Editing Microsatellite (section)

==Mutation mechanisms and mutation rates==
[[File:STR-Slippage Dr.Peter Forster.jpg|thumb|DNA strand slippage during replication of an STR locus. Boxes symbolize repetitive DNA units. Arrows indicate the direction in which a new DNA strand (white boxes) is being replicated from the template strand (black boxes). Three situations during DNA replication are depicted. (a) Replication of the STR locus has proceeded without a mutation. (b) Replication of the STR locus has led to a gain of one unit owing to a loop in the new strand; the aberrant loop is stabilized by flanking units complementary to the opposite strand. (c) Replication of the STR locus has led to a loss of one unit owing to a loop in the template strand. (Forster et al. 2015)]]
Unlike [[point mutations]], which affect only a single nucleotide, microsatellite mutations lead to the gain or loss of an entire repeat unit, and sometimes two or more repeats simultaneously. Thus, the [[mutation rate]] at microsatellite [[Locus (genetics)|loci]] is expected to differ from other mutation rates, such as base substitution rates.<ref>{{cite journal |author1 = Jeffreys AJ|author-link1 =Alec Jeffreys|author2 =  Wilson V|author3 =  Thein SL|author-link3 =
Swee Lay Thein| title = Hypervariable 'minisatellite' regions in human DNA | journal = Nature | volume = 314 | issue = 6006 | pages = 67–73 | date = 1985 | pmid = 3856104 | doi = 10.1038/314067a0 | s2cid = 4356170 | bibcode = 1985Natur.314...67J }}</ref><ref name="Andreasson">{{cite journal | vauthors = Andreassen R, Egeland T, Olaisen B | title = Mutation rate in the hypervariable VNTR g3 (D7S22) is affected by allele length and a flanking DNA sequence polymorphism near the repeat array | journal = American Journal of Human Genetics | volume = 59 | issue = 2 | pages = 360–367 | date = August 1996 | pmid = 8755922 | pmc = 1914730 }}</ref> The mutation rate at microsatellite loci depends on the repeat motif sequence, the number of repeated motif units and the purity of the canonical repeated sequence.<ref name="Molecular basis of genetic instabil">{{cite journal | vauthors = Wells RD | title = Molecular basis of genetic instability of triplet repeats | journal = The Journal of Biological Chemistry | volume = 271 | issue = 6 | pages = 2875–2878 | date = February 1996 | pmid = 8621672 | doi = 10.1074/jbc.271.6.2875 | doi-access = free }}</ref>  A variety of mechanisms for mutation of microsatellite loci have been reviewed,<ref name="Molecular basis of genetic instabil"/><ref>{{cite journal | vauthors = Hancock JM, Santibáñez-Koref MF | title = Trinucleotide expansion diseases in the context of micro- and minisatellite evolution, Hammersmith Hospital, April 1-3, 1998 | journal = The EMBO Journal | volume = 17 | issue = 19 | pages = 5521–5524 | date = October 1998 | pmid = 9755151 | pmc = 1170879 | doi = 10.1093/emboj/17.19.5521 }}</ref>  and their resulting polymorphic nature has been quantified.<ref name="Biological effects">{{cite journal | vauthors = Wren JD, Forgacs E, Fondon JW, Pertsemlidis A, Cheng SY, Gallardo T, Williams RS, Shohet RV, Minna JD, Garner HR | display-authors = 6 | title = Repeat polymorphisms within gene regions: phenotypic and evolutionary implications | journal = American Journal of Human Genetics | volume = 67 | issue = 2 | pages = 345–356 | date = August 2000 | pmid = 10889045 | pmc = 1287183 | doi = 10.1086/303013 }}</ref> The actual cause of mutations in microsatellites is debated.

One proposed cause of such length changes is replication slippage, caused by mismatches between DNA strands while being replicated during [[meiosis]].<ref name="Tautz 1994">{{cite journal | vauthors = Tautz D | title = Simple sequences | journal = Current Opinion in Genetics & Development | volume = 4 | issue = 6 | pages = 832–7 | date = December 1994 | pmid = 7888752 | doi = 10.1016/0959-437X(94)90067-1 }}</ref> [[DNA polymerase]], the enzyme responsible for reading DNA during replication, can slip while moving along the template strand and continue at the wrong nucleotide. DNA polymerase slippage is more likely to occur when a repetitive sequence (such as CGCGCG) is replicated. Because microsatellites consist of such repetitive sequences, DNA polymerase may make errors at a higher rate in these sequence regions. Several studies have found evidence that slippage is the cause of microsatellite mutations.<ref name="Klintschar 2004">{{cite journal | vauthors = Klintschar M, Dauber EM, Ricci U, Cerri N, Immel UD, Kleiber M, Mayr WR | title = Haplotype studies support slippage as the mechanism of germline mutations in short tandem repeats | journal = Electrophoresis | volume = 25 | issue = 20 | pages = 3344–8 | date = October 2004 | pmid = 15490457 | doi = 10.1002/elps.200406069 | s2cid = 22298567 }}</ref><ref name="Forster 2015">{{cite journal | vauthors = Forster P, Hohoff C, Dunkelmann B, Schürenkamp M, Pfeiffer H, Neuhuber F, Brinkmann B | title = Elevated germline mutation rate in teenage fathers | journal = Proceedings. Biological Sciences | volume = 282 | issue = 1803 | pages = 20142898 | date = March 2015 | pmid = 25694621 | pmc = 4345458 | doi = 10.1098/rspb.2014.2898 }}</ref> Typically, slippage in each microsatellite occurs about once per 1,000 generations.<ref name="Weber 1993">{{cite journal | vauthors = Weber JL, Wong C | title = Mutation of human short tandem repeats | journal = Human Molecular Genetics | volume = 2 | issue = 8 | pages = 1123–8 | date = August 1993 | pmid = 8401493 | doi = 10.1093/hmg/2.8.1123 | doi-access = free }}</ref> Thus, slippage changes in repetitive DNA are three orders of magnitude more common than [[point mutation]]s in other parts of the genome.<ref name="Jarne 1996">{{cite journal | vauthors = Jarne P, Lagoda PJ | title = Microsatellites, from molecules to populations and back | journal = Trends in Ecology & Evolution | volume = 11 | issue = 10 | pages = 424–9 | date = October 1996 | pmid = 21237902 | doi = 10.1016/0169-5347(96)10049-5 }}</ref> Most slippage results in a change of just one repeat unit, and slippage rates vary for different allele lengths and repeat unit sizes,<ref name="Brinkmann-1998">{{cite journal | vauthors = Brinkmann B, Klintschar M, Neuhuber F, Hühne J, Rolf B | title = Mutation rate in human microsatellites: influence of the structure and length of the tandem repeat | journal = American Journal of Human Genetics | volume = 62 | issue = 6 | pages = 1408–15 | date = June 1998 | pmid = 9585597 | pmc = 1377148 | doi = 10.1086/301869 }}</ref> and within different species.<ref name="Kruglyak 1998">{{cite journal | vauthors = Kruglyak S, Durrett RT, Schug MD, Aquadro CF | title = Equilibrium distributions of microsatellite repeat length resulting from a balance between slippage events and point mutations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 18 | pages = 10774–8 | date = September 1998 | pmid = 9724780 | pmc = 27971 | doi = 10.1073/pnas.95.18.10774 | bibcode = 1998PNAS...9510774K | doi-access = free }}</ref><ref>{{cite journal | vauthors = Laidlaw J, Gelfand Y, Ng KW, Garner HR, Ranganathan R, Benson G, Fondon JW | title = Elevated basal slippage mutation rates among the Canidae | journal = The Journal of Heredity | volume = 98 | issue = 5 | pages = 452–460 | date = 1 July 2007 | pmid = 17437958 | doi = 10.1093/jhered/esm017 | doi-access = free }}</ref><ref name="Mutation mechanisms and rates">{{cite journal | vauthors = Lian Y, Garner HR | title = Evidence for the regulation of alternative splicing via complementary DNA sequence repeats | journal = Bioinformatics | volume = 21 | issue = 8 | pages = 1358–1364 | date = April 2005 | pmid = 15673565 | doi = 10.1093/bioinformatics/bti180 | doi-access = free }}</ref> If there is a large size difference between individual alleles, then there may be increased instability during recombination at meiosis.<ref name="Jarne 1996"/>

Another possible cause of microsatellite mutations are point mutations, where only one nucleotide is incorrectly copied during replication. A study comparing human and primate genomes found that most changes in repeat number in short microsatellites appear due to point mutations rather than slippage.<ref name="Amos-2010">{{cite journal | vauthors = Amos W | title = Mutation biases and mutation rate variation around very short human microsatellites revealed by human-chimpanzee-orangutan genomic sequence alignments | journal = Journal of Molecular Evolution | volume = 71 | issue = 3 | pages = 192–201 | date = September 2010 | pmid = 20700734 | doi = 10.1007/s00239-010-9377-4 | bibcode = 2010JMolE..71..192A | s2cid = 1424625 }}</ref>

===Microsatellite mutation rates===
Direct estimates of microsatellite mutation rates have been made in numerous organisms, from insects to humans. In the [[desert locust]] ''Schistocerca gregaria'', the microsatellite mutation rate was estimated at 2.1&nbsp;× 10<sup>−4</sup> per generation per locus.<ref name="Chapuis-2015">{{cite journal | vauthors = Chapuis MP, Plantamp C, Streiff R, Blondin L, Piou C | title = Microsatellite evolutionary rate and pattern in Schistocerca gregaria inferred from direct observation of germline mutations | journal = Molecular Ecology | volume = 24 | issue = 24 | pages = 6107–19 | date = December 2015 | pmid = 26562076 | doi = 10.1111/mec.13465 | s2cid = 33307624 | doi-access = free | bibcode = 2015MolEc..24.6107C }}</ref> The microsatellite mutation rate in human male germ lines is five to six times higher than in female germ lines and ranges from 0 to 7&nbsp;× 10<sup>−3</sup> per locus per gamete per generation.<ref name="Brinkmann-1998"/> In the nematode ''[[Pristionchus pacificus]]'', the estimated microsatellite mutation rate ranges from 8.9&nbsp;× 10<sup>−5</sup> to 7.5&nbsp;× 10<sup>−4</sup> per locus per generation.<ref name="Molnar-2012">{{cite journal | vauthors = Molnar RI, Witte H, Dinkelacker I, Villate L, Sommer RJ | title = Tandem-repeat patterns and mutation rates in microsatellites of the nematode model organism Pristionchus pacificus | journal = G3 | volume = 2 | issue = 9 | pages = 1027–34 | date = September 2012 | pmid = 22973539 | pmc = 3429916 | doi = 10.1534/g3.112.003129 }}</ref>

Microsatellite mutation rates vary with base position relative to the microsatellite, repeat type, and base identity.<ref name="Amos-2010"/> Mutation rate rises specifically with repeat number, peaking around six to eight repeats and then decreasing again.<ref name="Amos-2010"/> Increased heterozygosity in a population will also increase microsatellite mutation rates,<ref name="Amos-2016">{{cite journal | vauthors = Amos W | title = Heterozygosity increases microsatellite mutation rate | journal = Biology Letters | volume = 12 | issue = 1 | pages = 20150929 | date = January 2016 | pmid = 26740567 | pmc = 4785931 | doi = 10.1098/rsbl.2015.0929 }}</ref> especially when there is a large length difference between alleles. This is likely due to [[homologous chromosomes]] with arms of unequal lengths causing instability during meiosis.<ref name="Amos-Rubinsztein-1996">{{cite journal | vauthors = Amos W, Sawcer SJ, Feakes RW, Rubinsztein DC | title = Microsatellites show mutational bias and heterozygote instability | journal = Nature Genetics | volume = 13 | issue = 4 | pages = 390–1 | date = August 1996 | pmid = 8696328 | doi = 10.1038/ng0896-390 | s2cid = 6086527 }}</ref>