The evolutionary fate of the genes encoding the purine catabolic enzymes in hominoids, birds, and reptiles

Abstract

Gene loss has been proposed to play a major role in adaptive evolution, and recent studies are beginning to reveal its importance in human evolution. However, the potential consequence of a single gene-loss event upon the fates of functionally interrelated genes is poorly understood. Here, we use the purine metabolic pathway as a model system in which to explore this important question. The loss of urate oxidase (UOX) activity, a necessary step in this pathway, has occurred independently in the hominoid and bird/reptile lineages. Because the loss of UOX would have removed the functional constraint upon downstream genes in this pathway, these downstream genes are generally assumed to have subsequently deteriorated. In this study, we used a comparative genomics approach to empirically determine the fate of UOX itself and the downstream genes in five hominoids, two birds, and a reptile. Although we found that the loss of UOX likely triggered the genetic deterioration of the immediate downstream genes in the hominoids, surprisingly in the birds and reptiles, the UOX locus itself and some of the downstream genes were present in the genome and predicted to encode proteins. To account for the variable pattern of gene retention and loss after the inactivation of UOX, we hypothesize that although gene loss is a common fate for genes that have been rendered obsolete due to the upstream loss of an enzyme a metabolic pathway, it is also possible that same lack of constraint will foster the evolution of new functions or allow the optimization of preexisting alternative functions in the downstream genes, thereby resulting in gene retention. Thus, adaptive single-gene losses have the potential to influence the long-term evolutionary fate of functionally interrelated genes.

FIG. 1.

The purine catabolic pathway. The substrates, products, and enzymes of UOX and downstream enzymes in the vertebrate purine catabolic pathway. UOX (substrate uric acid), HIU hydrolase (EC 3.5.2.17, substrate HIU), OHCU decarboxylase (EC 4.1.1.–, substrate OHCU), ALLN (EC 3.5.2.5; substrate is allantoin), ALLC (EC 3.5.3.4; substrate is allantoate and products are ureidoglycolate and urea).

FIG. 2.

Gene content of the purine catabolic pathway in vertebrates. The tree on the left represents the accepted vertebrate phylogeny with divergence dates (Ma) (Kumar and Hedges 1998). The species included in each category are teleosts (stickleback, fugu and tetraodon, and zebrafish), an amphibian (Xenopus), a reptile (Anolis lizard), two birds (chicken and zebra finch), and placental mammals, including the hominoids (gibbon, gorilla, orangutan, human, and chimpanzee) and other placental mammals (mouse, rat, dog, and cow). The gene content and classification of the purine catabolic pathway for each group of species is summarized on the right. Genes were defined as having an open-reading frame, were evolving under purifying selection, and had a conserved intron/exon structure. Predicted pseudogenes were identified by protein-coding sequences interrupted by truncating mutations and/or a K_a/K_s not significantly different than 1. Note that in the case of the marmoset ALLC gene, two potential frameshift mutations were used to classify it as a predicted pseudogene. When no ortholog could be identified, the gene was classified as absent. “*” Indicates the hominoid branches and “**” the birds and reptile branches used to calculate the K_a/K_s for those clades (see Materials and Methods).

FIG. 3.

Intron–exon structure of the UOX gene. The intron–exon structures of UOX along with the neighboring DNASE2B gene and supporting ESTs and partial mRNAs are shown relative to their chromosomal locations for mouse (chr3:146244338–146294447, mm9) (A), zebra finch (chr8:13247864-13271492, taeGut1) (B), and Anolis lizard (scaffold_16:5170254-5205217, anoCar1) (C). Boxes indicate the location of exons and arrows indicate the direction of transcription for each gene. ESTs are labeled with their GenBank accession number. Note the differences in scale between the panels.