Project description:We used buccal samples from two different dog breeds with well established differences in average lifespan to perform genome-scale identification of ageing-associated differentially methylated positions (aDMPs) in a total of 48 different dogs. A significant proportion of aDMPs that gained methylation with age replicated in an independent cohort. Furthermore, we also show that human aDMPs show similar ageing-associated dynamics at the homologous genomic regions in the dog. The replicated aDMPs show a faster rate of change with age in the shorter lived dog species. Strikingly, these aDMPs also show a faster rate of change with age in dogs overall compared with humans.
Project description:BackgroundMammalian species exhibit a wide range of lifespans. To date, a robust and dynamic molecular readout of these lifespan differences has not yet been identified. Recent studies have established the existence of ageing-associated differentially methylated positions (aDMPs) in human and mouse. These are CpG sites at which DNA methylation dynamics show significant correlations with age. We hypothesise that aDMPs are pan-mammalian and are a dynamic molecular readout of lifespan variation among different mammalian species.ResultsA large-scale integrated analysis of aDMPs in six different mammals reveals a strong negative relationship between rate of change of methylation levels at aDMPs and lifespan. This relationship also holds when comparing two different dog breeds with known differences in lifespans. In an ageing cohort of aneuploid mice carrying a complete copy of human chromosome 21, aDMPs accumulate far more rapidly than is seen in human tissues, revealing that DNA methylation at aDMP sites is largely shaped by the nuclear trans-environment and represents a robust molecular readout of the ageing cellular milieu.ConclusionsOverall, we define the first dynamic molecular readout of lifespan differences among mammalian species and propose that aDMPs will be an invaluable molecular tool for future evolutionary and mechanistic studies aimed at understanding the biological factors that determine lifespan in mammals.
Project description:The rate of ageing-associated DNA methylation dynamics is a molecular readout of lifespan variation amongst mammalian species [Macaque_450k]
Project description:The rate of ageing-associated DNA methylation dynamics is a molecular readout of lifespan variation amongst mammalian species [TC1_450k]
Project description:The rate of ageing-associated DNA methylation dynamics is a molecular readout of lifespan variation amongst mammalian species [Bis-PCR: naked mole-rat]
Project description:Although lifespan in mammals varies over 100-fold, the precise evolutionary mechanisms underlying variation in longevity remain unknown. Species-specific genetic changes have been observed in long-lived species including the naked mole-rat, bats, and the bowhead whale, but these adaptations do not generalize to other mammals. We present a novel method to identify associations between rates of protein evolution and continuous phenotypes across the entire mammalian phylogeny. Unlike previous analyses that focused on individual species, we treat absolute and relative longevity as quantitative traits and demonstrate that these lifespan traits affect the evolutionary constraint on hundreds of genes. Specifically, we find that genes related to cell cycle, DNA repair, cell death, the IGF1 pathway, and immunity are under increased evolutionary constraint in large and long-lived mammals. For mammals exceptionally long-lived for their body size, we find increased constraint in inflammation, DNA repair, and NFKB-related pathways. Strikingly, these pathways have considerable overlap with those that have been previously reported to have potentially adaptive changes in single-species studies, and thus would be expected to show decreased constraint in our analysis. This unexpected finding of increased constraint in many longevity-associated pathways underscores the power of our quantitative approach to detect patterns that generalize across the mammalian phylogeny.