Biased generation and retention of oligonucleotide motifs in the human genome

Abstract

During evolution, variation is created by mutational processes in an organism's genome, and then these variants remain or are purged as a result of selective pressures and drift. Mutation rates are biased at many scales across the genome, and the selective pressure acting on the generated variation as a result of mutations also varies greatly. One well studied example of mutational heterogeneity at single-base resolution concerns methylated cytosines, which mutate at an approximately 10-fold higher rate than their unmethylated counterpart. In Chapter 1, I demonstrate that cytosine methylation not only affects mutation risk at the methylated base but also exerts mutational effects on its neighbouring nucleotides. In human, bases surrounding the methylated cytosine accrue fewer SNPs than bases in the vicinity of unmethylated sites. In plants, on the other hand, I demonstrate that the opposite is true. I show that this difference is not driven by differential sampling of sequence or chromatin contexts, and is instead likely due to alternative lesion processing between the species. Regarding selective heterogeneity, studies in the past have largely focused on differential conservation of genetic elements between species, an approach ill-equiped to capture selection against gaining a novel deleterious function. In Chapter 2, I develop and validate a novel approach to interrogate selection against deleterious gain-of-function motifs in protein coding sequences, which is based on derived allele frequency distributions. I show how derived allele frequencies can be used to detect selection against particular amino acid motifs genome-wide. This thesis elucidates forces biasing the creation and persistence of genetic variation and highlights the entwined nature of mutational bias, selective pressures, and the technical challenges involved.