DNA-binding histone-3-lysine-4,36-trimethyltransferase PRDM9 specifies meiotic recombination hotspots in mice, rats and humans. Interallelic variation at the Prdm9 locus plays a role in hybrid male sterility. Sterile mouse F1 hybrid male offspring from the PWD × C57BL/6J (B6) cross exhibit meiosis breakdown reminiscent of that observed in Prdm9-deficient B6 sterile mice. However, reciprocal (B6 × PWD)F1 hybrids and some rodent models lacking PRDM9, i.e., PWD and SHR rat males execute meiotic recombination, produce sperm, raising the possibility that PRDM9's role may extend beyond meiosis. Here I demonstrate that PRDM9 is important for post- meiotic male gamete development and release. Unlike their parents, (B6 × PWD)F1 generated spermatozoa of lower quantity and motility but higher percentage of deformations, thus resembling oligoasthenoteratozoospermic (OAT) (semi)sterile men. Histopathological and (ultra)structural analysis revealed compromised spermiogenesis characterized by acrosome detachment and aberrant nucleus elongation in (B6 × PWD)F1 hybrids. Consequently, F1 spermatozoa had malformed acrosomes and nuclear DNA breaks with elevated base oxidation. While deletion of one Prdm9 copy improved sperm phenotypes in (B6 × PWD)F1, copy number gains of the surrounding genes had the opposite effect....

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Chromosome segregation errors that occur in the developing germline generate aneuploidies which are among the leading causes of embryonic lethality, spontaneous abortions and chromosomal disorders, such as Down’s syndrome. Compared to other species, human oocytes appear to be particularly prone to suffer chromosome missegregation and the risk of aneuploid pregnancies in humans increases drastically with maternal age. Despite its particular importance for human health, relatively little is known about the basis for the high incidence of aneuploidies in human oocytes and the maternal-age effect. The identification and analysis of molecular pathways that promote genetic and chromosomal stability is important for our understanding of mechanisms that lead to aneuploidy and how it can be prevented. Here, I examine the role of the pluripotency associated Tex19.1 gene, in preventing aneuploidy during mouse female germ cell development. I demonstrate that Tex19.1-/- females are subfertile when mated with wild type males due to defects in chromosome segregation during meiosis. In contrast to Tex19.1-/- male gem cells, synaptonemal complex formation appears to be completed normally in Tex19.1-/- females but high levels of aneuploidy are evident during the second meiotic stages of oogenesis. The Tex19.1-/- females transmit these aneuploidies to their offspring likely resulting in the observed embryonic death and subfertility. In addition to its role in the female germline, I investigated the function of Tex19.1 during embryonic development. I found that Tex19.1-/- knockout mice are born at a sub- Mendelian frequency and this reduction is exacerbated in diapaused embryos, suggesting that Tex19.1 plays a role during a stage where a pluripotent state is maintained for a prolonged period of time. Furthermore, I identified high levels of aneuploidy accumulating in pluripotent stem cells in the absence of Tex19.1.

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Thesis advisor: Charles Hoffman / Faithful chromosome segregation is necessary for the successful completion of mitosis and meiosis. The centromere is the site of kinetochore and microtubule attachment during chromosome segregation, and it is critical that the centromere is properly formed and maintained. Many proteins contribute to centromere formation, and this process has been extensively studied during the mitotic cell cycle. However, the roles of the centromere and its associated proteins during meiosis and their contribution to the fidelity of chromosome segregation process are not as well understood. Here, I aim to elucidate a mechanism that may contribute to aneuploidy in gametes, which is a major contributing factor in human infertility. In this study, I investigate the role of Abp1, the most prominent member of the transposase-derived protein family homologous to mammalian CENP-B in the assembly of centromeric chromatin during meiosis in the fission yeast Schizosaccharomyces pombe. I reveal that in contrast to its known role as a major regulator of LTR retrotransposons during the mitotic and meiotic cell cycles, Abp1 has a specialized role at the centromere during meiosis. My results indicate that Abp1 displays dynamic localization to the centromeres during meiosis compared to the vegetative cell cycle. I show that loss of abp1 impairs pericentromeric heterochromatin and the localization of Cnp1, a CENP-A ortholog, to the centromere central cores during meiosis. Moreover, Abp1 appears to suppress formation of meiotic neocentromeres by restricting deposition of Cnp1 at certain heterochromatin loci. Loss of abp1 has a drastic effect on chromosome segregation, resulting in dramatic frequency of aneuploidy. Furthermore, the genome surveillance role for retrotransposons by Abp1 appears to encompass centromeres as the mere insertion of an LTR sequence within the centromere central cores further exacerbates incidence of meiotic aneuploidy in abp1 null cells. This study provides intriguing insights into factors controlling the assembly of centromeric chromatin and its impact on the fidelity of chromosome segregation process during meiosis with important implications for advancing our understanding of the evolutionary forces driving the evolution of eukaryotic centromeres. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Meiosis is the process by which diploid cells undergo DNA synthesis, homologous recombination and pairing, followed by the reductional division then the equational division. I present work in this PhD thesis which furthers the understanding of the coordination of the initiation of meiotic recombination and the reductional division. Ten genes are required to initiate recombination in Saccharomyces cerevisiae. The presence of a subset of recombination initiation proteins creates a Recombination Initiation Signal (RIS) that delays the start of MI in wild type cells. I present experiments demonstrating the first division kinetics of the two remaining recombination initiation genes that our lab had not yet studied. Rec107 is part of the RIS, while Ski8 is not. The RIS is conserved in a divergent Saccharomyces strain background. rec102 and rec104 SK1 strains both start the first division earlier that wildtype SK1 strains. I present evidence that suggests that the RIS acts independently of the pathway that controls securin (PDS1) degradation. The work in this thesis expands our knowledge of the mechanism by which the RIS delays the reductional division. In this thesis I present experiments showing that the DNA damage, spindle and S phase checkpoints do not transduce the RIS. I establish the meiosis-specific candidate Mek1 as a candidate for relaying the RIS. Lastly, experiments described in these chapters show that the transcriptional activator of Middle Meiosis, NDT80, is the target of the RIS. NDT80 transcription and activity are both necessary and sufficient to affect an earlier reductional division, similar to the early MI seen in RIS mutants.

Includes bibliographical references (leaves 178-212) / xii, 212, [3] leaves : ill., plates (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Plant Science, 2002