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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM036827-18
Application #
8760602
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Janes, Daniel E
Project Start
1989-08-01
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Indiana University Bloomington
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Long, Hongan; Miller, Samuel F; Strauss, Chloe et al. (2016) Antibiotic treatment enhances the genome-wide mutation rate of target cells. Proc Natl Acad Sci U S A 113:E2498-505
Sung, Way; Ackerman, Matthew S; Dillon, Marcus M et al. (2016) Evolution of the Insertion-Deletion Mutation Rate Across the Tree of Life. G3 (Bethesda) 6:2583-91
Keith, Nathan; Tucker, Abraham E; Jackson, Craig E et al. (2016) High mutational rates of large-scale duplication and deletion in Daphnia pulex. Genome Res 26:60-9
Kucukyildirim, Sibel; Long, Hongan; Sung, Way et al. (2016) The Rate and Spectrum of Spontaneous Mutations in Mycobacterium smegmatis, a Bacterium Naturally Devoid of the Postreplicative Mismatch Repair Pathway. G3 (Bethesda) 6:2157-63
Lynch, Michael (2016) Mutation and Human Exceptionalism: Our Future Genetic Load. Genetics 202:869-75
Bréchignac, François; Oughton, Deborah; Mays, Claire et al. (2016) Addressing ecological effects of radiation on populations and ecosystems to improve protection of the environment against radiation: Agreed statements from a Consensus Symposium. J Environ Radioact 158-159:21-9
Lynch, Michael (2015) Genetics: Feedforward loop for diversity. Nature 523:414-6
Lynch, Michael; Hagner, Kyle (2015) Evolutionary meandering of intermolecular interactions along the drift barrier. Proc Natl Acad Sci U S A 112:E30-8
Gout, Jean-Francois; Lynch, Michael (2015) Maintenance and Loss of Duplicated Genes by Dosage Subfunctionalization. Mol Biol Evol 32:2141-8
Long, Hongan; Kucukyildirim, Sibel; Sung, Way et al. (2015) Background Mutational Features of the Radiation-Resistant Bacterium Deinococcus radiodurans. Mol Biol Evol 32:2383-92

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