Cell-to-cell stochastic variation in gene expression is a complex genetic trait

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.
Author Summary Although most inter-individual phenotypic variabilities are largely attributable to DNA differences, a wealth of examples illustrate how a single biological system can vary stochastically over time and between individuals. Identical twins are not identical, and similarly, clonal microbial cells differ in many aspects even when grown simultaneously in a common environment. Using yeast as a model system, we show that a population of isogenic cells all carrying genotype A showed higher cell-to-cell heterogeneity in gene expression than a population of isogenic cells of genotype B. We considered this level of intra-clonal heterogeneity as a quantitative trait and performed genetic linkage (on AxB) to search for regulators of it. This led to the demonstration that transcriptional elongation impairment increases stochastic variation in gene expression in vivo. Our results show that the two levels of inter-individual diversity, genetic and stochastic, are connected by a complex control of the former on the latter. We invite the community to revisit the interpretation of incomplete penetrance, which defines cases where a mutation does not cause the associated phenotype in all its carriers. We propose that, in the case of cancer or other diseases triggered by single cells, such mutations might increase stochastic molecular fluctuations and thereby the fraction of deviant cellular phenotypes in a human body.