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| Development of the African killifish N. furzeri as a genetic model to identify the genetic architecture of vertebrate aging
The search for genes that control longevity in vertebrates has been hampered by the absence of short-lived vertebrate models, as mice live on average 2.5 years and zebrafish 3.5 years. We are pioneering the development of a new genetic model for longevity, the extremely short-lived African killifish Nothobranchius furzeri, to discover novel genes that regulate lifespan in vertebrates. N. furzeri lives in ephemeral pools of water in Africa, and has a mean lifespan of about 10 weeks in laboratory conditions. Interestingly, N. furzeri comprises several natural populations that live in different ecological niches and that strikingly differ in life expectancy, with 2-3 fold difference in median lifespan. This difference in lifespan is stable for at least 6 generations in captivity, suggesting that it is likely due to genetic factors. The exceptionally short lifespan and the significant variation in longevity among distinct populations make N. furzeri an ideal genetic model to characterize the architecture of the longevity trait in vertebrates. We have developed a series of tool to promote this fish as a new vertebrate model for aging. We created the first genome-wide microsatellite linkage map in N. furzeri, which provides a framework to map traits, such as longevity, that differ between different strains of N. furzeri (Valenzano et al, Genetics, 2009). We are currently mapping quantitative trait locus (QTL) responsible for the variance in longevity between the strains of N. furzeri. Importantly, we are using ultra-high throughput sequencing to sequence the genome of this fish and identify the genomic regions corresponding to the longevity QTL. In May 2010, we conducted a field trip to Zimbabwe and Mozambique, which allowed us to capture five new wild populations of N. furzeri. Finally, we generated the first transgenic fish lines in this species, using the Tol2 transposase system (Valenzano et al, Genes, Genetics, Genomes 2011). Our development of genetic tools in N. furzeri and the collection of different populations with differences in longevity are major steps in isolating novel longevity genes that are possibly vertebrate-specific. This project also has the potential to reveal the evolutionary forces that shape lifespan differences in the wild. Publications Valenzano DR, Kirschner J, Kamber RA, Zhang E, Weber D, Cellerino A, Englert C, Platzer M, Reichwald K, and Brunet A (2009) Mapping loci associated with tail color and sex determination in the short-lived fish Nothobranchius furzeri. Genetics, 183: 1385-1395. Abstract PDF Valenzano DR, Sharp S and Brunet A (2011) Transposon-mediated transgenesis in the short-lived African killifish Nothobranchius furzeri, a vertebrate model for aging. G3, Genes Genome Genetics, in press. Cover article.
Specific projects Regulation of the FOXO transcription factor network Importance of pro-longevity genes in aging neural stem cells Role of FOXO transcription factors in cognitive function Mechanisms underlying longevity by dietary restriction in C. elegans: role of the energy sensor AMPK Unbiased screen to identify novel AMPK substrates in mammalian cells Epigenetic regulation of aging in C. elegans
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