Origin and Frequency of Different Types of Mutations

Figure 4-4 Examples of mutations in a portion of a hypothetical gene with five codons shown (delimited by the dotted lines). The first base pair of the second codon in the reference sequence (shaded in blue) is mutated by a base substitution, deletion, or insertion. The base substitution of a G for the T at this position leads to a codon change (shaded in green) and, assuming that the upper strand is the sense or coding strand, a predicted nonsynonymous change from a serine to an alanine in the encoded protein (see genetic code in Table 3-1); all other codons remain unchanged. Both the single base pair deletion and insertion lead to a frameshift mutation in which the translational reading frame is altered for all subsequent codons (shaded in green), until a termination codon is reached.

DNA Replication Errors

Repair of DNA Damage

A particularly common spontaneous mutation is the substitution of T for C (or A for G on the other strand). The explanation for this observation comes from considering the major form of epigenetic modification in the human genome, DNA methylation, introduced in Chapter 3. Spontaneous deamination of 5-methylcytosine to thymidine (compare the structures of cytosine and thymine in Fig. 2-2) in the CpG doublet gives rise to C to T or G to A mutations (depending on which strand the 5-methylcytosine is deaminated). Such spontaneous mutations may not be recognized by the DNA repair machinery and thus become established in the genome after the next round of DNA replication. More than 30% of all single nucleotide substitutions are of this type, and they occur at a rate 25 times greater than those of any other single nucleotide mutations. Thus the CpG doublet represents a true “hot spot” for mutation in the human genome.

Overall Rate of DNA Mutations

As might be predicted, the vast majority of these mutations will be single nucleotide changes in noncoding portions of the genome and will probably have little or no functional significance. Nonetheless, at the level of populations, the potential collective impact of these new mutations on genes of medical importance should not be overlooked. In the United States, for example, with over 4 million live births each year, approximately 6 million new mutations will occur in coding sequences; thus, even for a single protein-coding gene of average size, we can anticipate several hundred newborns each year with a new mutation in the coding sequence of that gene.

Conceptually similar studies have determined the rate of mutations in CNVs, where the generation of a new length variant depends on recombination, rather than on errors in DNA synthesis to generate a new base pair. The measured rate of formation of new CNVs (≈1.2 × 10−2 per locus per generation) is orders of magnitude higher than that of base substitutions.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Origin and Frequency of Different Types of Mutations

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