A fascination with chromosome rescue in uniparental disomy: Mendelian recessive outlaws and imprinting copyrights infringements

Abstract

With uniparental disomy (UPD), the presence in a diploid genome of a chromosome pair derived from one genitor carries two main types of developmental risk: the inheritance of a recessive trait or the occurrence of an imprinting disorder. When the uniparentally derived pair carries two homozygous sequences (isodisomy) with a duplicated mutant, this 'reduction to homozygosity' determines a recessive phenotype solely inherited from one heterozygote. Thus far, some 40 examples of such recessive trait transmission have been reported in the medical literature and, among the current 32 known types of UPDs, UPD of chromosomes 1, 2, and 7 have contributed to the larger contingent of these conditions. Being at variance with the traditional mode of transmission, they constitute a group of 'Mendelian outlaws'. Several imprinted chromosome domains and loci have been, for a large part, identified through different UPDs. Thus, disomies for paternal 6, maternal 7, paternal 11, paternal and maternal 14 and 15, maternal 20 (and paternal 20q) and possibly maternal 16 cause as many syndromes, as at the biological level the loss or duplication of monoparentally expressed allele sequences constitutes 'imprinting rights infringements'. The above pitfalls represent the price to pay when, instead of a Mendelian even segregation and independent assortment of the chromosomes, the fertilized product with a nondisjunctional meiotic error undergoes correction (for unknown or fortuitous reasons) through a mitotic adjustment as a means to restore euploidy, thereby resulting in UPD. Happily enough, UPDs leading to the healthy rescue from some chromosomal mishaps also exist.