Rethinking disomy: Autosomal expression bias

Humans are disomic. At birth, all nucleated cells in the body have the same genetic material, composed of 22 pairs of autosomes and a pair of sex chromosomes. Half the chromosomes are maternal, and half are paternal. It is thought that the two copies of autosomal genes are equally transcribed and translated in a given cell. This notion, based on Mendelian genetics, has guided the identification of genetic variants capable of causing disease for a century. These variants have been classified as displaying dominant or recessive inheritance. The term "penetrance" was coined to explain why some individuals carrying disease-causing variants do not develop the disease. Differences in penetrance are often assumed to be due to largely unproven effects of the environment, polygenic effects, and/or mosaicism. More recently, autosomal random monoallelic expression (aRMAE)-a phenomenon in which one of the two parental alleles of a gene is more strongly or exclusively expressed in some, but not all, cells-has been put forward to account for the incomplete penetrance observed in a growing number of genetic conditions. Here, we review aRMAE from historical, biochemical, genetic, epigenetic, and disease-influencing perspectives and propose a new framework.