Cross-Species and Evolutionary Biology

PROJECT SUMMARY - PROJECT 2 There exists a vast diversity of observed lifespans across species. However, our understanding of the genetic, molecular, and mechanistic underpinnings of aging differences between species remains largely unknown. Within mammalian lineages alone, exceptional long and short lifespans have evolved multiple times. This homoplasy renders evolution a powerful tool to identify mechanisms within humans and other species that underlie lifespan differences. Furthermore, by understanding which aspects of human longevity are conserved or divergent from other species at the molecular level,biologically relevant information is elucidated that can influence our use of model organisms to test geroprotective therapies. However, identifying the individual phylogenetic changes responsible for lifespan differences across species and linking them to phenotypic effects at scale has remained a challenge for the field. This is due to both the complexity of cross-species phylogenetic analysis and the difficulty in surveying gene regulatory elements at-scale which are known to be a primary driver of evolutionary change. To address this The Longevity Consortium Cross Species and Evolutionary Biology (CSEB) Project will integrate sophisticated evolutionary algorithms, high-throughput functional genomics tools, and advanced phenotype-relevant neuronal models, to uncover the genetic basis of longevity across species. First, we will leverage and expand on a large collection of multiomic data from hundreds of mammalian species to construct a curated genomic database that is combined with longevity data. Using state-of-the-art algorithms, many developed by members of the CSEB, we will identify genes, regulatory elements, and pathways associated with differences in longevity across species. Second, we will deploy high-throughput CRISPR screens to systematically perturb hundreds of longevity-associated loci in neurons and fibroblasts of 8 species. This allows us to build longevity gene-regulatory networks and assess their divergence across species. Across these same species and cell types, we will use massively parallel reporter assays to interrogate cis-regulatory elements and genetic variation within these elements to uncover the precise genetic mechanism underlying longevity difference both across species and within the human population. Together, these assays will (i) validate associations from our phylogenetic analysis and from findings from across the consortium, and (ii) allow the construction of comprehensive gene regulatory models across multiple species for use by the integrative analysis core. Lastly, we will extend the legacy cross-species fibroblast resource by developing an iPSCs collection of 20 species allowing the functional characterization in differentiated cell types.