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Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation.

Non-homologous end joining (NHEJ) is a major pathway for repairing double-strand breaks.

NHEJ involves removal of a few nucleotides to allow somewhat inaccurate alignment of the two ends for rejoining followed by addition of nucleotides to fill in gaps. Gene mutations have varying effects on health depending on where they occur and whether they alter the function of essential proteins.

Mutations in the structure of genes can be classified into several types.

Naturally occurring oxidative DNA damages arise at least 10,000 times per cell per day in humans and 50,000 times or more per cell per day in rats.Mutationism, along with other alternatives to Darwinism like Lamarckism and orthogenesis, was discarded by most biologists as they came to see that Mendelian genetics and natural selection could readily work together; mutation took its place as a source of the genetic variation essential for natural selection to work on. In 1940, Richard Goldschmidt again argued for single-step speciation by macromutation, describing the organisms thus produced as "hopeful monsters", earning widespread ridicule.Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of naturally occurring DNA damage (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens.Mutations in genes can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. One study on genetic variations between different species of Drosophila suggests that, if a mutation changes a protein produced by a gene, the result is likely to be harmful, with an estimated 70 percent of amino acid polymorphisms that have damaging effects, and the remainder being either neutral or marginally beneficial.Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as DNA repair to prevent or correct mutations by reverting the mutated sequence back to its original state.

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