An Ancient Mutation in the TPH1 Gene is Consistent with the Changes in Mammalian Reproductive Rhythm

The reproductive rhythm undergoes several changes during the evolution of mammals to adapt to local environmental changes. Although the critical roles of melatonin (MLT) in the formation of reproductive rhythm have been well established, the genetic basis for the changes of reproductive rhythm remains uncertain. Here, we constructed the phylogenetic trees of 13 melatonin synthesis, metabolism and receptor genes, estimated their divergence times, and calculated their selection pressures. Then, we evaluated the effect of positively selected and functionally related mutations on protein activity. Our results showed that there were significant positive selection sites in the three major genes, including tryptophan hydroxylase 1 (TPH1), tryptophan hydroxylase 2 (TPH2) and indoleamine-2,3-dioxygenase 1 (IDO1) that are involved in melatonin synthesis, metabolism and function. At the protein level, amino acids at the 442nd site of TPH1 protein and the 194th, 286th, 315th and 404th sites of IDO1 protein were under positive selection, and the variants of the amino acid in these sites might lead to the changes in protein function. Remarkably, the 442nd site of these positive selection sites is in the tetramerization domain of TPH1 protein, and it is proline or leucine. At this site, 89.5% of the amino acid of non-seasonal reproducing mammals was proline, while that of 88.9% of seasonal reproducing mammals was leucine. This variation of the amino acid was derived from the T/C polymorphism at the 1325th site of the TPH1 gene coding sequence, which significantly altered the TPH1 activity (p < 0.01). Interestingly, the predicted age of the allele C in the mammalian genome appeared about 126.6 million years ago, and allele T appeared about 212.6 million years ago, indicating that the evolution of the TPH1 gene was affected by the two mammalian split events and the K-T extinction event. In conclusion, the T/C polymorphism at the 1325th site in the TPH1 gene coding sequence altered TPH1 activity, suggesting that this polymorphism is consistent with the reproductive rhythm of mammals.