The effects of cancer predisposition and increased tumorigenic radiosensitivity of the predisposed genotypes on radiation cancer risks (in the general population and in sisters and first cousins of affected probands) are studied using an autosomal dominant model of cancer predisposition and radiosensitivity. The model assumes that the predisposing alleles, which confer enhanced tumorigenic radiosensitivity, are incompletely penetrant. In addition, the model also allows for sporadic cancers, unrelated to the predisposing locus. The predictions of the model are illustrated using current estimates of BRCA1 mutant gene frequencies; the estimates of the strength of predisposition and radiosensitivity differentials used are based on animal and human studies. It is shown that, unless both the strength of predisposition and radiosensitivity differential are large (say, >100-fold in comparison with normal homozygotes), (i) the effect of risk heterogeneity on cancer risk is marginal; (ii) dose-dependent radiation effect remains virtually the same as in a homogeneous irradiated population that has no predisposed subgroups; (iii) for the same radiation dose, relatives of affected probands show an enhancement of cancer risks; and (iv) most extra cancers in relatives can be attributed to radiosensitivity differentials. This simple model can give an upper bound of the effect of risk heterogeneity on radiation-induced breast cancer risks even when the cumulative breast cancer risk is age-dependent. Further, our model predicts that the benefits of mammography outweigh the risks.

The radioprotective effects of misoprostol, a synthetic stable analogue of prostaglandin E1, on spermatogonial stem cells of C3H/HeH×101/F1 hybrid mice (3H1) were analysed by establishing dose–response relationships for stem cell killing by X-rays in mice that were pretreated with misoprostol. Spermatogonial stem cell killing was studied through determination of the percentage of tubular cross-sections showing repopulation at 10 days after irradiation. In control mice, the D0 values ranged between 1·7 and 3·6 Gy, dependent on the stage of the cycle of the seminiferous epithelium the cells were in. As found previously, proliferating spermatogonial stem cells were much more radioresistant than quiescent stem cells. In the misoprostol-pretreated animals the spermatogonial stem cells were more radioresistant, the D0 values ranging from 3·6 to 5·0 Gy. Both proliferating and quiescent spermatogonial stem cells were protected by misoprostol. As the dose–response curves in control and misoprostol-pretreated mice showed about the same extrapolation number to the y-axis it was concluded that the misoprostol pretreatment did not alter the kinetics of the repopulation process.

The murine Xce locus, first identified by Bruce Cattanach, infiuences the primary choice of the X chromosome to be inactivated. Methylation of a GC-rich region (DXPas34) that includes multiple 34 bp repeats and lies some 15 kb 3′ to Xist has been shown to vary with Xce haplotype. The degree of methylation on the active X chromosome at this locus represents one of the few molecular correlates of Xce action currently available. Data relating to the specificity and other characteristics of this association are presented.

This Special Issue of Genetical Research constitutes a tribute to the work and achievements of Bruce Cattanach on the occasion of his official retirement. Bruce began his career working on mutagenesis in mice. His interest in mutagenesis continued throughout his career but through it he was led to a wide range of major discoveries in mammalian genetics. The contributions from his colleagues in this issue provide a flavour of the various fields his work has covered.

Tetraploid (4n) cells do not contribute equally to all tissues of midgestation mouse chimaeras and mosaics. Our previous studies of early blastocysts showed that 4n cells are preferentially allocated to the mural trophectoderm of the early blastocyst and this may contribute to the restricted distribution pattern seen at later stages. In this study of later-stage blastocysts we found evidence for selection against 4n cells. The contribution of 4n cells to 4n[harr]2n chimaeric blastocysts decreased between E3·5 and E4·5 days, whereas the composition of 2n[harr]2n controls changed little over this period. These results suggest that, prior to implantation, blastocysts have already lost some tetraploid cells from their embryonic and extra-embryonic lineages due to a combination of preferential allocation of 4n cells to the mural trophectoderm and selection against 4n cells throughout the embryo.

Genomic imprinting is an epigenetic mode of gene regulation that results in expression of the autosomal ‘imprinted’ genes from only a single allele, determined exclusively by parental origin. To date over 20 imprinted genes have been identified in mouse and man and these appear to lie in clusters in restricted regions on a subset of chromosomes. This may be a critical feature of imprinting suggesting a domain-type mode of regulation. Imprinted domains are replicated asynchronously, show sex-specific meiotic recombination frequencies and have CpG-rich regions that are differentially methylated, often associated with the imprinted genes themselves. Mouse distal chromosome 7 is one such domain, containing at least nine imprinted genes spanning over 1 Mb of DNA. For the maternally expressed p57Kip2 gene, passage through the female germline is essential to generate the active state, whereas passage through the male germline is needed to force the maternally expressed H19 gene into an inactive state. It is therefore possible that the mouse distal chromosome 7 imprinted domain is actually composed of two or more independently regulated subdomains.

We report here a novel X-linked mutant, named faint lined (Fnl), which was discovered in the litter of an irradiated 3H1 male (Dr Bruce Cattanach, personal communication). The mutation is associated with fine dorsal striping in affected heterozygous females and prenatal lethality in males. Approximately 50% of Fnl/+ females die in utero and surviving animals have a reduced weight at birth and weaning. Histological studies failed to reveal the underlying basis of the phenotype or any gross structural abnormalities in internal organs (Fnl/+×Mus spretus) F1 affected females were backcrossed to 3H1 males and haplotype analysis positioned Fnl in the proximal region of the mouse X chromosome distal to Ant2 and proximal to Hprt. Therefore, Fnl lies within a defined conserved segment and its human homologue can be predicted to lie in the ANT2–HPRT region in Xq25. Further genetic resolution of co-segregating markers flanking Fnl established that Fnl lies in a 7·6±2·6 cM interval between DXMit50 and DXMit82.

This review concerns the general problem of understanding growth control in the whole organism, starting with a saltatory change in size generated by a chromosome translocation or a mutation in a single gene. In particular, changes in insulin-like growth factor-II levels, by genetic and embryological manipulation, have major effects on wet weight size, but the intermediary events that link these levels to this measure of growth are uncertain. Thus it is currently impossible to eliminate any of the intermediary candidate processes that have been observed in model systems, including changed rates of apoptosis, cell multiplication, protein synthesis, capillary permeability and fluid transport.

The occurrence of homozygous-viable dilute–short ear (Myo5a–Bmp5) double mutants in mouse specific locus mutation experiments has generally been assumed to be the result of double non-disjunction such that the mutant inherits two copies of chromosome 9 carrying the recessive alleles from the test-stock. A homozygous viable Myo5a–Bmp5 double mutant was recovered recently in our laboratory. We were able to genetically analyse both the Myo5a–Bmp5 region and proximal and distal markers in the original mutant as well as in offspring of the original mutant. Our results indicate the mutational event to be due to mitotic recombination and not double non-disjunction.

Previous studies have shown that the distal region on mouse chromosome (Chr) 2 is subject to imprinting as mice with maternal duplication/paternal deficiency (MatDp.dist2) and the reciprocal (PatDp.dist2) for this region exhibit phenotypic anomalies at birth and die neonatally. We show here that imprinting effects are detectable in utero. Notably PatDp.dist2 embryos show an increase in wet weight compared with normal, which peaks at 16·5 d post coitum (dpc), and diminishes by birth, whereas the wet weight of placenta is slightly reduced in the latter half of gestation. Newborns have increased length of the long bones. By contrast, the wet weight of MatDp.dist2 embryos decreases during the second half of gestation. Measurements of dry weights of embryos at 16·5 dpc have indicated that there is no difference in either PatDp.dist2 or MatDp.dist2 compared with normal so that the wet weight differences are due to fluid retention in PatDp.dist2 but fluid loss in MatDp.dist2. In PatDp.dist2 embryos excess fluid is particularly prominent in the subcuticular skin layer, whereas by birth fluid is evident around the neck and tongue. At 16·5 dpc the PatDp.dist2 embryos are severely oedematous, as the average fluid content per unit dry weight per embryo was increased by 40%, whereas the MatDp.dist2 embryos are dehydrated as the average water content per unit dry weight per embryo was reduced by 6%. A preliminary conclusion is that there is neither growth enhancement in PatDp.dist2 nor growth retardation in MatDp.dist2 offspring.

The identification of novel mutants and their genetic and phenotypic characterization leads initially to fairly well-defined areas of experimentation. However, some mutant models lend themselves to investigations in fields that at first glance may appear remote from the original observation.

This has been true of the hypogonadal (hpg) mouse first discovered by Bruce Cattanach (Cattanach et al., 1977). In these mutant mice there is a failure of postnatal gonadal development such that paired testicular weight in 60-d-old hpg males is less than 10 mg whilst in normal littermates the testes weigh nearly 200 mg. The seminal vesicles of the mutants are extremely atrophic, indicating a failure of androgen production by the testes. In female mutants ovarian follicles rarely advance beyond the pre-antral stage and the uterus is thin and thread-like.