Abstract
Genetic variability, epigenetic variability, and gene expression variability (noise) are generally considered independently in their relationship with phenotypic variation. However, they appear to be intrinsically interconnected and influence it in combination. The study of the interplay between genetic and epigenetic variability has the longest history. This article rather considers the introduction of gene expression variability in its relationships with the two others and reviews for the first time experimental evidences over the four relationships connected to gene expression noise. They show how introducing this third source of variability complicates the way of thinking evolvability and the emergence of biological novelty. Finally, cancer cells are proposed to be an ideal model to decipher the dynamic interplay between genetic, epigenetic, and gene expression variability when one of them is either experimentally increased or therapeutically targeted. This interplay is also discussed in an evolutionary perspective in the context of cancer cell drug resistance.
Highlights
The major technological breakthroughs made during the last 20 years allowed the analysis of many biological processes at the single-cell level and revolutionized molecular biology
These stochastic fluctuations in gene expression started to be finely quantified in the early 2000s when the rate of protein synthesis was measured in genetically identical cells placed in a homogeneous environment (Blake et al, 2003; Elowitz et al, 2002; Ozbudak et al, 2002; Raser & O'Shea, 2004)
The role of molecular interactions within chromatin has been emphasized in the generation of this variability
Summary
The major technological breakthroughs made during the last 20 years allowed the analysis of many biological processes at the single-cell level and revolutionized molecular biology. As the reactions governing gene expression involve a small number of molecules, it was previously assumed that they may exhibit random fluctuations, a phenomenon often called gene expression noise (McAdams & Arkin, 1999). These stochastic fluctuations in gene expression started to be finely quantified in the early 2000s when the rate of protein synthesis was measured in genetically identical cells placed in a homogeneous environment (Blake et al, 2003; Elowitz et al, 2002; Ozbudak et al, 2002; Raser & O'Shea, 2004). Positive and negative feedback regulation can affect the level of variability, and positive feedback can preserve phenotypic states over many
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