In Search of Mammalian Gene Duplications Correlated with Species Longevity

Duplication of a genetic sequence is a common occurrence over evolutionary time, one of the mechanisms by which species evolve. Noteworthy duplications include the many versions of cancer suppressor gene TP53 that are observed in the elephant genome. Large animals have many more cells than small animals, and so the evolution of greater size must be accompanied by the evolution of ways to greatly reduce cancer risk per cell.

Researchers here report on the results of searching for specific gene duplications in mammalian species that correlate with species longevity. This provides starting points for further study of the mechanisms that determine sizable differences in mammalian life spans, at present a poorly understood area of biochemistry. Whether or not such mechanisms can provide a basis for therapies to slow or reverse degenerative aging in humans in the near term of the next few decades remains a question mark.

Duplications of human longevity-associated genes across placental mammals

Natural selection has shaped a wide range of lifespans across mammals, with a few long-lived species showing negligible signs of ageing. Approaches used to elucidate the genetic mechanisms underlying mammalian longevity usually involve phylogenetic selection tests on candidate genes, detections of convergent amino acid changes in long-lived lineages, analyses of differential gene expression between age cohorts or species, and measurements of age-related epigenetic changes. However, the link between gene duplication and evolution of mammalian longevity has not been widely investigated.

Here, we explored the association between gene duplication and mammalian lifespan by analysing 287 human longevity-associated genes across 37 placental mammals. We estimated that the expansion rate of these genes is eight times higher than their contraction rate across these 37 species. Using phylogenetic approaches, we identified 43 genes whose duplication levels are significantly correlated with longevity quotients. In particular, the strong correlation observed for four genes (CREBBP, PIK3R1, HELLS, FOXM1) appears to be driven mainly by their high duplication levels in two ageing extremists, the naked mole rat (Heterocephalus glaber) and the greater mouse-eared bat (Myotis myotis). Further sequence and expression analyses suggest that the gene PIK3R1 may have undergone a convergent duplication event, whereby the similar region of its coding sequence was independently duplicated multiple times in both of these long-lived species.

Collectively, this study identified several candidate genes whose duplications may underlie the extreme longevity in mammals, and highlighted the potential role of gene duplication in the evolution of mammalian long lifespans.

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