Meiosis and recombination

  • In sexually reproducing species, meiosis allows the formation of haploid gametes from diploid cells. The halving of the DNA content results from a specialized cell cycle, where a single phase of DNA replication is followed by two divisions. The reductional segregation of homologous chromosomes (homologues) at the first meiotic division requires the establishment of connections between homologues. In most species, these connections are established during a long and specialized prophase by reciprocal exchanges between homologues. These exchanges, also called crossing over, result from a highly regulated homologous recombination pathway that drives the recognition and interaction between homologues and the formation of at least one crossing over per homologue pair. Crossovers also generate new allele combinations and thus increase genetic diversity and contributes to genome evolution. The absence of crossover leads to chromosome segregation defects and sterility, and alteration of the meiotic recombination pathway can lead to genome rearrangements and aneuploidy.

    Our team is investigating several aspects of the mechanism and regulation of meiotic recombination and its evolutionary implication using the mouse as a model system. Meiotic recombination events are initiated by the formation of DNA double-strand breaks (DSBs, several hundred per nucleus in mice), the repair of which leads to both crossovers and non-crossovers (gene conversion without crossover). The main steps and factors involved in this pathway are evolutionary conserved.

    Figure 1

    To date, our research is funded by:

    logo CNRS
    logo frm
    logo anr
    logo MSD avenir
    logo Fondation Bettencourt-Schueller

      Learn more

    Members

    Frédéric Baudat
    Baudat Frédéric
    Julie Clement
    Clement Julie
    Bernard De Massy
    De Massy Bernard
    Corinne Grey
    Grey Corinne
    Christine Brun
    Brun Christine
    Louise Badruna
    Badruna Louise
    Julia Antonia Brinkmeier
    Antonia Brinkmeier Julia
    Mathilde Biot
    Biot Mathilde
    Akbar Zainu
    Zainu Akbar
    Amelie Dellong
    Dellong Amelie

    Publications

    Mouse ANKRD31 Regulates Spatiotemporal Patterning of Meiotic Recombination Initiation and Ensures Recombination between X and Y Sex Chromosomes.

    Papanikos F, Clément JAJ, Testa E, Ravindranathan R, Grey C, Dereli I, Bondarieva A, Valerio-Cabrera S, Stanzione M, Schleiffer A, Jansa P, Lustyk D, Fei JF, Adams IR, Forejt J, Barchi M, de Massy B, Toth A

    2019 - Mol Cell

    Request for full article31000436

    Sex chromosome quadrivalents in oocytes of the African pygmy mouse Mus minutoides that harbors non-conventional sex chromosomes.

    Baudat F, de Massy B, Veyrunes F

    2019 - Chromosoma

    Request for full article30919035

    Mouse REC114 is essential for meiotic DNA double-strand break formation and forms a complex with MEI4.

    Kumar R, Oliver C, Brun C, Juarez-Martinez AB, Tarabay Y, Kadlec J, de Massy B

    2018 - Life Sci Alliance, 1(6):e201800259

    Request for full article30569039

    PRDM9, a driver of the genetic map.

    Grey C, Baudat F, de Massy B

    2018 - PLoS Genet, 14(8):e1007479

    Request for full article30161134
    Display all the publications

    Publications of the team

  • We are interested in understanding how the timing, frequency and distribution of these DSBs are regulated, and how DSB formation and repair are coordinated.

    The control of the distribution of meiotic DSBs:
    We and two other groups, have discovered a major component that determines the sites where DSBs are formed in mammals: the Prdm9 gene. This gene encodes a protein with a methyl-transferase activity and a tandem array of C2H2 zinc fingers. PRDM9 recognizes specific DNA motifs in the genome and is thought to promote trimethylation of lysine 4 of Histone H3 at these sites. How does this protein actually function in vivo and how its activity allows the recruitment of the recombination machinery remains to be determined. In addition, a remarkable property of PRDM9 is its rapid evolution and diversity. We are currently investigating both its molecular and evolutionary features. Prenant avantage des données de ChIP-seq et de RNA-seq à l’échelle du génome générées par ENCODE et le projet ROADMAP Epigenomic, nous identifions les signatures chromatiniennes qui marquent différemment les exons inclus ou exclus et ce que ces évènements ont en commun entre eux, tels que les motifs de fixation à l’ARN. Notre but est d’améliorer les algorithmes de prédiction de l’épissage alternatif actuels tout en ajoutant l’information inclue au niveau de la chromatine.

    Figure 2

    DSB formation:
    The catalytic activity responsible for break formation is carried by the SPO11 protein as shown in S. cerevisiae (Keeney et al., 1997; Bergerat et al., 1997). Spo11 is evolutionary conserved, is related to the A subunit of TopoVI and is acting as a complex with a second subunit, TOPOVIB-Like (Robert et al., 2016; Vrielynck et al., 2016). These proteins share similarity and differences with the TopoVI complex, but unlike a topoisomerase reaction, the activity generating meiotic DSBs seems to be channelled towards the formation of breaks where SPO11 is covalently linked to DNA ends. The biochemical properties of these proteins remain to be understood.

    Figure 3

    DSB regulation:
    Additional proteins are required for meiotic DSB formation (MEI4, REC114, IHO1). Interestingly they are located on meiotic chromosome axis. Their role might be to regulate the frequency and the spatial context for meiotic DSB formation. Indeed, meiotic chromosome organization is known to be important for proper control of DSB repair, ie the choice of the homologue vs the sister and the pathway for repair with or without crossing over. IHO1 is known to interact with the axis protein HORMAD1, but other components of meiotic chromosomes axis (SYCP3, cohesins…) are also known to play a role direct or indirect in DSB formation. We have identified the evolutionary conservation of the Mei4 and Rec114 protein family and are analyzing their functions and activities.

    Figure 4