PT - JOURNAL ARTICLE AU - Gustavo Valadares Barroso AU - Natasa Puzovic AU - Julien Y Dutheil TI - Selection at the pathway level drives the evolution of gene-specific transcriptional noise AID - 10.1101/104216 DP - 2017 Jan 01 TA - bioRxiv PG - 104216 4099 - http://biorxiv.org/content/early/2017/05/12/104216.short 4100 - http://biorxiv.org/content/early/2017/05/12/104216.full AB - Biochemical reactions within individual cells result from the interactions of molecules, often in small numbers. Consequently, the inherent stochasticity of binding and diffusion processes generate noise along the cascade that leads to the synthesis of a protein from its encoding gene. As a result, isogenic cell populations display phenotypic variability even in homogeneous environments. The extent and consequences of this stochastic gene expression have only recently been assessed on a genome-wide scale, in particular owing to the advent of single cell transcriptomics. However, the evolutionary forces shaping this stochasticity have yet to be unraveled. We took advantage of two recently published data sets of the single-cell transcriptome of the domestic mouse Mus musculus in order to characterize the effect of natural selection on gene-specific transcriptional stochasticity. We showed that noise levels in the mRNA distributions (a.k.a. transcriptional noise) significantly correlate with three-dimensional nuclear domain organization, evolutionary constraint on the encoded protein and gene age. The position of the encoded protein in biological pathways, however, is the main factor that explains observed levels of transcriptional noise, in agreement with models of noise propagation within gene networks. Because transcriptional noise is under widespread selection, we argue that it constitutes an important component of the phenotype and that variance of expression is a potential target of adaptation. Stochastic gene expression should therefore be considered together with mean expression level in functional and evolutionary studies of gene expression.