A missense mutation in FBXL3 links circadian regulation to out-of-season estrus in sheep

Seasonal breeding is a remarkable adaptive trait, but it constrains efficient production in the sheep industry. Recent studies have shown that seasonal breeding is associated with endogenous circannual rhythms, which are regulated in part by the circadian clock system. FBXL3, a pivotal component of the SCF (SKP1 – CUL1 – F-box) E3 ubiquitin ligase complex, is a known determinant of the mammalian circadian period. In this study, we identified a missense mutation, T183M, in FBXL3 through selective sweep analysis. The allele frequency of this mutation differed significantly between sheep breeds exhibiting year-round estrus and those showing seasonal breeding patterns. The association between the T183M mutation and seasonal breeding was further validated using an ovariectomized, estradiol-implanted sheep model. We then generated mice carrying the homologous T183M mutation and found that they exhibited significantly lengthened circadian periods, accompanied by reduced CRY1 expression and increased CLOCK expression. Co-immunoprecipitation assays confirmed that the mutation reduced the interaction between FBXL3 and CRY1. These findings demonstrate an evolutionarily conserved role of FBXL3 in the circadian clock system. We propose that the T183M mutation disrupts day-length recognition, thereby influencing seasonal estrus in sheep.