Positive Selection and Enhancer Evolution Shaped Lifespan and Body Mass in Great Apes

Abstract

Within primates, the great apes are outliers both in terms of body size and lifespan, since they include the largest and longest-lived species in the order. Yet, the molecular bases underlying such features are poorly understood. Here, we leveraged an integrated approach to investigate multiple sources of molecular variation across primates, focusing on over ten thousand genes, including ∼1,500 previously associated with lifespan, and additional ∼9,000 for which an association with longevity has never been suggested. We analyzed dN/dS rates, positive selection, gene expression (RNA-seq) and gene regulation (ChIP-seq). By analyzing the correlation between dN/dS, maximum lifespan and body mass we identified 276 genes whose rate of evolution positively correlates with maximum lifespan in primates. Further, we identified 5 genes, important for tumor suppression, adaptive immunity, metastasis and inflammation, under positive selection exclusively in the great ape lineage. RNA-seq data, generated from the liver of six species representing all the primate lineages, revealed that 8% of ∼1,500 genes previously associated with longevity are differentially expressed in apes relative to other primates. Importantly, by integrating RNA-seq with ChIP-seq for H3K27ac (which marks active enhancers), we show that the differentially expressed longevity genes are significantly more likely than expected to be located near a novel “ape-specific” enhancer. Moreover, these particular ape-specific enhancers are enriched for young transposable elements, and specifically SINE-Vntr-Alus (SVAs). In summary, we demonstrate that multiple evolutionary forces have contributed to the evolution of lifespan and body size in primates.

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

“…Tejada-Martinez et al [40] also focused on protein evolution in their study of lifespan and body mass in primates, although they then linked their findings to enhancer evolution. Their approach was to perform phylogenetic regressions, relating dN/dS to maximum lifespan and body mass for around 10,000 genes.…”

“…Their approach was to perform phylogenetic regressions, relating dN/dS to maximum lifespan and body mass for around 10,000 genes. In contrast to Kowalczyk et al [15], Tejada-Martinez et al [40] focus on positive (directional) selection on protein-coding genes rather than conservation. The authors identified 276 candidate genes whose rate of adaptive evolution positively correlated with maximum life span in a phylogenetic context.…”

“…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.…”

A phylogenetic review of cancer resistance highlights evolutionary solutions to Peto’s Paradox

“…As in other mammalian lineages, the maximum life span and body mass are correlated in primates, and the great apes are the largest body size and long-lived species among them. Tejada-Martinez et al (2022 ) investigated the molecular evolution in coding genes and cis-regulatory sequences and gene expression evolution related to the development and maintenance of maximum lifespan and body size in the great apes and their association with pathways related to cancer suppression. They found only five genes with positive selection signals for the great ape lineage (IRF3, SCRN3, DIAPH2, GASK1B, and SELENO), all of which have functions related to cancer development and inflammatory responses.…”

“…The authors also identified footprints of evolution related to SINE-Vntr-Alu (SVA) insertions and LTR transposons, reinforcing the importance of the action of these transposable elements in the evolution of great apes' gene-regulatory networks, especially in humans ( Trizzino et al , 2017 ). The results of Tejada-Martinez et al (2022 ) show that the evolution of strategies for cancer resistance in the primate lineage is quite diverse, with modifications that can be found at the coding, expression, and regulatory levels, and that although the great apes lineage provides evidence of specific changes capable of giving greater longevity to the species of the group, the understanding of the relationship with cancer resistance is still developing for nonhuman species and needs to be further investigated.…”