CODON USAGE IN HUMAN MITOCHONDRIAL GENES IN THE CONTEXT OF CANCER
Abstract
Objective: Mitochondria are the powerhouse of the cell. Mitochondrial DNA is more susceptible to oxidative damage due to the lack of histone protein and chromatin structure. The alteration in the level of gene expression in cytochrome c oxidase gene is associated with cancer. The expression of coxiii gene was found to be lower in human colonic carcinoma. However, a systematic analysis of codon usage in human mitochondrial protein-coding genes has not been reported yet. This study gives an insight into the understanding of the pattern of codon usage and expression in human mitochondrial genes.
Methods: We used a bioinformatics approach to analyse the codon usage parameters by using bioinformatics tools like an effective number of codons (ENC), codon adaptation index (CAI), relative synonymous codon usage (RSCU) etc.
Results: The comparison of codon usage pattern among different mitochondrial genes suggests that mitochondrial genes have a lower level of codon usage bias and high expression level. Highly significant positive correlation between ENC and GC3 (r=0.782**, p<0.01), nucleobases C and C3 (r=0.655*, p<0.05), GC and GC3 (r=0.690**, p<0.01) suggest that mutation pressure played an important role in codon usage bias. Highly significant positive correlation was found between ENC and CAI (r=0.762**, p<0.01). The over-represented codons are TCA, TCC, CTA, CTC, CAA, CGC, TGA, ATA, AAA, GTA, GCC, GAA and GGC while the under-represented codons are TCG, AGT, CTG, CCG, CAG, CGT, ACG, AAT, GTG, GAT, GGG and ATG.
Conclusion: Mutation pressure is found to play major roles in shaping the low bias in the protein-coding genes of human mitochondrial DNA, although codon usage bias is weak. The over-represented and under-represented codons are used to increase or decrease the expression level. In addition, codon usage bias has influenced the gene expression in human mitochondrial genes.
Keywords: Mitochondrial DNA, Synonymous codon usage bias, Gene expression
Downloads
References
Ikemura T. Correlation between the abundance of Escherichia coli transfer RNAs and the occurrence of the respective codons in its protein genes. J Mol Biol 1981;146:1-21.
Akashi H, Eyre-Walker A. Translational selection and molecular evolution. Curr Opin Genet Dev 1998;8:688-93.
Akashi H. Gene expression and molecular evolution. Curr Opin Genet Dev 2001;11:660-6.
Roth A, Anisimova M, Cannarozzi GM. Measuring codon usage bias. Codon evolution: mechanisms and models New York: Oxford University Press Inc; 2012. p. 189-17.
Sharp PM, Bailes E, Grocock RJ, Peden JF, Sockett RE. Variation in the strength of selected codon usage bias among bacteria. Nucleic Acids Res 2005;33:1141-53.
Bulmer M. Are codon usage patterns in unicellular organisms determined by selectionâ€mutation balance? J Evol Biol 1988;1:15-26.
Francino MP, Ochman H. Isochores result from mutation not selection. Nature 1999;400:30-1.
Powell JR, Moriyama EN. Evolution of codon usage bias in Drosophila. Proc Natl Acad Sci USA 1997;94:7784-90.
Plotkin JB, Kudla G. Synonymous but not the same: the causes and consequences of codon bias. Nat Rev Genet 2011;12:32-42.
Sharp PM, Emery LR, Zeng K. Forces that influence the evolution of codon bias. Philosophical Transactions of the Royal Society B: Bioll Sci 2010;365:1203-12.
Singh KK. Mitochondrial DNA mutations in aging, disease and cancer: Springer New York; 1998. p. 1-412.
Schatz G. The protein import system of mitochondria. J Biol Chem 1996;271:31763-6.
Warburn O, Dickens F. The metabolism of tumors. Am J Med Sci 1931;182:23.
Modica-Napolitano JS, Kulawiec M, Singh KK. Mitochondria and human cancer. Curr Mol Med 2007;7:121-31.
Sharp PM, Li WH. The codon adaptation index-a measure of directional synonymous codon usage bias, and its potential applications. Nucleic Acids Res 1987;15:1281-95.
Wright F. The ‘effective number of codons’ used in a gene. Gene 1990;87:23-9.
Butt AM, Nasrullah I, Tong Y. Genome-wide analysis of codon usage and influencing factors in chikungunya viruses. PloS One 2014;9:e90905. Doi: 10.1371/journal.pone.0090905. [Article in Press]
Carlini DB, Chen Y, Stephan W. The relationship between third-codon position nucleotide content, codon bias, mRNA secondary structure and gene expression in the drosophilid alcohol dehydrogenase genes Adh and Adhr. Genetics 2001;159:623-33.
Wei L, He J, Jia X, Qi Q, Liang Z, Zheng Hao, et al. Analysis of codon usage bias of mitochondrial genome in Bombyx mori and its relation to evolution. BMC Evol Biol 2014;14:262.
Behura SK, Severson DW. Comparative analysis of codon usage bias and codon context patterns between dipteran and hymenopteran sequenced genomes. PloS One 2012;7:e43111. Doi:10.1371/journal.pone.0043111. [Article in Press]
Sueoka N, Kawanishi Y. DNA G+C content of the third codon position and codon usage biases of human genes. Gene 2000;261:53-62.
Zhang Z, Dai W, Dai D. Synonymous codon usage in TTSuV2: analysis and comparison with TTSuV1. PloS One 2013;8:e81469. Doi: 10.1371/journal.pone.0081469. [Article in Press]
Shackelton LA, Parrish CR, Holmes EC. Evolutionary basis of codon usage and nucleotide composition bias in vertebrate DNA viruses. J Mol Evol 2006;62:551-63.