Genetics of vertebrate life span - mapping and analysis of life span QTLs in the short-lived killifish Nothobranchius furzeri

• Applicant: Dr. Kathrin Reichwald
• Subject Area: General Genetics and Functional Genome Biology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 231816995

Aging research in vertebrates is hampered by the lack of short-lived model species. The life span of established genetic models such as mice, zebrafish or medaka is well over three years, being almost prohibitive for life-long experiments and studies aimed at elucidating genetic determinants underlying longevity. Thus, there is a need for alternative vertebrate model organisms, which ideally should show a short life span yet exhibit large life span differences, and can be reared at reasonable cost. The short-lived teleost fish Nothobranchius furzeri represents such a model. Its natural habitat in the Southeast of Africa covers a region with a cline in yearly precipitation. Survival of wild N. furzeri from different localities differs because the presence of respective ponds is limited to the rainy season. Similarly, survival of N. furzeri captive populations differs, even under optimal laboratory conditions including unlimited water supply. Captive life span is between 11 and 16 weeks for the shortest-lived strain and up to one year for longer-lived strains, making N. furzeri the shortest-lived vertebrate that can be cultured in the laboratory and opening up the possibility to use this species as model to study the genetics of vertebrate life span.To facilitate a systematic search for genetic determinants of the N. furzeri life span, we provided genomic, genetic and transcriptomic resources and mapped for the first time quantitative trait loci (QTLs) affecting life span. We detected one genome-wide highly significant QTL (P < 0.01) and three suggestive QTLs, explaining together 27.4% of the total life span variance in the F2 population. While this work clearly illustrates the potential of N. furzeri as a genetic model for aging research, QTL intervals are still large and contain numerous positional candidates, rendering the identification of causative genetic factors challenging.To address this, a project combining classical and next-generation genetics with transcriptome profiling and mitochondrial physiology analyses over lifetime is proposed. A reciprocal crossing panel will be generated, of which F2 populations will be analyzed. The design allows confirming initial life span QTLs and studying gender-specific effects. To fine-map QTLs, a crossing panel will be the source of an advanced intercross line (AIL), of which filial generation 10 will be studied; this is possible due to the genuinely short generation time of N. furzeri. To make full use of F2 panels and AIL, RAD-sequencing of F2/F10 populations will be applied and provide an ultra-dense set of markers as well as sequence information for identification of positional candidates. Transcriptome profiling will allow relating gene expression with candidate genes. In addition, analyses of mitochondrial physiology over lifetime in parental strains and F1 progeny will provide a link of strain-specific sequence variations with mitochondrial function and life span.

• DFG Programme: Research Grants