Robust Crossover Assurance and Regulated Interhomolog Access Maintain Meiotic Crossover Number

Rosu, Simona; Libuda, Diana E.; Villeneuve, Anne M.

doi:10.1126/science.1212424

Cited by 125 publications

(185 citation statements)

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“…Markers of meiotic progression appear normal in him-6 mutants: Several recent studies have provided evidence for a checkpoint-like negative feedback network that operates during C. elegans meiosis to couple multiple aspects of meiotic prophase progression to the formation of crossovereligible recombination intermediates (Rosu et al 2011;Rosu et al 2013;Stamper et al 2013;Woglar et al 2013). These Figure 3 Timely transition in pachytene progression in the him-6 mutant.…”

Section: Resultsmentioning

confidence: 99%

DNA Helicase HIM-6/BLM Both Promotes MutSγ-Dependent Crossovers and Antagonizes MutSγ-Independent Interhomolog Associations During Caenorhabditis elegans Meiosis

et al. 2014

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Meiotic recombination is initiated by the programmed induction of double-strand DNA breaks (DSBs), lesions that pose a potential threat to the genome. A subset of the DSBs induced during meiotic prophase become designated to be repaired by a pathway that specifically yields interhomolog crossovers (COs), which mature into chiasmata that temporarily connect the homologs to ensure their proper segregation at meiosis I. The remaining DSBs must be repaired by other mechanisms to restore genomic integrity prior to the meiotic divisions. Here we show that HIM-6, the Caenorhabditis elegans ortholog of the RecQ family DNA helicase BLM, functions in both of these processes. We show that him-6 mutants are competent to load the MutSg complex at multiple potential CO sites, to generate intermediates that fulfill the requirements of monitoring mechanisms that enable meiotic progression, and to accomplish and robustly regulate CO designation. However, recombination events at a subset of CO-designated sites fail to mature into COs and chiasmata, indicating a pro-CO role for HIM-6/BLM that manifests itself late in the CO pathway. Moreover, we find that in addition to promoting COs, HIM-6 plays a role in eliminating and/or preventing the formation of persistent MutSg-independent associations between homologous chromosomes. We propose that HIM-6/BLM enforces biased outcomes of recombination events to ensure that both (a) CO-designated recombination intermediates are reliably resolved as COs and (b) other recombination intermediates reliably mature into noncrossovers in a timely manner.

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Section: Resultsmentioning

confidence: 99%

DNA Helicase HIM-6/BLM Both Promotes MutSγ-Dependent Crossovers and Antagonizes MutSγ-Independent Interhomolog Associations During Caenorhabditis elegans Meiosis

et al. 2014

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Section: Discussionmentioning

confidence: 99%

“…In C. elegans, the distribution of DSBs is not fully characterized. Strong crossover interference allows only one DSB to resolve as a crossover, and current data suggest that each pair of homologs receives multiple DSBs (Rosu et al 2011;Saito et al 2013), leaving unresolved the molecular basis for the species' nonuniform crossover distribution.Despite the modest fine-scale crossover rate heterogeneity we have detected, C. elegans exhibits dramatic broadscale rate variation. We localized a boundary between a low-rate chromosomal center and a high-rate chromosomal arm to an interval of just a few kilobases.…”

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confidence: 99%

Crossover Heterogeneity in the Absence of Hotspots inCaenorhabditis elegans

Kaur

Rockman

2014

Genetics

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Crossovers play mechanical roles in meiotic chromosome segregation, generate genetic diversity by producing new allelic combinations, and facilitate evolution by decoupling linked alleles. In almost every species studied to date, crossover distributions are dramatically nonuniform, differing among sexes and across genomes, with spatial variation in crossover rates on scales from whole chromosomes to subkilobase hotspots. To understand the regulatory forces dictating these heterogeneous distributions a crucial first step is the fine-scale characterization of crossover distributions. Here we define the wild-type distribution of crossovers along a region of the C. elegans chromosome II at unprecedented resolution, using recombinant chromosomes of 243 hermaphrodites and 226 males. We find that well-characterized large-scale domains, with little fine-scale rate heterogeneity, dominate this region's crossover landscape. Using the Gini coefficient as a summary statistic, we find that this region of the C. elegans genome has the least heterogeneous fine-scale crossover distribution yet observed among model organisms, and we show by simulation that the data are incompatible with a mammalian-type hotspot-rich landscape. The large-scale structural domains-the low-recombination center and the high-recombination arm-have a discrete boundary that we localize to a small region. This boundary coincides with the armcenter boundary defined both by nuclear-envelope attachment of DNA in somatic cells and GC content, consistent with proposals that these features of chromosome organization may be mechanical causes and evolutionary consequences of crossover recombination. MEIOTIC recombination creates novel combinations of parental alleles and is a powerful force shaping the genetic variation observed within a population. The frequency of recombination has a profound impact on the efficacy of natural selection in both purging deleterious mutations and in the formation of beneficial allelic combinations (Hill and Robertson 1966;Cutter and Payseur 2013). However, the intensity of recombination in different parts of a genome is rarely constant. Heterogeneity in the meiotic recombination rate has been observed across chromosome lengths and at finer scales of a few kilobase in diverse organisms.In Caenorhabditis elegans, meiotic recombination rates show a striking and reproducible chromosome-wide pattern of variation. Genetic maps of the five autosomes and X chromosome show that each has a low-recombination central domain flanked by high-recombination arm domains (Barnes et al. 1995;Rockman and Kruglyak 2009). This domain structure has dramatic effects on genetic variation and evolution (Cutter and Payseur 2003;Rockman et al. 2010;Andersen et al. 2012), but the underlying causes generating this pattern are not completely understood.The domain structure relates to unusual characteristics of the C. elegans chromosomes. The chromosomes lack localized centromeres and exhibit holocentric segregation during mitosis, with kinetochore pro...

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“…Several recent studies have converged on the conclusion that formation and repair of DSBs during meiosis are governed by a checkpoint-like negative feedback network in which germ cells monitor the formation of recombination intermediates that have the capacity to become interhomolog crossovers ("CO-eligible intermediates") and couple detection of such intermediates to progression through meiotic prophase (Rosu et al 2011Stamper et al 2013;Woglar et al 2013). If sufficient intermediates have formed to guarantee a CO for each homolog pair, the cell will be permitted to undergo a major transition affecting multiple distinct aspects of the meiotic program, including cessation of competence for DSB formation and shutting down of access to the homolog as a template for DSB repair; if the condition is not met, this transition will be delayed.…”

Section: Implications Of a Two-state View Of The Scmentioning

confidence: 99%

Manipulation of Karyotype inCaenorhabditis elegansReveals Multiple Inputs Driving Pairwise Chromosome Synapsis During Meiosis

2015

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Meiotic chromosome segregation requires pairwise association between homologs, stabilized by the synaptonemal complex (SC). Here, we investigate factors contributing to pairwise synapsis by investigating meiosis in polyploid worms. We devised a strategy, based on transient inhibition of cohesin function, to generate polyploid derivatives of virtually any Caenorhabditis elegans strain. We exploited this strategy to investigate the contribution of recombination to pairwise synapsis in tetraploid and triploid worms. In otherwise wild-type polyploids, chromosomes first sort into homolog groups, then multipartner interactions mature into exclusive pairwise associations. Pairwise synapsis associations still form in recombination-deficient tetraploids, confirming a propensity for synapsis to occur in a strictly pairwise manner. However, the transition from multipartner to pairwise association was perturbed in recombination-deficient triploids, implying a role for recombination in promoting this transition when three partners compete for synapsis. To evaluate the basis of synapsis partner preference, we generated polyploid worms heterozygous for normal sequence and rearranged chromosomes sharing the same pairing center (PC). Tetraploid worms had no detectable preference for identical partners, indicating that PC-adjacent homology drives partner choice in this context. In contrast, triploid worms exhibited a clear preference for identical partners, indicating that homology outside the PC region can influence partner choice. Together, our findings, suggest a two-phase model for C. elegans synapsis: an early phase, in which initial synapsis interactions are driven primarily by recombination-independent assessment of homology near PCs and by a propensity for pairwise SC assembly, and a later phase in which mature synaptic interactions are promoted by recombination.

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Robust Crossover Assurance and Regulated Interhomolog Access Maintain Meiotic Crossover Number

Cited by 125 publications

References 42 publications

DNA Helicase HIM-6/BLM Both Promotes MutSγ-Dependent Crossovers and Antagonizes MutSγ-Independent Interhomolog Associations During Caenorhabditis elegans Meiosis

DNA Helicase HIM-6/BLM Both Promotes MutSγ-Dependent Crossovers and Antagonizes MutSγ-Independent Interhomolog Associations During Caenorhabditis elegans Meiosis

Crossover Heterogeneity in the Absence of Hotspots inCaenorhabditis elegans

Manipulation of Karyotype inCaenorhabditis elegansReveals Multiple Inputs Driving Pairwise Chromosome Synapsis During Meiosis

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