Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity

Abstract

The genetic basis of the large species differences in longevity and aging remains a mystery. Thanks to recent large-scale genome sequencing efforts, the genomes of multiple species have been sequenced and can be used for cross-species comparisons to study species divergence in longevity. By analyzing proteins under accelerated evolution in several mammalian lineages where maximum lifespan increased, we identified genes and processes that are candidate targets of selection when longevity evolves. We identified several proteins with longevity-specific selection patterns, including COL3A1 that has previously been related to aging and proteins related to DNA damage repair and response such as DDB1 and CAPNS1. Moreover, we found that processes such as lipid metabolism and cholesterol catabolism show such patterns of selection and suggest a link between the evolution of lipid metabolism, cholesterol catabolism, and the evolution of longevity. Lastly, we found evidence that the proteasome-ubiquitin system is under selection specific to lineages where longevity increased and suggest that its selection had a role in the evolution of longevity. These results provide evidence that natural selection acts on species when longevity evolves, give insights into adaptive genetic changes associated with the evolution of longevity in mammals, and provide evidence that at least some repair systems are selected for when longevity increases.

Accelerated pathway evolution in mouse-like rodents involves cell cycle control

“…The combined pathway network reveals that the ubiquitin-dependent protein degradation is a core of the enriched pathway system. Notably, it was reported that the proteasome-ubiquitin system is involved in the evolution of longevity (Li and de Magalhaes 2013). On the example of telomere recovery, it is known that there is a trade-off between cancer resistance and longevity: the higher telomere recovery enables the higher cell renewal, which is necessary for longer lifespan, but increases the risk of cancer (Gomes et al 2011).…”

Distinctive topology of age-associated epigenetic drift in the human interactome

“…Many integral housekeeping cellular functions are carried out by proteins occupying these highly central positions in the network (46). These hubs not only are essential, but also modulate longevity, and may also play a key role in promoting and regulating the observed robustness of cells that are constantly being battered by intrinsic and extrinsic perturbations (47,48). It is therefore plausible that gene promoters undergoing age-associated epigenetic drift should be of typically lower degree, as otherwise induced changes in gene expression at hubs could likely compromise essential cellular functions.…”

Comparative genetics of longevity and cancer: insights from long-lived rodents

“…Another approach is to carry out analyses of positive selection, unique amino acid replacements or accelerated evolution 58 . Applied across whole mammalian genomes, these searches identify a multitude of genes (and sites within genes), and hence require robust filtering methods to remove false positives, such as genes with repeats.…”