Y-autosome translocation and infertility: usefulness of molecular, cytogenetic and meiotic studies.

An apparently balanced reciprocal translocation 46,X,t(Y;6) (q11.23 approximately q12;p11.1) was observed in an infertile man with severe oligozooteratozoospermia. Different mitotic chromosome banding patterns were performed and fluorescence in situ hybridization indicated a breakpoint in the fluorescent Yq heterochromatin. Molecular genetic deletion experiments for the azoospermia factor region in distal Yq11 showed the retention of the DAZ gene and meiotic pairing configurations suggested that the man's infertility could be due to the pairing behaviour of the Y;6 translocation chromosome with the X chromosome visualised by synaptonemal complex analysis at the electron microscopy level. The morphological appearance of the normal chromosome 6 and the Y;6 translocated chromosome included in the compartment of the sex vesicle may allow an explanation of the degeneration of most spermatocytes after the pachytene stage.

Synaptic behaviour of sex chromosome in two XYY men.

Analysis of meiotic pairing behavior in two XYY males presenting at subfertility clinic brings evidence that the abnormal mode of pairing caused by the presence of the extra Y chromosome, disturbs achievement of spermatogenesis resulting in severe oligoastheno-teratozoospermia. In contrast, the loss of the supernumerary Y before meiosis, allows achievement and normal sperm production.

The meiotic pairing behaviour in human spermatocytes carrier of chromosome anomalies and their repercussions on reproductive fitness. II. Robertsonian and reciprocal translocations. A European collaborative study.

The pairing behaviour of pachytene chromosomes was studied in men carrier of Robertsonian and reciprocal translocations, by analysis of synaptonemal complexes at the electron microscopy level. The human meiotic data were collected from European laboratories in order to test the current theories and to link the spermatogenic breakdown, and the pregnancy wastage to the mode of pairing and their consequences.

XY-quadrivalent association and sterility in a man carrier of a reciprocal autosomal translocation involving the whole arm of an acrocentric chromosome t(2;15)(q21.3;cen).

Meiotic and synaptonemal complex studies using electron microscopy were carried out on an infertile man with a 46,XY t(2q;15p). Synaptonemal complex analysis showed terminal asynapsis in the totality of quadrivalents and a high and significant frequency of association with the XY vesicle (80%), possibly related to the high amount of satellite DNA of the acrocentric chromosome 15. In this translocation carrier, the XY quadrivalent association at pachytene stage is positively correlated with the degree of spermatogenic breakdown after pachytene stage. Whether association with the non-paired segment represents the causative factor or only a secondary effect has still to be clarified.

Male sterility and double heterozygosity for chromosomal inversion.

A meiotic analysis has been carried out on male mice heterozygous for one of two inversions in Chromosome 2, In(2)5Rk and In(2)2H, as well as on double heterozygotes for these two overlapping inversions. Electron microscopic observation of synaptonemal complexes revealed that heterosynapsis had occurred in a large number of spermatocytes, producing a small number of cells with an inversion loop. Heterozygous carriers of a single inversion loop reproduced quite normally, whereas doubly heterozygous carriers of a double loop showed a reduction in spermatogenesis. These data shed new light on the role of inversions in speciation.

Supernumerary chromosomes and spermatogenesis in a human male carrier.

A 57-year-old patient was referred because of primary sterility. Spermogram and testicular histology showed moderate oligospermia and irregular hypospermatogenesis. Karyotypic analysis revealed the presence of a metacentric supernumerary chromosome. Synaptonemal complex analysis using the surface-spreading technique was undertaken to study the meiotic behaviour of the extra chromosome during the pachytene stages. The relationship of the extra chromosome to the infertility of the carrier is discussed.

Pattern of ribonucleic acid synthesis in human primary spermatocytes.

RNA synthesis was studied autoradiographically using [3H]-uridine at different stages of human spermatogenesis and especially at the pachytene stage. Morphological and functional evidence have shown the X Chromosome to be allocyclic relatively to the autosomes, and apparently inactive throughout the whole meiosis. No RNA precursor was incorporated by the X at any stage of male meiosis. The authors suggest that this technique could be used in cases of human rearranged chromosomes, in order to elucidate the mechanism of spermatogenic breakdown in cases of hypofertility or sterility in humans.

The meiotic pairing behaviour in human spermatocytes carrier of chromosome anomalies and their repercussions on reproductive fitness. I: Inversions and insertions. A European collaborative study.

The synaptic behavior of pachytene chromosomes was studied in men heterozygous for inversions and one inversion-insertion by analysis of synaptonemal complexes at the electron microscopy level. The human meiotic data were collected from European laboratories in order to test the current theories and to link the arrest of spermatogenesis and the risk of chromosome imbalance to the mode of pairing and their consequences. The breakpoint location would allow to predict the synaptic and recombinational behavior of chromosome aberrations and particularly the risk of aneusomie de recombinaison in the progeny of inversion carriers.

Chromosomal anomalies and disturbance of transcriptional activity at the pachytene stage of meiosis: relationship to male sterility.

Morphological analysis of pachytene spermatocytes obtained from male mice carrying three chromosomal rearrangements--a Robertsonian translocation, Rb(X-2)2Ad; an autosomal reciprocal translocation, T(16;17)43H; and a tertiary trisomic, Ts(113)70H--demonstrated frequent association between the XY bivalent and the T43H and T70H translocation chromosomes. Quantitative autoradiographic data revealed that the normal transcriptional inactivity of the XY bivalent was not significantly disturbed, in contrast to that of the 16;17 quadrivalent and the extra 1(13) marker chromosome. These results are interpreted as an extension of the XY inactivation process to the associated autosomes and discussed in relation to male sterility.

Heterosynapsis in two fertile but hypoprolific boars carriers of reciprocal translocations.

The authors report here two new cases of reciprocal translocations in two fertile and hypoprolific boars. Silver stained synaptonemal complexes in surface-spread pachytene nuclei from a boar heterozygous for a reciprocal translocation, and from another one carrying two different reciprocal translocations, were analyzed by electron microscopy. In such heterozygotes, cross-shaped quadrivalent configurations are expected to form in order to allow homologous pairing. In the same boar, the lengths of the fully synapsed arms of the quadrivalent varies from one quadrivalent to the other and heterosynapsis was obvious. Heterosynapsis was also observed with asymmetrical pairing of the non-homologous partners of the quadrivalent. This heterosynapsis is assumed to be a mechanism preventing spermatocyte loss, but inducing a secondary segregational type of impairment of fertility due to foetal wastage leading to reduced prolificacy.

Analysis of synaptonemal complexes in a heterozygous human male carrier of a reciprocal translocation involving an acrocentric chromosome: heterosynapsis without previous homosynapsis.

Silver-stained synaptonemal complexes in surface-spread pachytene nuclei from an oligospermic man, heterozygous for a reciprocal translocation involving an acrocentric chromosome, were analyzed by electron microscopy. Contrary to the classically expected configuration, nonhomologous pairing was observed with asymmetrical association of the lateral elements of the nonhomologous arms of the quadrivalents. A possible role of heterosynapsis in germ cell conservation is discussed.

Synaptonemal complex analysis in a human male carrier of a 4;6 translocation: heterosynapsis without previous homosynapsis.

Silver-stained synaptonemal complexes in surface-spread pachytene nuclei from a man, heterozygous for a reciprocal translocation, were analysed by electron microscopy. Contrary to the classically expected cross-shaped configuration, extensive non-homologous pairings were observed with asymmetrical association in the lateral elements of the non-homologous arms of the quadrivalents. A possible role of the heterosynapsis in reproductive failure is discussed.

Deletion of the pseudoautosomal region and lack of sex-chromosome pairing at pachytene in two infertile men carrying an X;Y translocation.

Two males with a 46,Y,der(X),t(X;Y)(p22.3;q11) complement were referred independently for evaluation of sterility with azoospermia. Both patients exhibited minimal symptomatology, characterized only by psychological disturbances. Study of X-chromosome breakpoints with pseudoautosomal probes 68B (DXYZ2 elements), 113D (locus DXYS15), and 19B (locus MIC2) indicated in both patients that at least 97% of the X pseudoautosomal sequences are lost. Hybridization with Xp22.3-specific probes DXS283, DXS284, and DXS31 shows that these loci are retained on the rearranged chromosome. Thus, the X-chromosome breakpoints are located close to the proximal boundary of the pseudoautosomal region, between MIC2 and DXS284.

Pattern of ribonucleic acid synthesis in vitro in primary spermatocytes from mouse testis carrying an X-autosome translocation.

In an attempt to elucidate the mechanism of sterility of X-autosome translocations in the mouse, we studied the distribution of [3H]-uridine incorporation in sterile males carrying the balanced X-16 reciprocal translocation. The results failed to show an overall reactivation of the X as has been postulated by Lifschytz and Lindsley (1972) but there was some spreading of X inactivation along the translocated and normal chromosome 16 in those regions that were close to the X breakpoint. We feel that this process could be responsible for metabolic disturbances leading to degeneration of primary spermatocytes and, therefore, to sterility.

Correlation between chromosomal breakpoint positions and synaptic behaviour in human males heterozygous for a pericentric inversion.

The examination of synaptic data and localization of chromosomal breakpoints in a review of human pericentric inversions suggest that synaptic and recombination behaviour in rearranged chromosomes during meiosis can be predicted by determining the subband in which the breakpoint is located. According to this hypothesis, it can be postulated that loops in pericentric inversions are routinely formed only in cases when both breaks occur in G-light bands, with the genetic consequences of crossing-over. In other cases, heterosynapsis is accomplished without previous homosynapsis, thereby minimizing the production of unbalanced gametes.

Analysis of synaptonemal complexes in two fertile heterozygous boars, both carriers of a reciprocal translocation involving an acrocentric chromosome.

An electron microscopic study of synaptonemal complexes in two heterozygous fertile boars, one a carrier of a 4;14 reciprocal translocation and the second a carrier of this translocation associated with a 3;7 reciprocal translocation, is reported. The results showed heterologous pairing in almost all quadrivalents, as well as a lack of XY-quadrivalent association. This seemed to be a common feature of translocations in pigs, even if at least one acrocentric chromosome is involved, and may represent a significant meiotic mechanism that prevents spermatocyte loss, while the production of genetically unbalanced gametes leads to loss of progeny through abortion.

Robertsonian heterozygosity and male sterility.

Meiotic and synaptonemal complex studies using electron microscopy were carried out on infertile man with a 13/14 translocation. Synaptonemal complex analysis showed a typical trivalent with incomplete pairing of the acrocentric elements. The sterilizing effect caused by the failure of synapsis is discussed. This pairing failure has a diagnostic value and a poor prognosis.

Synaptonemal complexes in a subfertile man with a pericentric inversion in chromosome 21. Heterosynapsis without previous homosynapsis.

Analysis of surface-spread synaptonemal complexes of zygotene and pachytene spermatocytes was carried out on a human male carrier of a pericentric inversion of chromosome 21 ascertained after four miscarriages. The synaptic behavior of the bivalent, which could be unambiguously identified by its nonaligned kinetochores, was analyzed. All zygotene and pachytene spermatocytes had 22 linearly paired autosomal bivalents, with apparently normal synaptonemal complexes, and no evidence of a loop configuration in the 50 cells analyzed. According to the XY type (classification of Solari), the cells were distributed across zygotene and pachytene stages, not exclusively in the late pachytene to which adjustment is conventionally thought to be confined. It is suggested that inverted segments heterosynapse at early pachytene, without previous homosynapsis. It is expected that this meiotic process leads to failure of crossing-over, reduces the production of unbalanced gametes, and the risk of recombinant offspring, but can increase the incidence of aneuploidy as a result of nondisjunction during meiosis I (a frequent cause of pregnancy wastage).

Heterosynapsis in a heterozygous fertile boar carrier of a 3;7 translocation.

Silver-stained synaptonemal complexes (SCs) in surface-spread pachytene nuclei from a boar, heterozygous for a reciprocal translocation, were analysed by electron microscopy. In such heterozygotes, cross-shaped quadrivalent configurations are expected to form in order to maximize homologous pairing. Contrary to the classical, expected cross-shaped configuration, heterosynapsis was often observed, with asymmetrical association in the lateral elements of the non-homologous partners of the quadrivalents. This heterosynapsis is assumed to be a mechanism preventing spermatocyte loss, but inducing a secondary segregational type of impairment of fertility due to foetal wastage leading to reduced prolificacy.