"Point mutations" are small changes in the sequence of DNAbases within a gene. These are what are most commonly meant by the word "mutation." Point mutations include substitutions, insertions, and deletions of one or more bases.
If one base is replaced by another, the mutation is called a base substitution. Because the DNA is double-stranded, a change on one strand is always accompanied by a change on the other (this change may occur spontaneously during DNA replication, or it can be created by errors during DNA repair. Consequently, it is often difficult to know which base of the pair was mutated and which was simply the result of repairing the mismatch at the mutation.
For example, the most common mutation in mammalian cells is the substitution of a G-C pair with an A-T pair. This could arise if G is replaced by A and subsequently the A is replicated to give T on the other strand. Alternatively, the C could be replaced by a T and the T could then be replicated to give an A on the complementary strand, the final result being the same. It is believed that the G-C to A-T conversion most commonly begins with a C-to-T mutation. This is because most of these mutations occur at DNA sequences in which C is methylated (i.e., chemically modified by the addition of a-CH3 group). The methylated form of C can be converted to a base that resembles T (and thus pairs with A) by removal of an-NH2 group (deamination)—a relatively common event.
Base substitution mutations are classified as transitions or transversions. Transitions are mutations in which one pyrimidine (C or T) is substituted by the other and one purine (G or A) is substituted on the complementary strand. The G-C to A-T conversion is a transition mutation, since C becomes T.
Transversions are mutations in which a purine is replaced by a pyrimidine or vice versa. Sickle cell anemia is caused by a transversion: T is substituted for A in the gene for a hemoglobin subunit. This mutation has arisen numerous times in human evolution. It causes a single amino acid change, from glutamic acid to valine, in the β subunit of hemoglobin. Sickle cell anemia was the first genetic condition for which the change in the protein was demonstrated in 1954 by Linus Pauling (a Nobel laureate from the California Institute of Technology) and subsequently shown to be a single amino acid difference by Vernon Ingram (a Nobel laureate from the Massachusetts Institute of Technology).
Base substitutions are sometimes silent mutations—mutations that do not change the amino acid sequence in the protein encoded by the gene. Silent mutations are possible because the original and mutated sequences can code for the same amino acid, given the redundancy of the genetic code. In the divergence between sea urchins and humans, for example, one of the histone proteins has only two amino acid substitutions, although the gene has many base pair substitutions. Histones are proteins around which DNA is wrapped in chromosomes. The very close similarity in sequence between such distantly related organisms is an indication of how critical the structure is for the function: Most mutations that change it are very disadvantageous.
One type of substitution mutation that almost always inactivates the gene is mutation to a stop codon. A stop codon ends the assembly of the protein, and a truncated protein is usually not active biochemically. Many recessive genetic diseases occur when a mutation converts a coding triplet to a stop codon.
Other mutations involve the insertion or deletion of one or more base pairs in the DNA. When they occur in genes, such mutations typically inactivate the encoded protein, because they change the "reading frame" of the gene. The DNA sequence is translated in groups of three nucleotides. Insertion or deletion of a nucleotide changes the sets of triplets, and thus every subsequent amino acid is altered, changing the protein completely, as shown in Figure 2. Stop codons also frequently arise from insertions or deletions.
Naturally occurring trinucleotide repeat sequences (e.g., CAGCAG CAGCAG) are hot spots for certain important human mutations that involve the insertion of more copies of the repeated sequence. For example at the locus for Huntington's disease, a sequence of 10-29 copies of CAG is normal and stable, but if there are 30-38, there is a high rate of mutation to increased numbers of copies, and if there are 39 or more copies, middle-age dementia called Huntington's disease results.
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