Our study utilizes newly engineered mouse models to demonstrate that the rs1254319 variant in human SIX6OS1 (Leu524Phe) modifies genome-wide recombination rates in mice. This variation disrupts crossover interference, leading to an increase in MLH1 foci, indicative of elevated recombination. We further show that this disruption shifts the utilization of recombination hotspots from PRDM9-dependent to PRDM9-independent sites. This is the first functional evidence linking a structural SC component to crossover interference in mammals.
To investigate the mechanistic basis of these findings, we generated deletion mutants around the p.Leu524 residue. One such mutant, Six6os1C-term/C-term, exhibits normal synapsis but a complete absence of COs, resulting in univalents at metaphase I—similar to the phenotype seen in mice lacking key pro-CO factors such as the recent described RNF212B, MLH1, or CNTD1. We show that CO maturation is dependent on the intact C-terminal domain of SIX6OS1, revealing a synapsis-dependent pathway for CO formation.
Our work uncovers a previously unrecognized role for the Synaptonemal Complex protein Six6os1 in coordinating synapsis and CO maturation and offers new insights into the molecular regulation of meiosis, with implications for fertility and genetic stability.
