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European Journal of Human Genetics (2006) 14, 1158–1169

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REVIEW

A fascination with chromosome rescue in uniparental disomy: Mendelian recessive outlaws and imprinting copyrights infringements
Eric Engel*,1
1

Department of Medical Genetics and Development, University of Geneva, Geneva,Switzerland

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 arecessive 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 sequencesconstitutes ‘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. Happilyenough, UPDs leading to the healthy rescue from some chromosomal mishaps also exist. European Journal of Human Genetics (2006) 14, 1158–1169. doi:10.1038/sj.ejhg.5201619; published online 17 May 2006

Keywords: uniparental disomy; isodisomy; trisomy rescue; gamete complementation; imprinting; monosomy rescue

Part 1
Preamble Mendelian recessive outlaws are traits inherited outside the undisputedMendel laws, which are the even segregation
*Correspondence: Professor E Engel, Department of Medical Genetics and Development, University of Geneva, CMU 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland. Tel. þ 41 22 379 5707; Fax þ 41 22 379 5706; E-mail: e.engel@wanadoo.fr This text is the elaboration of a lecture delivered on March 17, 2005, in Amsterdam, in the honour of Professor Leo tenKate on the occasion of his retirement. Received 2 June 2005; revised 10 October 2005; accepted 23 February 2006; published online 17 May 2006

and independent assortment of alleles in germ cells. In uniparental disomy (UPD), by contrast, the meiotic missegregation of alleles on a chromosome pair is followed, in general, by a revised early mitotic balancing reassortment. Such a reassortment, tobe conducive to UPD, resorts to the loss of the normally inherited member of a trisomy or, more rarely, to the duplication of the lone member of a monosomy. If all ends well, the euploid status is restored but one of the 23 pairs lacks the other parent’s partner. In rarer situations, instead of a dual, that is meiotic and mitotic compensating mistake, two meiotic errors, one in the fertilizinggerm cell of each sex, complement each other. Although hypothetical, the latter probability

Chromosome rescue in uniparental disomy E Engel

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served as the basis of the UPD concept, by taking into account the high rate of gametal aneuploidy in humans. of crossing over and the meiotic stage at which missegregation had occurred. If so, by inheriting a (paternal) XY pair, male-to-male...