Multigenic analysis of aging markers in C. elegans using directed evolution.
2013 new Scholar Award in aging
Many human traits, including aging, have a strong genetic, or heritable, component. Despite the robustness of this observation, it has been incredibly difficult to identify the molecular causes for these differences. Genetic variants can have a very subtle affect on a phenotype, rather, the collective action of multiple genetic changes is responsible for differences in aging rates. In other words, trait differences between two individuals are typically multigenic. An underappreciated implication of these results is that classical genetic methods we use to study biological traits in model organisms are insufficient to understand the molecular mechanisms controlling biological traits. Classical genetic methods are biased towards alleles of strong affect – these are easy to identify during screens and easy to map. But we are missing classes of genetic changes and potentially genes that can subtly influence traits. Furthermore, we are typically blind to interactions between two genetic variants that can have a strong affect on phenotype. The goal of the research in the McGrath laboratory is to develop new approaches to generate and study multigenic trait changes in model organisms. Isolation of such mutants would allow the study of the genetic networks controlling aging and result in discovery of new genes that affect aging. This will help us understand the mechanisms that control aging and also ameliorate aging-related deterioration of human health. To accomplish this we are tweaking classical forward genetics in C. elegans to make the strength of the allele a parameter of the screen. We refer to this approach as selection of weak alleles using directed evolution (or SWADE). This approach is preferable to the study of natural variation for two reasons: 1) It is orders of magnitude more difficult to identify natural causative mutations due to the extensive number of candidate polymorphisms between two wild strains and 2) natural, segregating polymorphisms are a subset of mutations that can survive the sieve of selection. Thus, mutations isolated through SWADE will be easier to map and identify and will be unbiased (or less biased) towards its selective strength. We will use SWADE to study the aging process in C. elegans.