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Computational studies of the genome dynamics of mammalian transposable elements and their relationships to genes

University of British Columbia

Sequences derived from transposable elements (TEs) comprise nearly 40 - 50% of the genomic DNA of most mammalian species, including mouse and human. However, what impact they may exert on their hosts is an intriguing question. Originally considered as merely genomic parasites or “selfish DNA”, these mobile elements show their detrimental effects through a variety of mechanisms, from physical DNA disruption to epigenetic regulation. On the other hand, evidence has been mounting to suggest that TEs sometimes may also play important roles by participating in essential biological processes in the host cell. The dual-roles of TE-host interactions make it critical for us to understand the relationship between TEs and the host, which may ultimately help us to better understand both normal cellular functions and disease. This thesis encompasses my three genome-wide computational studies of TE-gene dynamics in mammals. In the first, I identified high levels of TE insertional polymorphisms among inbred mouse strains, and systematically analyzed their distributional features and biological effects, through mining tens of millions of mouse genomic DNA sequences. In the second, I examined the properties of TEs located in introns, and identified key factors, such as the distance to the intron-exon boundary, insertional orientation, and proximity to splice sites, that influence the probability that TEs will be retained in genes. In the third, a study specifically focused on genes with extremely high or low TE content in three mammalian species, I showed associations between TE density and the function/conservation of genes, as well as the relevance of chromatin state to TE accumulation in genes. While most of my results clearly support the idea that today’s TE distribution pattern is an outcome of natural selection or genetic drift during evolution, the final part of my work, which compares TE density to chromatin state in embryonic stem cells, suggests that traces of the initial integration preference of TEs still exist. Taken together, these results demonstrated the effects of both initial TE integration and natural selection in shaping the landscape of today’s mammalian genomes and, most importantly, shed light on the roles of mobile elements in evolution.

Text

2012-05-29

Attribution-NonCommercial-NoDerivs 3.0 Unported

http://hdl.handle.net/2429/42419

Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/3.0/