Abstract
Genetic variation within and between species can be shaped by population-level processes and mutation; however, the relative impact of “survival of the fittest” and “arrival of the fittest” on phenotypic evolution remains unclear. Assessing the influence of mutation on evolution requires understanding the relative rates of different types of mutations and their genetic properties, yet little is known about the functional consequences of new mutations. Here, we examine the spectrum of mutations affecting a focal gene in Saccharomyces cerevisiae by characterizing 231 novel haploid genotypes with altered activity of a fluorescent reporter gene. 7% of these genotypes had a nonsynonymous mutation in the coding sequence for the fluorescent protein and were classified as “coding” mutants; 2% had a change in the S. cerevisiae TDH3 promoter sequence controlling expression of the fluorescent protein and were classified as “cis-regulatory” mutants; 10% contained two copies of the reporter gene and were classified as “copy number” mutants; and the remaining 81% showed altered fluorescence without a change in the reporter gene itself and were classified as “trans-acting” mutants. As a group, coding mutants had the strongest effect on reporter gene activity and always decreased it. By contrast, 50%–95% of the mutants in each of the other three classes increased gene activity, with mutants affecting copy number and cis-regulatory sequences having larger median effects on gene activity than trans-acting mutants. When made heterozygous in diploid cells, coding, cis-regulatory, and copy number mutant genotypes all had significant effects on gene activity, whereas 88% of the trans-acting mutants appeared to be recessive. These differences in the frequency, effects, and dominance among functional classes of mutations might help explain why some types of mutations are found to be segregating within or fixed between species more often than others.
Highlights
Mutations are the ultimate source of genetic variation, understanding the properties of new mutations is important for both medical and evolutionary genetics
From the perspective of a single gene, mutations affecting its activity can be divided into four functional classes: [nonsynonymous] coding mutations that alter the sequence of the encoded RNA or protein gene product, cis-regulatory mutations that alter sequences that regulate the gene’s expression in an allele-specific manner, trans-acting mutations that alter coding or cis-regulatory sequences of other genes in the genome and affect activity of the focal gene via a diffusible gene product, and copy number mutations resulting from duplications or deletions that change the number of copies of the focal gene in the genome
Genetic dissection of phenotypic differences within and between species has shown that mutations affecting either the expression or function of a gene product can contribute to phenotypic evolution; mutations that alter gene copy number have been shown to be an important source of phenotypic variation
Summary
Mutations are the ultimate source of genetic variation, understanding the properties of new mutations is important for both medical and evolutionary genetics. As the raw material of evolutionary change, all of these types of mutations have the potential to become polymorphisms segregating at an appreciable frequency within a species and/or substitutions fixed between species, yet studies identifying the genetic basis of trait differences suggest that some types of changes underlie phenotypic differences more often than others (reviewed by [7,8,9]). Increased pleiotropy is assumed to increase the chance that a mutation has deleterious effects on fitness and will be disfavored by natural selection. One example of this is that coding mutations are commonly expected to be more pleiotropic (and have lower average fitness) than
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