Molecular basis of chromosome synapsis and genetic exchange in mammalian meiosis

Meiotic cell division is defined by a unique and highly dynamic programme of events that results in homologous chromosome segregation following crossover formation. In mammals, the telomeric ends of chromosomes become tethered to the nuclear envelope by the meiotic telomere complex (MTC), where they undergo rapid movements, driven by microtubule forces transmitted by the LINC complex, that facilitate the identification and alignment of homologous chromosome pairs through recombination. Once established, homologue chromosome pairs become synapsed along their length by the zipper-like assembly of the synaptonemal complex (SC), which provides the unique three-dimensional architecture necessary for recombination intermediate resolution and crossover formation. We will uncover the structure, assembly mechanism and recombination function of the SC, the mechanistic basis of nuclear envelope tethering by the MTC and the mechanism of force transduction by the LINC complex. This will be achieved through a structural biology approach of biophysics, crystallography and cryo-EM, coupled with collaborative structure-directed mutation in mouse meiosis. Our work will result in unprecedented molecular understanding of how the mammalian SC, MTC and LINC complex operate together as an integrated molecular machine to achieve their essential functions of mammalian meiosis, and crucially how their dysfunction leads to human infertility, miscarriage and aneuploidy.