Sexual reproduction depends on meiosis, the specialized cell division process that partitions homologous chromosomes to generate haploid gametes. Proper segregation of homologous chromosomes requires the formation of physical links known as chiasmata, which later direct the linked partners to different daughter cells. A tightly regulated number of chiasmata are created through crossover recombination during meiotic prophase. Each pair of chromosomes must undergo a crossover to segregate faithfully, but the total number of crossovers per cell is typically quite low – often just one per chromosome pair. In organisms where multiple crossovers can occur between one pair of homologues, they are nonrandomly far apart. This phenomenon, known as “crossover interference,” was first described over a century ago, but the molecular basis for this patterning mechanism has never been elucidated.
Crossing-over requires the assembly of the synaptonemal complex (SC), a ladder-like protein structure, which holds homologous chromosomes in side-by-side alignment. Crossovers are are preceded by the emergence of “recombination nodules,” large aggregates of pro-crossover factors that form a widely spaced pattern along the SC during late meiotic prophase. A variety of evidence has indicated that the SC is not a passive glue between homologues, but that it plays a central role in crossover regulation. Through live imaging in the nematode Caenorhabditis elegans, we discovered that the SC is not a stable polymer, but rather a dynamic, liquid crystalline condensate (Rog et al., 2017 eLife DOI: 10.7554/eLife.21455). Thus, this unusual compartment provides a conduit for protein diffusion at the interface between paired chromosomes, providing a potential mechanism for long-distance communication. Diffusion can also give rise to a wide variety of pattern-forming mechanisms, such as Turing patterns, which are thought to underlie diverse biological patterns and asymmetry.
Recombination nodules in all known species contain meiosis-specific RING finger proteins that are required for crossover recombination. Four such proteins (ZHP-1–4) are expressed in C. elegans. We found that these four proteins form two heterodimeric complexes, both of which diffuse within the SC. One of these pairs eventually coalesces within recombination nodules. These proteins thus show unique properties that may underlie the patterning of meiotic recombination (Zhang et al. (2018) eLife, doi: 10.7554/eLife.30789).
We propose that crossover patterning may arise through a mechanism known as “dewetting.” Specifically, our cytological analysis, together with a body of other evidence, suggests that ZHP-3/4 initially have high affinity for the SC, but that this affinity drops precipitously in response to a drop the activity of a key kinase at mid-prophase. This in turn drives their coalescence into widely spaced droplets, or recombination nodules, along the surface of the SC. Remarkably, this model shares key features in common with a speculative model for crossover interference proposed by Robin Holliday in 1977.