DNA change within a gene (point mutation) generally entails one or a few base pairs. Single-base-pair substitutions can create missense codons or nonsense (translation termination) codons. A purine replaced by the other purine (or a pyrimidine replaced by the other pyrimidine) is a transition. A purine replaced by a pyrimidine (or vice versa) is a transversion. Single-base-pair additions or deletions (indels) produce frameshift mutations. Certain human genes that contain trinucleotide repeats—especially those that are expressed in neural tissue—become mutated through the expansion of these repeats and can thus cause disease. The formation of monoamino acid repeats within the polypeptides encoded by these genes is often responsible for the mutant phenotypes.

Mutations can occur spontaneously as a by-product of normal cellular processes such as DNA replication or metabolism, or they can be induced by mutagenic radiation or chemicals. Mutagens often result in a specific type of change because of their chemical specificity. For example, some produce exclusively G · C → A · T transitions; others, exclusively frameshifts.

Although mutations are necessary to generate diversity, many mutations are associated with inherited genetic diseases such as xeroderma pigmentosum. In addition, mutations that occur in somatic cells are the source of many human cancers. Many biological pathways have evolved to correct the broad spectrum of spontaneous and induced mutations. Some pathways, such as base- and nucleotide-excision repair and mismatch repair, use the information inherent in base complementarity to execute error-free repair. Other pathways that use bypass polymerases to correct damaged bases can introduce errors in the DNA sequence.

The correction of double-strand breaks is particularly important because these lesions can lead to destabilizing chromosomal rearrangements. Nonhomologous end joining is a pathway that ligates broken ends back together so that a stalled replication fork does not result in cell death. In replicating cells, double-strand breaks can be repaired in an error-free manner by the synthesis-dependent strandnnealing pathway, which utilizes the sister chromatid to repair the break.

Hundreds of programmed double-strand breaks initiate meiotic crossing over between nonsister chromatids. Just like other double-strand breaks, the meiotic breaks must be processed quickly and efficiently to prevent serious consequences such as cell death and cancer. Just how this repair is done is still being explored.

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