Abstract
The majority of autosomal genes in mamma are believed to be expressed from both alleles. However a number of imprinted genes exist and an increasing number of loci may be expressed monoallelically in a random fashion, similar to the X chromosome in females where one of the two X's is randomly chosen for inactivation. Classical examples of random monoallelic expression (RME) include members of large gene families, such as immunoglobulins and odorant receptors but also single copy genes. Nevertheless, the extent, identity and pattern of expression of such genes are poorly known. We derived clonal neural progenitor cell lines (NPC) from male and female FI hybrid ES cells that are highly polymorphie for the parental chromosomes (1 29S1/Cast) i n order to screen for RME genes in the mouse genome. Using mRNA deep sequencing and stringent statistical criteria, we identified 407 autosomal genes showing RME, of which 140 show moderatelhigh expression. RME genes were validated for their monoallelic expression in NPCs by RT-PCR, pyrosequencing, as well as by RNA ASH in cells and embryos from inbred mice, thus providing formal proof of the epigenetic basis of RME. We found that most RME genes show monoallelic expression in sorne but not ail NPC clones. However, monoallelic expression is highly stable through cell passaging and during differentiation of NPC towards astrocytes. I ntriguingly, in several cases, members of the same gene family were found to be monoallelically expressed. Several of the RME genes we identified are known to be involved in autosomal dominant disorders. Using RNA FISH on developing inbred mouse embryos, we find that these genes have a tendency to be monoallelic in organs known to be affected in these diseases and in heterozygous knock out mouse models. This implies that RME may have profound implications for both development and disease. We discuss the potential implications of these findings for the etiology of human autosomal dominant disorders.
