Genetic Architecture of Immune Disorders
Humans are fundamentally disomic: at birth, all nucleated cells carry 22 pairs of autosomes and one pair of sex chromosomes, with one set inherited from each parent. Traditionally, it has been assumed that both alleles of autosomal genes are expressed equally within a given cell. This Mendelian framework has guided the interpretation of genetic variation for over a century, leading to the classification of disease-causing variants as either dominant or recessive.
To account for the observation that some individuals carrying pathogenic variants remain unaffected, the concept of “penetrance” was introduced. Variation in penetrance is often attributed to environmental influences, polygenic background, or somatic mosaicism, albeit with limited proof. However, emerging evidence points to an additional layer of regulation: autosomal random monoallelic expression (aRMAE). In this phenomenon, one parental allele is preferentially or exclusively expressed in a subset of cells, resulting in cellular heterogeneity despite an identical underlying genotype. aRMAE provides a compelling mechanistic explanation for incomplete penetrance in an increasing number of genetic disorders.
Department of Pediatrics, Center for Genetic Errors of Immunity
Columbia University
To be held in the: McIntyre Medical Building, Palmer Amphitheatre (Room 522), 3655 Promenade Sir William Osler