A Theory of Age-Dependent Mutation and Senescence

J.A. Moorad, D.E.L. Promislow

Research output: Contribution to journalArticlepeer-review

Abstract

Laboratory experiments show us that the deleterious character of accumulated novel age-specific mutations is reduced and made less variable with increased age. While theories of aging predict that the frequency of deleterious mutations at mutation-selection equilibrium will increase with the mutation's age of effect, they do not account for these age-related changes in the distribution of de novo mutational effects. Furthermore, no model predicts why this dependence of mutational effects upon age exists. Because the nature of mutational distributions plays a critical role in shaping patterns of senescence, we need to develop aging theory that explains and incorporates these effects. Here we propose a model that explains the age dependency of mutational effects by extending Fisher's geometrical model of adaptation to include a temporal dimension. Using a combination of simple analytical arguments and simulations, we show that our model predicts age-specific mutational distributions that are consistent with observations from mutationaccumulation experiments. Simulations show us that these age-specific mutational effects may generate patterns of senescence at mutation-selection equilibrium that are consistent with observed demographic patterns that are otherwise difficult to explain.
Original languageEnglish
Pages (from-to)2061-2073
Number of pages13
JournalGenetics
Volume179
Issue number4
DOIs
Publication statusPublished - Aug 2008

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