Turner, James Michael Andrew; (2000) An investigation into the role of sex chromosome synapsis in meiotic sex chromosome inactivation and fertility. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

During male meiosis in a number of species, the sex chromosomes become transcriptionally inactive (termed meiotic sex chromosome inactivation, or MSCI) and form a peripheral, densely staining structure termed the sex body. The function of MSCI is not known, but it may serve to silence 'poisonous' sex-linked genes, or to prevent the asynapsed portions of the sex chromosomes from triggering a checkpoint that monitors synapsis, recombination, or both. It has been postulated that MSCI is mediated by the Xist gene, and that Y chromosome inactivation proceeds by 'quasi-cis' spreading of Xist RNA from the X chromosome to the Y chromosome via the synapsed pseudoautosomal regions. The purpose of the present study was to examine the quasi-cis hypothesis, by analysing MSCI in Xist-disrupted spermatocytes, and Y chromosome inactivation in spermatocytes with high levels of X-Y synaptic failure. The first two chapters were aimed at identifying an MSCI marker that could be used to carry out the experiments described above. The MSCI-specificity of three sex body proteins: ASY, XMR/XLR and XY77 was examined by analysing the expression of each in oocytes from XYTdym1 females. The sex chromosomes in these oocytes failed to exhibit MSCI and were therefore suitable as negative controls. ASY and XMR/XLR coated the asynapsed X chromosome in XYTdym1 oocytes and also the asynapsed autosomes in T(2;5)72H oocytes, indicating that their presence in the sex body is related to the asynaptic and not transcriptionally inactive state of the sex chromosomes. XY77, in contrast, was sex body-specific. Next, the quasi-cis model was investigated by examination of MSCI in Xist-disrupted males and in males with sex chromosome synaptic failure (XYYd1, XYY*x). MSCI and sex body formation proceeded normally in the absence of Xist, but both were disrupted in XYYd1 spermatocytes. XYYd1 spermatocytes exhibiting defects in sex body formation and/or MSCI were eliminated between mid and late pachytene, indicating that MSCI is indispensable for meiosis and that it is disrupted by excess sex chromatin. Finally, an inherited genetic effect was characterised that could partially circumvent the pachytene checkpoint in XY*O mice. This effect allowed the normally sterile XY*O males to be fertile. The fertility was found to be due to the inheritance of an autosomal, dominant C3H factor (the major factor) together with a recessive MFl factor. Inheritance of a second, dominantly-acting C3H allele (the minor factor) further augmented the sperm counts of the XY*O males. Neither of the C3H factors was Hstl, a gene that confers fertility to interspecific hybrid male mice. Inheritance of these XY*O fertility factors was unable to restore fertility in XY*YTdym1 males, possibly due to the additional defects in MSCI that these males would be expected to experience.

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