Monoallelically expressed genes as a novel mechanism of genetic errors of immunity

Project Summary – Project 1 The transcription of autosomal genes is thought to occur from both inherited alleles, maternal and paternal. However, it has recently become clear that approximately 1-5% of autosomal genes can be expressed from a single allele in a random manner across the cells of a given individual. This restriction of allele expression, known as autosomal random monoallelic expression (aRMAE), is established by specific chromatin marks during development and remains stable, unaffected by mitosis, in the lineage concerned. Unlike X-chromosome inactivation or genomic imprinting, allele selection is independent of other genes and may differ between neighboring cells. Our understanding of this epigenetic phenomenon is growing, but the mechanism involved has yet to be dissected in detail and its functional consequences remain unclear. It has been suggested that aRMAE functions as a means of extending intercellular variability within an individual. This may facilitate the maintenance of homeostasis, and regulation of the functional impact of deleterious mutations in cases of genetic disease. In this respect, aRMAE may help explain phenotypic variation in genetic disease. Even in well-studied Mendelian disorders, in which single-gene defects result in severe phenotypes, incomplete penetrance is often observed. Environmental factors may account for some of the phenotypic variability observed but cannot explain discordance between monozygotic twins or asymmetric disease manifestations within a single individual. Inborn errors of immunity (IEIs) are the principal example of this phenomenon. Genetic errors of more than 500 unique genes have been identified that underlie IEIs, a diverse class of monogenic diseases, often with incomplete penetrance and disease expressivity among members of the same family with the mutated allele. This phenotypic variability is common and remains a challenge in the study and clinical management of these disorders. Our preliminary data suggest that aRMAE is a key determinant of IEI penetrance, but aRMAE has never been systematically studied in IEIs. We plan to identify all the known all IEI genes displaying aRMAE, to elucidate the epigenetic mechanisms governing this molecular process and to determine the phenotype consequences of aRMAE in IEI patients. The identification and dissection of mechanisms governing aRMAE in IEIs should reveal novel genetic principles underlying pathophysiology.