The mutation process ultimately defines the genetic features of all populations, and hence has a bearing on the full range of issues in evolutionary genetics, inheritance, and genetic disorders. Yet, despite the centrality of mutation to biology, formidable technical barriers have constrained our understanding of the rate at which mutations arise and the molecular spectrum of their effects. The proposed research takes advantage of newly emergent technology for mutation detection to address a number of central issues. First, performing whole-genome sequencing with long-term mutation-accumulation lines, we will ascertain the rate and full molecular spectrum of spontaneously arising mutations (germline replication errors) in a wide range of eukaryotic microbial species. This work will complete a phylogenetically wide survey of mutation-rate variation (involving ~50 species), test the hypothesis that microbial eukaryotes have extraordinarily low mutation rates, and contribute to an emergent general theory on mutation-rate evolution (the drift-barrier hypothesis). Second, applying a newly developed method to the full set of study species, we will estimate the rate at which errors arise during transcription of DNA to RNA. Preliminary data suggest that such transient errors arise at rates several orders of magnitude higher than those during replication. If confirmed, this would imply that a large fraction of gene transcripts contain errors;and we will also test whether transcriptin and replication error rates scale in the same way in accordance with the drift-barrier hypothesis. Third, using the same method, we will estimate the somatic mutation rate in several tissues in a variety of multicellular species, testing the hypothesis that such rates greatly exceed those in the germline. Because mutations are the ultimate source of all inherited genetic disorders and of somatically acquired cancers, the results of this work will be of central relevance to a wide array of human-health related issues. In addition, the unbiased rates and spectra of mutation that emerge from this study will provide a powerful resource for evolutionary geneticists concerned with the sources of natural variation at the molecular level.

Public Health Relevance

Using newly developed techniques for mutation detection, this study will reveal the rate and molecular spectrum of spontaneously arising mutations in the germline, somatic tissues, and gene transcripts. Because mutations are the ultimate source of all inherited genetic disorders and of somatically acquired cancers, the results will be of central relevance to a wide array of human-health related issues.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Genetic Variation and Evolution Study Section (GVE)
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Janes, Daniel E
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Indiana University Bloomington
Schools of Arts and Sciences
United States
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Long, Hongan; Sung, Way; Kucukyildirim, Sibel et al. (2018) Evolutionary determinants of genome-wide nucleotide composition. Nat Ecol Evol 2:237-240
Lynch, Michael (2018) Phylogenetic divergence of cell biological features. Elife 7:
Senra, Marcus V X; Sung, Way; Ackerman, Matthew et al. (2018) An Unbiased Genome-Wide View of the Mutation Rate and Spectrum of the Endosymbiotic Bacterium Teredinibacter turnerae. Genome Biol Evol 10:723-730
Long, Hongan; Doak, Thomas G; Lynch, Michael (2018) Limited Mutation-Rate Variation Within the Paramecium aurelia Species Complex. G3 (Bethesda) 8:2523-2526
Long, Hongan; Miller, Samuel F; Williams, Emily et al. (2018) Specificity of the DNA Mismatch Repair System (MMR) and Mutagenesis Bias in Bacteria. Mol Biol Evol 35:2414-2421
Dillon, Marcus M; Sung, Way; Sebra, Robert et al. (2017) Genome-Wide Biases in the Rate and Molecular Spectrum of Spontaneous Mutations in Vibrio cholerae and Vibrio fischeri. Mol Biol Evol 34:93-109
Gout, Jean-Francois; Li, Weiyi; Fritsch, Clark et al. (2017) The landscape of transcription errors in eukaryotic cells. Sci Adv 3:e1701484
Tincher, Clayton; Long, Hongan; Behringer, Megan et al. (2017) The Glyphosate-Based Herbicide Roundup Does not Elevate Genome-Wide Mutagenesis of Escherichia coli. G3 (Bethesda) 7:3331-3335
Sun, Ying; Powell, Kate E; Sung, Way et al. (2017) Spontaneous mutations of a model heterotrophic marine bacterium. ISME J 11:1713-1718
Jiang, Xiaoqian; Tang, Haixu; Ye, Zhiqiang et al. (2017) Insertion Polymorphisms of Mobile Genetic Elements in Sexual and Asexual Populations of Daphnia pulex. Genome Biol Evol 9:362-374

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