Deleterious mutations show increasing negative effects with age in Drosophila melanogaster

Martin I Brengdahl,Christopher M Kimber,Josephine Thompson,Urban Friberg,Phoebe Elias

doi:10.1186/s12915-020-00858-5

Martin I Brengdahl, Christopher M Kimber + Show 3 more

Open Access

https://doi.org/10.1186/s12915-020-00858-5

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Journal: BMC biology	Publication Date: Sep 30, 2020
Citations: 6	License type: open-access

Affiliation: Linköping University

Abstract

BackgroundIn order for aging to evolve in response to a declining strength of selection with age, a genetic architecture that allows for mutations with age-specific effects on organismal performance is required. Our understanding of how selective effects of individual mutations are distributed across ages is however poor. Established evolutionary theories assume that mutations causing aging have negative late-life effects, coupled to either positive or neutral effects early in life. New theory now suggests evolution of aging may also result from deleterious mutations with increasing negative effects with age, a possibility that has not yet been empirically explored.ResultsTo directly test how the effects of deleterious mutations are distributed across ages, we separately measure age-specific effects on fecundity for each of 20 mutations in Drosophila melanogaster. We find that deleterious mutations in general have a negative effect that increases with age and that the rate of increase depends on how deleterious a mutation is early in life.ConclusionsOur findings suggest that aging does not exclusively depend on genetic variants assumed by the established evolutionary theories of aging. Instead, aging can result from deleterious mutations with negative effects that amplify with age. If increasing negative effect with age is a general property of deleterious mutations, the proportion of mutations with the capacity to contribute towards aging may be considerably larger than previously believed.

Highlights

In order for aging to evolve in response to a declining strength of selection with age, a genetic architecture that allows for mutations with age-specific effects on organismal performance is required
Since our focus was on the effect of deleterious mutations on aging, we first asked which of the 20 mutations are deleterious with respect to fecundity
By fitting a generalized linear mixed model (GLMM) with age as a covariate across the three age-specific measures of fecundity, we tested if the deleterious mutations had an increasing negative effect on fecundity with age and find that this is the case for 14 of the 16 deleterious mutations (Fig. 1, Additional file 2: Table S2)

Summary

Introduction

In order for aging to evolve in response to a declining strength of selection with age, a genetic architecture that allows for mutations with age-specific effects on organismal performance is required. While AP predicts a negative association, the initial formulation of Brengdahl et al BMC Biology (2020) 18:128 the MA theory, based on mutations with effects spanning very short age intervals, predicts no association [2, 30]. These predictions stand in sharp contrast to the positive pleiotropy often observed between early and late life performance (e.g., [31,32,33,34,35,36,37,38,39,40,41,42]). Aging through mutations with gradually increasing negative effects has rarely been considered (see discussions in [30, 33, 44, 45]), but is predicted by recent theory [46, 47]

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