Mammalian-specific MSH5 domain drives key step in meiotic crossover designation, preprint reports

A preprint posted to bioRxiv on 18 June 2026 investigates the function of a short, mammalian-specific domain at the C-terminus of the meiotic recombination protein MSH5, a component of the MutSγ complex (MSH4/MSH5) that licences DNA double-strand break repair intermediates during meiosis.

In all sexually reproducing eukaryotes, only a subset of double-strand breaks are resolved as crossovers — the reciprocal exchanges between homologous chromosomes that are essential for accurate chromosome segregation and that generate heritable genetic diversity. The MutSγ complex licences sites for crossover repair, but a mismatch has long been noted in mammals: there are more MutSγ foci than the number of final crossovers marked by the downstream MutLγ complex (MLH1/MLH3), implying additional regulatory steps or functions.

Using mice engineered to lack the 38-amino-acid mammalian-specific C-terminal extension of MSH5, the authors provide genetic evidence that this domain is required for the normal transition from crossover licensing to designation — the committed step at which a licensed intermediate is directed into the class I crossover pathway. The findings suggest this domain may also influence how some intermediates are directed through the minor class II pathway.

The work is directly relevant to researchers in meiosis biology, reproductive genetics, and mammalian genomics. It is also of interest to educators and students studying recombination mechanisms and the evolution of meiotic machinery. The manuscript is a preprint and has not yet been peer-reviewed.