Monoallelic Gene Expression: Stochastic or Clonal? From Detection to Mechanisms and Clinical Significance

There are several forms of monoallelic expression, in which the 50:50 ratio in the expression activity of each of the two copies of the gene is disrupted. This review focuses on the phenomenon of random autosomal monoallelic expression (aRME), a process in which only one of the two alleles is transcribed in a single cell, and the allele choice is not determined by the parental origin. One of the central problems in studying this phenomenon is the differentiation of the two forms of aRME: clonal, in which the expression pattern is mitotically inherited, and stochastic, when the allele choice can change over time due to transcriptional bursting. Distinguishing these events is methodologically challenging: divergent experimental approaches and the lack of standardized detection criteria have produced strikingly contradictory estimates of aRME prevalence. Furthermore, single-cell transcriptomic approaches are particularly susceptible to technical artefacts that can generate false-positive monoallelic calls, complicating the distinction between heritable and transient states. In this review, we critically evaluate the evidence for clonal and stochastic aRME, examine the epigenetic mechanisms proposed to maintain monoallelic expression, and discuss its clinical significance, focusing on the role of monoallelic expression in the penetrance of autosomal dominant diseases (including congenital immune disorders and cardiomyopathy), neurodevelopmental disorders, and cancer progression.