The consequences of uniparental disomy and copy number neutral loss-of-heterozygosity during human development and cancer

UPD (uniparental disomy) describes the inheritance of a pair of chromosomes from only one parent. Mechanisms that lead to UPD include trisomy rescue, gamete complementation, monosomy rescue and somatic recombination. Most of these mechanisms can involve aberrant chromosomes, particularly isochromosomes and Robertsonian translocations. In the last decade, the number of UPD cases reported in the literature has increased exponentially. This is partly due to the advances in genomic technologies that have allowed for high-resolution SNP (single nucleotide polymorphism) studies, which have complemented traditional methods relying on polymorphic microsatellite markers. In this review, we discuss aberrant cellular mechanisms leading to UPD and their impact on gene expression. Special emphasis is placed on the unmasking of mutant recessive alleles and the disruption of imprinted gene dosage, which give rise to specific and recurrent imprinting phenotypes. Finally, we discuss how copy number maps determined from SNP array datasets have helped identify not only deletions and duplications but also recurrent copy number neutral regions of loss-of-heterozygosity, which have been reported in many cancer types and that may constitute an important driving force in cancer. These tiny regions of UPD also alter imprinted gene dosage, which may have cumulative tumourgenic effects in addition to that of unmasking homozygous cancer-associated mutations.