Date Published: April , 2012
Publisher: Blackwell Publishing Ltd
Author(s): Jeanette Kirschner, David Weber, Christina Neuschl, Andre Franke, Marco Böttger, Lea Zielke, Eileen Powalsky, Marco Groth, Dmitry Shagin, Andreas Petzold, Nils Hartmann, Christoph Englert, Gudrun A Brockmann, Matthias Platzer, Alessandro Cellerino, Kathrin Reichwald.
The African annual fish Nothobranchius furzeri emerged as a new model for age research over recent years. Nothobranchius furzeri show an exceptionally short lifespan, age-dependent cognitive/behavioral decline, expression of age-related biomarkers, and susceptibility to lifespan manipulation. In addition, laboratory strains differ largely in lifespan. Here, we set out to study the genetics of lifespan determination. We crossed a short- to a long-lived strain, recorded lifespan, and established polymorphic markers. On the basis of genotypes of 411 marker loci in 404 F2 progeny, we built a genetic map comprising 355 markers at an average spacing of 5.5 cM, 22 linkage groups (LGs) and 1965 cM. By combining marker data with lifespan values, we identified one genome-wide highly significant quantitative trait locus (QTL) on LG 9 (P < 0.01), which explained 11.3% of the F2 lifespan variance, and three suggestive QTLs on LG 11, 14, and 17. We characterized the highly significant QTL by synteny analysis, because a genome sequence of N. furzeri was not available. We located the syntenic region on medaka chromosome 5, identified candidate genes, and performed fine mapping, resulting in a c. 40% reduction of the initial 95% confidence interval. We show both that lifespan determination in N. furzeri is polygenic, and that candidate gene detection is easily feasible by cross-species analysis. Our work provides first results on the way to identify loci controlling lifespan in N. furzeri and illustrates the potential of this vertebrate species as a genetic model for age research.
Lifespan is a quantitative trait, which reflects the interplay of genetic and environmental factors and varies largely across animal species. Two interventions have been identified to date in invertebrate, vertebrate, and mammalian model organisms, which consistently extend lifespan: dietary restriction and repression of growth hormone/insulin-like growth factor 1/insulin receptor pathways. However, the underlying molecular mechanisms remain unclear (e.g., Kirkwood, 2008), and current knowledge of genetic players is largely based on the analysis of single-gene mutations. An unbiased approach to identify genetic factors controlling lifespan would ideally consist of the analysis of genotype–phenotype associations in crosses of inbred strains that largely differ in the trait. This approach is named quantitative trait locus (QTL) mapping and offers also the possibility to identify natural alleles relevant for trait variation. A number of lifespan QTLs have been identified in fly and worm (e.g., Shmookler Reis et al., 2006; Lai et al., 2007), yet the detection of underlying gene(s) has proven challenging. Also in the mouse, many lifespan QTLs have been detected (e.g., Lang et al., 2010; Leduc et al., 2010), but crosses are both time-consuming and expensive, and the underlying functional loci have still proven elusive. It would be desirable to identify additional vertebrate/mammalian model organisms, which show larger lifespan differences and a shorter lifespan and could be reared at reasonable cost.
We present first results of our ongoing efforts to unravel the genetic architecture of lifespan in N. furzeri, a new vertebrate model organism for aging research.