Genome Sequencing of Bat Species in Search of Causes of Longevity
Long-lived bats are extreme outliers in the normal mammalian relationships between species body size, metabolic rate, and life span. They are small, have a high metabolic rate, and unlike near all other mammals with those characteristics, many bat species are long-lived. But bat species do exhibit a very wide range of life spans; near neighbor species can have very different paces of aging. Researchers here sequence the genomes of a number of different bat species in search of insight into the mechanisms driving longevity in bats. As is usually the case, the distant end goal of this sort of comparative biology of aging research is to find potential approaches to the development of longevity therapies. That is a long road, and little progress has been made beyond investigation. Only in recent years have the first speculative transfers of genes from long-lived species to short-lived species occurred, for example.
The genus Myotis is one of the largest clades of bats, and it exhibits some of the most extreme variation in lifespans among mammals, alongside unique adaptations to viral tolerance and immune defence. Here, to study the evolution of these phenotypes, we generated cell lines and near-complete genome assemblies for eight closely related Myotis species. Using genome-wide screens of positive selection, analyses of structural variation and functional experiments in primary cells, we identify patterns of adaptation contributing to longevity, cancer resistance, and viral interactions.
We demonstrate distinct modes of adaptation to DNA and RNA viruses compared with all other mammals, with bats exhibiting genome-wide over-representation of positive selection for DNA-virus-interacting proteins and elevated rates of copy-number variation for RNA-virus-interacting proteins. Characterization of Myotis-specific duplications of the key immune factor EIF2AK2 (also known as PKR) reveals multiple ancient segregating trans-species copy-number polymorphisms. We show that the recurrent evolution of longevity seen in Myotis is associated with positive selection in cancer pathways, and demonstrate a unique response to DNA damage in primary cells of the long-lived Myotis lucifugus. Together, our results suggest that bats' remarkable longevity and immunity are linked through pleiotropic adaptations to viruses and ageing-related disease.