Biomedical subjects

Dominika M Wloch

Publications and source records attributed to Dominika M Wloch.

2 recordsLinked to original sources

PubMed2006

Why molecular chaperones buffer mutational damage: a case study with a yeast Hsp40/70 system.

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.

Adenosine Triphosphatases↗

PubMed2003

Small fitness effects and weak genetic interactions between deleterious mutations in heterozygous loci of 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.

Clone Cells↗