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Title: The evolutionary dynamics of genomic regulatory blocks in metazoan genomes
Author: Nash, Alex
ISNI:       0000 0004 7658 7514
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Developmental genes require intricate control of the timing, location and magnitude of their expression. This is provided by multiple evolutionarily conserved enhancers, known as conserved non-coding elements (CNEs). CNEs cluster around their target genes, forming long syntenic arrays known as genomic regulatory blocks (GRBs). Current methods for GRB identification rely on the selection of arbitrary minimum conservation thresholds, impeding their performance in many contexts. In this thesis, I propose a novel measure of pairwise genome conservation that eliminates the need for conservation thresholds, and use this measure to study the evolutionary dynamics of GRBs in metazoa. I define sets of GRBs based on their rate of regulatory turnover - high turnover GRBs (htGRBs) and low turnover GRBs (ltGRBs) - in three independent metazoan lineages. I show that ht- and ltGRBs target functionally distinct classes of genes, and that these genes tend to be expressed during late and early development respectively, potentially contributing to their differing tolerance of regulatory turnover. Moreover, the differences between ht- and ltGRBs are consistent across all three lineages, suggesting that similar evolutionary pressures have defined the rate of turnover in these GRBs since their emergence in the metazoan ancestor. Next I identify GRBs in the extremely compact Caenorhabditis elegans and Oikopleura dioica genomes for the first time, and use these GRBs to investigate the effects of genome compaction on GRB size and composition. I show that GRB size scales proportionally with genome size and that GRBs exhibit similar enrichment and depletion of specific genomic features. This suggests that regardless of background genome content, GRBs are under similar pressure to maintain a permissive environment for long-range gene regulation. The development of a threshold-free GRB identification method has facilitated the analysis of GRBs in both closely related species and compact genomes, providing further insights into their origin and evolution.
Supervisor: Lenhard, Boris Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral