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The revolution in sequencing technologies has made it feasible to identify de novo mutations in transmissions from parents to offspring, providing an unprecedented opportunity to learn about the genesis and properties of germline mutations. As we show, however, when these recent pedigree studies are considered jointly and alongside results from other methodologies, it becomes clear that the pieces of the puzzle do not fit together. We discuss these gaps in our understanding in terms of three sets of questions: (i) On a mechanistic level, what proportion of mutations is introduced through mistakes in the replication process versus non-replicative, “spontaneous” errors? (ii) In terms of variation among individuals, why do mutation rates depend so strongly on sex and age, and are there other sources of variation? (iii) From an evolutionary perspective, how do mating systems and life history traits shape the mutation rate of a species? Specifically, we focus on the “generation time effect” widely reported for mammals, i.e., the observation that a decrease in the generation time is associated with an increased mutation rate per year. As we show, the existence of a generation time effect implies specific conditions on mutation rates per cell division over ontogenesis. Thus, answers to these three sets of questions are interwoven.

Department:  Biology

Contact: Maria Magana-Lopez | 650-723-2413 | mmagana@stanford.edu

Presenter(s):

• Molly Przeworski Columbia University

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