A functional genomics approach to elucidate the role of genome maintenance in human longevity
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The genetic control of longevity and pro-longevity phenotypes is likely to be determined by subtle variations in many genes involved in multiple genetic pathways. The challenge is to identify the combinations of alleles that are associated with healthy aging and longevity, and to ascertain the functional relevance of positive associations by providing mechanistic insights. There is strong evidence that genome maintenance is a major "Longevity Assurance Pathway" because genetic defects in this pathway cause a shorter life span and premature aging in humans and mice. The goal of my project is to elucidate the role of genome maintenance in human longevity by testing the hypothesis that a cluster of protective genotypes in the genome maintenance pathways is necessary to achieve exceptional longevity. To address this hypothesis, I conducted a systematic functional genomics approach to discover "functional genetic variants" involved in genome maintenance that are either enriched (beneficial alleles) or depleted (deleterious alleles) in Ashkenazi Jewish families with exceptional longevity. For this purpose, I utilized targeted sequence capture and next generation sequencing to discover all possible genetic variation in the coding and regulatory regions of 397 candidate genes acting in genome maintenance pathways. I discovered novel, potentially functional variants, including rare missense and regulatory variants that are significantly enriched in centenarians as compared to controls. Also, gene-based rare variation analysis followed by pathway analysis indicated that double strand break repair genes were enriched with longevity-associated rare variants. Since it is important to directly test the impact of rare variants by functional analysis for their longevity association and biological significance, in vitro cell culture study to assess the functional relevance of the rare double SIRT6 variant in the same haplotype was performed. The results demonstrated that the double SIRT6 mutant increased SIRT6 deacetylase activity specifically on H3K56Ac but not H3K9Ac in cell-based assays.;This study presents the first large scale candidate gene association study on human longevity utilizing high-throughput sequencing. We discovered new longevity loci enriched with rare variants within the genome maintenance pathway that could potentially provide important insights into the molecular basis of human longevity.