Uvizl, M. | Search bioRxiv

bioRxiv2023

Duplications of human longevity-associated genes across placental mammals

Natural selection has shaped a wide range of lifespans across mammals, with a few long-lived species showing negligible signs of ageing. Approaches used to elucidate the genetic mechanisms underlying mammalian longevity usually involve phylogenetic selection tests on candidate genes, analyses of differential gene expression between age cohorts or species, and measuring age-related epigenetic changes. However, the link between gene duplication and evolution of mammalian longevity has not been widely investigated. Here, we explored the association between gene duplication and mammalian lifespan by analysing 287 human longevity-associated genes across 37 placental mammals. We estimated that the expansion rate of these genes is eight times higher than their contraction rate across these 37 species. Using phylogenetic approaches, we identified 43 genes whose duplication levels are significantly correlated with longevity quotients (FDR < 0.05). In particular, strong correlation observed for four genes (CREBBP, PIK3R1, HELLS, FOXM1) appears to be driven mainly by their high duplication levels in two ageing extremists, the naked mole rat (Heterocephalus glaber) and the greater mouse-eared bat (Myotis myotis). Further sequence and expression analyses suggest that the gene PIK3R1 may have undergone a convergent duplication event, whereby the similar region of its coding sequence was independently duplicated multiple times in both of these long-lived species. Collectively, this study identified several candidate genes whose duplications may underlie the extreme longevity in mammals, and highlighted the potential role of gene duplication in the evolution of mammalian long lifespans.

evolutionary biology↗

bioRxiv2023

Comparative genome microsynteny illuminates the fast evolution of nuclear mitochondrial segments (NUMTs) in mammals

The escape of DNA from mitochondria into the nuclear genome (nuclear mitochondrial DNA, NUMT) is an ongoing process. Although pervasively observed in eukaryotic genomes, their evolutionary trajectories in a mammal-wide context are poorly understood. The main challenge lies in the orthology assignment of NUMTs across species due to their fast evolution and chromosomal rearrangements over the past [~]200 million years. To address this issue, we systematically investigated the characteristics of NUMT insertions in 45 mammalian genomes, and established a novel, synteny-based method to accurately predict orthologous NUMTs and ascertain their evolution across mammals. With a series of comparative analyses across taxa, we revealed that NUMTs may originate from non-random regions in mtDNA, tend to locate in transposon-rich and intergenic regions, and unlikely code for functional proteins. Using our synteny-based approach, we leveraged 630 pairwise comparisons of genome-wide microsynteny and predicted the NUMT orthology relationships across 36 mammals. With the phylogenetic patterns of NUMT presence-and-absence across taxa, we constructed the ancestral state of NUMTs given the mammal tree using a coalescent method. We found support on the ancestral node of Fereuungulata within Laurasiatheria, whose subordinal relationships are still controversial. This strongly indicates that NUMT gain-and-loss over evolutionary time provides great insights into mammal evolution. However, we also demonstrated that one should be cautious when using ancestral NUMT trees to infer phylogenetic relationships. This study broadens our knowledge on NUMT insertion and evolution in mammalian genomes and highlights the merit of NUMTs as alternative genetic markers in phylogenetic inference.

evolutionary biology↗