Abstract
Understanding the genetic and environmental factors that affect variation in life span and senescence is of major interest for human health and evolutionary biology. Multiple mechanisms affect longevity, many of which are conserved across species, but the genetic networks underlying each mechanism and cross-talk between networks are unknown. We report the results of a screen for mutations affecting Drosophila life span. One third of the 1,332 homozygous P–element insertion lines assessed had quantitative effects on life span; mutations reducing life span were twice as common as mutations increasing life span. We confirmed 58 mutations with increased longevity, only one of which is in a gene previously associated with life span. The effects of the mutations increasing life span were highly sex-specific, with a trend towards opposite effects in males and females. Mutations in the same gene were associated with both increased and decreased life span, depending on the location and orientation of the P–element insertion, and genetic background. We observed substantial—and sex-specific—epistasis among a sample of ten mutations with increased life span. All mutations increasing life span had at least one deleterious pleiotropic effect on stress resistance or general health, with different patterns of pleiotropy for males and females. Whole-genome transcript profiles of seven of the mutant lines and the wild type revealed 4,488 differentially expressed transcripts, 553 of which were common to four or more of the mutant lines, which include genes previously associated with life span and novel genes implicated by this study. Therefore longevity has a large mutational target size; genes affecting life span have variable allelic effects; alleles affecting life span exhibit antagonistic pleiotropy and form epistatic networks; and sex-specific mutational effects are ubiquitous. Comparison of transcript profiles of long-lived mutations and the control line reveals a transcriptional signature of increased life span.
Highlights
Understanding the genetic and environmental factors affecting variation in life span and health span is of major interest for human health and evolutionary biology
To identify the individual P–element insert lines that contributed to the significant variation in life span, we computed the confidence intervals (CIs) of deviations of line means from their corresponding controls (Figure 1), and performed Dunnett’s t–tests to assess deviations of insert lines from the control line within each experimental block
We have shown here that antagonistic pleiotropy is pervasive, in that all P–element insert lines associated with increased longevity were associated with at least one deleterious pleiotropic effect on resistance to starvation stress, recovery after chill coma, and/or a general measure of health at one week and/or six weeks of age (Figure 4)
Summary
Understanding the genetic and environmental factors affecting variation in life span and health span is of major interest for human health and evolutionary biology. Life span extension is often accompanied by a decline in reproduction [23,24,25,26,27], a well–known trade–off that could explain limits to life span and maintenance of genetic variation for longevity within species [28,29,30]. This relationship is not universal [31,32,33,34]. Positive correlations between life span and stress resistance [18] are not always observed [35]
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