Codon usage in vertebrates is associated with a low risk of acquiring nonsense mutations
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Schmid and Flegel Journal of Translational Medicine 2011, 9:87 http://www.translational-medicine.com/content/9/1/87 (8 June 2011)
Schmid and Flegel Journal of Translational Medicine 2011, 9:87 http://www.translational-medicine.com/content/9/1/87
RESEARCH
Open Access
Codon usage in vertebrates is associated with a low risk of acquiring nonsense mutations Pirmin Schmid and Willy A Flegel*
Abstract Background: Codon usage in genomes is biased towards specific subsets of codons. Codon usage bias affects translational speed and accuracy, and it is associated with the tRNA levels and the GC content of the genome. Spontaneous mutations drive genomes to a low GC content. Active cellular processes are needed to maintain a high GC content, which influences the codon usage of a species. Loss-of-function mutations, such as nonsense mutations, are the molecular basis of many recessive alleles, which can greatly affect the genome of an organism and are the cause of many genetic diseases in humans. Methods: We developed an event based model to calculate the risk of acquiring nonsense mutations in coding sequences. Complete coding sequences and genomes of 40 eukaryotes were analyzed for GC and CpG content, codon usage, and the associated risk of acquiring nonsense mutations. We included one species per genus for all eukaryotes with available reference sequence. Results: We discovered that the codon usage bias detected in genomes of high GC content decreases the risk of acquiring nonsense mutations (Pearson’s r = -0.95; P < 0.0001). In the genomes of all examined vertebrates, including humans, this risk was lower than expected (0.93 ± 0.02; mean ± SD) and lower than the risk in genomes of non-vertebrates (1.02 ± 0.13; P = 0.019). Conclusions: While the maintenance of a high GC content is energetically costly, it is associated with a codon usage bias harboring a low risk of acquiring nonsense mutations. The reduced exposure to this risk may contribute to the fitness of vertebrates.
Background Codon usage bias in genomes is relevant for organisms. It influences the translation speed and thus gene expression [1]. Artificially deoptimized codon usage can decrease gene expression and create an attenuated viral virulence that may be used for vaccine production [2]. HIV-1 modifies the tRNA pool of the infected cells to increase translation efficiency of its own genes [3]. Initial studies on codon usage bias were based on few genes in single species: lists of the codon usage [4], determination of the number of codons used in genes [5], and models, such as the codon adaptation index (CAI). The CAI compared the codon usage of each gene with an “optimal” codon usage, which is inferred from high-expression gene sets [6]. Whole genome sequencing data and newer algorithms have allowed * Correspondence: [email protected] National Institutes of Health, Clinical Center, Bethesda, MD, USA
researchers to overcome previous limitations, study more genes, and classify genes in more detailed categories [7]. Codon usage bias is associated with t
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