Identification and analysis of genetic determinants of natural telomere length variation

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 DESCRIPTION (provided by applicant) Telomeres are evolutionarily conserved protein-DNA complexes at the physical ends of linear eukaryotic chromosomes. The initial length of the repetitive telomeric DNA set at birth shortens with age in most human cells, thus serving as a marker of proliferation history and pre-determining cellular lifespan. Mutations in telomere maintenance genes lead to premature aging and a number of age-related disorders. Mean telomere length in humans shows considerable inter-individual variation and appears to be under strong genetic control, but the exact nature of factors establishing telomere length set point remains elusive. Here we propose to identify and characterize genetic factors establishing telomere length set point in the model plant Arabidopsis thaliana. In our preliminary results, we show that, similar to humans and yeast, natural Arabidopsis populations display significant variation in telomere length set point, and we identify a major effect telomere length QTL on chromosome 5. The main approach of this proposal takes advantage of the major recent technical breakthroughs in Arabidopsis QTL mapping using genetically advanced Recombinant Inbred MAGIC Lines to discover genetic factors establishing population-specific telomere length set point. Aim 1 takes advantage of the remarkable genetic diversity of natural Arabidopsis populations and the easy assays for precise monitoring of telomere length. We will continue measuring telomere length in the MAGIC population and fine-map one major and several minor QTL using a combination of candidate gene approach and population- wide comparative sequence and expression analysis. In Aim 2, we will utilize multiple genetic assays, such as knock-out and transgenic rescue experiments, to functionally characterize candidate genes and validate their role in telomere biology. Our results will lead to better understanding of genetic differences underlying telomere length polymorphism in natural Arabidopsis populations, and may also provide important insights into the molecular basis for different rates of aging among humans and predisposition to aging-associated diseases.