? Studies of longevity mutants in laboratory populations have been critical for identifying which genes can affect longevity, but do not indicate whether the same genes influence variation in longevity in natural populations. I will use the nematode Caenorhabditis remanei as a model for the discovering naturally relevant candidate aging genes. Importantly, C. remanei are amenable to genetic manipulation and contain two orders of magnitude more molecular genetic variation within and among populations than the common model genetic organism, C. elegans.
I aim to: 1. Map genes responsible for natural variation in longevity. I will first map QTL affecting variation among inbred lines using RAD-tag high throughput genotyping on thousands of marker loci throughout the genome. I will evaluate candidate genes via functional genomic tests. Next, I will identify genes contributing to natural variation for longevity in wild-caught isolates (outbred, not lab-adapted) of C. remanei, using high-throughput genotyping and bulk segregant analysis to screen populations for differences in genome-wide allele frequencies between youth and old age. Regions of the genome experiencing changes in allele frequency with age will yield QTL on which I will use functional analyses to confirm the role of candidate genes. This will provide a basis for comparative studies between C. remanei and other species used in biogerontology, identify genes responsible for variation in lifespan, and reveal whether the genes identified by mutation screening affect variation in longevity in natural populations. 2. Critically evaluate the biological role of the dauer resting stage in creating individual-level differences in longevity. Several genes involved in the insulin/insulin-like growth factor signaling pathway have dramatic effects on longevity and are also known to regulate the dauer phase of Caenorhabditids. Preliminary evidence suggests significant polymorphisms at several loci in this pathway in C. remanei. I will select on the ability to survive through longer and longer periods of dauer. I will then identify the genes responsible for the response to selection and evaluate their effects on longevity and stress response. Relevance: This work will provide the first steps toward a genetic map and functional analysis of genes responsible for individual differences in propensity for age-related decline. Genes responsible for naturally extended lifespan are likely to provide insights into safe methods for extending the healthy, independent lives of humans ? ? ? ?
