Abstract
Natural populations harbor considerable genetic variation for lifespan. While evolutionary theory provides general explanations for the existence of this variation, our knowledge of the genes harboring naturally occurring polymorphisms affecting lifespan is limited. Here, we assessed the genetic divergence between five Drosophila melanogaster lines selected for postponed senescence for over 170 generations (O lines) and five lines from the same base population maintained at a two week generation interval for over 850 generations (B lines). On average, O lines live 70% longer than B lines, are more productive at all ages, and have delayed senescence for other traits than reproduction. We performed population sequencing of pools of individuals from all B and O lines and identified 6,394 genetically divergent variants in or near 1,928 genes at a false discovery rate of 0.068. A 2.6 Mb region at the tip of the X chromosome contained many variants fixed for alternative alleles in the two populations, suggestive of a hard selective sweep. We also assessed genome wide gene expression of O and B lines at one and five weeks of age using RNA sequencing and identified genes with significant (false discovery rate < 0.05) effects on gene expression with age, population and the age by population interaction, separately for each sex. We identified transcripts that exhibited the transcriptional signature of postponed senescence and integrated the gene expression and genetic divergence data to identify 98 (175) top candidate genes in females (males) affecting postponed senescence and increased lifespan. While several of these genes have been previously associated with Drosophila lifespan, most are novel and constitute a rich resource for future functional validation.
Highlights
IntroductionLifespan and senescence (the post-reproductive decline in survival and fertility with advancing age) vary enormously within and among taxa, with some organisms attaining exceptional longevity and negligible senescence [1,2,3]
Lifespan and senescence vary enormously within and among taxa, with some organisms attaining exceptional longevity and negligible senescence [1,2,3]
Of the ~18,000 genes in the Drosophila genome, ~11% have a variant that is genetically divergent between the O and B populations at our reporting threshold of P < 10−3 (FDR = 0.068), many of which are in a 2.6 Mb region of the X chromosome that appears to have undergone a hard selective sweep [128]
Summary
Lifespan and senescence (the post-reproductive decline in survival and fertility with advancing age) vary enormously within and among taxa, with some organisms attaining exceptional longevity and negligible senescence [1,2,3]. Natural selection declines with age [4], so mutations with late age-specific deleterious effects are nearly neutral with respect to natural selection and can accumulate in populations at appreciable frequencies [5]. Mutations with beneficial effects early in life but detrimental effects later in life will accumulate [6,7]. Both classes of mutations, in addition to unconditionally deleterious mutations affecting survival and fertility at all ages, will result in segregating genetic variation for lifespan in natural populations
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