Structural variation of the pseudoautosomal region between and within inbred mouse strains.

Abstract

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

Insertion of a Telomere Repeat Sequence into a Mammalian Gene Causes Chromosome Instability

“…The effects of telomeres and telomere sequence on homologous recombination are varied, sometimes stimulating it (4,5,22,27,39,74), sometimes inhibiting it (48,68), and sometimes leaving it unaffected (55). At the APRT locus, telomere sequence does not detectably affect homologous recombination, as assessed by rates of recombination, proportions of crossovers and conversions, and distribution of exchanges.…”

“…During meiosis in S. cerevisiae, ectopic recombination is significantly greater between inserts near telomeres than it is between more centrally located inserts (27), although recombination between directly repeated LEU2 gene segments was unaffected by proximity to the telomere (55). In humans, meiotic recombination is elevated near telomeres (5,39). By contrast, molecular and cytological studies of meiosis in grasshoppers show reduced recombination near telomeres (48).…”

Yeast telomeres exert a position effect on recombination between internal tracts of yeast telomeric DNA

“…Most relevant for our studies, double-strand breaks, which initiate most meiotic recombination events, are absent in the terminal ∼25 kb of yeast chromosomes (Klein et al 1996). In contrast, cytological and genetic evidence suggests that meiotic recombination occurs at elevated rates near some human telomeres (Ashley 1994;Kipling et al 1996).…”

A gene spans the pseudoautosomal boundary in mice

“…However the marker DXYCbl1 hybridizes in both males and females to a variable length PacI fragment of known pseudoautosomal origin (22,23) that cohybridizes with the probe pMov15.1 (Fig. 2).…”

“…Therefore the gene lies wholly within the highly variable PacI fragment that spans the boundary of the X chromosome and occupies a region of the PAR that contains a series of large repeats described above, the macrosatellite repeats of the DXYMov15 locus (25, 26) (also located in the 3Ј untranslated region of the Fxy gene; Fig. 4) and a region of telomere-derived (TTAGGG)n simple sequence repeats (22,23). To confirm that the whole of the gene is transcribed as a unit rather than as two separate genes on either side of the boundary, we performed RT-PCR with primers scattered through the gene (Fig.…”