A Liquid Crystalline Interface Between Chromosomes Regulates Meiotic Recombination
Authors: Dernburg Abby F. , Köhler Simone , Zhang Liangyu , Stauffer Weston T , Robinson Joseph D , Rog Ofer 
Published: November 2023

Meiosis is the specialized cell division process that enables sexual reproduction by generating haploid gametes from diploid germ cell precursors. This reduction in chromosome number depends on crossover recombination, also known as genetic exchange. Crossovers create links between homologous chromosomes that enable them to segregate to different daughter cells. Meiotic recombination is a highly orchestrated process that gives rise to new combinations of alleles, underlying genetic diversity. One of the major mysteries of meiosis is how cells ensure that every chromosome undergoes at least one crossover. Moreover, the total number of crossovers is usually far too low for this to occur by chance, and these crossovers show nonrandom, widely spaced distribution along individual chromosomes. These mechanisms are known as crossover assurance and crossover interference, but the mechanisms that underlie them have been obscure.

To undergo crossing‐over, chromosomes must first find and recognize their unique homologous partners. This pairing culminates with synapsis, the formation of a unique polymer known as the Synaptonemal Complex (SC) between paired homologs. Formation of the SC results in close, side‐by‐side alignment along the lengths of paired chromosomes. It has been unclear whether the SC passively holds homologous chromosomes in proximity to enable crossovers to occur, or instead might actively contribute to regulating the genome‐wide distribution of crossovers.

Through time‐lapse in vivo imaging in the nematode Caenorhabditis elegans, we investigated the kinetics of SC assembly between chromosomes. Through direct observation of this process, we began to suspect that the SC might assemble through a phase transition, or liquid‐liquid demixing process. Direct experiments revealed that this structure is held together by weak hydrophobic interactions, and that proteins within the assembled polymer are highly dynamic. Together with the high degree of molecular order, these liquid‐like properties indicate that the SC is an unusual biological material, a protein‐based liquid crystal, formation of which creates a phase‐separated compartment between meiotic chromosomes. We also find that these properties are conserved in diverse organisms, despite the weak conservation of SC proteins.

We have been exploring the implications of this discovery for the regulation of meiotic crossovers. In particular, we tested the idea that the SC might regulate recombination by concentrating and/or excluding meiotic recombination factors. Indeed, we identified a family of RING finger E3 ligases required for crossover formation that partition into the SC and dynamically relocalize during meiotic progression. Together with a cyclin‐related protein and a cyclin‐dependent kinase, these proteins form a regulatory circuit that ensures the formation of a crossover between each pair of chromosomes. The liquid‐like properties of the SC allow a biochemical signal to diffuse from the site of a crossover along the entire interface between paired chromosomes. As the signal is propagated, essential crossover factors are removed from the SC through protein degradation, thereby preventing the formation of additional crossovers in cis along the same chromosome. This unique circuitry can thus explain a large body of recombination data from diverse organisms.

Support or Funding Information

This work was supported by a European Molecular Biology Organization Long‐Term Fellowship (ALTF 564‐2010) to Ofer Rog, and support to Abby Dernburg from the National Institutes of Health (R01 GM065591) and the Howard Hughes Medical Institute.