Altered Cohesin Gene Dosage Affects Mammalian Meiotic Chromosome Structure and Behavior

Murdoch, Brenda M.; Owen, Nichole; Stevense, Michelle; Smith, Helen F.; Nagaoka, So I.; Hassold, Terry; McKay, Michael J.; Xu, Huiling; Fu, Jun; Revenkova, Ekaterina; Jessberger, Rolf; Hunt, Patricia A.

doi:10.1371/journal.pgen.1003241

Cited by 43 publications

(35 citation statements)

References 41 publications

(58 reference statements)

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“…aneuploidy is still being generated in large numbers of oocytes that maintain the integrity of their bivalents). This can be seen dramatically in mice that are heterozygous for mutations in meiosis-specific members of the cohesin ring (Murdoch et al, 2013). Here, in MI oocytes the presence of univalents is very low in both wild-type and heterozygous oocytes, but the rate of PSSC observed in MII eggs increases up to sixfold.…”

Section: Maternal Age and Aneuploidymentioning

confidence: 93%

Molecular causes of aneuploidy in mammalian eggs

2013

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SummaryMammalian oocytes are particularly error prone in segregating their chromosomes during their two meiotic divisions. This results in the creation of an embryo that has inherited the wrong number of chromosomes: it is aneuploid. The incidence of aneuploidy rises significantly with maternal age and so there is much interest in understanding this association and the underlying causes of aneuploidy. The spindle assembly checkpoint, a surveillance mechanism that operates in all cells to prevent chromosome mis-segregation, and the cohesive ties that hold those chromosomes together, have thus both been the subject of intensive investigation in oocytes. It is possible that a lowered sensitivity of the spindle assembly checkpoint to certain types of chromosome attachment error may endow oocytes with an innate susceptibility to aneuploidy, which is made worse by an age-related loss in the factors that hold the chromosomes together.

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Section: Maternal Age and Aneuploidymentioning

confidence: 93%

Molecular causes of aneuploidy in mammalian eggs

2013

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“…However, interference distances (expressed as mm of synaptonemal complex) are comparable between the sexes (Petkov et al 2007). Although the basis for such variation in chromatin organization remains unclear, levels of cohesin subunits and other axis components may be important (Novak et al 2008;Mets and Meyer 2009;Vranis et al 2010;Murdoch et al 2013).…”

Section: Crossover Control Crossover Assurance and Interferencementioning

confidence: 99%

“…A number of studies indicate that axis integrity and continuity are important for regulating crossover rate and interference (Hillers and Villeneuve 2003; Kleckner et al 2004;Nabeshima et al 2004;Novak et al 2008;Storlazzi et al 2008;Tsai et al 2008;Joshi et al 2009;Mets and Meyer 2009;Thacker and Keeney 2009;Zanders and Alani 2009;Qiao et al 2012b;Libuda et al 2013;Murdoch et al 2013;Zhang et al 2014d). These data suggest that homolog axes may be the conduits for transmission of interference signaling, or at least that axis integrity is important for spreading of interference (e.g., Zhang et al 2014d).…”

Section: Crossover Control Crossover Assurance and Interferencementioning

confidence: 99%

Meiotic Recombination: The Essence of Heredity

Hunter

2015

Cold Spring Harb Perspect Biol

648

847

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The study of homologous recombination has its historical roots in meiosis. In this context, recombination occurs as a programmed event that culminates in the formation of crossovers, which are essential for accurate chromosome segregation and create new combinations of parental alleles. Thus, meiotic recombination underlies both the independent assortment of parental chromosomes and genetic linkage. This review highlights the features of meiotic recombination that distinguish it from recombinational repair in somatic cells, and how the molecular processes of meiotic recombination are embedded and interdependent with the chromosome structures that characterize meiotic prophase. A more in-depth review presents our understanding of how crossover and noncrossover pathways of meiotic recombination are differentiated and regulated. The final section of this review summarizes the studies that have defined defective recombination as a leading cause of pregnancy loss and congenital disease in humans. MEIOSIS AND THE ROOTS OF RECOMBINATION RESEARCHT he concept of recombination emerged during the early 20th century, following the post-Mendel era of heredity research. Thomas Hunt Morgan's formal theory of gene linkage and crossing-over (Morgan 1913) was a synthesis of three key concepts: "the chromosome theory of inheritance," imparted by Wilhelm Roux, Walther Flemming, Theodor Boveri, and Walter Sutton; "gene linkage," an exception to Mendel's law of independent assortment, first reported by Carl Correns; and the "chiasmatype theory," derived from Frans Janssens' cytological observations of meiotic chromosomes. The first proof of the crossover theory came from Harriet Creighton and Barbara McClintock (Creighton and McClintock 1931), who were able to correlate cytological and genetic exchanges in maize.Experiments aimed at understanding the mechanism of meiotic recombination became dominated by fungal genetics because of the huge advantage afforded by being able to recover all four meiotic products. These elegant studies culminated in four key concepts that formed the foundation of molecular models of recombination: gene conversion, an exception to Mendel's principle of segregation, signaled a local nonreciprocal transfer of genetic information (Winkler 1930;Lindergren 1953;Mitchell 1955); postmeiotic segregation (PMS) indicated the presence of heteroduplex DNA (Olive 1959;Kitani et al. 1962) (Lissouba and Rizet 1960;Murray 1960); and the strong correlation between gene conversion/ PMS events and crossing-over led to the proposal that these processes were mechanistically linked (Kitani et al. 1962;Perkins 1962;Whitehouse 1963). MOLECULAR MODELS OF MEIOTIC RECOMBINATIONHolliday's classic model reconciled gene conversion, PMS, and crossing-over into a single mechanism with the key features of hybrid (heteroduplex) DNA formed via strand exchange, mismatch correction of hybrid DNA to yield gene conversion, and a four-way exchange junction that could be resolved to yield either crossover or noncrossover duplex products (Holliday...

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“…Heterozygous mutants of cohesin components lead to age-related increases in oocyte aneuploidy (Murdoch et al, 2013). Therefore, it is possible that a heterozygous mutation of a SMC5/6 component could lead to age-related errors during oogenesis too.…”

Section: Smc5/6 Protein Levels Are Diminished In Aging Oocytesmentioning

confidence: 99%

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes

et al. 2017

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SMC complexes include three major classes: cohesin, condensin and SMC5/6. However, the localization pattern and genetic requirements for the SMC5/6 complex during mammalian oogenesis have not previously been examined. In mouse oocytes, the SMC5/6 complex is enriched at the pericentromeric heterochromatin, and also localizes along chromosome arms during meiosis. The infertility phenotypes of females with a Zp3-Cre-driven conditional knockout (cKO) of Smc5 demonstrated that maternally expressed SMC5 protein is essential for early embryogenesis. Interestingly, protein levels of SMC5/6 complex components in oocytes decline as wild-type females age. When SMC5/6 complexes were completely absent in oocytes during meiotic resumption, homologous chromosomes failed to segregate accurately during meiosis I. Despite what appears to be an inability to resolve concatenation between chromosomes during meiosis, localization of topoisomerase IIα to bivalents was not affected; however, localization of condensin along the chromosome axes was perturbed. Taken together, these data demonstrate that the SMC5/6 complex is essential for the formation of segregation-competent bivalents during meiosis I, and findings suggest that age-dependent depletion of the SMC5/6 complex in oocytes could contribute to increased incidence of oocyte aneuploidy and spontaneous abortion in aging females.

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Altered Cohesin Gene Dosage Affects Mammalian Meiotic Chromosome Structure and Behavior

Cited by 43 publications

References 41 publications

Molecular causes of aneuploidy in mammalian eggs

Molecular causes of aneuploidy in mammalian eggs

Meiotic Recombination: The Essence of Heredity

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes

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