Methods for Inter- and Intra-Species Genomics for the Detection of Variation and Function

Abstract

This thesis concerns itself with the development of methods for comparing genomes. Chapter 2 is a comparative genomics investigation of coding regions across multiple species. Regions of the genome coding for proteins show higher conservation than non-coding regions. Furthermore, we show that a portion of coding regions are conserved beyond the requirements of protein conservation, supporting functions such as microRNA binding and splicing enhancement, providing the non-coding functional impetus to conservation. In Chapter 3, we focus on the detection and characterization of a particular type of structural variation - mobile element insertions (MEIs). While there are many types of mobile elements in the human genome, three of these are active and cause most of the MEI variation observed in humans: ALU, L1 and SVA elements. We detect variation across 1000 Genomes Pilot populations caused by these elements, assemble ALU elements to single nucleotide resolution, and determine actively copying species of this element. We've developed a variety of algorithmic approaches to MEI detection, and present these. Chapter 4 outlines an approach to remedy reference bias via the incorporation of variation data into the reference. In particular, we construct a pan-genome reference, demonstrated concretely via resolving ALU regions, and develop new alignment software to align against this enriched reference structure.