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Unformatted text preview: Estimation of the Number of Nucleotide Substitutions in the Control Region of Mitochondrial DNA in Humans and Chimpanzees ’ Koichiro Tamura and Masatoshi Nei Department of Biology and Institute State University of Molecular Evolutionary Genetics, The Pennsylvania Examining the pattern of nucleotide substitution for the control region of mitochondrial DNA ( mtDNA ) in humans and chimpanzees, we developed a new mathematical method for estimating the number of transitional and transversional substitutions per site, as well as the total number of nucleotide substitutions. In this method, excess transitions, unequal nucleotide frequencies, and variation of substitution rate among different sites are all taken into account. Application of this method to human and chimpanzee data suggested that the transition / transversion ratio for the entire control region was - 15 and nearly the same for the two species. The 95% confidence interval of the age of the common ancestral mtDNA was estimated to be 80,000-480,000 years in humans and 0.57-2.72 Myr in common chimpanzees. Introduction The control region of mitochondrial DNA (mtDNA) in humans and apes is known to evolve very rapidly, and for this reason a number of authors (e.g., Horai and Hayasaka 1990; Vigilant et al. 199 1; Ward et al. 199 1) have used this region to study various problems of human evolution. However, the pattern of nucleotide substitution in this region is quite complicated; the ratio of transitional to transversional nucleotide substitutions is very high (Brown et al. 1982; Aquadro and Greenberg 1983)) and the rate of nucleotide substitution (h) varies extensively among different sites ( Kocher and Wilson 199 1) . Furthermore, the transitional changes between purines and between pyrimidines do not occur with equal frequency, as will be seen later. Therefore, it is necessary to develop an appropriate mathematical method to use this region of mtDNA for the study of human evolution. The main purpose of this paper is to develop a mathematical method to estimate the number of nucleotide substitutions between sequences. However, before developing the mathematical method, we first investigate the pattern of nucleotide substitution in the control region of mtDNA in humans. We shall also apply the mathematical formula developed for estimating the number of nucleotide substitutions between humans and chimpanzees, as well as for the age of the common ancestral mtDNA in humans and chimpanzees. 1. Key words: mtDNA evolution, chimpanzees. control region, nucleotide substitutions, transition / transversion bias, human Address for correspondence and reprints: and Department of Biology, The Pennsylvania Pennsylvania 16802. Masatoshi Nei, Institute of Molecular Evolutionary Genetics State University, 328 Mueller Laboratory, University Park, M ol. Biol. Evol. 10(3):5 12-526. 1993. 0 1993 by The University of Chicago. All rights reserved. 0131~4038/93/1003-0002$02.00 512 Nucleotide Substitution in mtDNA 5 13 Pattern of Nucleotide Substitution Vigilant et al. ( 199 1) sequenced the control region of mtDNA for 135 humans sampled from around the world. Although the control region is highly variable at the sequence level, this variation is mainly confined to the hypervariable segments on the 5’ and 3’ sides of the control region ( -630 nucleotide sites), and the central portion shows virtually no variation among human sequences. Vigilant et al. ( 199 1) therefore did not sequence the central portion, except for 20 individuals. Furthermore, some sequences included unidentified nucleotides even in the hypervariable segments. We therefore used 95 sequences in which nucleotides are known for 625 sites....
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