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The existing XYY meiotic data for mice present a very heterogeneous picture with respect to the relative frequencies of different sex chromosome associations, both at pachytene and diakinesis/metaphase I. Furthermore, where both pachytene and diakinesis/MI data are available for the same males, the frequencies of the different configurations at the two stages are very different. In the present paper we utilise "XYY" and "XY/XYY" mosaic mice with cytologically distinguishable Y chromosomes to investigate the factors responsible for this heterogeneity between different males and between the two meiotic stages. It is concluded (1) that the initial pattern of synapsis is driven by the relatedness of the three pseudoautosomal regions (PARs); (2) that the order and extent of PAR synapsis within radial trivalents are also affected by PAR relatedness and that this leads to chiasmata being preferentially formed between closely related PARs; (3) that trivalents with a single chiasma resolve into a bivalent + univalent by the diakinesis stage; (4) that although many spermatocytes with asynapsed sex chromosomes are eliminated between pachytene and diakinesis, those that survive this phase of elimination progress to the first meiotic metaphase (MI) and accumulate in large numbers, leading to an over-representation of those with univalents as compared to radial trivalents; and (5) that the arrested MI cells are eventually eliminated, so that very few "XYY" cells contribute products to MII., (Copyright 2000 S. Karger AG, Basel.)

There is extensive evidence for the existence of a meiotic checkpoint that acts to eliminate spermatocytes that fail to achieve full sex chromosome synapsis at the pachytene stage of the first meiotic prophase. XYY mice are nearly always sterile, with clear signs of meiotic impairment, and sex chromosome asynapsis has been proposed to underlie this impairment. However, a study of XYY*(X) mice (mice having three sex chromosomes but only a single dose of Y genes) revealed that these mice are fertile, and thus implicated Y gene dosage as a major factor in the sterility of XYY mice. To address this question further, sex chromosome synapsis and spermatogenic proficiency were compared between XYY*(X) and XYY mice generated in the same litters. This established that differences in spermatogenic proficiency within and between the two genotypes correlated with the frequency of radial trivalent formation (full sex chromosome synapsis); XYY*(X) males, as a group, had double the radial trivalent frequency of XYY males. This observation provides strong support for the view that sex chromosome asynapsis (or some consequence thereof), rather than Y gene dosage, is the major factor leading to the meiotic impairment of XYY mice., (Copyright 2000 S. Karger AG, Basel.)

It has previously been reported that 19% of the daughters of males carrying the X-linked mutation patchy fur (Paf) are XO with a maternally derived X chromosome. We now report that hemizygous Paf males that also carry the variant Y chromosome Y*, show a much increased XO production ( approximately 40% of daughters). We hypothesize that the Paf mutation is associated with an inversion spanning the pseudoautosomal region (PAR) boundary, and that this leads to preferential crossing over between the resulting inverted region of PAR and an equivalent inverted PAR region within the compound Y* PAR. This would lead to the production of dicentric X and acentric Y products and consequent sex chromosome loss. This interpretation is supported by analysis of the sex chromosome complements at the second meiotic metaphase, which revealed a high incidence of dicentrics. Another curious feature of the Paf mutation is that mice that are homozygous Paf have more hair than mice that are hemizygous Paf. This can be explained if the Paf mutation is a hypomorphic mutation that escapes X inactivation because, unlike the wild type allele, it is now located within the PAR., (Copyright 2001 S. Karger AG, Basel)

In essence, the Y* rearrangement in the mouse is a Y chromosome that has been hijacked by a non-Y centromere attached distal to the pseudoautosomal region (PAR). All the Y-unique material is thought to be unaltered, but the recombinatory behaviour of the Y* with the X during male meioisis led to the conclusion that part of the PAR is inverted. In the course of a cross set up to introduce the X-linked mutation Patchy fur (Paf) into XY* males, the Y* chromosome was found to carry the wild type allele of Paf. Paf maps close to the X PAR boundary, so we hypothesised that the inverted region of the Y* PAR originated from an X chromosome that provided not only an inverted copy of proximal PAR, but also an X PAR boundary together with some adjacent X-unique material that included the Paf locus. This hypothesis was validated by Southern analysis using an X PAR boundary probe to show that Y* has an X PAR boundary. Thus the Y* PAR has resulted from an end to end fusion of an X and a Y PAR. Furthermore, it was shown that in conjunction with this PAR-PAR fusion, there has been deletion of both copies of the distally located pseudoautosomal gene Steroid sulfatase (Sts).

The relative frequencies of XYY and XY cells in XO/XY/XYY mosaic mice were compared between somatic cells (bone marrow) and spermatogonia, and between spermatogonia and pachytene or MI spermatocytes. The results indicated there was no selection either for or against XYY spermatogonia. There was, however, a strong selection against XYY spermatocytes during pachytene, with their almost total elimination by the first meiotic metaphase. At pachytene, most XYY cells had trivalent or X univalent/YY bivalent configurations. These findings are contrasted with previous studies of XYY spermatogenesis in mice and are discussed with respect to a model that invokes sex-chromosome univalence as the cause of XYY spermatogenic failure.

It has been observed previously that there is an association between sex chromosome pairing failure during meiosis and spermatocyte death. An hypothesis is advanced suggesting a similar association between a disruption of sex chromosome pairing (specifically, a failure of Y chromosome pairing) and spermatocyte loss in XYY mice and men.

A cytogenetic and histological study of nine XO/XY or XO/XY/XYY mosaic mice revealed that XO germ cells were selectively eliminated from the spermatogenic epithelium. Although the XO contribution to the bone marrow in seven mice exceeded 50%, in only two cases were significant numbers of dividing XO spermatogonia present. These XO germ cells only occasionally progressed to meiosis and then degenerated prior to first meiotic metaphase. It was concluded that the mouse Y chromosome carries a "spermatogenesis gene" (or genes) which acts autonomously in the germ cells.

Microdensitometry of Feulgen-stained spermatogenic cell preparations from six XOSxr and four T31H/+ male mice revealed large numbers of spermatids with a diploid amount of DNA. In XOSxr mice, where the diploid spermatids usually constituted the majority of the spermatid population, there were large differences from mouse to mouse in the proportion of diploid spermatids (range, 35%-94%). There were large losses of both haploid and diploid spermatids during spermiogenesis, and the later condensed spermatids of both types were grossly misshapen. It is suggested that the omission of one meiotic division, and the other spermiogenic anomalies may be manifestations of a meiotic "quality control" mechanism that destroys the products of those pachytene spermatocytes which have unsynapsed or incompletely synapsed chromosomes.