Because the process of mutation introduces new genetic variation at random, it has been thought that too high a mutation rate will cause a population to go extinct. A phenomenon known as error catastrophe is predicted to occur when the mutation rate of a population surpasses the point at which the accumulation of mutations overpowers the strength of natural selection to maintain the fittest genotype. Recent work gives a quantitative prediction for the necessary relationship between genomic mutation rate and fitness variation in a population that will precipitate error catastrophe. In the current study we will conduct a detailed experimental characterization of a set of asexual bacterial populations engineered to have extraordinarily high mutation rates. These populations have been observed to decline to extinction in the laboratory, suggesting the occurrence of error catastrophe. The results may help explain the longstanding observation that many asexual populations are short-lived. In addition, the results may provide a basic science rationale for novel approaches to the treatment of viral and bacterial infections and cancers.

This research is novel in that it is the first well-controlled experimental test of error catastrophe. This project is associated with several broad impacts. Two undergraduates and a high school student have contributed to the preliminary results. At present, one undergraduate at the University of Pennsylvania is directly involved in related research. Additionally, a pilot program is being launched in our department which will expose local high school students to research in the laboratory. This project combines both theoretical and experimental components that students of varying backgrounds may take interest in. The results of this project will likely may provide the basis for another undergraduate student?s thesis project which may ultimately produce published research.

Project Report

The goal of this project was to experimentally investigate the causes and consequences of mutation rate evolution in asexual populations. Simulations of asexual populations undergoing continual adaptation present a definite prediction: mutator hitchhiking should drive the mutation rate upwards in an asexual population until it reaches an intolerable level, at which point the population will be driven extinct. Experimental studies have shown that a mutator allele can readily hitchhike to fixation with beneficial mutations in an asexual population having a low, wild-type mutation rate. Using Escherichia coli, I show that a genotype bearing two mutator alleles can supplant an asexual population already fixed for one mutator allele. My results provide experimental support for recent theory predicting that mutator alleles will tend to accumulate in asexual populations by hitchhiking with beneficial mutations, causing an ever-higher genomic mutation rate. Interestingly, results from recent simulations also suggest that the deleterious mutational load which accompanies an increased mutation rate is not immediately incurred. The delay in accruing a mutational load may potentially allow a succession of mutator hitchhiking events to occur before the cost of the initial hitchhiking event is incurred. Ultimately, mutation rates in asexual populations may evolve upwards to a rate that threatens extinction due to overwhelming mutational pressure. To test this prediction, I established independent populations of E. coli bearing either a single- or double-mutator genotype and propagated them for several thousand generations. At the conclusion of the experiment, the growth rate of the single-mutator populations had risen substantially, consistent with the substitution of beneficial mutations; in contrast, the growth rate of the double-mutator populations had fallen significantly, consistent with erosion of fitness by deleterious mutations. In addition, both sets of populations had maintained the mutation rate present at the outset of the experiment. Strikingly, the experiment seems to have provided evidence of mutation-driven fitness decline in the double-mutator populations despite the presence of beneficial mutations. In an effort to determine the process contributing to fitness decline and extinction, I conducted a detailed experimental characterization of one single- and one double-mutator bacterial populations. As noted previously, the double-mutator population had been observed to decline toward extinction in the laboratory, suggesting the occurrence of error catastrophe or a similar process. Analysis of the fitness variance of the populations over the course of the experiment supported the notion that the double-mutator population was undergoing an error catastrophe. This research is novel in that it is the first well-controlled experimental test of error catastrophe. The results may help explain the longstanding observation that many asexual populations are relatively short-lived. In addition, the results may provide a basic science rationale for novel approaches to the treatment of viral and bacterial infections and cancers.

Agency
National Science Foundation (NSF)
Institute
Division of Environmental Biology (DEB)
Type
Standard Grant (Standard)
Application #
1110202
Program Officer
Samuel M. Scheiner
Project Start
Project End
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
Fiscal Year
2011
Total Cost
$13,350
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104