A Functional SNP in the Promoter Region of Ovine IDO2 Associated With Melatonin Levels via Affecting Transcription Activity by

ABSTRACT

Sheep seasonal reproduction is regulated by photoperiod via melatonin. Indoleamine 2,3‐dioxygenase 2 (IDO2), an enzyme involved in tryptophan metabolism through the kynurenine pathway and belonging to the IDO family, may contribute to melatonin homeostasis, but its role in reproductive seasonality remains unclear. In this study, genome‐wide selection analyses combining Z ( F _ST ) and XP‐EHH between seasonal and non‐seasonal sheep identified a selection signature encompassing the IDO2 region and revealed g.−809T>C as a functional candidate variant within this region. Experiments employing electrophoretic mobility shift assay (EMSA) and luciferase assays revealed that this site lies within the CLOCK transcription factor binding domain. The −809C variant reduced promoter activity compared to −809T ( p  < 0.05). Sheep with the CC genotype had higher plasma melatonin levels than TC/TT counterparts ( p  < 0.05). These findings suggest that the g.−809C allele decreases IDO2 transcription by reducing CLOCK binding affinity, thereby potentially affecting IDO2 ‐associated tryptophan/melatonin metabolism and increasing melatonin levels, which may contribute to photoperiodic responses in sheep. This IDO2 variation provides new insights into the genetic regulation of melatonin‐mediated reproductive seasonality and represents a potential marker for genetic improvement of reproductive seasonal traits in sheep.