The origin and consequences of mutational processes in the human germline

Abstract

Mutational processes in the germline tissue can generate heritable genetic variation and have the potential to shape disease risk as well as species evolution. In this dissertation, by leveraging data from multiple sources, I explored three mutational processes in the human germline, each having implications at cellular, individual, and population levels. First, I investigated the mitochondrial mutation profiles of the male germline tissue and found that, strikingly, this genomic compartment does not share the same level of mutational protection as the nucleus. Despite exhibiting a similar mutation burden to somatic tissues, the germline mitochondrial genome displayed a tissue-specific age-related increase in copy number. Furthermore, although likely driven by the same mutational processes as in somatic tissues, I found that mitochondrial mutations in the germline tissue preferentially accumulate in the regulatory region. Secondly, I developed a bioinformatic pipeline to identify post-zygotic mutations (PZMs) in parents from family trio whole-genome sequencing data. I applied careful bioinformatic filtering steps, informed by quality metrics and statistical testing, to generate a catalogue of 1,579 PZM events. Mutational signature analysis revealed that PZMs likely originate from endogenous processes like those driving de novo mutations (DNMs) in adult parental germline tissues. Importantly, four PZMs were identified as clinically relevant in the offspring of PZM carriers, highlighting the practical implications of this work. Finally, I explored the impact of genetic and environmental factors on DNM rate and spectra using data from ~10,000 whole-genome-sequenced family-trios. Genetically inferred ancestry was associated with variation in DNM rate and spectra, although it was not possible to dissect the environmental and genetic contributions to this signal. Additionally, no significant SNP heritability of DNM rate could be estimated within the most well-represented ancestry group in the cohort, suggesting that common genetic variants contribute minimally to the variation of DNM rate. Finally, smoking behaviour modestly but significantly increased the DNM rate, however differences in smoking behaviour did not account for the ancestry-associated variation. Together, this work sheds light on different mutational processes in the human germline, highlighting the unique behaviour of germline mitochondrial mutations in the male germline, the contribution of post-zygotic mutations to an individual’s de novo mutation profile, and the influence of genetic and environmental factors on de novo mutation, contributing to a deeper understanding of germline mutagenesis and its potential implications.