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During meiotic prophase I, telomeres attach to and move on the nuclear envelope (NE), regulating chromosome movement to promote homologous pairing. Meiosis-specific proteins TERB1, TERB2 and MAJIN play a key role in this process. Here, we report the crystal structures of human TERB1-TERB2 and TERB2-MAJIN subcomplexes. Specific disruption of the TERB1-TERB2 or the TERB2-MAJIN interaction in the mouse Terb2 gene abolishes the telomere attachment to the NE and causes aberrant homologous pairing and disordered synapsis. In addition, depletion of SUN1 also partially disrupts the telomere-NE connection. We propose that the telomere-TRF1-TERB1-TERB2-MAJIN-NE interaction network and the telomere-LINC complex connection are likely two separate but cooperative pathways to stably recruit telomeres to the NE in meiosis prophase I. Our work provides a molecular model of the connection between telomeres and the NE and reveals the correlation between aberrant synapsis and the defective telomere attachment to the NE. The TERB1-TERB2-MAJIN complex mediates the attachment of telomeres to the nuclear envelope. Here the authors present the crystal structures of the human TERB1-TERB2 and TERB2-MAJIN subcomplexes and show that Terb2 mutations, which abolish complex formation cause aberrant homologous pairing and disordered synapsis in mouse.

Recombination is a central biological process with implications for many areas in the life sciences. Yet we are only beginning to appreciate variation in the recombination rate along the genome and among individuals, populations and species. Spurred by technological advances, we are now able to bring variation in this key biological parameter to centre stage. Here, we review the conceptual implications of recombination rate variation and guide the reader through the assumptions, strengths and weaknesses of genomic inference methods, including population-based, pedigree-based and gamete-based approaches. Appreciation of the differences and commonalities of these approaches is a prerequisite to formulate a unifying and comparative framework for understanding the molecular and evolutionary mechanisms shaping, and being shaped by, recombination.Genetic recombination is a fundamental biological process generating genetic variation by shuffling combinations of alleles. In this Review, Peñalba and Wolf focus on how sequencing-based approaches are providing diverse insights into recombination rate variation across levels of biological organization and timescales, from individual gametes of single individuals to populations through evolutionary history.

Meiotic recombination drives eukaryotic sexual reproduction and the generation of genome diversity. Tetrad analysis, which examines the four chromatids resulting from a single meiosis, is an ideal method to study the mechanisms of homologous recombination. Here we develop a method to isolate the four microspores from a single tetrad in maize for the purpose of whole-genome sequencing. A high-resolution recombination map reveals that crossovers are unevenly distributed across the genome and are more likely to occur in the genic than intergenic regions, especially common in the 5′- and 3′-end regions of annotated genes. The direct detection of genomic exchanges suggests that conversions likely occur in most crossover tracts. Negative crossover interference and weak chromatid interference are observed at the population level. Overall, our findings further our understanding of meiotic recombination with implications for both basic and applied research. The crossovers and gene conversions that occur during meiotic recombination contribute to genome diversity in eukaryotes. Here Li et al . describe a method of isolating individual microspores for whole-genome sequencing, providing new insights into the generation of genome diversity through sexual reproduction.

Key Points Aneuploidy is extraordinarily common in humans, occurring in an estimated 20–40% of all conceptions. It is the most common cause of miscarriages and congenital defects in our species and is a leading impediment to the treatment of infertility. Most aneuploidy results from maternal meiotic nondisjunctional errors. However, there is remarkable variation among chromosomes in the way in which these errors originate, indicating that there are multiple mechanisms by which human aneuploidy occurs. Studies of human fetal oocytes indicate a high level of recombination errors, indicating that some oocytes are predisposed to nondisjoin because of events that occurred before birth. Cell cycle control checkpoints that operate in meiotic prophase and at the metaphase–anaphase transition are less stringent in females than in males. Consequently, abnormal cells that are eliminated in spermatogenesis may escape detection in the female, ultimately leading to aneuploid eggs. Studies from mice suggest that loss of cohesin proteins over the reproductive life of the female contribute to the maternal age effect on human trisomy. Exposure to endocrine disruptors (for example, bisphenol A) disrupts oogenesis at multiple stages and predisposes the oocyte to aneuploidy. Aneuploidy is the leading cause of congenital defects in humans and nearly always results from errors occurring in oocytes. Here, the authors review the evidence pointing towards the mechanistic basis of meiotic defects leading to aneuploidy and discuss the potential role of environmental factors. Trisomic and monosomic (aneuploid) embryos account for at least 10% of human pregnancies and, for women nearing the end of their reproductive lifespan, the incidence may exceed 50%. The errors that lead to aneuploidy almost always occur in the oocyte but, despite intensive investigation, the underlying molecular basis has remained elusive. Recent studies of humans and model organisms have shed new light on the complexity of meiotic defects, providing evidence that the age-related increase in errors in the human female is not attributable to a single factor but to an interplay between unique features of oogenesis and a host of endogenous and exogenous factors.

The synaptonemal complex (SC) connects homologous chromosomes in meiotic prophase, thus promoting genetic exchange and ensuring accurate chromosomal segregation at anaphase. In this Review, the authors discuss the structural organization of the SC and how its assembly, maintenance and disassembly are regulated in yeast and metazoans. The synaptonemal complex (SC) connects homologous chromosomes in meiotic prophase, thus promoting genetic exchange and ensuring accurate chromosomal segregation at anaphase. In this Review, the authors discuss the structural organization of the SC and how its assembly, maintenance and disassembly are regulated in yeast and metazoans. The synaptonemal complex (SC) is a meiosis-specific scaffold that links homologous chromosomes from end to end during meiotic prophase and is required for the formation of meiotic crossovers. Assembly of SC components is regulated by a combination of associated nonstructural proteins and post-translational modifications, such as SUMOylation, which together coordinate the timing between homologous chromosome pairing, double-strand-break formation and recombination. In addition, transcriptional and translational control mechanisms ensure the timely disassembly of the SC after crossover resolution and before chromosome segregation at anaphase I.

In meiotic prophase, chromosomes are organized into compacted loop arrays to promote homolog pairing and recombination. Here, we probe the architecture of the mouse spermatocyte genome in early and late meiotic prophase using chromosome conformation capture (Hi-C). Our data support the established loop array model of meiotic chromosomes, and infer loops averaging 0.8–1.0 megabase pairs (Mb) in early prophase and extending to 1.5–2.0 Mb in late prophase as chromosomes compact and homologs undergo synapsis. Topologically associating domains (TADs) are lost in meiotic prophase, suggesting that assembly of the meiotic chromosome axis alters the activity of chromosome-associated cohesin complexes. While TADs are lost, physically separated A and B compartments are maintained in meiotic prophase. Moreover, meiotic DNA breaks and interhomolog crossovers preferentially form in the gene-dense A compartment, revealing a role for chromatin organization in meiotic recombination. Finally, direct detection of interhomolog contacts genome-wide reveals the structural basis for homolog alignment and juxtaposition by the synaptonemal complex.Comparative Hi-C analysis of synchronized mouse spermatocyte populations reveals dynamic changes in chromosome organization during meiotic prophase that permit homolog pairing while sustaining gene expression.

Unlike most organs that mature during the fetal period, the male reproductive system reaches maturity only at puberty with the commencement of spermatogenesis. Robust modelling of human testicular organogenesis in vitro would facilitate research into mechanisms of and factors affecting human spermatogenic failure and male fertility preservation in prepubertal tumor patients. Here, we report successful recapitulation of human testicular organogenesis in vitro from fetal gonadal ridge. Our model displayed the formation of mature seminiferous epithelium and self-renewing spermatogonia. Remarkably, in vitro-derived haploid spermatids have undergone meiotic recombination, and showed increased genetic diversity as indicated by genetic analysis. Moreover, these spermatids were able to fertilize oocytes and support subsequent blastocyst formation. The in vitro testicular organogenesis system described here will play an important role in elucidating the regulation of human testis development and maintaining male fertility in prepubertal cancer patients.

FANCM suppresses crossovers in plants by unwinding recombination intermediates. In wheat, crossovers are skewed toward the chromosome ends, thus limiting generation of novel allelic combinations. Here, we observe that FANCM maintains the obligate crossover in tetraploid and hexaploid wheat, thus ensuring that every chromosome pair exhibits at least one crossover, by localizing class I crossover protein HEI10 at pachytene. FANCM also suppresses class II crossovers that increased 2.6-fold in fancm msh5 quadruple mutants. These data are consistent with a role for FANCM in second-end capture of class I designated crossover sites, whilst FANCM is also required to promote formation of non-crossovers. In hexaploid wheat, genetic mapping reveals that crossovers increase by 31% in fancm compared to wild type, indicating that fancm could be an effective tool to accelerate breeding. Crossover rate differences in fancm correlate with wild type crossover distributions, suggesting that chromatin may influence the recombination landscape in similar ways in both wild type and fancm . The FANCM helicase functions in limiting crossovers (COs) by unwinding inter-homolog repair intermediates. Here, the authors generate null mutants of fancm in tetraploid and hexaploid wheat and show that FANCM promotes class I interfering COs and suppresses class II noninterfering COs in wheat meiosis.

The accurate segregation of chromosomes during meiosis—which is critical for genome stability across sexual cycles—relies on homologous recombination initiated by DNA double-strand breaks (DSBs) made by the Spo11 protein 1 , 2 . The formation of DSBs is regulated and tied to the elaboration of large-scale chromosome structures 3 – 5 , but the protein assemblies that execute and control DNA breakage are poorly understood. Here we address this through the molecular characterization of Saccharomyces cerevisiae RMM (Rec114, Mei4 and Mer2) proteins—essential, conserved components of the DSB machinery 2 . Each subcomplex of Rec114–Mei4 (a 2:1 heterotrimer) or Mer2 (a coiled-coil-containing homotetramer) is monodispersed in solution, but they independently condense with DNA into reversible nucleoprotein clusters that share properties with phase-separated systems. Multivalent interactions drive this condensation. Mutations that weaken protein–DNA interactions strongly disrupt both condensate formation and DSBs in vivo, and thus these processes are highly correlated. In vitro, condensates fuse into mixed RMM clusters that further recruit Spo11 complexes. Our data show how the DSB machinery self-assembles on chromosome axes to create centres of DSB activity. We propose that multilayered control of Spo11 arises from the recruitment of regulatory components and modulation of the biophysical properties of the condensates. During meiosis, Mer2 and the Rec114–Mei4 complex form condensates that facilitate the formation of double-strand DNA breaks by recruiting the Spo11 transesterase complex.