The genetic code is written in DNA, a double helix structure of two strands linked by chemical base pairs. The pairing rules are strict: adenine (A) pairs with thymine (T), and guanine (G) pairs with cytosine (C). A DNA mismatch is a violation of this rule, such as an A incorrectly paired with a C, or the erroneous insertion or deletion of bases. These mistakes disrupt the DNA’s uniform shape and can alter genetic information if left uncorrected, which is why cells have sophisticated repair systems.
How DNA Mismatches Occur
DNA mismatches primarily arise from errors during DNA replication, the process where a cell duplicates its DNA before dividing. Although the machinery that copies DNA is highly accurate, an incorrect nucleotide can occasionally be incorporated into the new strand. These errors can happen due to the natural chemical properties of the bases themselves.
Bases can temporarily shift into a different chemical form, a phenomenon known as tautomerization, causing them to pair incorrectly. For example, a temporary shift in a thymine base can cause it to pair with guanine instead of adenine. While DNA polymerases, the enzymes that build new DNA, have a proofreading function, some mistakes still slip through.
Mismatches can also result from chemical damage. Agents in the cellular environment, like reactive oxygen species, can alter a base. This damage may cause the modified base to be misread during the next replication cycle, establishing a permanent mismatch.
The Cellular Correction System
To safeguard genetic integrity, cells use a system called DNA Mismatch Repair (MMR) to scan newly replicated DNA for errors and correct them. The process involves specialized proteins that detect, remove, and replace the incorrect DNA segment.
The first step is detection. In humans, a protein complex called MutSα (a combination of MSH2 and MSH6 proteins) patrols the DNA, recognizing single base-pair mismatches and small insertion-deletion loops. When it finds a distortion, it binds to the site and flags it for repair.
Once an error is identified, other proteins are recruited to remove the faulty DNA. The MutLα complex (formed by MLH1 and PMS2 proteins) coordinates the next steps, making a cut in the new DNA strand near the mismatch. This nick serves as an entry point for an exonuclease enzyme, which removes the mismatched nucleotide and a surrounding patch of DNA.
With the incorrect segment gone, the enzyme DNA polymerase synthesizes a new segment using the original strand as a template. Finally, the enzyme DNA ligase seals the gap in the DNA backbone, completing the repair and restoring the correct genetic sequence.
Health Implications of Faulty Repair
When the Mismatch Repair (MMR) system is defective, it can have significant health consequences. Mutations in the genes that produce MMR proteins—such as MLH1, MSH2, MSH6, and PMS2—can impair the cell’s ability to correct replication errors. As a result, mutations accumulate throughout the genome at a much higher rate than normal, a condition known as genomic instability.
A direct consequence of a faulty MMR system is microsatellite instability (MSI). Microsatellites are short, repetitive DNA sequences that are prone to errors during replication. A healthy MMR system corrects these slips, but in its absence, the lengths of these microsatellites can change. High levels of MSI are a strong indicator that the MMR system is not functioning correctly.
The accumulation of mutations in genes that control cell growth can lead to cancer. Lynch syndrome, or Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is the most common inherited condition caused by mutations in MMR genes. Individuals with Lynch syndrome inherit one non-working copy of an MMR gene. If the second, working copy becomes mutated in a cell, that cell loses its ability to repair mismatches, which can initiate tumor formation.
Lynch syndrome increases the lifetime risk of developing several cancers at a younger age. While colorectal cancer is the most prominent, the syndrome also elevates the risk for endometrial, stomach, ovarian, and pancreatic cancers. For this reason, testing tumors for MMR deficiency or MSI is standard practice for certain cancers, as it can identify individuals who may have Lynch syndrome and guide treatment.
The Role of Mismatches in Evolution
While unrepaired DNA mismatches are often detrimental, they play a foundational role in evolution. These uncorrected errors are a primary source of new genetic variation, the raw material for natural selection. Although most of these mutations are neutral or harmful, a small fraction may confer a beneficial new trait, allowing populations to adapt over time.
Inactivation of the MMR system leads to a “mutator” phenotype, where mutation rates increase. While this is risky for an individual organism, it can be advantageous for a population facing severe environmental stress. A higher mutation rate increases the chance that some individuals will acquire a random mutation that provides a survival advantage, such as antibiotic resistance in bacteria.
The relationship between mismatch repair and evolution is dynamic. A population might benefit from a temporarily high mutation rate to overcome a challenge, but in a stable environment, a functional MMR system is favored to maintain genomic integrity. This balance between stability and change, mediated by the fidelity of DNA repair, is a driver of the evolutionary process.