@misc{oai:ir.soken.ac.jp:00001206,
 author = {尾田, 真子 and オダ, マサコ and ODA, Masako},
 month = {2016-02-17},
 note = {Urate oxidase (Uox) and xanthine oxidoreductase (Xor) are purine metabolic enzymes.  It is known that the final product of purine metabolism has been altered from allantoin to uric acid due to loss of Uox activity during hominoid evolution.  I have focused on the Uox and Xor genes, which are directly involved in uric acid metabolism.  I have investigated molecular evolutionary changes of Uox and Xor genes, and their biological implical implications.<br />  Firstly, I have determined and compared the promoter, coding and intronic sequence of the Uox gene of various primate species.  Although I have confirmed the previous observation that inactivation of the gene in the clade of humans and great apes has resulted from a single CGA to TGA nonsense mutation in exon 2, l have found that the inactivation in the gibbon lineage has resulted from an independent nonsense mutation at a different CGA codon in exon 2, or from either one base deletion in exon 3 or one base insertion in exon 5.  This is contrary to a previous claim that suggests that the cause is a 13 bp deletion in exon 2.  I have also found that, compared to other organisims, the primate functional Uox gene is exceptional in terms of usage of CGA codons which are prone to TGA nonsense mutations.  Nevertheless, I have demonstrated a rather strong selective constraint against nonsynonymous sites of the functional Uox gene and argued that this observation is consistent with the fact that the Uox gene is unique in the genome and is evolutionarily conserved not only among animals but also among eukaryotes.  A further observation has indicated that there are a few substitutions in the cis-acting element or CAAT-box (or both) of primate functional Uox genes, which may explain the lowered transcriptional activity.  I have therefore suggested that although the inactivation of the hominoid Uox gene is caused by independent nonsense or frameshift mutations, the gene has taken a two-step deterioration process, firstly in the promoter region and secondly in the coding region during primate evolution.<br />  Secondly, I have examined molecular evolution of the Xor gene in relation to Uox inactivation.  It is known that Xor activity is lower in humans than in other mammals, including rats and mice.  The coding sequences (around 4 kb) of one human, six mammals and one chicken were retrieved from GenBank.  From these sequences I have examined lineage-specific amino acid substitutions and estimated the degree of functional constraints by the maximum parsimony method.  There are no amino acid substitutions that are responsible for the lowered Xor activity in hominoids.  I have therefore determined and analyzed the promoter sequences (around 900 bp to 3.7kb) of the Xor gene of one human, one chimpanzee, one pygmy chimpanzee, one gorilla, one orangutan, one white-handed gibbon, siamang, three Old World monkeys, New World monkeys, two prosimians, one tupaia and four other other mammals.  It is found that a promoter module of activator protein 1 (AP-1) and glucocorticoid receptor (GR), predicted by an in silico approach, is present in most of the hominoids examined but absent in other species.  The promoter module may render the X or gene down modulated by interacting AP-1 and GR.  In addition, I have found two independent substitutions caused by T to G transvergions in repressor elements of the Xor gene, an E-box with the consensus sequence GTTTC.  One substitution is in the white-handed gibbon lineage and the other is in the lineage leading to the great ape clade.  The presence of these repressor elements correlates well with reduced transcriptional activity of the Xor gene., 総研大甲第708号},
 title = {Molecular Coevolution of Urate Oxidase (Uox) and Xanthine Oxidoreductase (Xor) Genes and Its Biiological Implications},
 year = {}
}