Silencing of unpaired meiotic chromosomes and altered recombination patterns in an azoospermic carrier of a t(8;13) reciprocal translocation.

BACKGROUND Male carriers of structural chromosomal abnormalities provide a useful model for studying the effects of impaired synapsis on human meioses and male fertility. METHODS We used immunofluorescent techniques to examine recombination (MLH1), synapsis (SYCP3/SYCP1) and transcriptional inactivation (BRCA1/gammaH2AX/RNA polymerase II) of meiotic chromosomes in an azoospermic carrier of a t(8;13) reciprocal translocation. Two biopsies were performed 1 year apart and on different testes. RESULTS Global recombination rates differed between the two biopsies. Although global recombination rates were not altered when compared with control men, recombination frequencies were reduced specifically on the rearranged chromosomes. Asynapsed quadrivalents were observed in 90% and 87% of pachytene nuclei from the first and second biopsies, respectively, and were frequently associated with the sex chromosomes. BRCA1 and gammaH2AX, two proteins implicated in meiotic sex chromosome inactivation, localized along asynapsed regions regardless of whether or not they were associated with the sex chromosomes. Immunostaining for RNA polymerase II provided further evidence that unsynapsed regions are silenced during human meiosis. CONCLUSIONS The fidelity of synapsis is a critical factor in determining the outcome of gametogenesis in humans, as the transcriptional inactivation of asynapsed regions may silence meiotic genes, leading to meiotic arrest and infertility.

[1]  Y. Rumpler,et al.  Chromosomal anomalies and disturbance of transcriptional activity at the pachytene stage of meiosis: relationship to male sterility. , 1993, Cytogenetics and cell genetics.

[2]  S. Perreault,et al.  Individual variation in the frequency of sperm aneuploidy in humans , 2005, Cytogenetic and Genome Research.

[3]  J. Hoeijmakers,et al.  Silencing of Unpaired Chromatin and Histone H2A Ubiquitination in Mammalian Meiosis , 2005, Molecular and Cellular Biology.

[4]  M. Braekeleer,et al.  Cytogenetic studies in male infertility: a review. , 1991, Human reproduction.

[5]  M. Mitchell,et al.  Pachytene asynapsis drives meiotic sex chromosome inactivation and leads to substantial postmeiotic repression in spermatids. , 2006, Developmental cell.

[6]  T. Liehr,et al.  Meiotic studies in two human reciprocal translocations and their association with spermatogenic failure. , 2005, Human reproduction.

[7]  R. Sciurano,et al.  Changes in crossover distribution along a quadrivalent in a man carrier of a reciprocal translocation t(11;14). , 2005, Biocell : official journal of the Sociedades Latinoamericanas de Microscopia Electronica ... et. al.

[8]  C. Deng,et al.  Prizes awarded at the 15th International Chromosome Conference, Brunel University, London, UK, September 2004 , 2005, Chromosome Research.

[9]  A. Rademaker,et al.  Variation in meiotic recombination frequencies among human males , 2005, Human Genetics.

[10]  Michel C. Nussenzweig,et al.  Genomic Instability in Mice Lacking Histone H2AX , 2002, Science.

[11]  U. Löhrs,et al.  Two different XY-quadrivalent associations and impairment of fertility in men. , 1987, Cytogenetics and cell genetics.

[12]  M. Hultén,et al.  Crossing over analysis at pachytene in man , 1998, European Journal of Human Genetics.

[13]  C. Deng,et al.  BRCA1, Histone H2AX Phosphorylation, and Male Meiotic Sex Chromosome Inactivation , 2004, Current Biology.

[14]  A. Clarke,et al.  The meiotic checkpoint monitoring sypapsis eliminates spermatocytes via p53-independent apoptosis , 1998, Nature Genetics.

[15]  A. Rademaker,et al.  Variation in MLH1 distribution in recombination maps for individual chromosomes from human males. , 2006, Human molecular genetics.

[16]  S. Schwartz,et al.  Cytological studies of meiotic recombination in human males , 2004, Cytogenetic and Genome Research.

[17]  R. Sciurano,et al.  The asynaptic chromatin in spermatocytes of translocation carriers contains the histone variant gamma-H2AX and associates with the XY body. , 2007, Human reproduction.

[18]  P. Schlegel,et al.  Defective recombination in infertile men. , 2004, Human molecular genetics.

[19]  J. Forejt,et al.  Chromosomal rearrangement interferes with meiotic X chromosome inactivation. , 2007, Genome research.

[20]  P. Turek,et al.  Meiotic studies in an azoospermic human translocation (Y;1) carrier. , 2005, Molecular human reproduction.

[21]  K. Ferguson,et al.  Reduced recombination associated with the production of aneuploid sperm in an infertile man: a case report. , 2006, Human reproduction.

[22]  B. Dutrillaux,et al.  Meiotic association between the XY chromosomes and the autosomal quadrivalent of a reciprocal translocation in two infertile men, 46,XY,t(19;22) and 46,XY,t(17;21). , 1986, Cytogenetics and cell genetics.

[23]  J. Navarro,et al.  Segregation of chromosomes in sperm of reciprocal translocation carriers: a review , 2005, Cytogenetic and Genome Research.

[24]  K. Ferguson,et al.  Abnormal meiotic recombination in infertile men and its association with sperm aneuploidy. , 2007, Human molecular genetics.

[25]  A. Chandley,et al.  A human 9;20 reciprocal translocation associated with male infertility analyzed at prophase and metaphase I of meiosis. , 1986, Cytogenetics and cell genetics.

[26]  M. Oliver-Bonet,et al.  Male infertility in reciprocal translocation carriers: the sex body affair , 2005, Cytogenetic and Genome Research.

[27]  C. Deng,et al.  Impaired meiotic DNA-damage repair and lack of crossing-over during spermatogenesis in BRCA1 full-length isoform deficient mice , 2003, Development.