Parental origin effects in mice

Abstract

Nuclear transplantation experiments in mice, reviewed elsewhere in this Symposium, have clearly demonstrated that the maternal and paternal genomes from which the embryo is formed are not functionally equivalent. The paternal genome appears to be essential for the normal development of extraembryonic tissues and the maternal genome for some stage of embryonic development. These findings provide some explanation for the observations that in mammals diploid parthenotes possessing two maternal genomes fail to survive (Markert, 1982) and that, in man, embryos with two paternal chromosome sets are inviable, forming hydatidiform moles (Kajii & Ohama, 1977). It has been proposed that a specific ‘imprinting’ of the paternal genomes occurs during gametogenesis so that the presence of both a female and male pronculeus is essential in an egg for full-term development (Barton, Surani & Norris, 1984; McGrath & Solter, 1984a; Surani, Barton & Norris, 1984).The term ‘imprinting’ was coined by Crouse (1960) to describe the modification of chromosomes in the germlines of Sciara that causes the maternal and paternal autosomes and X-chromosomes to behave differently in the early cleavage stages of the embryo and at meiosis in the adult. Selective chromosome elimination was the phenomenon observed. The term has also been used in connection with the heterochromatic behaviour and genetic inactivation of the paternal chromosome set in male mealy bugs (Brown & Nelson-Rees, 1961) and, more recently, it has been applied to a process that causes the paternal X to be preferentially inactivated and heterochromatic in mouse extraembryonic membranes (Takagi, 1983). Imprinting can therefore be regarded as a chromosome phenomenon. Indeed, genetic studies in the mouse using various chromosome rearrangements have shown that it cannot be the whole genome that is imprinted because parental origin seems unimportant for many chromosomes. With others, however, a zygotic lethality, known as noncomplementation lethality, results when two members of a homologous pair of chromosomes or chromosome regions derive from only one parent. With yet others, anomalous opposite phenotypes result and this suggests a differential functioning of the chromosomes or regions involved according to parental origin. This paper summarizes the genetic data on these parental origin effects with special reference to those causing anomalous phenotypes.Chromosomally balanced mice carrying a pair of homologous chromosomes derived from only one parent, i.e. maternal or paternal disomy (with corresponding nullisomy) can readily be produced with the use of Robertsonian translocations that cause high frequencies of nondisjunction when heterozygous. Thus, intercrosses between Robertsonian heterozygotes allow a chromosomal gain from one parent to be complemented by a corresponding chromosome loss from the other, and, when the parents differ for alleles at a marker gene locus, those young that are monoparental for the chromosome concerned can readily be distinguished by marker gene phenotype (Tease & Cattanach, 1986). Further detail is given in Fig. 1. The frequency of maternal and paternal disomic mice produced in this way is dependent upon the nondisjunction levels associated with the various Robertsonian translocations but, typically, is about 2%. Higher frequencies can be obtained by intercrossing animals heterozygous for two different Robertsonian translocations having one chromosome arm in common (monobrachial homology) since this combination forces yet higher levels of nondisjunction (White, Tjio, van der Water & Crandall, 1972; Gropp & Winking, 1981).Intercrosses between heterozygotes for reciprocal translocations can similarly generate chromosomally balanced young which have two copies of a region of chromosome either distal or proximal to the translocation breakpoint from one parent, i.e. maternal or paternal duplication (with corresponding deficiency) (Snell, 1946; Searle & Beechey, 1985). Further detail is given in Fig. 2. The frequency of distal duplication/deficiency is high, about 17 %; that for proximal duplication/deficiency is much lower, less than 5 % (Searle & Beechey, 1978).Studies with Robertsonian translocations have demonstrated that mice that are monoparental for either maternal or paternal chromosomes 1,3,4,5,9,13,14 and 15 (denoted maternal and paternal disomy, respectively) are viable and normal. Paternal disomy 6 is also normal. Maternal or paternal disomy for chromosomes 2, 7, 10, 12, 16, 17 and 18 have not been investigated. Crosses to generate disomy 19 have been carried out (Lyon, Ward & Simpson, 1976) but because the Robertsonian translocation employed gives only very low frequencies of nondisjunction, the failure to detect any disomy 19 progeny may not be significant. Data consistent with the viability of some monoparentals have been obtained from work with reciprocal translocations. In addition, such studies have shown normal complementation occurs for certain regions of chromosomes 7,10 and 18 (Searle, 1985).The evidence on noncomplementation lethality has recently been reviewed (Searle & Beechey, 1985). Only a brief summary of the facts will therefore be given here. The phenomenon has been reported for four different chromosomes, 2,6,7 and 8, and a possibly related finding has been described for chromosome 17.Searle & Beechey (1985) have provided data from studies with two reciprocal translocations, T(2;9)11H and T(2;8)26H, that indicate that maternal duplication/paternal deficiency for a distal region of chromosome 2 (distal 2) causes perinatal death. With T11H the reciprocal type was indicated to be viable, but with T26H, which involves a smaller distal region, perinatal death was found. The latter was attributed to noncomplementation lethality associated with the chromosome 8 constitution (maternal duplication/paternal deficiency for distal 8). But more recent data, to be described shortly,...