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Abstract
Ten-eleven translocation (TET) proteins, a family of Fe2+- and 2-oxoglutarate-dependent dioxygenases, are involved in DNA demethylation. They also help regulate various cellular functions. Three TET paralogs have been identified (TET1, TET2, and TET3) in humans. This study focuses on the evolution of mammalian TET genes. Distinct patterns in TET1 and TET2 vs. TET3 were revealed by codon-based tests of positive selection. Results indicate that TET1 and TET2 genes have experienced positive selection more frequently than TET3 gene, and that the majority of codon sites evolved under strong negative selection. These findings imply that the selective pressure on TET3 may have been relaxed in several lineages during the course of evolution. Our analysis of convergent amino acid substitutions also supports the different evolutionary dynamics among TET gene subfamily members. All of the five amino acid sites that are inferred to have evolved under positive selection in the catalytic domain of TET2 are localized at the protein’s outer surface. The adaptive changes of these positively selected amino acid sites could be associated with dynamic interactions between other TET-interacting proteins, and positive selection thus appears to shift the regulatory scheme of TET enzyme function.
Highlights
DNA methylation, an important epigenetic mark of cytosine bases associated with transcriptional regulation, is known to play a crucial role in various cellular phenomena, including gametogenesis, embryonic development, and genomic imprinting [1,2]
The wide distribution of TET1, TET2 and TET3 genes in the variety of mammalian species suggests that the Ten-eleven translocation (TET) genes underwent two successive duplications before mammalian diversification [4,7]
In the case of TET3, these relationships were noticeable, we observed extremely lower divergence probabilities and somewhat higher convergence probabilities compared to TET1 and TET2. These results suggest that TET3 experienced different evolutionary dynamics during mammalian evolution
Summary
DNA methylation, an important epigenetic mark of cytosine bases associated with transcriptional regulation, is known to play a crucial role in various cellular phenomena, including gametogenesis, embryonic development, and genomic imprinting [1,2]. The enzymatic processes of DNA methylation and demethylation are mediated by various specific enzymes such as DNA methyl transferases and dioxygenases, which catalyze methyl transfer or oxidative modification of bases in DNA [3,4]. The regulation of these enzymatic reactions is thought to be critical in many biological processes [5,6]. Ten-eleven translocation (TET) proteins are Fe2+- and 2-oxoglutarate-dependent dioxygenases. Their name “TET” reflects the ten-eleven translocation (t(10;11)(q22;q23)) that is observed in chromosomes of patients with acute myeloid leukemia or lymphocytic leukemia [7]. Several reports have demonstrated that TET proteins are able to catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC)
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