Point mutations in the protein-encoding DNA
If point mutations occur in the DNA protein-encoding section, it is possible and frequently useful to classify mutations according to their effect on the structure of that protein.Because of the degeneration of the genetic code, i.e. in relation to the fact that a single aminoacid is encoded by a number of various codons, i.e. nucleotide triplets, replacement of a nucleotide in the codon need not be manifested in the structure of the protein.These are termed synonymous (samesense) mutations.Mutations of this type, similar to most mutations in the area of introns or pseudogenes, i.e. in genes that have lost their functionality and are not rewritten in the cell and translated to proteins, are important in that they are invisible, neutral, from the standpoint of natural selection.However, in actual fact it was found that synonymous mutations are not neutral in the true sense of the word.It can be important for the organism whether a certain triplet-encoded aminoacid is translated by rare or common tRNA.In addition, synonymous mutations also affect the regulation of transcription of the given gene, the secondary structure of the synthesized RNA, its stability and the intensity of the translation.In drosophila, the average selection coefficient acting against mutation in the synonymous site has been estimated at s= 2,3/Ne, where Ne is the effective size of the population (Akashi 1995).In human beings, it has been estimated that approximately 3% of synonymous, 12% of nonsynonymous and 100% of nonsense mutations (see below) are detrimental.
Missense (nonsynonymous) mutations are mutations through which one aminoacid is replaced by a different one.If the aminoacid is replaced by an aminoacid with similar physical-chemical properties, then this is termed a conservative substitution.A conservative substitution need not substantially change the tertiary structure and biological function of the protein.The genetic code is arranged so that most aminoacid substitutions that can occur through mutation of a single nucleotide in the triplet are conservative.For example, 97% of transitions at the third position of the codon are synonymous and the remaining 3% lead to conservative substitutions.Of the less common transversions, 59% of those in the third position are synonymous (Wakeley 1996).It is not currently apparent whether this arrangement of the genetic code is a useful adaptation of organisms preventing drastic changes in the protein structure as a consequence of substitution mutations or whether this is only an indication of the way in which the evolution of the genetic code occurred (see X.3.3).The individual aminoacids differ very substantially in their degree of conservativeness.For example, during evolution in proteins, the aminoacid glycine is substituted by another aminoacid only very rarely, while, in contrast, asparagine is replaced far more frequently.Differences in the rates of evolution of the individual proteins can be explained to a considerable degree by various contents of conservative and nonconservative aminoacids.For example, the differences in the content of glycine alone can explain 39% of the total variability in the rate of development of 27 studied mammal proteins; if we take into account the content of 5 aminoacids with the greatest effect on the rate of evolution, then 73% of the variability can be explained (Graur 1985).
Another type of substitution mutation consists in nonsense mutations.In these mutations, one of the three termination codons is formed from the codon for the aminoacid, so that translation at this site leads to premature termination of synthesis of the protein chain.This is, of course, a drastic change in the protein structure, which mostly leads to the formation of a nonfunctional protein.
Drastic changes also occur through the effect of insertion ordeletion of a nucleotide.These changes, frameshift mutations, lead to a shift (disruption) of the reading frame so that a basically unaltered sequence of nucleotides is translated on the ribosome as a sequence of completely different triplets to a completely different sequence of aminoacids (Fig. III.1).In addition, the shift in the reading frame means that, sooner or later, a termination codon appears in the sequence of new codons, so that protein synthesis is prematurely terminated at the given site.