Quantitative and Molecular Genetic Analyses of Mutations Increasing Drosophila Life Span

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.

Complex genetic architecture of Drosophila aggressive behavior

“…There are many more possible genotypes from n mutations than those mutations represented by the n(n − 1)/2 double heterozygotes, and the many mutations without significant homozygous effects could still participate in epistatic interactions. Third, estimates of the effect of a single mutation are likely to vary depending on the genetic background (10,12). Finally, we find substantial enhancing and suppressing epistasis with just six segregating loci and only pairwise epistasis among them; therefore, epistasis is also likely to occur for segregating variants affecting complex traits in natural populations, including humans.…”

“…E-MTAB-653). combining ability (GCA) of each mutation represents its average degree of dominance combined with all other mutations, whereas the specific combining ability (SCA) of each genotype indicates whether there is epistasis (i.e., the aggressive phenotype of the double heterozygous genotype is enhanced or suppressed relative to the expected phenotype based on the additive combination of GCAs of the parental mutant alleles) (7)(8)(9)(10). We found significant (P < 0.0001) variation in aggression among the double heterozygotes, which is attributable to variation in both GCA (P < 0.0001) and SCA (P < 0.0001) effects (Table S1).…”

“…Several mutations with homozygous and epistatic effects on aggression had pleiotropic effects on other traits (8)(9)(10). Pleiotropy at the level of organismal phenotype was recapitulated at the level of gene expression: 4,038 transcripts were differentially expressed in heads of the homozygous mutant lines and the control.…”

“…These problems can be circumvented by assessing epistatic and pleiotropic effects of single mutations in a common homozygous background. In Drosophila melanogaster, diallel crosses among all mutant alleles affecting the same trait have revealed extensive epistasis (7)(8)(9)(10), whereas studies assessing the same mutations for multiple quantitative traits, including genome-wide variation in gene expression, have shown that pleiotropy is pervasive (10)(11)(12)(13). However, pleiotropic effects of epistatic interactions have not been well-explored.…”

Interactive effects of sex, social environment, dietary restriction, and methionine on survival and reproduction in fruit flies

“…These interventions range from single-gene alterations (Fontana et al 2010;Magwire et al 2010) to dietary compounds that are directly implicated in basic cellular processes (Bjedov et al 2010) or compounds that potentially mimic the lifespanextending effect of DR (Valenzano et al 2006). Out of the second mentioned category, the effect of dietary methionine on lifespan has been examined in some detail (Troen et al 2007;Grandison et al 2009a;Dick et al 2011;Kabil et al 2011).…”