Dataset Information

Deleterious mutations show increasing negative effects with age in Drosophila melanogaster.

ABSTRACT:

Background

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. 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.

Results

To 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.

Conclusions

Our 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.

SUBMITTER: Brengdahl MI

PROVIDER: S-EPMC7526172 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Deleterious mutations show increasing negative effects with age in Drosophila melanogaster.

Brengdahl Martin I MI Kimber Christopher M CM Elias Phoebe P Thompson Josephine J Friberg Urban U

BMC biology 20200930 1

<h4>Background</h4>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. 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 ...[more]

PMID: 32993647

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Project description:ABSTRACT MAGWIRE, MICHAEL MAHLON. Mutations Increasing Drosophila melanogaster Life Span. (Under the direction of Trudy F. C. Mackay.) Better living conditions and advances in medicine have made it possible for humans to live considerably longer than before. This has uncovered many health problems associated with age. By identifying genes involved in the limitation of life span, we may better understand the processes that lead to aging. In model organisms, we can use mutagenesis to discover mutations that increase life span, and hence infer that the wild-type allele limits life span by some means. We have assessed longevity in a collection of 1332 co-isogenic gene-trap P-element insertion lines and determined changes in life span of each insert line relative to the corresponding control line. Significant lines were determined via two different methods of analysis: A 95% confidence interval was established based on deviations of the mutant life spans from the controls and Dunnett’s two tailed t-tests were used to examine differences between mutant and control in each individual block. Based on the 95% confidence interval, 139 inserts displayed an increase in life span and 194 inserts a decrease. Using Dunnett’s, 70 lines increased in life span, while 270 decreased in life span. An additional 48 increased longevity lines were close enough to meeting Dunnett’s criteria to be considered for additional investigation. Combining these two analyses, we chose 83 inserts associated with increased life span for a secondary screen using an additional twelve replicates. 58 of these lines remained significant. We have determined the P-element insertion site for 50 of these lines. Starvation resistance, chill coma recovery time and climbing activity were measured on the lines remaining significant after the the secondary screen to identify pleiotropic effects. A positive correlation was found for males between life span and starvation resistance as well as between life span and chill coma recovery. Females only displayed a correlation between life span and chill coma recovery, which was negative. None of the lines indicated increased fitness for all phenotypes, indicating there may be some type of trade-off. There also appears to be a lot of pleiotropic variation depending on background and sex. Ten of the lines, all with the same parental background, were chosen for a half-diallel cross to identify epistasis between the mutants. There were substantial epistatic interactions between all ten lines. Furthermore, males and females displayed vastly different patterns of epistasis, again indicating major differences in life span regulation between the sexes. Finally, a subset of seven of the lines used in the epistatic study, in addition to the corresponding parental control, were chosen for microarray analysis to look for possible pathways and novel genes involved in increasing life span. 1,996 probe sets were significant at a false discovery rate q-value threshold of q < 0.0001. Tukeys tests were carried out for these probe sets to determine how each of the seven mutant backgrounds differed compared to the control and each other. In addition, each mutant background was compared individually with the control to identify any changes in expression. Gene ontologies were determined for each of the lines to identify over-represented biological functions which would indicate possible longevity pathways. Dozens of pathways were suggested, including several novel pathways. Keywords: Genetic (P-element insertion) modification and comparison to control line

Dataset Information

Deleterious mutations show increasing negative effects with age in Drosophila melanogaster.

Background

Results

Conclusions

Publications

Deleterious mutations show increasing negative effects with age in Drosophila melanogaster.

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