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

Nature Reviews Genetics volume 16, pages 653–664 (2015)Cite this article

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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.

Abstract

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.

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Figure 1: Modes of monoallelic gene expression.
Figure 2: Causes of fixed and dynamic aRME.
Figure 3: Models for phenotypic consequences of aRME.

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Acknowledgements

The authors are grateful to T. Perlmann and G. Winberg for their comments on the text, and to Q. Deng and D. Ramsköld for comments on the figures.

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  1. and the Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Box 240, Karolinska Institutet, 171 77 Stockholm, Sweden.,

    Björn Reinius & Rickard Sandberg

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Correspondence to Rickard Sandberg.

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PowerPoint slides

Glossary

Mosaic expression

When populations of cells within the organism express different alleles or genotypes, which can give rise to phenotypic patchiness.

Allelic exclusion

The process through which only one allele is expressed and the other is kept silent. Allelic exclusion most often, but not exclusively, refers to monoallelic expression of immunoglobulins in B cells or T cells and olfactory receptor expression in sensory neurons.

Fixed aRME

Clonally stable random monoallelic expression of an autosomal gene.

Dynamic aRME

Transient random monoallelic expression of an autosomal gene, resulting from stochastic allelic transcription.

Allele-biased expression

When the expression output of the two alleles is skewed towards higher expression of one of the parental copies, although both alleles are still expressed (in contrast to strict monoallelic expression).

Allelic dropout

The loss of allelic RNA species due to technical limitations in the sampling technique. This may result in a gene that is actually biallelically transcribed getting a false monoallelic call in the analysis of the data.

Allelic calls

The classification of allelic expression of genes by analysis of expression data. Gene expression can be classed as biallelic, maternal monoallelic, paternal monoallelic or not detected.

Lineage-tracing techniques

Methods that allow tracking of cell lineage from a given time-point, often by introducing or activating a fluorescent marker that is transmitted to each cell during mitotic division.

Split-cell experiments

Control experiments that estimate allelic dropout by dividing the cell lysate into two equal portions, which are independently processed, analysed and checked for coherence in the allelic calls (see Box 1).

RNA-dilution experiments

Control experiments that estimate allelic dropout by diluting bulk RNA in series and sampling for sequencing library preparation at amounts comparable to those of single cells.

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Reinius, B., Sandberg, R. Random monoallelic expression of autosomal genes: stochastic transcription and allele-level regulation. Nat Rev Genet 16, 653–664 (2015). https://doi.org/10.1038/nrg3888

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