Sequence analysis of cDNAs for the human and bovine ATP synthase β subunit: mitochondrial DNA genes sustain seventeen times more mutations |
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Authors: | Douglas C Wallace Jianhong Ye S Nicolas Neckelmann Gurparkash Singh Keith A Webster Barry D Greenberg |
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Institution: | (1) Departments of Biochemistry, Pediatrics and Anthropology, Woodruff Memorial Building, Emory University Medical School, 30322 Atlanta, GA, USA;(2) Department of Medicine, Stanford University Medical Center and Veterans Administration Medical Center, 94305 Palo Alto, CA, USA;(3) California Biotechnology, Inc., 2450 Bayshore Parkway, 94043 Mountain View, CA, USA |
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Abstract: | We have cloned and sequenced human and bovine cDNAs for the subunit of the ATP synthase (ATP-synß), a nuclear DNA (nDNA) encoded oxidative phosphorylation (OXPHOS) gene. The two cDNAs were found to share 99% amino acid homology and 94% nucleotide homology. The evolutionary rate of ATPsynß was then compared with that of two mitochondrial DNA (mtDNA) ATP synthase genes (ATPase 6 and 8), seven other mtDNA OXPHOS genes, and a number of nuclear genes. The synonymous substitution rate for ATPsynß proved to be 1.9 × 10–9 substitutions per site per year (substitutions × site–1 × year–1) (SSY). This is less than 1/2 that of the average nDNA gene, 1/12 the rate of ATPase 6 and 8, and 1/17 the rate of the average mtDNA gene. The synonymous and replacement substitution rates were used to calculate a new parameter, the selective constraint ratio . This revealed that even the most variable mtDNA protein was more constrained than the average nDNA protein. Thus, the high substitution mutation rate and strong selective constraints of mammalian mtDNA proteins suggest that mtDNA mutations may result in a disproportionately large number of human hereditary diseases of OXPHOS. |
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Keywords: | ATP synthase " target="_blank">gif" alt="beta" align="MIDDLE" BORDER="0"> Selective constraint mtDNA Evolution |
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