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Gruhn J.R.,Washington State University | Rubio C.,Preimplantation Genetic Diagnosis Unit | Broman K.W.,University of Wisconsin - Madison | Hunt P.A.,Washington State University | Hassold T.,Washington State University
PLoS ONE | Year: 2013

Meiotic recombination is sexually dimorphic in most mammalian species, including humans, but the basis for the male:female differences remains unclear. In the present study, we used cytological methodology to directly compare recombination levels between human males and females, and to examine possible sex-specific differences in upstream events of double-strand break (DSB) formation and synaptic initiation. Specifically, we utilized the DNA mismatch repair protein MLH1 as a marker of recombination events, the RecA homologue RAD51 as a surrogate for DSBs, and the synaptonemal complex proteins SYCP3 and/or SYCP1 to examine synapsis between homologs. Consistent with linkage studies, genome-wide recombination levels were higher in females than in males, and the placement of exchanges varied between the sexes. Subsequent analyses of DSBs and synaptic initiation sites indicated similar male:female differences, providing strong evidence that sex-specific differences in recombination rates are established at or before the formation of meiotic DSBs. We then asked whether these differences might be linked to variation in the organization of the meiotic axis and/or axis-associated DNA and, indeed, we observed striking male:female differences in synaptonemal complex (SC) length and DNA loop size. Taken together, our observations suggest that sex specific differences in recombination in humans may derive from chromatin differences established prior to the onset of the recombination pathway. © 2013 Gruhn et al.

Al-Asmar N.,Preimplantation Genetic Diagnosis Unit | Al-Asmar N.,Instituto Valenciano Of Infertilitad | Peinado V.,Preimplantation Genetic Diagnosis Unit | Vera M.,Preimplantation Genetic Diagnosis Unit | And 5 more authors.
Fertility and Sterility | Year: 2012

Objective: To compare the incidence of chromosomal abnormalities in preimplantation embryos from couples undergoing preimplantation genetic screening (PGS) after previous aneuploid miscarriage after either natural conception (NC) or assisted reproductive technology (ART) versus fertile couples who underwent PGS for sex-linked diseases as a control group. Design: Retrospective study. Setting: IVF clinic. Patient(s): Patients with previous aneuploid conception undergoing PGS. Intervention(s): Embryo biopsy, fluorescence in situ hybridization. Main Outcome Measure(s): Embryo aneuploidy rates and pregnancy and implantation rates in couples with a previous aneuploidy for autosomes or sex chromosomes. Result(s): The overall rates of chromosomal abnormalities in groups with previous autosomal aneuploidy were significantly higher compared with the control group (67.8% for those whose previous aneuploidy arose after NC and 65.8% for those previously arising after ART, vs. 34.0%). No significant differences were observed in those with previous sex chromosome abnormalities compared with control subjects. Within couples with previous aneuploidies after NC, no difference existed in the incidence of chromosomal abnormalities compared with the ART groups. Clinical outcomes were better (trend) in patients with previous autosomal aneuploidy after NC. Conclusion(s): In preimplantation embryos, the incidence of chromosomal abnormalities due to a previous aneuploid miscarriage after either NC or ART is significantly higher than in the control group. Furthermore, this incidence is higher when the previous aneuploidy was for autosomes; PGS is recommended in these couples. © 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.

Gruhn J.R.,Washington State University | Al-Asmar N.,Preimplantation Genetic Diagnosis Unit | Fasnacht R.,Washington State University | Maylor-Hagen H.,Washington State University | And 5 more authors.
American Journal of Human Genetics | Year: 2016

Meiotic recombination is initiated by programmed double strand breaks (DSBs), only a small subset of which are resolved into crossovers (COs). The mechanism determining the location of these COs is not well understood. Studies in plants, fungi, and insects indicate that the same genomic regions are involved in synaptic initiation and COs, suggesting that early homolog alignment is correlated with the eventual resolution of DSBs as COs. It is generally assumed that this relationship extends to mammals, but little effort has been made to test this idea. Accordingly, we conducted an analysis of synaptic initiation sites (SISs) and COs in human and mouse spermatocytes and oocytes. In contrast to our expectation, we observed remarkable sex- and species-specific differences, including pronounced differences between human males and females in both the number and chromosomal location of SISs. Further, the combined data from our studies in mice and humans suggest that the relationship between SISs and COs in mammals is a complex one that is not dictated by the sites of synaptic initiation as reported in other organisms, although it is clearly influenced by them. © 2016 The American Society of Human Genetics.

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