Random monoallelic expression of autosomal genes: stochastic transcription and allele-level regulation

Key Points Analyses of clonal cell populations have revealed fixed autosomal random monoallelic expression (aRME), in which allele-specific expression is conserved in daughter cells after division. More recently, single-cell analyses have revealed dynamic aRME, in which stochastic transcription renders shorter-term periods of expression frequently from only one allele. Distinguishing features of the two forms of aRME (clonally fixed and dynamic) are discussed, and literature on their nature, pervasiveness and regulation is revisited. Open outstanding questions in this emerging field of research are highlighted. Clonally fixed and dynamic aRME can be studied simultaneously via single-cell analyses of allelic transcription in clonal cells, and such analyses of in vivo cell types will propel our understanding of transcriptional regulation. aRME increases the heterogeneity among cells and probably contributes to the variance of phenotypes — including disease manifestations — among individuals of identical genotype. In diploid organisms, expression from only one allele is frequently observed. This Review focuses on the widespread random monoallelic expression (RME) of autosomal genes, highlighting both the mitotically stable form observed in bulk analyses of cell populations and the recently discovered dynamic form identified through single-cell studies. The article also addresses the implications of different experimental criteria for calling monoallelic expression and potential biological roles in disease manifestations. Random monoallelic expression (RME) of genes represents a striking example of how stochastic molecular processes can result in cellular heterogeneity. Recent transcriptome-wide studies have revealed both mitotically stable and cell-to-cell dynamic forms of autosomal RME, with the latter presumably resulting from burst-like stochastic transcription. Here, we discuss the distinguishing features of these two forms of RME and revisit literature on their nature, pervasiveness and regulation. Finally, we explore how RME may contribute to phenotypic variation, including the incomplete penetrance and variable expressivity often seen in genetic disease.