Due to its central role in both evolutionary change and human disease, mutation has been the focus of intensive research. The probability that a spontaneous mutation will occur and its impact on fitness are parameters of central importance for making predictions in evolutionary biology. However, estimates of these parameters are difficult to make, and exist only for a handful of taxonomically-restricted eukaryotic species. Here we introduce a new experimental system for elucidating these mutational parameters: the ciliate Tetrahymena thermophila. T. thermophila has some unusual features that make it particularly well-suited to studying spontaneous mutations. Crucially, the sequestration of a transcriptionally-inactive germline genome, within the same cell as a somatic genome, means that mutations in the germline can be sheltered from selection over the course of thousands of cell divisions. We propose to use T. thermophila in a mutation accumulation experiment. Follow-up experiments with the lines that we generate using a range of complementary genetic and genomic tools, combined with powerful computational and statistical analyses will allow us to estimate germline mutational parameters with high robustness and accuracy, including: the overall mutation rate;the rate and effect sizes of mutations deleterious to fitness;their dominance and epistatic relationships;the rate of recessive lethal mutations;and the spectrum of mutations at the molecular level.

Public Health Relevance

Mutation is the ultimate source of all variation responsible for evolutionary change and the underlying cause of genetic diseases and many cancers. We propose to study the rate of mutation and distribution of their effects on fitness. Robust estimates of these parameters will contribute toward gaining a more complete understanding of the causes and consequences of genetic variation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM101352-01A1
Application #
8506865
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
2013-05-01
Project End
2018-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$296,226
Indirect Cost
$59,435
Name
University of Houston
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204
Long, Hongan; Zufall, Rebecca A (2015) Mutational robustness of morphological traits in the ciliate Tetrahymena thermophila. J Eukaryot Microbiol 62:249-54
Long, Hong-An; Paix√£o, Tiago; Azevedo, Ricardo B R et al. (2013) Accumulation of spontaneous mutations in the ciliate Tetrahymena thermophila. Genetics 195:527-40