Whole-genome analyses point to new candidate genes underlying aestivation in amphibians

Abstract When amphibians invaded the terrestrial realm, a strategy such as aestivation may have helped them to survive water and oxygen stress in the novel environment. In fact, aestivation appears to be an ancestral state in amphibians. We conducted a literature review about the genes previously linked to aestivation and then we searched for additional candidate genes related to the aestivation phenotype by comparing evolutionary rates of 13,578 genes in 31 amphibian species, including 10 aestivating species and 21 non-aestivating species. Based on the assumption that aestivation has two main requirements – a) metabolic regulation needed to control transitions to/from dormancy, and b) cell preservation strategies needed to sustain biological processes over long-term dormancy – we expected to find distinct relative evolutionary rates (RER) in genes related to those traits. We identified 323 genes with accelerated or decelerated RERs; these genes were enriched for some processes overlapping with our predictions and with literature findings, such as different modes of ATP production. Other genes related to protein and membrane trafficking (TRAPP, SNARE, and Arp2/3 protein complexes) are newly associated with aestivation. RER patterns suggest that aestivation in amphibians relies on a set of highly conserved core processes and other auxiliary processes that have diversified across the phylogeny. Given the vast number and diversity of aestivating amphibian lineages, we predict that more in-depth molecular studies of amphibian aestivation will offer novel insight into hypometabolic processes that could inspire medical innovations to prevent organ atrophy, address problems with angiogenesis, and combat processes underlying cancer.