Uncovering genes contributing to exceptional longevity and immunity in bats by comparative genomic analysis across all bat families

蝙蝠是唯一一种进化出动力飞行的哺乳动物，并表现出其他哺乳动物罕见的特征。经过体型校正后，蝙蝠的平均寿命是不会飞的哺乳动物的三倍，而且它们很少得癌症。蝙蝠感染对人类致命的病毒通常是没有症状的，因为它们的免疫系统能够有效地抑制炎症免疫反应。因此，蝙蝠是健康衰老和增强对肿瘤形成和传染病的抵抗力的重要模型，这与人类衰老、癌症和炎症相关疾病有关。然而，蝙蝠异常长寿和独特免疫力背后的分子机制仍然不清楚。为了对蝙蝠异常长寿和免疫相关的基因提供新的见解，我们将对所有21个公认的蝙蝠科的高质量基因组进行全面的比较分析。为此，我们将使用最大证据方法为所有21个科的代表性物种生成基因注释，该方法集成了基于同源性的、从头开始的和基于转录组的基因预测。为了揭示可能有助于长寿和免疫的基因，我们将系统地发现蝙蝠中表现出突变功能丧失或功能获得特征的基因。具体地说，我们将在已建立的比较基因组学方法的基础上，筛选蝙蝠中失活的祖先基因、在宽松或积极选择下进化的基因，以及在蝙蝠中出现的新基因。这一针对所有蝙蝠家族的史无前例的基因组分析将为蝙蝠异常长寿和免疫的进化和基因组基础提供新的见解，并有望为未来的实验测试揭示有希望的目标。生成的21个蝙蝠家族的高质量参考基因注释代表了一个具有长期价值的重要资源，因为它们能够在数百只蝙蝠中进行比较基因注释，这些基因注释将在未来进行测序。

Bats are the only mammals that evolved powered flight and exhibit traits that are rarely found in other mammals. Bats live on average three-times longer than non-flying mammals after correcting for body size and they rarely get cancer. Infections with viruses that are deadly for humans is often asymptomatic in bats, because their immune system is able to efficiently dampen inflammatory immune responses. Thus, bats are important models for healthy aging and enhanced resistance to tumorigenesis and infectious diseases, which is relevant for human senescence, cancer, and inflammation-related disorders. However, the molecular mechanisms underlying their exceptional longevity and unique immunity remain elusive.To provide novel insights into the genes that are involved in exceptional longevity and immunity of bats, we will conduct a comprehensive comparative analysis of high-quality genomes of all 21 recognized bat families. To this end, we will generate gene annotations for representative species of all 21 families using a maximum evidence approach that integrates homology-based, de novo and transcriptome-based gene predictions. To reveal genes that likely contribute to longevity and immunity, we will systematically uncover genes that exhibit mutational loss- or gain-of-function signatures in bats. Specifically, building on established comparative genomics approaches, we will screen for ancestral genes that are inactivated in bats, genes that evolved under relaxed or positive selection, and novel genes that arose in bats.This unprecedented genomic analysis across all bat families will provide new insights into the evolution and the genomic basis of exceptional longevity and immunity in bats and is expected to reveal promising targets for future experimental tests. The generated high-quality reference gene annotations of 21 bat families represent an important resource of long term value as they enable comparative gene annotation in hundreds of bats that will be sequenced in future.