Autosomal monoallelic expression: genetics of epigenetic diversity? Virginia Savova 1 , Se ´ bastien Vigneau 2,3 and Alexander A Gimelbrant 1 In mammals, relative expression of the two parental alleles of many genes is controlled by one of three major epigenetic phenomena: X chromosome inactivation, imprinting, and mitotically stable autosomal monoallelic expression (MAE). MAE affects a large fraction of human autosomal genes and introduces enormous epigenetic heterogeneity in otherwise similar cell populations. Despite its prevalence, many functional and mechanistic aspects of MAE biology remain unknown. Several lines of evidence imply that MAE establishment and maintenance are controlled by a variety of genetic elements. Based on known genomic features regulating X-inactivation and imprinting, we outline likely features of MAE-controlling elements. We also assess implications of MAE for genotype– phenotype relationship, with a focus on haploinsufficiency. Addresses 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, United States 2 Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States Corresponding author: Gimelbrant, Alexander A (gimelbrant@mail.dfci.harvard.edu, gimelbrant@genetics.med.harvard.edu) 3 Present address: Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, United States. Current Opinion in Genetics & Development 2013, 23:642–648 This review comes from a themed issue on Genetics of system biology Edited by Shamil Sunyaev and Fritz Roth For a complete overview see the Issue and the Editorial Available online 24th September 2013 0959-437X/$ – see front matter, # 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.gde.2013.09.001 Introduction From the systems level perspective, analysis of origins and consequences of cell-to-cell variability is essential to the understanding of biological processes as diverse as organogenesis, incomplete trait penetrance, and tumor evolution. During the course of development, various differentiation mechanisms create cells with deeply dis- tinct morphologies, functions, and gene expression pro- grams. A relatively neglected source of additional cell diversity is found in epigenetic mechanisms that differ- entially regulate the two parental copies of genes within the same cell type. In mammals, several major epigenetic mechanisms are involved in the generation of mitotically stable cell sub-populations through the separate regula- tion of each allele. Perhaps the best-known of these is X chromosome inactivation, which affects most X-linked genes [1] in female embryos: at the time of implantation, about half of the cells choose to inactivate the maternal copy of the X, while the rest inactivate the paternal X [2– 4]. Another phenomenon is imprinting where regulation is uniform across cells [5]. The least understood phenom- enon is autosomal monoallelic expression (MAE), which resembles X-inactivation in some ways but affects auto- somal genes in both male and female cells. Here we review the current understanding of MAE biology and discuss functional consequences of cell-level heterogeneity introduced by MAE, as well as evidence for genetic mechanisms controlling its initiation and main- tenance. Clone-specific autosomal monoallelic expression MAE can be defined as a mosaic epigenetic inactivation of one allele of an autosomal gene. Similarly to X-inac- tivation, some cells express the paternal allele, while other cells of the same type in the same individual express the maternal allele (Figure 1 and Box 1). The choice of the active allele, once made, appears to be maintained indefinitely. For example, mouse cells kept one copy of p120 catenin silenced after a year in continuous culture [6]. More generally, since systematic assessments of MAE have been performed on cell populations grown from a single cell to more than 10 7 cells [7,8  ], we can conclude that the epigenetic allelic choices are maintained gen- ome-wide through dozens of cell divisions. Because the allelic state of an arbitrarily chosen cell from a polyclonal population is not known ahead of time, MAE is some- times called ‘random’. We prefer another term, ‘clone- specific’ MAE, which avoids possible confusion with the transient differences resulting from transcriptional noise. In addition, it underscores the mitotic stability of MAE, as well as the heterogeneity of allelic choice. The fraction of mammalian genes subject to MAE is surprisingly high. Allelic exclusion was discovered in immunoglobulins [9]. Later, MAE was found in olfactory receptors [10], which by themselves constitute about 5% of mammalian protein-coding genes, and also in some cytokines and other genes (reviewed in [11]). Recent systematic analyses of allele-specific expression in clonal Available online at www.sciencedirect.com ScienceDirect Current Opinion in Genetics & Development 2013, 23:642–648 www.sciencedirect.com