Originally published as Genetics Published Articles Ahead of Print on May 23, 2005.

Genetics, Vol. 170, 989-999, July 2005, Copyright © 2005
doi:10.1534/genetics.104.039438

The Rate of Compensatory Mutation in the DNA Bacteriophage X174

Art Poon¹ and Lin Chao

Division of Biological Sciences, Section of Ecology, Behavior and Evolution, University of California, San Diego, California 92093-0116

¹ Corresponding author: Division of Biological Sciences, University of California, 9500 Gilman Dr., Muir Biology Bldg., Room 3155, San Diego, CA 92093-0116.
E-mail: apoon{at}biomail.ucsd.edu

A compensatory mutation occurs when the fitness loss caused by one mutation is remedied by its epistatic interaction with a second mutation at a different site in the genome. This poorly understood biological phenomenon has important implications, not only for the evolutionary consequences of mutation, but also for the genetic complexity of adaptation. We have carried out the first direct experimental measurement of the average rate of compensatory mutation. An arbitrary selection of 21 missense substitutions with deleterious effects on fitness was introduced by site-directed mutagenesis into the bacteriophage X174. For each deleterious mutation, we evolved 8–16 replicate populations to determine the frequency at which a compensatory mutation, instead of the back mutation, was acquired to recover fitness. The overall frequency of compensatory mutation was 70%. Deleterious mutations that were more severe were significantly more likely to be compensated for. Furthermore, experimental reversion of deleterious mutations revealed that compensatory mutations have deleterious effects in a wild-type background. A large diversity of intragenic compensatory mutations was identified from sequencing fitness-recovering genotypes. Subsequent analyses of intragenic mutation diversity revealed a significant degree of clustering around the deleterious mutation in the linear sequence and also within folded protein structures. Moreover, a likelihood analysis of mutation diversity predicts that, on average, a deleterious mutation can be compensated by about nine different intragenic compensatory mutations. We estimate that about half of all compensatory mutations are located extragenically in this organism.

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