PhD defence: Lucie A. Bergeron

Pedigree-based estimation of germline mutation rates in vertebrates and the evolutionary implication

Supervisor: Guojie Zhang, Ecology and Evolution, Department of Biology

Chair: Anders Albrechtsen, Computational and RNA Biology, Department of Biology

Co-Examiner: Priya Moorjani (University of California, Berkeley) & Aylwyn Scally (University of Cambridge)

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Germline mutations are the fuel for evolution. An accurate estimation of germline mutation rate is important to date the molecular divergence time between related species, to understand the emergence of new genetic diseases, and to assess the effective population size of species, crucial to threatened species management. Additionally, the germline mutation rates of species result from evolutionary forces such as natural selection and genetic drift, like any other traits. Different hypotheses have attempted to explain how selective pressures drive the germline mutation rate evolution. Thus, disclosing the variation of mutation rate across species will build upon our understanding of the forces acting on the germline mutations. Historically, the germline mutation rate has been estimated with phenotypic methods from the observation of inherited genetic disorders and later, with phylogenetic methods analyzing the genomic divergence of related species. The rise of Next Generation Sequencing has allowed a new approach based on the whole-genome comparison of individuals from trios (mother, father, and offspring). This pedigree-based method has been applied on large pedigree datasets in humans, up to 3000 trios, yet, only a few studies have been published on non-human species. In my thesis, I developed three topics to explore the germline mutation rate in several vertebrate species by pedigree-based estimation, with the aim of understanding the causes of variation between species. In the first chapter, I applied this pedigree analysis to estimate the germline mutation rate of a primate species, the rhesus macaque (Macaca mulatta). From the large pedigree of 19 trios, we found that macaques have a strong male bias on the parental contribution to the germline mutations, with males contributing on average 80 % of the total germline mutations. Males also exhibited a strong paternal age effect. We reconstructed the primate phylogeny with the new estimated rate and inferred an older molecular divergence time with closely related species than previously estimated. In a second chapter, I estimated the germline mutation rate of 68 species of vertebrates; 36 mammals, 18 birds, 8 fishes, and 6 reptiles. With this large dataset of more than 150 trios, I explored the phylogenetic variation of the rate across taxa. The species with long maturation time, long life span, long generation time, and fewer offspring per generation presented a lower germline mutation rate than the opposite species. Yet, the most significant life-history trait that correlated with the yearly ix mutation rate was the number of offspring produced per generation. In the last chapter, I reviewed recently published studies to compare the methodology applied for estimating germline mutation rates from pedigrees in various species. This work emphasizes the effect of the various filters used to detect germline mutations on the estimated rate. It also provides suggestions toward a consistent methodology when estimating the germline mutation rate from pedigrees. The lack of standardization in filters to detect mutations and standardized methods to estimate the proportion of the genome with full detection power lead to difficulties in comparing mutation rates between species. I concluded that part of the differences in germline mutation rate between species could be due to methodological discrepancy instead of biological reasons. Finally, an appendix presents the work of collaborators on the chromosome-level diploid genome assembly of the common marmoset (Callithrix jacchus). In this project, I estimated the germline mutation rate of the species with a different method as the singular diploid assembly allowed detection on each parental haplotype independently. Altogether, these papers contribute to the understanding of the germline mutation rate across vertebrate species and the evolutionary forces that may drive their variation. Additionally, it stresses the importance of methodological awareness when estimating and comparing various species rates.