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Single nucleotide mutations form the majority of genetic polymorphisms (single nucleotide polymorphisms, SNPs) in populations. When found in gene protein coding regions, SNPs can be synonymous, i.e., causing no change in the amino acid encoded, or non-synonymous, when the amino acid is altered.  Until the current decade, synonymous mutations were assumed to be neutral, with no effect on the protein or any other functions of the organism.  Sequencing a vast array of genomes has revealed surprisingly, that many synonymous mutations were causing dysfunctions and illnesses in plants and animals. Synonymous mutations may lead to changes in protein folding related to translation pausing, RNA splicing, and alterations in enzyme specificity.

All current GM crops use protein coding genes from bacteria that have been  altered by introducing synonymous  codons, replacing plant-preferred codons for the  bacterial codons in order to enhance the production of protein from the transgenes. However, the toxicity of the transgenic proteins in animals and humans was not studied. Instead the original proteins produced in bacteria were used as surrogates in feeding trials.  The synonymous codons were assumed to be neutral and to have no effect on the transgenic proteins, and presumed to be safe (Bt Toxins in Genetically Modified Crops: Regulation by Deceit, SiS 22).

The genetic code is made up of 64 three letter codons (code words) for twenty amino acids (61 codons) plus words for translation start and stop. The number of code words for amino acid varies from one for methionine and tryptophan to six for arginine, leucine, and serine. The first two positions of the codon are fixed for a particular amino acid while the third position is said to ‘wobble’, allowing for alternate code letters, hence two or more codons for most amino acids. The frequency with which different codons are used varies between groups of organisms; so for example, genes from bacteria are poorly read in higher plants and vice versa.  For optimum expression, the code for a transgene frequently needs to be rewritten. The codon bias characteristic of each group of organisms is believed to be caused by the presence of distinct transfer RNA families in the different groups of organisms. In synthesizing transgenes for GM crops, say, a Bacillus thuringiensis (Bt) cry toxin gene, a table of plant preferred codons is used to substitute for the bacterial codons. Sometimes, it is necessary to substitute one or more of the amino acids (non-synonomously) so that the final cry toxin can function in the plant cell environment. As plant genetic engineering has “advanced” the crucial active domains of toxins, and enzyme are “improved” to such an extent that the gene for the original source protein is hardly recognizable.

There are many examples of synonymous mutations that are not neutral.  Synonymous mutations may lead to ribosome stalling, thereby changing protein folding pathways affecting enzyme activity or antigenicity. Synonymous mutations  in  the HIV gene Rev enhance HIV-1 replication,  providing resistance to the drug enfuvirtide. Synonymous codons in the oncogenes of the rabbit papillomavirus increased oncogenicity and immunogenicity. A single synonymous mutation was sufficient to alter the substrate specificity of a multidrug resistance phenotype in mammalian cells. Synonymous mutations affect the stability of mRNA secondary structure in mammals.