RoL: FELS: EAGER: Collaborative Research: Genomics of Exceptions to Scaling of Longevity to Body Size

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.