裸鼹鼠(异头鼠,NMRs)和盲mole鼠(Spalaxgalili,BMR)是具有代表性的地下啮齿动物,它们已经进化出许多非凡的特征,包括缺氧耐受性,长寿,和抗癌。尽管基因组研究已经发现了负责这些性状的多个候选基因座,它们中的许多仅限于氨基酸序列的功能改变,而对其他遗传事件的贡献知之甚少。为了解决这个问题,我们专注于基因丢失(单一假基因),并系统分析了NMR和BMR中的基因丢失,旨在阐明假基因在适应地下生活方式中的潜在作用。
我们在NMR和BMR中获得了假基因库,以及他们各自的地上亲属,豚鼠和大鼠,在全基因组范围内。因此,在NMR中鉴定了167、139、341和112个假基因,BMR,豚鼠,和老鼠,分别。功能富集分析确定了地下谱系中的4个共享和2个物种特异性富集官能团(EFG)。值得注意的是,这些EFG中的伪基因可能与两种回归(例如,视觉系统)或自适应(例如,改变的DNA损伤反应)性状。此外,包括TNNI3K和PDE5A在内的几种假基因可能与地下谱系中观察到的特定心脏特征相关。有趣的是,我们在NMR和BMR中观察到20个趋同基因丢失。鉴于这些基因的功能研究通常很少,我们提供了功能性证据表明,在NMR和BMR中TRIM17的独立丢失可能对缺氧下的神经元存活有益。支持消除TRIM17功能在低氧适应中的积极作用。我们的结果还表明假基因,连同积极选择的基因,合作加强地下适应。
我们的研究为地下适应的分子基础提供了新的见解,并强调了基因丢失在哺乳动物进化中的重要性。
Naked mole-rats (Heterocephalus glaber, NMRs) and blind mole-rats (Spalax galili, BMRs) are representative subterranean rodents that have evolved many extraordinary traits, including hypoxia tolerance, longevity, and cancer resistance. Although multiple candidate loci responsible for these traits have been uncovered by genomic studies, many of them are limited to functional changes to amino acid sequence and little is known about the contributions of other genetic events. To address this issue, we focused on gene losses (unitary pseudogenes) and systematically analyzed gene losses in NMRs and BMRs, aiming to elucidate the potential roles of pseudogenes in their adaptation to subterranean lifestyle.
We obtained the pseudogene repertoires in NMRs and BMRs, as well as their respective aboveground relatives, guinea pigs and rats, on a genome-wide scale. As a result, 167, 139, 341, and 112 pseudogenes were identified in NMRs, BMRs, guinea pigs, and rats, respectively. Functional enrichment analysis identified 4 shared and 2 species-specific enriched functional groups (EFGs) in subterranean lineages. Notably, the pseudogenes in these EFGs might be associated with either regressive (e.g., visual system) or adaptive (e.g., altered DNA damage response) traits. In addition, several pseudogenes including TNNI3K and PDE5A might be associated with specific cardiac features observed in subterranean lineages. Interestingly, we observed 20 convergent gene losses in NMRs and BMRs. Given that the functional investigations of these genes are generally scarce, we provided functional evidence that independent loss of TRIM17 in NMRs and BMRs might be beneficial for neuronal survival under hypoxia, supporting the positive role of eliminating TRIM17 function in hypoxia adaptation. Our results also suggested that pseudogenes, together with positively selected genes, reinforced subterranean adaptations cooperatively.
Our study provides new insights into the molecular underpinnings of subterranean adaptations and highlights the importance of gene losses in mammalian evolution.