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Title: The evolution of recombination hotspots and of their relationships with DNA sequences
Author: Tumian, Afidalina
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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This thesis attempts to address various aspects of the evolution of recombination hotspots, focusing on the impact of biased gene conversion (BGC) on DNA sequences. My analyses identify thousands of sites in the genome which were active hotspots millions of years ago, illuminate the rate of evolution of PRDM9 across great apes, and help us to understand details of how recombination has shaped over genome. I began by exploring the extent of BGC on the 13-bp human hotspot motifs by comparing their occurrences in the human and chimp genomes. I observed very strong evidence of motif evolution acting unequally between human and chimp, across multiple genomic backgrounds , with much more rapid motif losses on the human lineage. Next, using Neanderthal and Denisovan genomes, I estimated the motif activation time and relative accelerated loss rate parameters using Bayesian model-based inference. The motif activation time for the human hotspot motif is estimated at around 1.1 MYA, which is recent, though older than the split time of humans and Neanderthals / Denisovans. Motivated by the fact that PRDM9 evolves different binding motifs due to changes in its zinc fingers, I then searched for novel ancestral BGC targets in primate species by looking for short words that have undergone rapid losses/ gains in each species. I found many such words , differing across lineages, with multiple distinct clusters of related motifs found within most lineages. This implies a rapidly evolving mechanism landscape of BGC targets, with around one new motif cluster every million years, across lineages. The final chapter focuses on quantifying a distinct BGC effect, diagnostic of recombination activity, and involving a systematic change towards GC bases (gcBGC) on human and chimp ancestral BGC targets. I found a strong gcBGC effect very near to the identified cluster members, validating these clusters as historical recombination sites. Further, patterns seen support the model that gcBGC occurs at all GC bases near hotspots centres, extending across ~1kb region.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available