Genetics and analysis of quantitative traits

The distribution of fitness effects (DFE) of new mutations is a fundamental entity in genetics that has implications ranging from the genetic basis of complex disease to the stability of the molecular clock. It has been studied by two different approaches: mutation accumulation and mutagenesis experiments, and the analysis of DNA sequence data. The proportion of mutations that are advantageous, effectively neutral and deleterious varies between species, and the DFE differs between coding and non-coding DNA. Despite these differences between species and genomic regions, some general principles have emerged: advantageous mutations are rare, and those that are strongly selected are exponentially distributed; and the DFE of deleterious mutations is complex and multi-modal.

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The distribution of fitness effects of new mutations

Microorganisms have been mutating and evolving on Earth for billions of years. Now, a field of research has developed around the idea of using microorganisms to study evolution in action. Controlled and replicated experiments are using viruses, bacteria and yeast to investigate how their genomes and phenotypic properties evolve over hundreds and even thousands of generations. Here, we examine the dynamics of evolutionary adaptation, the genetic bases of adaptation, tradeoffs and the environmental specificity of adaptation, the origin and evolutionary consequences of mutators, and the process of drift decay in very small populations.

http://personales.upv.es/sfelena/Nature%20Rev.%20Genetics%201.pdf

Evolution experiments with microorganisms: the dynamics and genetic bases of adaptation.

https://www.d.umn.edu/biology/documents/Winkler1.pdf

The Evolutionary Consequences of Polyploidy

Evolution of the mutation rate.

Estimates of the rate and frequency distribution of deleterious effects were obtained for the first time by direct scoring and characterization of individual mutations. This was achieved by applying tetrad analysis to a large number of yeast clones. The genomic rate of spontaneous mutation deleterious to a basic fitness-related trait, that of growth rate, was U = 1.1 × 10 −3 per diploid cell division. Extrapolated to the fruit fly and humans, the per generation rate would be 0.074 and 0.92, respectively. This is likely to be an underestimate because single mutations with selection coefficients s s ≥ 0.01 was studied both for spontaneous and induced mutations. The latter were induced by ethyl methanesulfonate (EMS) or resulted from defective mismatch repair. Lethal changes accounted for ~30–40% of the scored mutations. The mean s of nonlethal mutations was fairly high, but most frequently its value was between 0.01 and 0.05. Although the rate and distribution of very small effects could not be determined, the joint share of such mutations in decreasing average fitness was probably no larger than ~1%.

https://www.genetics.org/content/genetics/159/2/441.full.pdf

Direct Estimate of the Mutation Rate and the Distribution of Fitness Effects in the Yeast Saccharomyces cerevisiae

Rare, random mutations were induced in budding yeast by ethyl methanesulfonate (EMS). Clones known to bear a single non-neutral mutation were used to obtain mutant heterozygotes and mutant homozygotes that were later compared with wild-type homozygotes. The average homozygous effect of mutation was an approximately 2% decrease in the growth rate. In heterozygotes, the harmful effect of these relatively mild mutations was reduced approximately fivefold. In a test of epistasis, two heterozygous mutant loci were paired at random. Fitness of the double mutants was best explained by multiplicative action of effects at single loci, with little evidence for epistasis and essentially excluding synergism. In other experiments, the same mutations in haploid and heterozygous diploid clones were compared. Regardless of the haploid phenotypes, mildly deleterious or lethal, fitness of the heterozygotes was decreased by less than half a per cent on average. In general, the results presented here suggest that most mutations tend to exhibit small and weakly interacting effects in heterozygous loci regardless of how harmful they are in haploids or homozygotes.

Small fitness effects and weak genetic interactions between deleterious mutations in heterozygous loci of the yeast Saccharomyces cerevisiae.

Several important biological phenomena, including genetic recombination and sexual reproduction, could have evolved to counteract genome contamination by deleterious mutations This postulate would be especially relevant if it were shown that deleterious mutations interact in such a way that their individual negative effects are reinforced by each other The hypothesis of synergism can be tested experimentally by crossing organisms bearing deleterious mutations and comparing the fitness of the parents and their progeny The present study used laboratory strains of the budding yeast burdened with mutations resulting from absence of a major DNA mismatch repair function Only in one, or possibly two, crosses out of eight did fitness of the progeny deviate from that of their parents in a direction indicating synergism Furthermore, the distributions of progeny fitness were not skewed as would be expected if strong interactions were present The choice of experimental material ensured that genetic recombination was extensive, all four meiotic products were available for fitness assays, and that the mutations were probably numerous Despite this generally favourable experimental setting, synergism did not appear to be a dominating force shaping fitness of yeast containing randomly generated mutations

Epistatic interactions of spontaneous mutations in haploid strains of the yeast Saccharomyces cerevisiae

The malfunctioning of molecular chaperones may result in uncovering genetic variation. The molecular basis of this phenomenon remains largely unknown. Chaperones rescue proteins unfolded by environmental stresses and therefore they might also help to stabilize mutated proteins and thus mask damages. To test this hypothesis, we carried out a genomewide mutagenesis followed by a screen for mutations that were synthetically harmful when the RAC–Ssb1/2 cytosolic chaperones were inactive. Mutants with such a phenotype were found and mapped to single nucleotide substitutions. However, neither the genes identified nor the nature of genetic lesions implied that folding of the mutated proteins was being supported by the chaperones. In a second screen, we identified temperature-sensitive (ts) mutants, a phenotype indicative of structural instability of proteins. We tested these for an association with sensitivity to loss of chaperone activity but found no such correlation as might have been expected if the chaperones assisted the folding of mutant proteins. Thus, molecular chaperones can mask the negative effects of mutations but the mechanism of such buffering need not be direct. A plausible role of chaperones is to stabilize genetic networks, thus making them more tolerant to malfunctioning of their constituents.

https://www.genetics.org/content/genetics/174/2/937.full.pdf

Dominika M. Wloch

Papers

Direct Estimate of the Mutation Rate and the Distribution of Fitness Effects in the Yeast Saccharomyces cerevisiae

Small fitness effects and weak genetic interactions between deleterious mutations in heterozygous loci of the yeast Saccharomyces cerevisiae.

Epistatic interactions of spontaneous mutations in haploid strains of the yeast Saccharomyces cerevisiae

Why Molecular Chaperones Buffer Mutational Damage: A Case Study With a Yeast Hsp40/70 System