Oota Hiroki, Dunn Casey W, Speed William C, Pakstis Andrew J, Palmatier Meg A, Kidd Judith R, Kidd Kenneth K
Department of Genetics, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520-8005, USA.
Gene. 2007 May 1;392(1-2):64-76. doi: 10.1016/j.gene.2006.11.008. Epub 2006 Nov 23.
Humans 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 arrayed within the ADH cluster on chromosome 4 and have very high nucleotide similarity to each other (exons: >90%; introns: >70%), suggesting the genes have been generated by duplication event(s). One explanation for maintaining similarity of such clustered genes is homogenization via gene conversion(s). Alternatively, recency of the duplications or some other functional constraints might explain the high similarities among the genes. To test for gene conversion, we sequenced introns 2, 3, and 8 of all three Class I genes (total>15.0 kb) for five non-human primates--four great apes and one Old World Monkey (OWM)--and compared them with those of humans. The phylogenetic analysis shows each intron sequence clusters strongly within each gene, giving no evidence for gene conversion(s). Several lines of evidence indicate that the first split was between ADH1C and the gene that gave rise to ADH1A and ADH1B. We also analyzed cDNA sequences of the three genes that have been previously reported in mouse and Catarrhines (OWMs, chimpanzee, and humans) and found that the synonymous and non-synonymous substitution (dN/dS) ratios in all pairs are less than 1 representing purifying selection. This suggests that purifying selection is more important than gene conversion(s) in maintaining the overall sequence similarity among the Class I genes. We speculate that the highly conserved sequences on the three duplicated genes in primates have been achieved essentially by maintaining stability of the hetero-dimer formation that might have been related to dietary adaptation in primate evolution.
人类有七个酒精脱氢酶基因（ADH），分为五类。属于第一类的七个基因中的三个（ADH1A、ADH1B和ADH1C）主要在肝脏中表达，并编码催化乙醇氧化的主要酶。这三个基因在4号染色体上的ADH簇中串联排列，彼此之间具有非常高的核苷酸相似性（外显子：>90%；内含子：>70%），表明这些基因是通过重复事件产生的。维持此类成簇基因相似性的一种解释是通过基因转换实现同质化。或者，重复事件的近期性或其他一些功能限制可能解释了这些基因之间的高度相似性。为了测试基因转换，我们对五只非人类灵长类动物——四只大猩猩和一只旧世界猴（OWM）——的所有三个第一类基因的内含子2、3和8进行了测序（总计>15.0 kb），并将它们与人类的进行了比较。系统发育分析表明，每个内含子序列在每个基因内强烈聚类，没有证据表明发生了基因转换。几条证据表明，第一次分裂发生在ADH1C与产生ADH1A和ADH1B的基因之间。我们还分析了先前在小鼠和狭鼻猴类（OWM、黑猩猩和人类）中报道的这三个基因的cDNA序列，发现所有基因对中的同义替换和非同义替换（dN/dS）比率均小于1，代表纯化选择。这表明在维持第一类基因之间的整体序列相似性方面，纯化选择比基因转换更重要。我们推测，灵长类动物中这三个重复基因上的高度保守序列基本上是通过维持异二聚体形成的稳定性而实现的，这可能与灵长类动物进化中的饮食适应有关。
