Convergent genomics of longevity in rockfishes highlights the genetics of human life span variation

Abstract

Longevity is a defining, heritable trait that varies dramatically between species. To resolve the genetic regulation of this trait, we have mined genomic variation in rockfishes, which range in longevity from 11 to over 205 years. Multiple shifts in rockfish longevity have occurred independently and in a short evolutionary time frame, thus empowering convergence analyses. Our analyses reveal a common network of genes under convergent evolution, encompassing established aging regulators such as insulin signaling, yet also identify flavonoid (aryl-hydrocarbon) metabolism as a pathway modulating longevity. The selective pressures on these pathways indicate the ancestral state of rockfishes was long lived and that the changes in short-lived lineages are adaptive. These pathways were also used to explore genome-wide association studies of human longevity, identifying the aryl-hydrocarbon metabolism pathway to be significantly associated with human survival to the 99th percentile. This evolutionary intersection defines and cross-validates a previously unappreciated genetic architecture that associates with the evolution of longevity across vertebrates.

A phylogenetic method linking nucleotide substitution rates to rates of continuous trait evolution

“…The top genes identified in their study do not feature in our notes on our top 25 LLL loci though, as all of us do, the authors find a relationship between their loci of interest and p53, in this case via PLA2R1. We note Treaster et al [41] and Kowalczyk et al [15] emphasize insulin signaling pathways, though apparently the particular pathways are under increased constraint in mammals (gene IGF1) but accelerated in Rockfish (gene INSR).…”

“…A key part of the analysis pipeline was the detection of rate shifts using the TRACCER tool [7]. Unlike Kolora et al [42], and the other studies we mention, Treaster et al [41] treated longevity as a binary trait and argued against the need to correct for body size. The authors found the ancestral rockfish state to be long-lived, and linked positive selection to glycogen biosynthesis and flavonoid metabolism via GO analysis.…”

“…It is possible then that PhyloAcc-C will sometimes identify processes that would otherwise be missed. Indeed, Treaster et al [41] specifically mention that an attempt was made to analyze the CNE data captured as part of their study, but that their approach was underpowered when working with short conserved sequences. This suggests PhyloAcc-C might be used in a complementary manner to existing methodologies, potentially extracting further insight from a given sequencing data set.…”

“…A third study by Treaster et al [41] takes yet a different approach to understanding longevity. By focusing on 23 species of rockfish that are both closely related and feature a wide range of lifespans (11 to more than 200 years), the authors aimed to identify longevity related protein coding genes while minimizing false positives due to (other) convergent evolution.…”

“…The above studies either focus exclusively on protein coding genes [15, 41] or examine non-coding sequences only insofar as they are identified as byproduct of an analysis with genes as the starting point and main consideration [40]. One distinguishing factor of PhyloAcc-C when compared to these approaches is that its focus is on identifying relevant non-coding sequences.…”