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The effects of a semidominant autosomal meiotic mutant, orientation disruptor (symbol: ord), located at 2-103.5 on the genetic map and in region 59B-D of the salivary map, have been examined genetically and cytologically. The results are as follows. (1) Crossing over in homozygous females is reduced to about seven percent of controls on all chromos...
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... the cause of this inequality, however, the conclusions to be drawn are not dependent on this ratio. Some of the ord females that were crossed to attached-2 and -3 males to measure autosomal nondisjunction were heterozygous for the centromere markers pr on chromosome-2 and st o n chromosome-3 (Table 6). In these cases, it is possible to measure equational nondisjunction for the major autosomes, since half of the equational exceptions for a particular autosome will be homozygous for the centromere marker for that chromosome. ...
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Citations
... In Drosophila, however, a canonical Rec8 cohesin complex does not exist [55,56]. Instead, a functionally analogous complex containing the proteins Solo and Sunn is clearly required for sister KT mono-orientation during M I, as well as Ord, a potential loading factor of this complex [57][58][59][60][61][62]. However, the involvement of these proteins in sister KT linkage before MI might be indirect, as these proteins localize primarily to the pericentromeric region and maintain sister chromatid cohesion until late metaphase II. ...
Sister kinetochores are connected to the same spindle pole during meiosis I and to opposite poles during meiosis II. The molecular mechanisms controlling the distinct behavior of sister kinetochores during the two meiotic divisions are poorly understood. To study kinetochore behavior during meiosis, we have optimized time lapse imaging with Drosophila spermatocytes, enabling kinetochore tracking with high temporal and spatial resolution through both meiotic divisions. The correct bipolar orientation of chromosomes within the spindle proceeds rapidly during both divisions. Stable bi-orientation of the last chromosome is achieved within ten minutes after the onset of kinetochore-microtubule interactions. Our analyses of mnm and tef mutants, where univalents instead of bivalents are present during meiosis I, indicate that the high efficiency of normal bi-orientation depends on pronounced stabilization of kinetochore attachments to spindle microtubules by the mechanical tension generated by spindle forces upon bi-orientation. Except for occasional brief separation episodes, sister kinetochores are so closely associated that they cannot be resolved individually by light microscopy during meiosis I, interkinesis and at the start of meiosis II. Permanent evident separation of sister kinetochores during M II depends on spindle forces resulting from bi-orientation. In mnm and tef mutants, sister kinetochore separation can be observed already during meiosis I in bi-oriented univalents. Interestingly, however, this sister kinetochore separation is delayed until the metaphase to anaphase transition and depends on the Fzy/Cdc20 activator of the anaphase-promoting complex/cyclosome. We propose that univalent bi-orientation in mnm and tef mutants exposes a release of sister kinetochore conjunction that occurs also during normal meiosis I in preparation for bi-orientation of dyads during meiosis II.
... Null alleles of ord and solo cause large decreases in recombination, particularly in distal regions of the chromosomes, and a subset of the residual COs appear to be between sister chromatids (Mason 1976;Webber et al. 2004;Yan and McKee 2013). These studies indicate that the Ord complex may play a role in promoting exchange between homologs over sister chromatid exchange (Webber et al. 2004;Yan and McKee 2013). ...
A century of genetic studies of the meiotic process inDrosophila melanogasterfemales has been greatly augmented by both modern molecular biology and major advances in cytology. These approaches, and the findings they have allowed, are the subject of this review. Specifically, these efforts have revealed that meiotic pairing inDrosophilafemales is not an extension of somatic pairing, but rather occurs by a poorly understood process during premeiotic mitoses. This process of meiotic pairing requires the function of several components of the synaptonemal complex (SC). When fully assembled, the SC also plays a critical role in maintaining homolog synapsis and in facilitating the maturation of double-strand breaks (DSBs) into mature crossover (CO) events. Considerable progress has been made in elucidating not only the structure, function, and assembly of the SC, but also the proteins that facilitate the formation and repair of DSBs into both COs and noncrossovers (NCOs). The events that control the decision to mature a DSB as either a CO or an NCO, as well as determining which of the two CO pathways (class I or class II) might be employed, are also being characterized by genetic and genomic approaches. These advances allow a reconsideration of meiotic phenomena such as interference and the centromere effect, which were previously described only by genetic studies. In delineating the mechanisms by which the oocyte controls the number and position of COs, it becomes possible to understand the role of CO position in ensuring the proper orientation of homologs on the first meiotic spindle. Studies of bivalent orientation have occurred in the context of numerous investigations into the assembly, structure, and function of the first meiotic spindle. Additionally, studies have examined the mechanisms ensuring the segregation of chromosomes that have failed to undergo crossing over.
... Thought to be comprised of coiled-coil domains much like C(3)G, it is also essential for SC function and recombination. All of these proteins have roles exclusive to female meiosis except for ORD, which also functions in sister-chromatid cohesion in Meiosis I and II and is necessary for gametogenesis in both Drosophila sexes [30,31]. ...
Background
The synaptonemal complex (SC) is a highly conserved meiotic structure that functions to pair homologs and facilitate meiotic recombination in most eukaryotes. Five Drosophila SC proteins have been identified and localized within the complex: C(3)G, C(2)M, CONA, ORD, and the newly identified Corolla. The SC is required for meiotic recombination in Drosophila and absence of these proteins leads to reduced crossing over and chromosomal nondisjunction. Despite the conserved nature of the SC and the key role that these five proteins have in meiosis in D. melanogaster, they display little apparent sequence conservation outside the genus. To identify factors that explain this lack of apparent conservation, we performed a molecular evolutionary analysis of these genes across the Drosophila genus.
Results
For the five SC components, gene sequence similarity declines rapidly with increasing phylogenetic distance and only ORD and C(2)M are identifiable outside of the Drosophila genus. SC gene sequences have a higher dN/dS (ω) rate ratio than the genome wide average and this can in part be explained by the action of positive selection in almost every SC component. Across the genus, there is significant variation in ω for each protein. It further appears that ω estimates for the five SC components are in accordance with their physical position within the SC. Components interacting with chromatin evolve slowest and components comprising the central elements evolve the most rapidly. Finally, using population genetic approaches, we demonstrate that positive selection on SC components is ongoing.
Conclusions
SC components within Drosophila show little apparent sequence homology to those identified in other model organisms due to their rapid evolution. We propose that the Drosophila SC is evolving rapidly due to two combined effects. First, we propose that a high rate of evolution can be partly explained by low purifying selection on protein components whose function is to simply hold chromosomes together. We also propose that positive selection in the SC is driven by its sex-specificity combined with its role in facilitating both recombination and centromere clustering in the face of recurrent bouts of drive in female meiosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12862-016-0670-8) contains supplementary material, which is available to authorized users.
... Weiterhin scheint es so, als ob im Drosophila-Genom kein Rec8-Ortholog zu finden ist. Jedoch wurde mit C(2)M ein weiteres α-Kleisinprotein gefunden, was mit SMC3 wechselwirkt und mit dem SC assoziiert ist (Schleiffer et al., 2003 (Mason, 1976, Miyazaki und Orr-Weaver, 1992, Bickel et al., 1996. Zum Beispiel führt das Fehlen von ord zur Aufhebung der meiotischen Kohäsion sowohl in Weibchen als auch in männlichen Fliegen (Bickel et al., 1997). ...
... Die Reduktion der crossover-Anzahl liegt dabei in einer vergleichbaren Größenordnung wie die der ord-mutanten Oozyten (10-fache für SOLO bzw. 6-fache Reduktion für ORD; Yan und McKee, 2013, Mason, 1976. ...
... Ein Großteil der solo-mutanten Oozyten wies deutlich fragmentierte DNA-Massen auf (Abb. (Yan und McKee, 2013, Mason, 1976 ...
Für die Aufrechterhaltung der genetischen Stabilität ist es von entscheidender Bedeutung, dass die gesamte genetische Information nach einer Zellteilung gleichmäßig auf die entstandenen Tochterzellen aufgeteilt wird. Während der S-Phase wird die DNA repliziert, sodass zwei identische Kopien vorliegen, welche bis zum Ende der Mitose miteinander verbunden bleiben. Hierfür wird der ringförmige Cohesinkomplex benötigt, der die DNA topologisch umschließt. Dieser Multiproteinkomplex setzt sich aus vier Kernuntereinheiten zusammen: SMC1, SMC3 und den zwei nicht-SMC Untereinheiten Scc1/Rad21/Mcd1 und Scc3/SA. In Metazoen wird der Großteil der Cohesinmoleküle während der Prophase vom Chromatin entfernt, während ein kleiner Teil am zentromerischen Chromatin verbleibt und erst beim Metaphase-Anaphase-Übergang durch eine Separase-abhängige Spaltung von Scc1/Rad21/Mcd1 abgelöst wird. Dieser exakt regulierte Mechanismus ist die Grundlage für eine korrekte Segregation und Aufteilung der Schwesterchromatiden auf die entstehenden Tochterzellen.
Die Meiose stellt eine spezielle Art der Zellteilung dar, bei der zwei aufeinanderfolgende Teilungen durchlaufen werden, ohne eine dazwischen stattfindende DNA-Replikation. Dies hat die Reduktion des Chromosomengehalts zur Folge. Zur Aufrechterhaltung der Schwesterchromatidkohäsion wird ein Meiose-spezifischer Cohesinkomplex benötigt, welcher anstatt Scc1 die Meiose-spezifische Untereinheit Rec8 besitzt. Das an den Chromo-somenarmen befindliche Cohesin wird in Meiose I durch einen Separase-abhängigen Prozess gespalten und die zentromerische Fraktion wird erst beim Durchlaufen von Meiose II vom Chromatin abgelöst. Dieser genau regulierte Prozess ist die Voraussetzung für die Bildung von Gameten mit einem korrekten Chromosomensatz. Rec8 und Scc1/Rad21/Mcd1 gehören zur Proteinfamilie der Kleisine. Diese Proteine verbrücken die Kopfdomänen der SMC-Proteine und sind bereits in verschiedenen Organismen beschrieben worden, jedoch konnte in Drosophila bisher kein Rec8-Homolog identifiziert werden. Daran anknüpfend wurde im ersten Teil der Arbeit untersucht, inwiefern die mitotische Cohesinuntereinheit Rad21 eine Funktion bei der Aufrechterhaltung der meiotischen Kohäsion besitzt und welche Folgen der Oogenese-spezifische Abbau dieses Proteins auf die Struktur des Synapto-nemalen Komplexes (SC) hat. Dieser Komplex stellt ein Proteingerüst dar, welcher die Paarung und anschließende Rekombination der homologen Chromosomen ermöglicht. Die Oogenese-abhängige Inaktivierung von Rad21 hatte keine Beeinträchtigung der Chromosomensegregation zur Folge, sehr wohl jedoch Auswirkungen auf die Struktur des SCs, indem dessen Stabilität negativ beeinflusst wird. Durch in vitro Interaktionsstudien konnte darüber hinaus ein Hinweis für eine direkte Interaktion von Rad21 mit C(2)M, einer Komponente des lateralen Elements des SCs, erbracht werden. Diese Assoziation ist eventuell auch von entscheidender Bedeutung für die Stabilität des SCs.
Um auszuschließen, dass das Ausbleiben von meiotischen Defekten nach ektopischer Proteolyse von Rad21 nicht auf eine unvollständige Inaktivierung der Cohesinuntereinheit zurückzuführen ist, wurde eine Rad21-Version generiert, bei der die Separaseerkennungs-sequenzen mutiert waren. Nach Oogenese-spezifischer Expression dieser nicht-spaltbaren Rad21-Variante konnte ebenfalls keine Beeinträchtigung der Chromosomensegregation festgestellt werden, sodass anzunehmen ist, dass Rad21 keine bzw. nur eine unter-geordnete kohäsive Funktion in der weiblichen Meiose von Drosophila melanogaster innehat.
Im zweiten Teil der Arbeit wurden Funktionsanalysen eines weiteren Proteins (SOLO; sisters-on-the-loose) durchgeführt, für das bereits kohäsive Funktionen während der Meiose beschrieben wurden. Um zu testen, ob dieses Protein als funktionelles Rec8-Homolog fungieren könnte, wurden verschiedene Interaktionsstudien durchgeführt. Diese legten jedoch nahe, dass SOLO vermutlich kein integraler Bestandteil eines meiotischen Cohesin-komplexes ist, sondern vielmehr als regulatorisches Protein fungiert. Auch die Expression einer SOLO-Version, bei der die vermuteten Separase-Spaltstellen modifiziert wurden, hatte keinen Einfluss auf den Verlauf der Meiose, sodass auch dieses Kriterium für ein kohäsives Kleisinprotein nicht erfüllt ist. Weiterhin konnte gezeigt werden, dass POLO-spezifische Phosphorylierungen im mittleren Teil des Proteins für die Rekrutierung von SOLO entlang der Chromosomen cores benötigt werden. Durch den Austausch mutmaßlich phosphorylierter Serin/Threonin-Reste gegen Alanine wurde das Level an SOLO in diesen Bereichen deutlich reduziert, was Auswirkungen auf die Paarung und Synapsis der homologen Chromosomen hatte. Mit Hilfe von 2-Hybridinteraktionsstudien in der Hefe konnten darüber hinaus auch noch Wechselwirkungen von SOLO mit verschiedenen Cohesin-assoziierten Proteinen, wie zum Beispiel dem Cohesinladeprotein Nipped-B/Scc2, Sororin/Dalmatian, SUNN und Pds5 nachgewiesen werden, deren Relevanz in initialen Experimenten in der weiblichen Meiose von Drosophila melanogaster bestätigt wurden. Zusammenfassend kann demnach festgehalten werden, dass SOLO vermutlich als regulatorisches Protein im Kontext mit verschiedenen Cohesin-assoziierten Proteinen (Pds5, Sororin, SUNN, Nipped-B) für die Schwesterchromatidkohäsion in der weiblichen Meiose und die Stabilität des SCs benötigt wird, nicht jedoch als Rec8-Homolog fungiert.
... the progeny of yem 1 heterozygous females, taking advantage of the sensitivity of meiotic recombination to gene dosage (Carpenter, 2003;Carpenter and Sandler, 1974;Hinton, 1966;Mason, 1976;Page and Hawley, 2001). We first determined the effect of yem 1 on crossover distribution along the X chromosome. ...
Meiosis is characterized by two chromosome segregation rounds (Meiosis I and II), which follow a single round of DNA replication, resulting in haploid genome formation. Chromosome reduction occurs at meiosis I. It relies on key structures, such as chiasma, which is formed by repair between homologous chromatids of a double-strand break (DSB) in one of them; to function for segregation of homologues chiasma in turn relies on maintenance of sister chromatid cohesion. In most species, chiasma formation requires the prior synapsis of homologous chromosome axes, which is signaled by the Synaptonemal Complex (SC), a tripartite proteinaceous structure specific to prophase I of meiosis. Yemanuclein (YEM) is a maternal factor that is crucial for sexual reproduction. It is required in the zygote for chromatin assembly of the male pronucleus as a histone H3.3 chaperone in complex with HIRA. We report here YEM association to the SC and the cohesin complex. A genetic interaction between yem(1) (V478E) and the Spo11 homologue mei-W68, added to a yem(1) dominant effect on crossover distribution suggest an early role in meiotic recombination. This is further supported by the impact of yem mutations on DSB kinetics. Hira mutant showed a similar effect presumably through disruption of HIRA-YEM complex.
... Although not a cohesin by sequence homology, ORD localizes along with the SMC cohesin subunits both at centromeres and on LEs and likely carries out some or most of its functions in collaboration with cohesin. The case is particularly clear for centromere cohesion where ord mutations lead to depletion of centromeric SMC cohesins in both male and female meiosis [30,43,474849505152. We have recently described a second meiosis-specific Drosophila cohesion protein, SOLO [53]. ...
... Crossover frequencies decreased in all four intervals in the mutants, very substantially and uniformly (7.5-to 7.6-fold) in the three euchromatic intervals, and more moderately (26%) in the fy + interval that encompasses the X centromere. The 7.6-fold reduction in crossovers between the distal (pn) and proximal (f) euchromatic X markers in our experiments falls within the fairly wide range of reported results for strong alleles of ord (6 to 20-fold reductions) and are in reasonable agreement with the reported 6.1-fold reduction for an ord-null genotype474849. Based on very limited data, both solo and ord mutants cause similar reductions (6 to 10-fold) in frequencies of crossovers in euchromatic autosomal intervals as well (Table 4) [47], but have much weaker effects on exchange in intervals near or encompassing centromeres474849. However, existing data do not reveal whether ord and solo function independently of each other in controlling exchange. ...
... The 7.6-fold reduction in crossovers between the distal (pn) and proximal (f) euchromatic X markers in our experiments falls within the fairly wide range of reported results for strong alleles of ord (6 to 20-fold reductions) and are in reasonable agreement with the reported 6.1-fold reduction for an ord-null genotype474849. Based on very limited data, both solo and ord mutants cause similar reductions (6 to 10-fold) in frequencies of crossovers in euchromatic autosomal intervals as well (Table 4) [47], but have much weaker effects on exchange in intervals near or encompassing centromeres474849. However, existing data do not reveal whether ord and solo function independently of each other in controlling exchange. ...
Cohesion between sister chromatids is mediated by cohesin and is essential for proper meiotic segregation of both sister chromatids and homologs. solo encodes a Drosophila meiosis-specific cohesion protein with no apparent sequence homology to cohesins that is required in male meiosis for centromere cohesion, proper orientation of sister centromeres and centromere enrichment of the cohesin subunit SMC1. In this study, we show that solo is involved in multiple aspects of meiosis in female Drosophila. Null mutations in solo caused the following phenotypes: 1) high frequencies of homolog and sister chromatid nondisjunction (NDJ) and sharply reduced frequencies of homolog exchange; 2) reduced transmission of a ring-X chromosome, an indicator of elevated frequencies of sister chromatid exchange (SCE); 3) premature loss of centromere pairing and cohesion during prophase I, as indicated by elevated foci counts of the centromere protein CID; 4) instability of the lateral elements (LE)s and central regions of synaptonemal complexes (SCs), as indicated by fragmented and spotty staining of the chromosome core/LE component SMC1 and the transverse filament protein C(3)G, respectively, at all stages of pachytene. SOLO and SMC1 are both enriched on centromeres throughout prophase I, co-align along the lateral elements of SCs and reciprocally co-immunoprecipitate from ovarian protein extracts. Our studies demonstrate that SOLO is closely associated with meiotic cohesin and required both for enrichment of cohesin on centromeres and stable assembly of cohesin into chromosome cores. These events underlie and are required for stable cohesion of centromeres, synapsis of homologous chromosomes, and a recombination mechanism that suppresses SCE to preferentially generate homolog crossovers (homolog bias). We propose that SOLO is a subunit of a specialized meiotic cohesin complex that mediates both centromeric and axial arm cohesion and promotes homolog bias as a component of chromosome cores.
... Similarly, traditional screening of either wild populations and/or EMS-mutagenized chromosomes have proved fruitful in their identification of genes such as ord, mei-S332, mei-S282, mei-P22, CycE, mei-W68, mei-S51, and sub (Giunta et al. 2002; Mason 1976; Sandler 1971; Sandler et al. 1968; Sekelsky et al. 1999). Taken together, the characterization of the mutants resulting from these screens has greatly contributed to our current understanding of fundamental processes in Drosophila female meiosis, including recombination, cohesion, achiasmate chromosome segregation, and meiotic spindle organization. ...
In an effort to isolate novel meiotic mutants that are severely defective in chromosome segregation and/or exchange, we employed a germline clone screen of the X chromosome of Drosophila melanogaster. We screened over 120,000 EMS-mutagenized chromosomes and isolated 19 mutants, which comprised nine complementation groups. Four of these complementation groups mapped to known meiotic genes, including mei-217, mei-218, mei-9, and nod. Importantly, we have identified two novel complementation groups with strong meiotic phenotypes, as assayed by X chromosome nondisjunction. One complementation group is defined by three alleles, and the second novel complementation group is defined by a single allele. All 19 mutants are homozygous viable, fertile, and fully recessive. Of the 9 mutants that have been molecularly characterized, 5 are canonical EMS-induced transitions, and the remaining 4 are transversions. In sum, we have identified two new genes that are defined by novel meiotic mutants, in addition to isolating new alleles of mei-217, mei-218, mei-9, and nod.
... Interestingly, the number of euchromatic initiation sites in mid-zygotene or in c(2)M mutants approximates the number of crossovers in the genome w6.3, [11]. Not only do these mid-zygotene sites depend on ORD, but in ord mutants, crossing over is reduced to less than 10% of wild-type [21], even though DSBs occur normally [14]. We suggest that the reduction in crossing over in ord mutants is due to the absence of the synapsis initiation sites at mid-zygotene. ...
Formation of the synaptonemal complex (SC), or synapsis, between homologs in meiosis is essential for crossing over and chromosome segregation [1-4]. How SC assembly initiates is poorly understood but may have a critical role in ensuring synapsis between homologs and regulating double-strand break (DSB) and crossover formation. We investigated the genetic requirements for synapsis in Drosophila and found that there are three temporally and genetically distinct stages of synapsis initiation. In "early zygotene" oocytes, synapsis is only observed at the centromeres. We also found that nonhomologous centromeres are clustered during this process. In "mid-zygotene" oocytes, SC initiates at several euchromatic sites. The centromeric and first euchromatic SC initiation sites depend on the cohesion protein ORD. In "late zygotene" oocytes, SC initiates at many more sites that depend on the Kleisin-like protein C(2)M. Surprisingly, late zygotene synapsis initiation events are independent of the earlier mid-zygotene events, whereas both mid and late synapsis initiation events depend on the cohesin subunits SMC1 and SMC3. We propose that the enrichment of cohesion proteins at specific sites promotes homolog interactions and the initiation of euchromatic SC assembly independent of DSBs. Furthermore, the early euchromatic SC initiation events at mid-zygotene may be required for DSBs to be repaired as crossovers.
... In Drosophila, orientation disruptor (ORD) is essential for sister chromatid cohesion during meiosis in both sexes (Mason 1976;Miyazaki and Orr-Weaver 1992;Bickel et al. 1996;Balicky et al. 2002;Webber et al. 2004). In the absence of ORD activity, chromosomes segregate randomly during both meiosis I and meiosis II, consistent with complete absence of both arm and centromere cohesion (Miyazaki and Orr-Weaver 1992;Bickel et al. 1996Bickel et al. , 1997. ...
... In the absence of ORD activity, chromosomes segregate randomly during both meiosis I and meiosis II, consistent with complete absence of both arm and centromere cohesion (Miyazaki and Orr-Weaver 1992;Bickel et al. 1996Bickel et al. , 1997. ORD function is also required for normal levels of homologous exchange in Drosophila oocytes (Mason 1976;Miyazaki and Orr-Weaver 1992;Bickel et al. 1997;Webber et al. 2004). Additional studies have shown that the recombination defect in ord mutant oocytes arises because sisterchromatid exchange is elevated, resulting in a lower number of crossovers between homologous chromosomes (Webber et al. 2004). ...
... In addition, consistent with its role in arm cohesion, ORD is also required for chiasma maintenance until anaphase I . Although some crossovers occur between homologous chromosomes in ord mutant oocytes, these bivalents still missegregate during meiosis I because chiasmata are not maintained (Mason 1976;Miyazaki and Orr-Weaver 1992;Bickel et al. 1997). ...
Normally, meiotic crossovers in conjunction with sister-chromatid cohesion establish a physical connection between homologs that is required for their accurate segregation during the first meiotic division. However, in some organisms an alternative mechanism ensures the proper segregation of bivalents that fail to recombine. In Drosophila oocytes, accurate segregation of achiasmate homologs depends on pairing that is mediated by their centromere-proximal heterochromatin. Our previous work uncovered an unexpected link between sister-chromatid cohesion and the fidelity of achiasmate segregation when Drosophila oocytes are experimentally aged. Here we show that a weak mutation in the meiotic cohesion protein ORD coupled with a reduction in centromere-proximal heterochromatin causes achiasmate chromosomes to missegregate with increased frequency when oocytes undergo aging. If ORD activity is more severely disrupted, achiasmate chromosomes with the normal amount of pericentric heterochromatin exhibit increased nondisjunction when oocytes age. Significantly, even in the absence of aging, a weak ord allele reduces heterochromatin-mediated pairing of achiasmate chromosomes. Our data suggest that sister-chromatid cohesion proteins not only maintain the association of chiasmate homologs but also play a role in promoting the physical association of achiasmate homologs in Drosophila oocytes. In addition, our data support the model that deterioration of meiotic cohesion during the aging process compromises the segregation of achiasmate as well as chiasmate bivalents.
... In order to assay loss of chiasma maintenance with age, we needed to verify that chiasma formation was not severely disrupted in smc1 +/2 oocytes. Cohesion between sister chromatids is required for normal levels of crossovers during meiosis1314151617. Therefore, we measured the frequency and distribution of exchange in smc1 +/2 heterozygous females (Figure 3B). ...
In humans, meiotic chromosome segregation errors increase dramatically as women age, but the molecular defects responsible are largely unknown. Cohesion along the arms of meiotic sister chromatids provides an evolutionarily conserved mechanism to keep recombinant chromosomes associated until anaphase I. One attractive hypothesis to explain age-dependent nondisjunction (NDJ) is that loss of cohesion over time causes recombinant homologues to dissociate prematurely and segregate randomly during the first meiotic division. Using Drosophila as a model system, we have tested this hypothesis and observe a significant increase in meiosis I NDJ in experimentally aged Drosophila oocytes when the cohesin protein SMC1 is reduced. Our finding that missegregation of recombinant homologues increases with age supports the model that chiasmata are destabilized by gradual loss of cohesion over time. Moreover, the stage at which Drosophila oocytes are most vulnerable to age-related defects is analogous to that at which human oocytes remain arrested for decades. Our data provide the first demonstration in any organism that, when meiotic cohesion begins intact, the aging process can weaken it sufficiently and cause missegregation of recombinant chromosomes. One major advantage of these studies is that we have reduced but not eliminated the SMC1 subunit. Therefore, we have been able to investigate how aging affects normal meiotic cohesion. Our findings that recombinant chromosomes are at highest risk for loss of chiasmata during diplotene argue that human oocytes are most vulnerable to age-induced loss of meiotic cohesion at the stage at which they remain arrested for several years.
