RoL: FELS: EAGER: Collaborative Research: Genomics of exceptions to scaling of longevity to body size

在哺乳动物中，随着体型的增加，最长寿命也会增加，但蝙蝠是这一规律的例外。该项目将使用详细的基因组分析来研究蝙蝠为何比预期寿命长得多。迄今为止研究过的蝙蝠物种可以比根据它们的体重预期的寿命长六倍。要获得超长的寿命，需要加强对细胞和组织的维护，维持免疫功能，避免导致癌症和其他与年龄有关的疾病的突变。因此，它们超长的寿命要求蝙蝠进化出能够实现这些特征的机制。为了发现健康老年的遗传基础，该项目将重点放在一对关系密切、寿命差异很大的蝙蝠物种上。在不同寿命的近亲物种之间进行详细的基因组比较，将检验不同的衰老理论。虽然包括一些蝙蝠在内的许多哺乳动物的基因组序列是可用的，但在大多数情况下，这些序列太不完整，无法进行详细的比较。出于这个原因，该项目还寻求结合现代DNA测序技术，以更高的分辨率和更低的成本产生基因组序列。由此产生的方法可以应用于许多其他哺乳动物，以及更普遍的脊椎动物。该项目还将支持为中学生编写关于进化生物学的新教材，为教师编写研究经验，以及发展新的研究和分析方法，供科学界使用。按体型划分寿命，将种群生物学与构成个体的细胞和组织的分子机制联系起来，但这种联系的本质仍存在争议。一些理论认为，衰老是由于老年个体繁殖机会的减少而导致的遗传权衡的结果（进化论），而另一些理论则认为，衰老是生物体在生命过程中受到分子和细胞损伤的结果（损伤理论）。这个项目将通过对高质量基因组序列的比较分析来检验这些广泛的理论。除了产生至少五个高质量的哺乳动物基因组来补充现有或正在进行的基因组外，该项目还将把长寿表型与基因组序列中的基因型联系起来，包括基因、假基因、转录因子和某些基因拷贝数的变异。结合基因组甲基化和RNA转录的分析，该项目将确定潜在不同寿命的候选区域，从而实现未来在组织、细胞和分子尺度上的功能分析。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

In mammals, as body size increases so does maximum lifespan, but bats represent an exception to this rule. This project will use a detailed genomic analysis to examine how bats live significantly longer than expected. Bat species studied to date can live up to six times longer than expected based on their body mass. Achieving unusually long life requires enhanced cell and tissue upkeep, maintaining immune function, and avoiding mutations that cause cancer and other age-related diseases. Hence, their exceptionally long lives require that bats evolve mechanisms to enable these features. To discover the genetic basis of healthy old age, this project focuses on pairs of closely related bat species that sharply differ in their longevity. Detailed genome comparisons between closely related species with different life spans will test different theories of aging. Although genome sequences are available for many mammals, including some bats, in most cases these are too incomplete to allow detailed comparisons. For this reason, the project also seeks to combine modern DNA sequencing techniques to produce genome sequences at greater resolution and lower cost than hitherto possible. The resulting methods can be applied across many other mammals, and vertebrates more generally. The project will also support the production of new teaching materials on evolutionary biology for secondary school students and research experiences for teachers, as well as the development of new research and analytical approaches for use by the scientific community.The scaling of longevity by body size relates the biology of populations to the molecular mechanisms of cells and tissues making up individuals, but the nature of the connections is debated. Some theories suggest that aging is the result of genetic trade-offs imposed by the diminishing chances of reproduction of older individuals (Evolutionary Theory), while others propose that aging results from molecular and cellular damage as organisms move through life (Damage Theory). This project will test these broad theories through comparative analyses of high-quality genome sequences. Besides generating at least five high quality mammalian genomes to complement existing or ongoing ones, the project will relate longevity phenotypes to genotypes across the genome sequence including genes, pseudogenes, transcription factors, and variation in the number of copies of certain genes. Coupled with analyses of genomic methylation and RNA transcripts, the project will identify candidate regions underlying divergent longevities, enabling future functional analyses at the scale of tissues, cells, and molecules.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.