Mutations arise from changes to the DNA of a gene. These changes can be quite small, affecting only one nucleotide pair, or they can be relatively large, affecting hundreds or thousands of nucleotides. Mutations in which one base is changed are called point mutations—for example, substitution of the nucleotide pair AT by GC, CG, or TA. Base substitutions can have different consequences at the protein level. Some base substitutions are “silent,” meaning that they result in a new codon that codes for the same amino acid as the wild type codon at that position or a codon that codes for a different amino acid that happens to have the same properties as those in the wild type. Substitutions that result in a functionally different amino acid are called “missense” mutations; these can lead to alteration or loss of protein function. A more severe type of base substitution, called a “nonsense” mutation, results in a stop codon in a position where there was not one before, which causes the premature termination of protein synthesis and, more than likely, a complete loss of function in the finished protein.

Another type of point mutation that can lead to drastic loss of function is a frameshift mutation, the addition or deletion of one or more DNA bases. In a protein-coding gene, the sequence of codons starting with AUG and ending with a termination codon is called the reading frame. If a nucleotide pair is added to or subtracted from this sequence, the reading frame from that point will be shifted by one nucleotide pair, and all of the codons downstream will be altered. The result will be a protein whose first section (before the mutational site) is that of the wild type amino acid sequence, followed by a tail of functionally meaningless amino acids. Large deletions of many codons will not only remove amino acids from a protein but may also result in a frameshift mutation if the number of nucleotides deleted is not a multiple of three. Likewise, an insertion of a block of nucleotides will add amino acids to a protein and perhaps also have a frameshift effect.

A number of human diseases are caused by the expansion of a trinucleotide pair repeat. For example, fragile-X syndrome, the most common type of inherited mental retardation in humans, is caused by the repetition of up to 1,000 copies of a CGG repeat in a gene on the X chromosome.

The impact of a mutation depends upon the type of cell involved. In a haploid cell, any mutant allele will most likely be expressed in the phenotype of that cell. In a diploid cell, a dominant mutation will be expressed over the wild type allele, but a recessive mutation will remain masked by the wild type. If recessive mutations occur in both members of one gene pair in the same cell, the mutant phenotype will be expressed. Mutations in germinal cells (i.e., reproductive cells) may be passed on to successive generations. However, mutations in somatic (body) cells will exert their effect only on that individual and will not be passed on to progeny.

The impact of an expressed somatic mutation depends upon which gene has been mutated. In most cases, the somatic cell with the mutation will die, an event that is generally of little consequence in a multicellular organism. However, mutations in a special class of genes called proto-oncogenes can cause uncontrolled division of that cell, resulting in a group of cells that constitutes a cancerous tumour.

Mutations can affect gene function in several different ways. First, the structure and function of the protein coded by that gene can be affected. For example, enzymes are particularly susceptible to mutations that affect the amino acid sequence at their active site (i.e., the region that allows the enzyme to bind with its specific substrate). This may lead to enzyme inactivity; a protein is made, but it has no enzymatic function. Second, some nonsense or frameshift mutations can lead to the complete absence of a protein. Third, changes to the promoter region of the gene can result in gene malfunction by interfering with transcription. In this situation, protein production is either inhibited or it occurs at an inappropriate time because of alterations somewhere in the regulatory region. Fourth, mutations within introns that affect the specific nucleotide sequences that direct intron splicing may result in an mRNA that still contains an intron. When translated, this extra RNA will almost certainly be meaningless at the protein level, and its extra length will lead to a functionless protein. Any mutation that results in a lack of function for a particular gene is called a “null” mutation. Less-severe mutations are called “leaky” mutations because some normal function still “leaks through” into the phenotype.

Most mutations occur spontaneously and have no known cause. The synthesis of DNA is a cooperative venture of many different interacting cellular components, and occasionally mistakes occur that result in mutations. Like many chemical structures, the bases of DNA are able to exist in several conformations called isomers. The keto form of a DNA base is the normal form that gives the molecule its standard base-pairing properties. However, the keto form occasionally changes spontaneously to the enol form, which has different base-pairing properties. For example, the keto form of cytosine pairs with guanine (its normal pairing partner), but the enol form of cytosine pairs with adenine. During DNA replication, this adenine base will act as the template for thymine in the newly synthesized strand. Therefore, a CG base pair will have mutated to a TA base pair. If this change results in a functionally different amino acid, then a missense mutation may result. Another spontaneous event that can lead to mutation is depurination, the complete loss of a purine base (adenine or guanine) at some location in the DNA. The resulting gap can be filled by any base during subsequent replications.

Researchers have demonstrated that ionizing radiation, some chemicals, and certain viruses are capable of acting as mutagens—agents that can increase the rate at which mutations occur. Some mutagens have been implicated as a cause of cancer. For example, ultraviolet (UV) radiation from the sun is known to cause skin cancer, and cigarette smoke is a primary cause of lung cancer.

Repair of mutation

A variety of mechanisms exists for repairing copying errors caused by DNA damage. One of the best-studied systems is the repair mechanism for damage caused by ultraviolet radiation. Ultraviolet radiation joins adjacent thymines, creating thymine dimers, which, if not repaired, may cause mutations. Special repair enzymes either cut the bond between the thymines or excise the bonded dimer and replace it with two single thymines. If both of these repair methods fail, a third method allows the DNA replication process to bypass the dimer; however, it is this bypass system that causes most mutations because bases are then inserted at random opposite the thymine dimer. Xeroderma pigmentosum, a severe hereditary disease of humans, is caused by a mutation in a gene coding for one of the thymine dimer repair enzymes. Individuals with this disease are highly susceptible to skin cancer.

Reverse mutation from the aberrant state of a gene back to its normal, or wild type, state can result in a number of possible molecular changes at the protein level. True reversion is the reversal of the original nucleotide change. However, phenotypic reversion can result from changes that restore a different amino acid with properties identical to the original. Second-site changes within a protein can also restore normal function. For example, an amino acid change at a site different from that altered by the original mutation can sometimes interact with the amino acid at the first mutant site to restore a normal protein shape. Also, second-site mutations at other genes can act as suppressors, restoring wild type function. For example, mutations in the anticodon region of a tRNA gene can result in a tRNA that sometimes inserts an amino acid at an erroneous stop codon; if the original mutation is caused by a stop codon, which arrests translation at that point, then a tRNA anticodon change can insert an amino acid and allow translation to continue normally to the end of the mRNA. Alternatively, some mutations at separate genes open up a new biochemical pathway that circumvents the block of function caused by the original mutation.