Mammalian meiotic silencing exhibits sexually dimorphic features.

During mammalian meiotic prophase I, surveillance mechanisms exist to ensure that germ cells with defective synapsis or recombination are eliminated, thereby preventing the generation of aneuploid gametes and embryos. Meiosis in females is more error-prone than in males, and this is in part because the prophase I surveillance mechanisms are less efficient in females. A mechanistic understanding of this sexual dimorphism is currently lacking. In both sexes, asynapsed chromosomes are transcriptionally inactivated by ATR-dependent phosphorylation of histone H2AFX. This process, termed meiotic silencing, has been proposed to perform an important prophase I surveillance role. While the transcriptional effects of meiotic silencing at individual genes are well described in the male germ line, analogous studies in the female germ line have not been performed. Here we apply single- and multigene RNA fluorescence in situ hybridization (RNA FISH) to oocytes from chromosomally abnormal mouse models to uncover potential sex differences in the silencing response. Notably, we find that meiotic silencing in females is less efficient than in males. Within individual oocytes, genes located on the same asynapsed chromosome are silenced to differing extents, thereby generating mosaicism in gene expression profiles across oocyte populations. Analysis of sex-reversed XY female mice reveals that the sexual dimorphism in silencing is determined by gonadal sex rather than sex chromosome constitution. We propose that sex differences in meiotic silencing impact on the sexually dimorphic prophase I response to asynapsis.

Assisted oocyte activation overcomes fertilization failure in globozoospermic patients regardless of the DPY19L2 status.

STUDY QUESTION: Does DPY19L2 status influence intracytoplasmic sperm injection (ICSI) outcomes with or without assisted oocyte activation (AOA)? SUMMARY ANSWER: DPY19L2 mutations have no major impact on ICSI outcomes in globozoospermic patients. WHAT IS KNOWN ALREADY: Globozoospermia is a rare and severe teratozoospermia characterized by round-headed spermatozoa lacking an acrosome. Recently, it has been shown that DPY19L2 mutations can be found in a vast majority of, but not all, globozoospermic patients (66.7%). These patients suffer from primary infertility due to a sperm-related oocyte activation deficiency secondary to the absence of an acrosome that can be overcome by the application of AOA. STUDY DESIGN, SIZE, DURATION: Cohort study, retrospective, 34 patients, 83 cycles. MATERIALS, SETTING, METHODS: Clinical and biologic data were collected from 29 patients mutated for DPY19L2 and 5 non-mutated patients. In total, 35 ICSI cycles using AOA and 48 conventional ICSI cycles were included in the analysis. Patients were divided into groups according to whether or not they were mutated for DPY19L2 and whether or not they received AOA. MAIN RESULTS AND THE ROLE OF CHANCE: Regardless of the presence of a DPY19L2 mutation, the fertilization rates with AOA are restored to normal when compared with conventional ICSI in our cohort of globozoospermic patients. Also, when performing ICSI plus AOA, both mutated and non-mutated cases have similar positive hCG rates, ongoing pregnancy rates and live birth rates per transfer. On the contrary, the fertilization rate in globozoospermic patients using conventional ICSI is correlated with the presence of a DPY19L2 mutation, with slightly better, although still very low, fertilization rates in patients carrying a DPY19L2 mutation. Nevertheless, when performing conventional ICSI, both mutated and non-mutated cases have similar very low positive hCG rates, ongoing pregnancy rates and live birth rates per transfer. LIMITATIONS: A limitation of this study is the low number of included non-mutated cases. WIDER IMPLICATIONS OF THE FINDINGS: We propose a pathway for the clinical management of globozoospermic patients depending on the phenotype that includes several diagnostic and therapeutic steps. STUDY FUNDING/COMPETING INTEREST(S): None.