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

在哺乳动物中，随着身体尺寸的增加，最长寿命也会增加，但蝙蝠是这一规则的例外。这个项目将使用详细的基因组分析来研究蝙蝠的寿命是如何显著长于预期的。根据蝙蝠的体重，到目前为止，研究的蝙蝠物种的寿命可以比预期的长6倍。要想获得超乎寻常的长寿，需要加强细胞和组织的维护，保持免疫功能，避免导致癌症和其他与年龄相关的疾病的突变。因此，蝙蝠超长的寿命需要它们进化出能够实现这些特征的机制。为了发现健康晚年的遗传基础，这个项目关注的是一对寿命截然不同、关系密切的蝙蝠物种。对具有不同寿命的密切相关物种进行详细的基因组比较，将检验不同的衰老理论。尽管包括蝙蝠在内的许多哺乳动物都有基因组序列，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，以比目前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，更广泛地说是脊椎动物。该项目还将支持为中学生编写关于进化生物学的新教材，为教师提供研究经验，以及开发供科学界使用的新研究和分析方法。按身体大小衡量寿命将种群生物学与组成个体的细胞和组织的分子机制联系起来，但这种联系的性质尚有争议。一些理论认为，衰老是老年人繁殖机会减少所强加的基因权衡的结果(进化论)，而另一些理论则提出，衰老是由于有机体在生命中移动时造成的分子和细胞损伤(损伤理论)。该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。除了生成至少五个高质量的哺乳动物基因组来补充现有的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类型联系起来，包括基因、伪基因、转录因子和某些基因拷贝数的变异。结合对基因组甲基化和RNA转录本的分析，该项目将确定潜在的不同寿命的候选区域，使未来能够在组织、细胞和分子层面进行功能分析。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.