The X Chromosome (Chr) controlling element locus (Xce) in the mouse has been shown to influence the X inactivation process. Xce maps to the central region of the X Chr, which also contains the Xist sequence, itself possibly implicated in the X inactivation process. Three microsatellite markers spanning the Xist locus have been isolated from an Xist containing YAC. All three microsatellite markers showed complete linkage with Xce in recombinants for the central span of the mouse X Chr between Ta and Moblo and strong linkage disequilibrium with Xce in all but one of the inbred mouse strains tested. In the standard Xceb typing strain JU/Ct, the two microsatellites most closely flanking Xist fail to carry the allelic forms expected if Xist and Xce are synonymous. Alternative explanations for this finding are presented in the context of our search for understanding the relation between Xist and Xce.

Genetic modifications of imprinted genes have been generated in the mouse to investigate the regulation of their expression. They show classical imprinted gene inheritances. Here we describe two imprinted gene mutations deriving from mutagenesis experiments. One is expressed only when transmitted through males. It causes a prenatal growth retardation which resembles that of the Igf2 knockout and maps close to the locus on chromosome 7. Differences from the knockout, which include an abnormal head phenotype, homozygous lethality, and an inability to rescue a TME: (Igf2r-deficient) lethality, suggest that Igf2 itself may not be directly affected. The second mutation maps close to the GNAS: cluster of imprinted genes on distal chromosome 2. It gives two distinct phenotypes according to parental origin, a gross neonatal oedema with microcardia and a postnatal growth retardation. The oedema phenotype is effectively lethal and resembles that of mice with paternal partial disomy for distal chromosome 2, as well as that of mice having a maternally derived GNAS: exon 2 knockout. However, the second growth retardation phenotype differs from that of the maternal partial disomy and the paternal knockout. A hypothesis to explain the phenotypes associated with the three genotypes based on the NESP:/NESPAS: sense/antisense and GNASXL: transcripts in the GNAS: cluster is offered.

An approach designed to map and generate mutations in the region of the short arm of the mouse Y chromosome, known to be involved in sex determination and spermatogenesis, is described. This relies on homologous Yp-Sxra pairing and asymmetrical exchange which can occur at meiosis in XY males carrying Sxra on their X chromosome. Such exchange potentially generates deficiencies and duplications of Yp or Sxra. Three fertile XY females were found out of about 450 XY offspring from XSxra/Y x XX crosses. In all three, despite evidence for deletion of Y chromosomal material, the Sry locus was intact. Each deletion involved a repeat sequence, Sx1, located at a distance from Sry. Since expression of Sry was affected these results suggest that long range position effects have disrupted Sry action.

Distal mouse chromosome 12 is imprinted. Phenotypic analysis of mouse embryos with maternal or paternal uniparental disomy for the whole of chromosome 12 has characterized the developmental defects associated with the altered dosage of imprinted genes on this chromosome. Here we conduct a characterization of maternal and paternal Dp(dist12) mice using the reciprocal translocation T(4;12)47H. This limits the region analysed to the chromosomal domain distal to the T47H breakpoint in B3 on mouse chromosome 12. Both MatDp(dist12)T47H and PatDp(dist12)T47H conceptuses are non-viable and the frequency of recovery of Dp(dist12) conceptuses by 10.5 days post coitum (dpc) was lower than expected after normal adjacent-1 disjunction. A subset of MatDp(dist12) embryos can survive up to one day post partum. In contrast to paternal uniparental disomy 12 embryos, no live PatDp (dist12) embryos were recovered after 16.5 days of gestation. Other phenotypes observed in maternal and paternal chromosome 12 uniparental disomy mice are recapitulated in the Dp(dist12) mice and include placental, muscle and skeletal defects. Additional defects were also noted in the skin of both MatDp(dist12) and maternal uniparental disomy 12 embryos. This study shows that the developmental abnormalities associated with the altered parent of origin for mouse chromosome 12 can be attributed to the genomic region distal to the T47H breakpoint.