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

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Conservative evolution in duplicated genes of the primate Class I ADH clusterIntroductionMaterials and methodsNomenclatureSample DNAsPrimer design for PCR and direct sequencingPublished data for analysesAlignments and phylogenetic analysesKc, dN and dS estimationResultsNucleotide sequence diversityPhylogenetic topology and rootingShared-site distributionNucleotide sequence difference comparisons in exonsDiscussionAcknowledgmentsSupplementary dataReferencesConservative evolution in duplicated genes of theprimate Class I ADH clusterHiroki Ootaa,⁎, Casey W. Dunnb,1, William C. Speeda, Andrew J. Pakstisa, Meg A. Palmatiera,Judith R. Kidda, Kenneth K. Kidda,b,⁎aDepartment of Genetics, Yale University School of Medicine, 333 Cedar St., New Haven, CT, USAbDepartment of Ecology and Evolutionary Biology, Yale University, 165 Prospect St., New Haven, CT, USAReceived 19 July 2006; received in revised form 11 November 2006; accepted 15 November 2006Received by J.G. ZhangAvailable online 23 November 2006AbstractHumans have seven alcohol dehydrogenase genes (ADH) falling into five classes. Three out of the seven genes (ADH1A, ADH1B and ADH1C)belonging to Class I are expressed primarily in liver and code the main enzymes catalyzing ethanol oxidization. The three genes are tandemly arrayedwithin the ADH cluster on chromosome 4 and have very high nucleotide similarity to each other (exons: N 90%; introns: N 70%), suggesting the geneshave been generated by duplication event(s). One explanation for maintaining similarity of such clustered genes is homogenization via geneconversion(s). Alternatively, recency of the duplications or some other functional constraints might explain the high similarities among the genes. Totest for gene conversion, we sequenced introns 2, 3, and 8 of all three Class I genes (total N 15.0 kb) for five non-human primates – four great apes andone Old World Monkey (OWM) – and compared them with those of humans. The phylogenetic analysis shows each intron sequence clusters stronglywithin each gene, giving no evidence for gene conversion(s). Several lines of evidence indicate that the first split was between ADH1C and the genethat gave rise to ADH1A and ADH1B. We also analyzed cDNA sequences of the three genes that have been previously reported in mouse andCatarrhines (OWMs, chimpanzee, and humans) and found that the synonymous and non-synonymous substitution (dN/dS) ratios in all pairs are lessthan 1 representing purifying selection. This suggests that purifying selection is more important than gene conversion(s) in maintaining the overallsequence similarity among the Class I genes. We speculate that the highly conserved sequences on the three duplicated genes in primates have beenachieved essentially by maintaining stability of the hetero-dimer formation that might have been related to dietary adaptation in primate evolution.© 2006 Elsevier B.V. All rights reserved.Keywords: Gene duplication; Gene conversion; ADH; Primates; Negative selection; Coenzyme binding domain1. IntroductionThe alcohol dehydrogenase (ADH) family exists widely inthe genomes of bacteria, insects, plants, and vertebrates(Guagliardi et al., 1996; Fischer and Maniatis, 1985; Martinezet al., 1996; Barth and Kunkel, 1979; Canestro et al., 2000;Reimers et al., 2004). All ADH classes form dimers andcatalyze oxidization of various kinds and concentrations ofalcohols using NAD+/NADH as coenzyme (Eklund et al.,1976a,b; Höög et al., 2001 ). The ADH family is classified intofive classes (I–V) based on biochemical properties, andnucleotide/amino acid sequence similarity. Humans have threeClass I ADH genes and one each of Classes II–V(Matsuo andYokoyama, 1989; Duester et al., 1986; Yokoyama et al., 1992;von Bahr-Lindstrom et al., 1991; Hur and Edenberg, 1992;Gene 392 (2007) 64 – 76www.elsevier.com/locate/geneAbbreviations: ADH, alcohol dehydrogenase; OWM, Old World Monkey;kb, kilo base pair(s); NWM, New World Monkey; bp, base pairs; cDNA, DNAcomplementary to RNA; dN/dS, synonymous and non-synonymous substitutionratio; Kc, nucleotide sequence difference; BAC, bacterial artificial chromosome;PCR, polymerase chain reaction; np, nucleotide position; MP, maximumparsimony; ML, maximum likelihood; NJ, neighbour joining; ILD, incongru-ence length difference; Has, Homo sapiens; Ptr, Pan troglodytes; Ppa, Panpaniscus; Ggo, Gorilla gorilla; Ppy, Pongo pygmaeus; Pap, Papio anubis;MyBP, million years before present; Fst, fixation index; qter, the long arm telomere;cen, the centromere.⁎Corresponding authors. Oota, is to be contacted at Graduate School of FrontierSciences, University of Tokyo, 5-1-5 Kashiwanoha, Seimeitou 502, Kashiwa,Chiba 277-8562, Japan. Tel.: +81 4 7136 5421; fax: +81 4 7136 6713. Kidd,Department of Genetics, Yale University School of Medicine, 333 Cedar St., NewHaven, CT 06520-8005, USA. Tel.: +1 203 785 2653; fax: +1 203 785 6568.E-mail addresses: [email protected] (H. Oota),[email protected] (K.K. Kidd).1Current address: PBRC University of Hawaii, 41 Ahui St., Honolulu, USA.0378-1119/$ - see front matter © 2006 Elsevier B.V. All rights reserved.doi:10.1016/j.gene.2006.11.008Yasunami et al., 1991; Satre et al., 1994); all ADH genes clusteron chromosome 4 (4q21–23) in tandem extending N 380 kb(International Human Genome Sequencing Consortium, 2001;Kent et al., 2002)(Fig. 1). The high similarity among sevenADH cDNA sequences (60–90%) suggests that those geneshave been generated by multip le duplications.The Class I ADH genes have been the best studied in theADH family, because all three Class I enzymes (ADH1A,ADH1B, ADH1C) of humans are expressed primarily in liver,catalyzing the oxidation of ethanol to acetaldehyde, and thevariants of the enzymes have been shown to be associated withprotection against alco holism (Osier et al., 1999, 2002;Edenberg, 2000). The human Class I ADH gene cluster spans80 kb in the physical order of qter-ADH1C–ADH1B–ADH1A-cen (Yasunami et al., 1990a,b), and the three genes are similar toeach other not only in the exon–intron structure (Fig. 1) but alsoin the nucleotide sequences of both the exons (N 90%) and theintrons (N 70%) (Matsuo and Yokoyama, 1989; Duester et al.,1986; Yokoyama et al., 1992). This leaves an importantquestion: what mechanism has led to the high degree ofconservation in the three Class I genes in the primate lineage?The currently favored explanation is homogenization via geneconversion(s) among the three genes. Cheung


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