Chromosome‐level Asian elephant genome assembly and comparative genomics of long‐lived mammals reveal the common substitutions for cancer resistance

Abstract

The naked mole rat (Heterocephalus glaber), bats (e.g., genus Myotis), and elephants (family Elephantidae) are known as long‐lived mammals and are assumed to be excellent cancer antagonists. However, whether there are common genetic changes underpinning cancer resistance in these long‐lived species is yet to be fully established. Here, we newly generated a high‐quality chromosome‐level Asian elephant (Elephas maximus) genome and identified that the expanded gene families in elephants are involved in Ras‐associated and base excision repair pathways. Moreover, we performed comparative genomic analyses of 12 mammals and examined genes with signatures of positive selection in elephants, naked mole rat, and greater horseshoe bat. Residues at positively selected sites of CDR2L and ALDH6A1 in these long‐lived mammals enhanced the inhibition of tumor cell migration compared to those in short‐lived relatives. Overall, our study provides a new genome resource and a preliminary survey of common genetic changes in long‐lived mammals.

Rapid evolution of genes with anti-cancer functions during the origins of large bodies and cancer resistance in elephants

“…There are several potential explanations for this low overlap, including differences in our alignments, which can have substantial impacts on inferences of selection (Fletcher and Yang, 2010;Franco et al, 2019;Jordan and Goldman, 2012;Markova-Raina and Petrov, 2011;Spielman et al, 2014) and differences in the number of species included in alignments (261 vs 12), with larger alignments likely having more power and reduced false positive inferences of selection but also paradoxical effects on inferences of selection, for example, by diluting the signal of d N /d S >1 by the addition of taxa in which positive selection did not occur (Chen and Sun, 2011;Murrell et al, 2012;Smith et al, 2015;Yokoyama et al, 2008); this signal loss may be more likely to occur in cases where the strength of selection is relatively weak or the proportion of sites or lineages under selection relatively small (Yang and Reis, 2011). Thus, we interpret our results as complementary to, rather than in contrast with, Li et al (2023). Indeed, studies of individual genes should include taxa inclusion sensitivity analyses (such as jackknifing or a priori exclusion of focal taxa) to infer the effects of alignment size and composition on inferences of positive selection.…”

“…Among these anti–cancer phenotypes are cells that induce apoptosis at low levels of DNA damage (Abegglen et al, 2015; Sulak et al, 2016a; Vazquez et al, 2018), are resistant to oxidative stress-induced cell death (Gomes et al, 2011), have faster DNA damage repair rates than smaller-bodied species (Francis et al, 1981; Hart and Setlow, 1974; Promislow, 1994), and resistant to experimental immortalization (Fukuda et al, 2016; Gomes et al, 2011). These cellular traits are at least partly mediated by an increase in the number of tumor suppressors in the elephant lineage (Caulin et al, 2015; Doherty and Magalhães, 2016; Sulak et al, 2016b; Tollis et al, 2020; Vazquez et al, 2018; Vazquez and Lynch, 2021), but many other mechanisms must also have contributed to enhanced cancer resistance including functional divergence of protein-coding genes (Li et al, 2023; Lynch and Wagner, 2008). Here, we used a suite of methods to characterize the strength and direction of selection acting on protein-coding genes in the elephant lineage, focusing on genes with evidence of positive selection and rapid evolution, which is likely associated with functional divergence (Slodkowicz and Goldman, 2020; Tennessen, 2008).…”

“…Li et al (2023) used BUSTED[S] to test for an episode of positive selection in the stem lineage of African and Asian elephants in a dataset of 12 species and 4,444 protein-coding genes and identified 618 positively selected genes. 492 of these genes were also tested for selection in our dataset, but only 32 (6.45%) were inferred to have been positively selected in our analyses.…”

“…Li et al (2023) used BUSTED[S] to test for an episode of positive selection in the stem lineage of African and Asian elephants in a dataset of 12 species and 4,444 protein-coding genes and identified 618 positively selected genes. To ensure a fair comparison between our results, mainly GO term enrichment results, Li et al (2023) provided the list of genes tested for selection and those identified by BUSTED[S] as positively selected.…”

“…Therefore, we used WebGestalt to reanalyze GO term enrichment for the 67 rapidly evolving genes identified by Goodman et al (2009) and found they were enriched (hypergeometric P≤0.05) in many GO biological process and cellular component terms related to the mitochondria (Supplementary dataset 1), but none the terms we identified. Li et al (2023) Li et al (2023) used BUSTED[S] to test for an episode of positive selection in the stem lineage of African and Asian elephants in a dataset of 12 species and 4,444 protein-coding genes and identified 618 positively selected genes. To ensure a fair comparison between our results, mainly GO term enrichment results, Li et al (2023) provided the list of genes tested for selection and those identified by BUSTED[S] as positively selected.…”