Analyses of functional sequence in mammalian and avian genomes

Thesis

The first draft sequence of the human genome was published over a decade ago, yet interpreting the functional importance of nucleotides in genomes is still an ongoing challenge. I took a comparative genomic approach to identify functional sequence using signatures of natural selection in DNA sequences. Mutations that are purged or propagated by selection mark sequences of significance for biological fitness. I developed and refined methods for estimating the quantity of sequence constrained with respect to insertions and deletions (indels) between two genome sequences, a quantity I termed α_selIndel. This sequence is evolving more slowly than surrounding neutral sequence due to the purging of deleterious indel variants, and thus this sequence is likely to be functional. I estimated α_selIndel between diverse mammalian and avian species pairs, and found a strong negative correlation between α_selIndel and the divergence between the species’ genome sequences. This implies that functional sequence turns over rapidly as it is lost and gained over time. I quantified the variable levels of sequence constraint, and rates of sequence turnover, for different types of human biochemically annotated element. Furthermore, I found that similar rates of functional turnover have occurred across mammalian and avian evolution. Finally, I identified positively selected amino acid residues that may be important for Darwin’s finch beak development, and found evidence of adaptively evolving reproductive proteins in the ancestral songbird lineage. Collectively these results demonstrate the wide-spread nature of lineage-specific functional sequence with implications for understanding species traits and the use of model organisms to inform human biology.

Authors: Rands, C; Chris M. D. Rands

• Publication date: 2014
• DOI: 10.5287/ora-540r14bx0
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: evolution; turnover; bioinformatics; genomics; indel
• Subjects: Biology; Evolution (zoology); Life Sciences; Genetics (life sciences); Bioinformatics (life sciences)