Longitudinal comparative transcriptomics reveals unique mechanisms underlying extended healthspan in bats

Abstract

Bats are the longest-lived mammals, given their body size. However, the underlying molecular mechanisms of their extended healthspans are poorly understood. To address this question we carried out an eight-year longitudinal study of ageing in longlived bats (Myotis myotis). We deep-sequenced ~1.7 trillion base pairs of RNA from 150 blood samples collected from known aged bats to ascertain the age-related transcriptomic shifts and potential microRNA-directed regulation that occurred. We also compared ageing transcriptomic profiles between bats and other mammals by analysis of 298 longitudinal RNA sequencing datasets. Bats did not show the same transcriptomic changes with age as commonly observed in humans and other mammals, but rather exhibited a unique, age-related gene expression pattern associated with DNA repair, autophagy, immunity and tumour suppression that may drive their extended healthspans. We show that bats have naturally evolved transcriptomic signatures that are known to extend lifespan in model organisms, and identify novel genes not yet implicated in healthy ageing. We further show that bats' longevity profiles are partially regulated by microRNA, thus providing novel regulatory targets and pathways for future ageing intervention studies. These results further disentangle the ageing process by highlighting which ageing pathways contribute most to healthy ageing in mammals. Articles Nature ecology & evolutioN results and discussion Overview of M. myotis ageing transcriptomes. Using a non-lethal sampling process developed to maximize transcript representation from bat blood (>60% of all protein-coding genes represented) 23 , we deep-sequenced ~1.7 trillion base pairs of RNA from 100 bat blood samples (69.6 ± 9.0 s.d. million reads per sample) using Illumina RNA-sequencing (RNA-Seq). These blood samples (~50-200 μl) were collected from 70 individual bats ranging in age from 0 to >7 years (for example, first caught as an adult 6 years before subsequent recapture) at five colonies in Brittany, France (Supplementary Tables 1-3 and Supplementary Fig. 1). The majority of the raw reads (98.5%) showed high quality (>Q30). On average, 77% of clean reads were successfully mapped to the reference genome (Myotis lucifugus), 64.2% of which had unique mapping coordinates. Of all mapped reads, 88.1% were concordantly aligned. Only those reads that were uniquely and concordantly mapped were used for downstream analyses. To gain an overview of the bat blood tran

The Evolution of Human Cancer Gene Duplications across Mammals

“…We found that the little brown bat (Myotis lucifugus) was an outlier compared to other laurasiatherians with high cancer gene copy numbers, in particular for tumor suppressor genes with both germline and somatic mutations (1.83 copies per ortholog versus 1.42 average for laurasiatherians). Recent comparative studies have suggested that bats in the long-lived genus Myotis do not display telomere shortening with age (Foley et al 2018), showed evidence of positive selection in genes that control DNA damage (Foley et al 2018), and have unique gene expression patterns in pathways controlling DNA repair and tumor suppression that increase with age (Huang et al 2019). Similarly, a previous study found accelerated protein evolution in DNA damage and response pathways that was unique to long-lived mammals (Li and de Magalhães 2013).…”

Six reference-quality genomes reveal evolution of bat adaptations

“…extended healthspan 4 , enhanced disease tolerance 3 , vocal communication 5 and sensory perception 6 . To understand the evolution of bats and the molecular basis of these traits, we generated reference-quality genomes for six bat species as part of the Bat1K global genome consortium 1 (http://bat1k.com) in coordination with the Vertebrate Genome Project (https://vertebrategenomesproject.org).…”

A comprehensive annotation and differential expression analysis of short and long non-coding RNAs in 16 bat genomes

“…Bats have developed a variety of unique biological features that are the rarest among all mammalian, including laryngeal echolocation 4,6 , vocal learning 7 , and the ability to fly 3 . They occupy a broad range of different ecological niches 2 , have an exceptional longevity [8][9][10] and a natural and unique resilience against various pathogenic viruses 1,11 .…”