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Title: Analysis of the epigenetics of meiotic silencing and its role in germ cell loss
Author: Cloutier, J.
ISNI:       0000 0004 8503 4524
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Numerical and structural chromosome abnormalities are common in the human population and cause infertility associated with germ cell losses during meiotic prophase I. The precise trigger of germ cell loss in response to chromosome abnormalities in mammals is still unclear, but several models have been postulated, including a DNA damage checkpoint, an asynapsis checkpoint, and meiotic silencing of asynapsed chromosomes. Here, I investigate the contribution of these mechanisms to oocyte loss in mice with chromosome abnormalities, such as X chromosome monosomy (XO). First, I show that asynapsed chromosomes trigger oocyte elimination during diplonema of meiotic prophase I, later than predicted by the pachytene checkpoint model that has been characterized in other organisms. Markers of DNA double-strand break repair disappear from asynapsed chromosomes during pachynema, suggesting that persistent DNA damage is unlikely to be the proximal cause of diplotene oocyte losses in chromosomally abnormal mice. I also show that oocytes with asynapsed accessory (i.e. supernumerary) chromosomes are not eliminated during diplonema, suggesting that asynapsis per se is not sufficient to cause germ cell loss. In support of the meiotic silencing model of germ cell loss, I find that deletion of the meiotic silencing factor H2afx prevents diplotene oocyte elimination in XO females. I show that meiotic silencing is less robust in oocytes compared to spermatocytes, and that this may be associated with sex-specific differences in the epigenetics of meiotic silencing. Finally, I report on the meiotic characterization of Brca1 and Hormad2 mutant mouse models, and in doing so ascribe critical roles for them in the meiotic silencing pathway. Together, these studies inform a meiotic silencing-based mechanism of prophase I surveillance against asynapsis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available