A novel sequencing method to explore two molecular mechanisms of rapid adaptation

Abstract

To survive in an ever-changing world, organisms need to rapidly adapt to new environments. In my dissertation, I address two molecular mechanisms that may contribute to rapid adaptation to new environments and help to address the "missing heritability" of complex traits. The first mechanism is short tandem repeats (STRs), short sequence units of two to ten nucleotides repeated head to tail, which mutate 10 to 10,000x faster than non-repetitive regions and have been shown to increase mutation rate under environmental stress. These highly variable, phenotypically important genetic elements have remained inaccessible to high-throughput analysis with short read sequencing and therefore have been excluded from genome-wide analyses of genotype-phenotype associations. I developed a novel method MIPSTR to accurately genotype STRs genome-wide across many individuals. The second mechanism is buffers of genetic variation, i.e. molecules or pathways that influence the penetrance of standing genetic variation by buffering its effect on phenotype. This mechanism could also be thought of as an epistatic interaction with loci across the genome. If a buffering mechanism is challenged or breaks, previously cryptic genetic variation will be revealed. In order to consider the robustness (i.e. buffering capacity) of an organism when associating genetic variants to complex traits, we need to measure robustness of individuals. MIPSTR can assess somatic STR variation within individuals as a measure of genome stability and thereby robustness. This new approach has allowed me to address two molecular mechanisms potentially important for adaptation and "missing heritability" in novel ways.