A first genetic portrait of synaptonemal complex variation

The synaptonemal complex (SC) is a proteinaceous scaffold required for synapsis and recombination between homologous chromosomes during meiosis. Although the SC has been linked to differences in genome-wide crossover rates, the genetic basis of standing variation in SC structure remains unknown. To investigate the possibility that recombination evolves through changes to the SC, we characterized the genetic architecture of SC divergence on two evolutionary timescales. Applying a novel digital image analysis technique to spermatocyte spreads, we measured total SC length in 9,532 spermatocytes from recombinant offspring of wild-derived mouse strains with differences in this fundamental meiotic trait. Using this large dataset, we identified the first known genomic regions involved in the evolution of SC length. Distinct loci affect total SC length divergence between and within subspecies, with the X chromosome contributing to both. Joint genetic analysis of MLH1 foci-immunofluorescent markers of crossovers-from the same spermatocytes revealed that two of the identified loci also confer differences in the genome-wide recombination rate. Causal mediation analysis suggested that one pleiotropic locus acts early in meiosis to designate crossovers prior to SC assembly, whereas a second locus primarily shapes crossover number through its effect on SC length. One genomic interval shapes the relationship between SC length and recombination rate, likely modulating the strength of crossover interference. Our findings pinpoint SC formation as a key step in the evolution of recombination and demonstrate the power of genetic mapping on standing variation in the context of the recombination pathway. Author summary During the first stages of meiosis, the chromosome axes are organized along a protein scaffold in preparation for recombination and their subsequent segregation. This scaffold, known as the synaptonemal complex (SC), is critical for the regular progression of recombination. A complex relationship exists between the organization of the SC, the frequency of recombination, and the likelihood of improper chromosome segregation. In this study, we investigate the genetics of synaptonemal complex variation in the house mouse and connect it with variation in the rate of recombination. We found five loci and several compelling candidate genes responsible for the evolution of synaptonemal complex length within and between mouse subspecies. Several of these loci also affect recombination rate, and our joint analyses of the phenotypes suggest an order by which their effects manifest within the recombination pathway. Our results show that evolution of SC length is crucial to recombination rate divergence. Our work here also demonstrates that genetic analysis of additional meiotic phenotypes can help explain the evolution of recombination, a fundamental evolutionary force.