Comparing the Genetics of Large and Small Long-Lived Rodents

Research into the comparative biology of aging seeks to identify important mechanisms determining life span and the progression of aging by comparing different near neighbor species with very different life spans. In this case, researchers are comparing the genetics of naked mole-rats, as a small long-lived rodent, with beavers, as a large long-lived rodent, in order to shed more light on mammalian aging.

Discerning the genetic factors that affect the aging process, in particular how they control lifespan, is one of the important yet unanswered questions in biology and evolution. Rodent species differ more than 10-fold in maximum lifespan, and long-lived rodents have been observed to show low susceptibility to certain age-related diseases. Therefore, analyses of their genomes could help discover genetic factors responsible for such diversity of lifespan. Motivated by this idea, an initial genome assembly of the naked mole rat (NMR), a rodent best known for its longevity (maximum lifespan of more than 35 years), was generated. It represented the first case of a mammalian genome being sequenced with the explicit purpose of providing insights into longevity. Analysis revealed several unique features and molecular mechanisms related to NMR phenotypes, such as cancer resistance, protein synthesis, visual function, etc.

The North American beaver has the second longest lifespan known for rodents, at more than 23 years. This species is famous for its ability to modify the environment by building complex dams and lodges, which sets them apart from other mammals. To date, two beaver genome assemblies have been reported, although extensive genome analyses have not been performed.

It should be noted that rodents have achieved long lives at least four times independently, and two contrasting combinations of longevity and body mass are recognized: i.e., species with large body mass and long lifespan (e.g., beaver and porcupine) and species with small body mass and long lifespan (e.g. naked mole-rat). Therefore, comparative analyses of these rodents and their closely related relatives that are characterized by small body mass and short lifespan could be useful for understanding how lifespan coevolved with body mass in rodents. It was proposed that the ability of organisms to effectively cope with both intrinsic and extrinsic stresses is linked with longevity.

With these goals in mind, we prepared high quality chromosome-level genome assemblies of the longest-lived rodents, the beaver and NMR. Our comparative genomic analyses reveal that amino acid substitutions at "disease-causing" sites are widespread in the rodent genomes and that identical substitutions in long-lived rodents are associated with common adaptive phenotypes, e.g., enhanced resistance to DNA damage and cellular stress. By employing a newly developed substitution model and likelihood ratio test, we find that energy metabolism and fatty acid metabolism pathways are enriched for signals of positive selection in both long-lived rodents.

Link: https://doi.org/10.1016/j.celrep.2020.107949

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