Genomic imprinting and allelic exclusion

Abstract

In diploid cells, allelic exclusion reduces genes to functional haploidy, because only one of two alleles is active. It is best known in cells producing immunoglobulins, but other examples also exist. X-chromosome inactivation in female mammals is related to allelic exclusion, but in this case the dosage compensation mechanism extends to the whole chromosome. Functional hemizygosity in some mammalian cell lines is probably also due to allelic exclusion, where one autosomal allele is active and the other is methylated and inactive. In early development, it may be important to have only one functional copy of specific regulatory genes. If one considers the possible mechanisms whereby genes are switched from an active to an inactive form, or vice versa, complications arise if the same type of switch operates in two homologous chromosomes segregating independently at mitosis. This complication is avoided if one of the genes is totally inactive. It is therefore suggested that important regulatory gene are subject to allelic exclusion and that this provides a basis for genomic imprinting. Male or female gametes complement in the zygote, because they may have different inactive genes, and the active allele in each case is then functionally haploid in the zygote and developing embryo. These haploid genes would be those involved in critical switches of gene activity during the developmental process. Allelic exclusion imposed by imprinting might be based on the heritable DNA methylation of the regulatory regions of silent genes.