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: To investigate the natural genetic diversity of noise in the expression of a representative gene, we integrated in the genome of five distant S. cerevisiae strains a reporter construct where the green fluorescent protein (GFP) was regulated by the inducible promoter of the MET17 (YLR303W) gene. The strains used were three unrelated laboratory strains (S288c, FL200 and CEN.PK), a wine strain from California (RM11-1a), and a wine strain from Japan (Y9J_1). In each case the construct was integrated at the same HIS3 chromosomal locus. We then quantified the level of expression in individual living cells by flow cytometry. Figure 1A shows representative experiments where 15,000 cells were recorded for each background after two hours of moderate induction. We found that although mean induction was similar between backgrounds, the variance of gene expression level differed. This observation was reproduced when the experiments were repeated at various dates (Figure 1B). This suggested the presence of genetic variation that might control noise without necessarily affecting mean expression of the cell population. To see if the difference in noise between S288c and RM11-1a was specific to the chromosomal environment of the HIS3 locus, we integrated the same reporter system at the LYS2 locus located on another chromosome (Figure S1). Noise and mean expression values were comparable to the results obtained when targeting HIS3, showing that the difference in noise between the two strains could not be accounted for by differences at the integration locus only.