Evolution of mammalian genome architecture through retrotransposition

Retrotransposons, mobile DNA elements that replicate via a copy and paste mechanism, are a major component of mammalian genome architecture. They account for at least one-third of the human genome and are major drivers of lineage-specific gain and loss of DNA. While there are many examples of how specific retrotransposons have impacted evolution, their interaction with large-scale genome architecture remains poorly characterised. Throughout my thesis I investigated two fundamental questions regarding genome evolution and retrotransposons. Firstly, how does genome architecture shape retrotransposon accumulation? Secondly, how does retrotransposon accumulation in turn impact on genome architecture? The current model of retrotransposon accumulation largely relies on local sequence composition. However, this model fails to account for genome-wide chromatin structure, an important factor that regulates DNA accessibility to insertion machinery. By analysing retrotransposon accumulation at open chromatin sites I showed that genome structure strongly associates with retrotransposon accumulation patterns. In addition, by mapping retrotransposon accumulation patterns of non-human mammals back to human, I was able to observe large-scale positional conservation of lineage-specific retrotransposons. These findings suggest that through conservation of synteny, gene regulation and nuclear organisation, retrotransposon accumulation in mammalian genomes follows similar evolutionary trajectories. Beneath the conserved structural framework of mammalian genomes there exists a high degree of lineage-specific turnover of DNA. Outside of whole genome duplication, retrotransposons are the largest contributing factor to genome growth. In contrast to this, accumulation of retrotransposons can also increase the probability of unequal crossing over causing DNA loss through large deletion events. Using multiple pairwise alignments I calculated regional levels of lineage-specific DNA gain and loss in the human and mouse genomes. I found that while lineage-specific DNA loss overlapped with open chromatin regions in both genomes, different sources for lineage-specific DNA gain drove divergence in genome architecture. These findings reveal the turbulent nature of lineage-specific evolution of large-scale genome architecture, ultimately questioning the evolutionary stability of structural chromosomal domains. In addition to analysing large-scale genome architecture I performed two separate analyses on retrotransposons in the bovine genome. Due to the presence of BovB retrotransposons, the bovine retrotransposon landscape is clearly distinct from other placental mammals. For the first analysis, I identified bovine-specific retrotransposon associated gene coexpression networks. Following the genomic distribution of bovine retrotransposons, my results show that gene expression strongly associates with genome architecture. For the second analysis, I characterised retrotransposons surrounding tandem duplicate copies of the bovine NK-lysin gene. My results were consistent with retrotransposon accumulation causing genomic rearrangements via non-allelic homologous recombination. Altogether, my thesis reveals hidden interactions between retrotransposon accumulation, and mammalian genome structure and function. By re-purposing publicly available datasets I have characterised various aspects of the complex co-evolutionary relationships between retrotransposons and the genomes in which they reside in.Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 201