Cell-to-cell stochastic variation in gene expression is a complex genetic trait.
Bottom Line: We found that noise was highly heritable and placed under a complex genetic control.Our results suggest that the level of stochasticity in particular molecular regulations may differ between multicellular individuals depending on their genotypic background.The complex genetic architecture of noise buffering couples genetic to non-genetic robustness and provides a molecular basis to the probabilistic nature of complex traits.
Affiliation: Université de Lyon, Lyon, France.
The genetic control of common traits is rarely deterministic, with many genes contributing only to the chance of developing a given phenotype. This incomplete penetrance is poorly understood and is usually attributed to interactions between genes or interactions between genes and environmental conditions. Because many traits such as cancer can emerge from rare events happening in one or very few cells, we speculate an alternative and complementary possibility where some genotypes could facilitate these events by increasing stochastic cell-to-cell variations (or 'noise'). As a very first step towards investigating this possibility, we studied how natural genetic variation influences the level of noise in the expression of a single gene using the yeast S. cerevisiae as a model system. Reproducible differences in noise were observed between divergent genetic backgrounds. We found that noise was highly heritable and placed under a complex genetic control. Scanning the genome, we mapped three Quantitative Trait Loci (QTL) of noise, one locus being explained by an increase in noise when transcriptional elongation was impaired. Our results suggest that the level of stochasticity in particular molecular regulations may differ between multicellular individuals depending on their genotypic background. The complex genetic architecture of noise buffering couples genetic to non-genetic robustness and provides a molecular basis to the probabilistic nature of complex traits.
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Mentions: The presence of ura3Δ0 at QTL3 prompted us to test if this mutation was responsible for noise modulation. When introduced in the S288c background, a significant increase in HIS3:PMET17-GFP noise was observed (Figure 4A–B). Consistently, restoring wild-type URA3 in the resulting mutant or in RM11-1a significantly reduced noise (Figure 4A–C), and another allele (ura3-52) could also increase noise (Figure S3A), as well as treatment with 6-azauracil, a drug inhibitor of the URA3 gene product (Figure 4D). Since random spores of the FL200×CENPK cross mentioned above displayed low noise despite bearing the ura3-52 mutation, we examined additional spores from tetrads and found that, as expected, Ura+ spores from this cross displayed even lower noise (Figure S2). Surprisingly, increasing the concentration of uracil in the culture medium did not reduce noise of a ura3Δ0 strain (Figure S3B). This might be due to limiting steps of the import mechanism. Finally, the ura1Δ and ura2Δ mutations were also found to increase noise levels (Figure S3C). Altogether, these observations validated ura3 as a responsible gene for QTL3 with ura3Δ0 accounting for most (74%) of the locus effect seen in segregants (Figure 3C and 4A). So if additional noise regulators resided at QTL3, we expect their contribution to be minor. The ura3Δ0 allele is not natural but was introduced in RM11-1a for laboratory purposes unrelated to this study. However, ura3 alleles exist in nature: ura3-52 results from a Ty transposable element insertion, and when searching the Saccharomyces Genome Resequencing Project we found three additional severe mutations (G->GA, G->GA, and TTG->TAG(stop) at 183, 219 and 94 nucleotides from ATG, respectively) in two unrelated natural isolates (NCYC361 from an Irish brewery and UWOPS87_2421 from a cladode in Hawaii). Also, ura3 mutations are not the sole source of natural genetic variation in noise, since high noise was found in the Y9J_1 background (a prototrophic strain with functional URA3), and since ura3Δ0 accounted for only 37% of the total noise difference between S288c and RM11-1a (Figure 4C and Materials and Methods).