RTEs as causal variants in GWAS risk loci. L1s, Alus, and SVA elements were significantly enriched in GWAS risk regions, suggesting the potential impact of RTEV on human health. Next, 354 novel RTE-TAS associations were identified via linkage analysis between RTEVs and genome-wide significant SNPs identified in European populations. Finally, SVA elements likely impose the highest impact on GF and human health based on their genomic accumulation in functional regions and their higher proportion in GWAS risk regions. Collectively, the results of this thesis depict the functional impact of RTEs on GF and human health, which have proven to be invaluable for future association studies to further the current knowledge regarding the aetiology of complex traits and disorders. Keywords: Transposable elements; Polymorphic retrotransposable elements; Structural variants; Causative variant; GWAS; Genome function; Human health |
