All living organisms mutate. Understanding the biology of any organism, past and future, requires understanding the mutational process. The ultimate objective of the proposed research is to understand the genetic and environmental factors underlying variation in the mutation rate. Those factors potentially include properties intrinsic to particular species and individuals.
The specific aims of this proposal are: (1) characterize within- and between-species variation in the rate and molecular spectrum of spontaneous mutations, (2) determine if the genomic mutation rate has evolved to different optimal values in different organisms, and (3) experimentally characterize the relationship between metabolic rate and mutation rate. To achieve aim (1) existing stocks of Rhabditid nematodes that have accumulated mutations in the absence of natural selection for 250 generations will be sequenced at 100Kb of random genomic DNA. To achieve aim (2) a similar mutation accumulation experiment will be performed using historically outcrossing nematodes to contrast to self-fertile nematodes. Significant differences between selfing and outcrossing taxa in the rate and/or effects of new mutations will provide evidence that the genomic mutation rate is subject to """"""""fine-tuning"""""""" by natural selection.
Aim (3) is motivated by the apparent positive correlation between metabolic rate and rate of evolution. The relationship is plausibly attributed to DNA damage caused by oxygen radicals generated as by-products of metabolism, but several alternative explanations exist. Evidence suggests that any two randomly chosen worms may vary by as much as ten-fold in their mutation rate, and that the underlying molecular mutation rate may actually be ten times higher than is generally thought. If those results prove general, there would be important consequences fort the understanding of how mutations occur in humans, and on the nature of disease caused by complex genetic factors. Perhaps of even more importance, the proposed work provides a critical validation of the methods currently used to infer mutation rate in any organism.
|Davies, Sarah K; Leroi, Armand; Burt, Austin et al. (2016) The mutational structure of metabolism in Caenorhabditis elegans. Evolution 70:2239-2246|
|Farhadifar, Reza; Ponciano, José Miguel; Andersen, Erik C et al. (2016) Mutation Is a Sufficient and Robust Predictor of Genetic Variation for Mitotic Spindle Traits in Caenorhabditis elegans. Genetics 203:1859-70|
|Etienne, Veronique; Andersen, Erik C; Ponciano, José Miguel et al. (2015) The red death meets the abdominal bristle: polygenic mutation for susceptibility to a bacterial pathogen in Caenorhabditis elegans. Evolution 69:508-19|
|Farhadifar, Reza; Baer, Charles F; Valfort, Aurore-Cécile et al. (2015) Scaling, selection, and evolutionary dynamics of the mitotic spindle. Curr Biol 25:732-40|
|Joyner-Matos, Joanna; Hicks, Kiley A; Cousins, Dustin et al. (2013) Evolution of a higher intracellular oxidizing environment in Caenorhabditis elegans under relaxed selection. PLoS One 8:e65604|
|Matsuba, Chikako; Ostrow, Dejerianne G; Salomon, Matthew P et al. (2013) Temperature, stress and spontaneous mutation in Caenorhabditis briggsae and Caenorhabditis elegans. Biol Lett 9:20120334|
|Matsuba, Chikako; Lewis, Suzanna; Ostrow, Dejerianne G et al. (2012) Invariance (?) of mutational parameters for relative fitness over 400 generations of mutation accumulation in Caenorhabditis elegans. G3 (Bethesda) 2:1497-503|
|Denver, Dee R; Wilhelm, Larry J; Howe, Dana K et al. (2012) Variation in base-substitution mutation in experimental and natural lineages of Caenorhabditis nematodes. Genome Biol Evol 4:513-22|
|Joyner-Matos, Joanna; Bean, Laura C; Richardson, Heidi L et al. (2011) No evidence of elevated germline mutation accumulation under oxidative stress in Caenorhabditis elegans. Genetics 189:1439-47|
|Braendle, Christian; Baer, Charles F; Félix, Marie-Anne (2010) Bias and evolution of the mutationally accessible phenotypic space in a developmental system. PLoS Genet 6:e1000877|
Showing the most recent 10 out of 17 publications