Aniridia in man and Small eye in mice are semidominant developmental disorders caused by mutations within the paired box gene PAX6. Whereas heterozygotes suffer from iris hypoplasia, homozygous mice lack eyes and nasal cavities and exhibit brain abnormalities. To investigate the role of gene dosage in more detail, we have generated yeast artificial chromosome transgenic mice carrying the human PAX6 locus. When crossed onto the Small eye background, the transgene rescues the mutant phenotype. Strikingly, mice carrying multiple copies on a wild-type background show specific developmental abnormalities of the eye, but not of other tissues expressing the gene. Thus, at least five different eye phenotypes are associated with changes in PAX6 expression. We provide evidence that not only reduced, but also increased levels of transcriptional regulators can cause developmental defects.

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The pseudoautosomal region (PAR) is a segment of shared homology between the sex chromosomes. Here we report additional probes for this region of the mouse genome. Genetic and fluorescence in situ hybridization analyses indicate that one probe, PAR-4, hybridizes to the pseudoautosomal telomere and a minor locus at the telomere of chromosome 9 and that a PCR assay based on the PAR-4 sequence amplifies only the pseudoautosomal locus (DXYHgul). The region detected by PAR-4 is structurally unstable; it shows polymorphism both between mouse strains and between animals of the same inbred strain, which implies an unusually high mutation rate. Variation occurs in the region adjacent to a (TTAGGG). array. Two pseudoautosomal probes can also hybridize to the distal telomeres of chromosomes 9 and 13, and all three telomeres contain DXYMov1S. The similarity between these telomeres may reflect ancestral telomere-telomere exchange.Pairing and exchange of DNA between the human X and Y chromosomes, which are largely different in sequence, is restricted to two small telomeric regions of homology termed pseudoautosomal regions (PARs) (1). Genetic analyses indicate that an obligatory crossover occurs in male meiosis within the main PAR (2). Failure to form the X-Y chiasma can disrupt progress of the entire chromosome set through the subsequent stages of segregation; mice with unpaired sex chromosomes show developmental arrest at metaphase I and subsequent spermatocyte degeneration (2, 3). The main human PAR extends 2.6 Mb from the short-arm telomere (1). The obligatory crossover within this PAR causes genetic markers located at the Xp/Yp telomere to show 50% recombination with sex in male meiosis (1). Occasional exchange occurs at a second human PAR found at the Xq/Yq telomere (4, 5).The mouse PAR, located at the distal telomere, is poorly understood at the molecular level. Although its cytological behavior and role in hybrid sterility have been extensively analyzed (2), only two DNA probes for this region have been reported. The first is the (TTAGGG), telomere repeat, which detects restriction fragment length polymorphisms that map to the PAR (6, 7). The second probe was isolated from the Movl5 transgenic mouse, which has a single Moloney murine leukemia virus integrated in the PAR (8). Proviral DNA is transferred from the X to Y chromosomes in 10-20% of male meioses, suggesting an integration site close to the PAR boundary. A sequence flanking the virus integration site, DXYMovl5, has been cloned (9) and is a tandem repeat array of 31-bp monomer units. It is detected by the probe pMovl5/1, which hybridizes to the distal telomeres of chromosomes X, Y, 4, 9, and 13 (9-12). The sex-reversed (Sxr) mutation (13), which involves a translocation of the male-determining region

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