Microsatellite instability

Microsatellite instability (MSI) is the condition of genetic hypermutability (predisposition to mutation) that results from impaired DNA mismatch repair (MMR). The presence of MSI represents phenotypic evidence that MMR is not functioning normally. Microsatellite instability (MSI) is the condition of genetic hypermutability (predisposition to mutation) that results from impaired DNA mismatch repair (MMR). The presence of MSI represents phenotypic evidence that MMR is not functioning normally. MMR corrects errors that spontaneously occur during DNA replication, such as single base mismatches or short insertions and deletions. The proteins involved in MMR correct polymerase errors by forming a complex that binds to the mismatched section of DNA, excises the error, and inserts the correct sequence in its place. Cells with abnormally functioning MMR are unable to correct errors that occur during DNA replication and consequently accumulate errors. This causes the creation of novel microsatellite fragments. Polymerase chain reaction-based assays can reveal these novel microsatellites and provide evidence for the presence of MSI. Microsatellites are repeated sequences of DNA. These sequences can be made of repeating units of one to six base pairs in length. Although the length of these microsatellites is highly variable from person to person and contributes to the individual DNA 'fingerprint', each individual has microsatellites of a set length. The most common microsatellite in humans is a dinucleotide repeat of the nucleotides C and A, which occurs tens of thousands of times across the genome. Microsatellites are also known as simple sequence repeats (SSRs). Microsatellite instability structure consists of repeated nucleotides, most often seen as GT/CA repeats. Researchers have yet to confirm the precise definition of the MSI structure. While all researchers agree that microsatellites are repeat sequences, the lengths of the sequences remain in question. Some research suggest that MSIs are short tandem DNA repeat sequences of one to six base pairs throughout the genome, while other research suggests that the range may be two to five. Although researchers do not agree on a specific threshold for the number of tandem repeats that constitute a microsatellite, there is a consensus around their relative size. Longer sequences are called minisatellite, and even longer sequences are called satellite DNA sites. Some scientists distinguish among the three categories by a minimum number of base pairs, and others use a minimum number of repeated units. The majority of repeats occur in untranslated regions, specifically introns. However, microsatellites that occur in coding regions often inhibit the expansion of most downstream events. Microsatellites make up approximately three percent of the human genome, or more than one million fragments of DNA. Microsatellite density increases with genome size and is seen twice as much at the ends of chromosome arms than in the chromosome bodies. MSI was discovered in the 1970s and 1980s. The first human disease attributed to MSI was xeroderma pigmentosum. This disease resulted from two alleles activating mutations on nucleotide excision repair. In a broad sense, MSI results from the inability of the mismatch repair (MMR) proteins to fix a DNA replication error. DNA replication occurs in the 'S' phase of the cell cycle; the faulty event creating an MSI region occurs during the second replication event. The original strand is unharmed, but the daughter strand experiences a frame-shift mutation due to DNA polymerase slippage. Specifically, DNA polymerase slips, creating a temporary insertion-deletion loop, which is usually recognized by MMR proteins. However, when the MMR proteins do not function normally, as in the case of MSI, this loop results in frame-shift mutations, either through insertions or deletions, yielding non-functioning proteins. MSI is unique to DNA polymorphisms in that the replication errors vary in length instead of sequence. The rate and direction of the mutations yielding MSIs are the major components in determining genetic differences. To date, scientists agree that the mutation rates differ in loci position. The greater the length of the MSI, the greater the mutation rate.