Tracing germline mutational processes in animal species through computational comparative genomics

Abstract

A recently emerging concept of mutational signature has expanded our understanding of mutational processes in human cells. It is now widely accepted that the DNA triplet pattern of nucleotide changes is uniquely shaped by endogenous processes, encompassing spontaneous mutations and DNA repairs, and exogenous mutagens such as UV light, tobacco smoking, reactive oxygen species, and many others. Mutational signature is a hallmark of each of these processes manifested as a spectrum of trinucleotide change and more existence of such signatures are appearing in recent years as more data is added. While mutational signatures have been extensively studied in cancers and recently in normal tissues, however, it has been largely limited to somatic cells. Mutations in germ cells are indeed trickier and laborious to study and practically only de novo germline mutations may be confidently studied at the cost of, for example, using family trio data in humans and multi-generation inbreeding in mice. In this thesis, we explore the possibility of studying germline mutations using only reference genomes. We will discuss germline mutational processes in the lens of mutational signature and in a broader context possible. Particularly, we aim to reveal traces of germline mutational signatures in various lineages of animal species. Studying germline mutational processes in this regard is challenging in many ways, for we are looking several million years into the past in evolutionary history where the identifiability of mutational signals is elusive. We developed a computational pipeline to overcome difficulties that arise upon accurately capturing germline mutations and mutational signatures. As such, several layers of uncertainties inherent in the problem are discussed and dealt with justifiable approximations and novel computational approaches. Recent advances in our understanding of somatic mutational signatures in human cancer and non-cancer cells take an integral part throughout. It is shown that our method can accurately capture presumably a true picture of mutational processes operative in a recent evolutionary time span and that mutational processes have been relatively regular throughout the history of genome evolution in animal lineages. The methodology and data produced in this research may be used as a valuable source and provide insight for mutation studies regarding ancient genomes and the nature of genome evolution.