Evolution of class I alcohol dehydrogenase genes in catarrhine primates: gene conversion, substitution rates, and gene regulation

Abstract

The three class I alcohol dehydrogenases (ADHs) in humans comprise homo- and heterodimers of three subunits (alpha, beta, and gamma) with greater than 90% sequence identity. These are encoded by distinct genes (ADH1, ADH2, and ADH3, respectively) and are all expressed in the liver. In baboons, only the beta ADH subunit is expressed in liver. A second class I ADH is expressed in the kidney; we isolated, cloned, and sequenced the cDNA corresponding to this ADH and conclude that it is of the gamma ADH lineage. We also amplified and sequenced the 5' noncoding regions of all three class I baboon ADH genes and the rhesus monkey ADH1 gene and compared their nucleotide sequences with the corresponding human sequences. There is clear evidence that the evolution of these genes has been reticulate. At least three gene conversion events, affecting the coding and 3' noncoding regions of the genes, are inferred from compatibility and partition matrices and phylogenetic analysis of the sequences. Our estimation of the evolutionary history of these genes provides a framework for the investigation of relative substitution rates and functional variation among the sequences. Relative-rate tests, designed to account for the reticulate evolution of these genes, indicate no difference in substitution rate either between genes encoding different subunits or between human and Old World monkey lineages. The human and baboon gamma ADH sequences do not show clear differences at functionally important sites within the coding region, but they do differ at a number of sites in regions previously proposed to be regulatory sites for transcriptional control. This variation may explain the different patterns of gene expression in humans and baboons.

Conservative evolution in duplicated genes of the primate Class I ADH cluster

“…Here we present the data and explore the mechanisms that have maintained the high similarity of the Class I ADH paralogous genes in the primate lineage. We pay particular attention to gene conversion because of the conclusions of Cheung et al (1999); but we find no evidence of gene conversion.…”

“…To assess the argument of Cheung et al (1999), we chose introns 2 and 3 (5′ side) and intron 8 (3′ side) because the sizes of introns 2 and 3 are almost the same in each of the three genes, and the size of intron 2 and 3 combined is almost the same as that of intron 8 in humans (see Fig. 1).…”

“…In addition to the new sequence data, we also used the chimpanzee, bonobo, and gorilla ADH1A intron 2 sequences previously reported by Jensen-Seaman et al (2001), human, chimpanzee, mouse, and rat genomic sequences, and the human, baboon, rhesus macaque, and mouse cDNA sequences (Matsuo and Yokoyama, 1989;Duester et al, 1986;Yokoyama et al, 1992;Trezise et al, 1989;Cheung et al, 1999;Light et al, 1992;Edenberg et al, 1985) in the database. Since the chimpanzee cDNA has not been isolated, we superimposed the human exon sequences on the chimpanzee genome sequences from the whole genome sequencing and obtained the chimpanzee exon sequences.…”

“…The currently favored explanation is homogenization via gene conversion(s) among the three genes. Cheung et al (1999) compared the exons and the 5′ and 3′ flanking regions of the Class I ADH genes between humans and OWMs, and argued that multiple gene conversion(s) have occurred in the three genes. However, such similar exon sequences (N90%), sharing a very small number of nucleotide differences, provide little information about evolution among such close species.…”

Predicting Nuclear Gene Coalescence From Mitochondrial Data: The Three-Times Rule

“…Other than selection at nuclear loci, possible reasons for failure of the three-times rule to explain nuclear patterns include selection on mtDNA (Nachman et al 1996;Templeton 1996), differential introgression of nuclear versus mitochondrial genes between species (Avise 1994), and chimeric recombination between nuclear loci (Cheung et al 1999). In addition, if ancestral populations were much larger and more genetically diverse than the ones studied now, a significant fraction of the divergence between mtDNA clades might have arisen before species formation , and this will deflate the coalescence ratio estimate.…”