Mutation induces genetic variation. Genetic variation, in turn, fuels evolutionary change. Experimental investigations into the rate and fitness effects of spontaneous mutations are central to the study of evolution and biology. Mutation accumulation (MA) experiments have been instrumental in measuring the rate of origin of deleterious mutations. However, the vast majority of MA studies to date are compromised by two major limitations: (i) the use of phenotypic data to indirectly estimate key mutational parameters, and (ii) the use of experimental lines maintained at a single, minimum effective population size. Although population-genetics theory predicts a wide range of fitness consequences for all classes of spontaneous mutations, their distribution of fitness effects remains obscure. Furthermore, the loss or fixation of mutations and their consequences for population fitness additionally depend upon their individual effect and the efficacy of natural selection, the latter being influenced by the population size. Spontaneous MA lines of the nematode Caenorhabditis elegans were evolved in parallel over 400 generations at three varying effective population sizes to manipulate the efficacy of natural selection in different genomic backgrounds. This represents the most ambitious experiment of its kind within any species. The combination of long-term spontaneous MA lines under varying intensities of selection and use of powerful high-throughput genomic techniques will enable unprecedented insights into (i) the rates of origin of diverse mutations, (ii) their differential accumulation under varying regimes of natural selection, and (iii) a framework to assess the interaction between mutation and selection at the molecular level on a genome-wide scale. The aims are to identify all acquired mutations at the mitochondrial and nuclear level, investigate their differential rates of accumulation under varying population sizes and infer their distribution of fitness effects. Phenotypic fitness-assays will quantify the rate of fitness decay at different population sizes and determine the extent to which larger populations are buffered from mutational degradation. By providing a unified account of the consequences of spontaneous mutations at the genetic and phenotypic levels, this research will yield significant insights into the evolutionary process for several different topics, including the genetic basis of variation, the evolutionary dynamics of mutations under the forces of natural selection and genetic drift, and their range of fitness effects.

Broader Impacts The experimental lines provide an unprecedented resource to study biological evolution at multiple scales, from phenotype to protein function. The experimental MA lines created as part of this research and the deposition of genome sequences in public databases represent an enormous community resource to be shared with colleagues in the scientific community. In addition to the training projects listed with individual aims, this project will have broad impacts in two areas: academic training/mentorship and public outreach in an environment with a large fraction of underrepresented minorities. Data generated by the research will be (i) disseminated to high school students and the general public via seminars and interactive panel discussions to communicate its evolutionary implications and promote scientific literacy, and (ii) employed in the creation of data sets and mini tutorials for high school students to demystify molecular evolution and introduce them to basic evolutionary computational methods for analyses of genomic sequences. The University of New Mexico is the only research-intensive University that is also Hispanic serving, with two extensive underrepresented student populations comprising Hispanics and Native Americans. This provides a unique opportunity to mentor undergraduate minority students, graduate students and postdocs, and instill in them an appreciation for interdisciplinary research in population-genomics and bioinformatics. Research stemming from this project is expected to greatly enhance our fundamental understanding of the evolutionary process and enable the quantification of several key rate parameters in biology, with implications for all spheres of biology including an understanding of the genetic and phenotypic consequences of maintaining populations at small sizes.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Arcady Mushegian
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University of New Mexico
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