Understanding the genetic mechanisms affecting variation in lifespan in natural populations is crucial for understanding the genetic basis of human age-related diseases. Lifespan is a complex trait, known to have substantial phenotypic variation in natural populations due to the segregation of multiple genetic factors as well as exposure to different environmental conditions, with a heritability ranging from 10-30% across many different species. The low heritability, combined with genetic heterogeneity and the inability to control environmental influences, makes determining the genetic basis of variation in lifespan in human populations extremely challenging, and only a few quantitative trait loci (QTLs) that encompass many candidate genes have been identified. Drosophila melanogaster is a powerful model system for studying the genetics of lifespan because it is relatively short-lived, genetic backgrounds and environmental conditions can be controlled, and both naturally occurring variants as well as mutations can be utilized to identify candidate genes. I propose to use an advanced intercross population (AIP) derived from 37 genetically diverse inbred lines with complete genome sequences from the Drosophila Genetic Reference Panel to perform extreme QTL mapping GWA analyses with large sample sizes to identify causal variants; to conduct a systems genetic analysis to identify transcriptional genetic networks and candidate causal regulatory variants associated with variation in lifespan; and to validate novel variants and genes affecting lifespan. Given the conservation of biological pathways among taxa, including humans and flies, these results are likely to provide insights into orthologous genetic factors that influence variation in human lifespan.
The world population is rapidly growing older, with associated increases in age-related diseases. Lifespan is a quantitative trait with significant genetic variation in human populations, but very few loci affecting variation in human lifespan have been identified. This study utilizes genetic and genomic analyses to identify and functionally validate variants, genes and transcriptional networks affecting lifespan using the Drosophila model system that are likely to have human orthologs and may give novel insights into evolutionarily conserved genetic mechanisms increasing lifespan.
