mutation rate

Different genetic variants within a species are referred to as alleles, therefore, a new mutation can create a new allele. In population genetics, each allele is characterized by a selection coefficient, which measures the expected change in an allele's frequency over time. The selection coefficient can either be negative, corresponding to an expected decrease, positive, corresponding to an expected increase, or zero, corresponding to no expected change. The distribution of fitness effects of new mutations is an important parameter in population genetics and has been the subject of extensive investigation.{{cite journal | vauthors = Eyre-Walker A, Keightley PD | title = The distribution of fitness effects of new mutations | journal = Nature Reviews. Genetics | volume = 8 | issue = 8 | pages = 610–618 | date = August 2007 | pmid = 17637733 | doi = 10.1038/nrg2146 | s2cid = 10868777 }} Although measurements of this distribution have been inconsistent in the past, it is now generally thought that the majority of mutations are mildly deleterious, that many have little effect on an organism's fitness, and that a few can be favorable.

Because of natural selection, unfavorable mutations will typically be eliminated from a population while favorable changes are generally kept for the next generation, and neutral changes accumulate at the rate they are created by mutations. This process happens by reproduction. In a particular generation, the 'best fit' survives with higher probability, passing their genes to their offspring. The sign of the change in this probability defines mutations to be beneficial, neutral or harmful to organisms.{{cite journal | vauthors = Scally A, Durbin R | title = Revising the human mutation rate: implications for understanding human evolution | journal = Nature Reviews. Genetics | volume = 13 | issue = 10 | pages = 745–753 | date = October 2012 | pmid = 22965354 | doi = 10.1038/nrg3295 | s2cid = 18944814 }}

An organism's mutation rates can be measured by a number of techniques.

One way to measure the mutation rate is by the fluctuation test, also known as the Luria–Delbrück experiment. This experiment demonstrated that bacterial mutations occur in the absence of selection rather than in the presence of selection.{{cite book | vauthors = Fry M | date = 2016 | chapter = Chapter 4.5: Luria–Delbrück experiment | title = Landmark Experiments in Molecular Biology | location = Netherlands | publisher = Elsevier Science |isbn=978-0-12-802108-8 | page = 120 | chapter-url = https://books.google.com/books?id=VROKCgAAQBAJ&dq=Luria–Delbrück+experiment&pg=PA120 }}

This is very important to mutation rates because it proves experimentally that mutations can occur without selection being a component—in fact, mutation and selection are completely distinct [https://www.livescience.com/1796-forces-evolution.html evolutionary forces]. Different DNA sequences can have different propensities to mutation (see below) and may not occur randomly.{{cite journal | vauthors = Monroe JG, Srikant T, Carbonell-Bejerano P, Becker C, Lensink M, Exposito-Alonso M, Klein M, Hildebrandt J, Neumann M, Kliebenstein D, Weng ML, Imbert E, Ågren J, Rutter MT, Fenster CB, Weigel D | title = Mutation bias reflects natural selection in Arabidopsis thaliana | journal = Nature | volume = 602 | issue = 7895 | pages = 101–105 | date = February 2022 | pmid = 35022609 | pmc = 8810380 | doi = 10.1038/s41586-021-04269-6 | bibcode = 2022Natur.602..101M }}

The most commonly measured class of mutations is substitutions, because they are relatively easy to measure with standard analyses of DNA sequence data. However, substitutions have a substantially different rate of mutation (10⁻⁸ to 10⁻⁹ per generation for most cellular organisms) than other classes of mutation, which are frequently much higher (~10⁻³ per generation for satellite DNA expansion/contraction{{cite journal | vauthors = Flynn JM, Caldas I, Cristescu ME, Clark AG | title = Selection Constrains High Rates of Tandem Repetitive DNA Mutation in Daphnia pulex | journal = Genetics | volume = 207 | issue = 2 | pages = 697–710 | date = October 2017 | pmid = 28811387 | pmc = 5629333 | doi = 10.1534/genetics.117.300146 | url = https://www.genetics.org/content/207/2/697 | access-date = 2020-03-21 | url-status = live | archive-url = https://web.archive.org/web/20200321203018/https://www.genetics.org/content/207/2/697 | archive-date = 2020-03-21 }}).

Many sites in an organism's genome may admit mutations with small fitness effects. These sites are typically called neutral sites. Theoretically, mutations under no selection become fixed between organisms at precisely the mutation rate. Fixed synonymous mutations, i.e. synonymous substitutions, are changes to the sequence of a gene that do not change the protein produced by that gene. They are often used as estimates of that mutation rate, even though some synonymous mutations have fitness effects. As an example, mutation rates have been directly inferred from the whole genome sequences of experimentally evolved replicate lines of Escherichia coli B.{{cite journal | vauthors = Wielgoss S, Barrick JE, Tenaillon O, Cruveiller S, Chane-Woon-Ming B, Médigue C, Lenski RE, Schneider D | title = Mutation Rate Inferred From Synonymous Substitutions in a Long-Term Evolution Experiment With Escherichia coli | journal = G3 | volume = 1 | issue = 3 | pages = 183–186 | date = August 2011 | pmid = 22207905 | pmc = 3246271 | doi = 10.1534/g3.111.000406 }}

A particularly labor-intensive way of characterizing the mutation rate is the mutation accumulation line.

Mutation accumulation lines have been used to characterize mutation rates with the Bateman-Mukai Method and direct sequencing of well-studied experimental organisms ranging from intestinal bacteria (E. coli), roundworms (C. elegans), yeast (S. cerevisiae), fruit flies (D. melanogaster), and small ephemeral plants (A. thaliana).{{cite journal | vauthors = Ossowski S, Schneeberger K, Lucas-Lledó JI, Warthmann N, Clark RM, Shaw RG, Weigel D, Lynch M | title = The rate and molecular spectrum of spontaneous mutations in Arabidopsis thaliana | journal = Science | volume = 327 | issue = 5961 | pages = 92–94 | date = January 2010 | pmid = 20044577 | pmc = 3878865 | doi = 10.1126/science.1180677 | bibcode = 2010Sci...327...92O }}

File:Molecular evolution bamboos.svg affects mutation rates: The long-lived woody bamboos (tribes Arundinarieae and Bambuseae) have lower mutation rates (short branches in the phylogenetic tree) than the fast-evolving herbaceous bamboos (Olyreae).]]

Mutation rates differ between species and even between different regions of the genome of a single species. Mutation rates can also differ even between genotypes of the same species; for example, bacteria have been observed to evolve hypermutability as they adapt to new selective conditions.{{cite journal | vauthors = Wielgoss S, Barrick JE, Tenaillon O, Wiser MJ, Dittmar WJ, Cruveiller S, Chane-Woon-Ming B, Médigue C, Lenski RE, Schneider D | title = Mutation rate dynamics in a bacterial population reflect tension between adaptation and genetic load | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 1 | pages = 222–227 | date = January 2013 | pmid = 23248287 | pmc = 3538217 | doi = 10.1073/pnas.1219574110 | doi-access = free | bibcode = 2013PNAS..110..222W }} These different rates of nucleotide substitution are measured in substitutions (fixed mutations) per base pair per generation. For example, mutations in intergenic, or non-coding, DNA tend to accumulate at a faster rate than mutations in DNA that is actively in use in the organism (gene expression). That is not necessarily due to a higher mutation rate, but to lower levels of purifying selection. A region which mutates at predictable rate is a candidate for use as a molecular clock.

If the rate of neutral mutations in a sequence is assumed to be constant (clock-like), and if most differences between species are neutral rather than adaptive, then the number of differences between two different species can be used to estimate how long ago two species diverged (see molecular clock). The mutation rate of an organism may change in response to environmental stress. For example, UV light damages DNA, which may result in error-prone attempts by the cell to perform DNA repair.

The human mutation rate is higher in the male germ line (sperm) than the female (egg cells), but estimates of the exact rate have varied by an order of magnitude or more. This means that a human genome accumulates around 64 new mutations per generation because each full generation involves a number of cell divisions to generate gametes.{{cite journal | vauthors = Drake JW, Charlesworth B, Charlesworth D, Crow JF | title = Rates of spontaneous mutation | journal = Genetics | volume = 148 | issue = 4 | pages = 1667–1686 | date = April 1998 | pmid = 9560386 | pmc = 1460098 | doi = 10.1093/genetics/148.4.1667 | url = http://www.genetics.org/cgi/content/full/148/4/1667 | access-date = 2007-09-27 | url-status = live | archive-url = https://web.archive.org/web/20100821100757/http://www.genetics.org/cgi/content/full/148/4/1667 | archive-date = 2010-08-21 }} Human mitochondrial DNA has been estimated to have mutation rates of ~3× or ~2.7×10⁻⁵ per base per 20 year generation (depending on the method of estimation);{{cite journal | vauthors = Schneider S, Excoffier L | title = Estimation of past demographic parameters from the distribution of pairwise differences when the mutation rates vary among sites: application to human mitochondrial DNA | journal = Genetics | volume = 152 | issue = 3 | pages = 1079–1089 | date = July 1999 | pmid = 10388826 | pmc = 1460660 | doi = 10.1093/genetics/152.3.1079 | url = http://www.genetics.org/cgi/reprint/152/3/1079 | access-date = 2008-02-25 | url-status = live | archive-url = https://web.archive.org/web/20080908074904/http://www.genetics.org/cgi/reprint/152/3/1079 | archive-date = 2008-09-08 }} these rates are considered to be significantly higher than rates of human genomic mutation at ~2.5×10⁻⁸ per base per generation.{{cite journal | vauthors = Nachman MW, Crowell SL | title = Estimate of the mutation rate per nucleotide in humans | journal = Genetics | volume = 156 | issue = 1 | pages = 297–304 | date = September 2000 | pmid = 10978293 | pmc = 1461236 | doi = 10.1093/genetics/156.1.297 | url = http://www.genetics.org/cgi/content/full/156/1/297 | access-date = 2007-10-19 | url-status = live | archive-url = https://web.archive.org/web/20110408213817/http://www.genetics.org/cgi/content/full/156/1/297 | archive-date = 2011-04-08 }} Using data available from whole genome sequencing, the human genome mutation rate is similarly estimated to be ~1.1×10⁻⁸ per site per generation.{{cite journal | vauthors = Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ | title = Analysis of genetic inheritance in a family quartet by whole-genome sequencing | journal = Science | volume = 328 | issue = 5978 | pages = 636–639 | date = April 2010 | pmid = 20220176 | pmc = 3037280 | doi = 10.1126/science.1186802 | bibcode = 2010Sci...328..636R }}

The rate for other forms of mutation also differs greatly from point mutations. An individual microsatellite locus often has a mutation rate on the order of 10⁻⁴, though this can differ greatly with length.{{cite journal | vauthors = Whittaker JC, Harbord RM, Boxall N, Mackay I, Dawson G, Sibly RM | title = Likelihood-based estimation of microsatellite mutation rates | journal = Genetics | volume = 164 | issue = 2 | pages = 781–787 | date = June 2003 | pmid = 12807796 | pmc = 1462577 | doi = 10.1093/genetics/164.2.781 | url = http://www.genetics.org/content/164/2/781.full | access-date = 2011-05-03 | url-status = live | archive-url = https://web.archive.org/web/20111128184524/http://www.genetics.org/content/164/2/781.full | archive-date = 2011-11-28 }}

Some sequences of DNA may be more susceptible to mutation. For example, stretches of DNA in human sperm which lack methylation are more prone to mutation.{{cite web | vauthors = Gravtiz L |title=Lack of DNA modification creates hotspots for mutations |date=28 June 2012 |publisher=Simons Foundation Autism Research Initiative |url=http://sfari.org/news-and-opinion/news/2012/lack-of-dna-modification-creates-hotspots-for-mutations |access-date=20 February 2014 |archive-date=5 March 2014 |archive-url=https://web.archive.org/web/20140305134537/http://sfari.org/news-and-opinion/news/2012/lack-of-dna-modification-creates-hotspots-for-mutations |url-status=live }}

In general, the mutation rate in unicellular eukaryotes (and bacteria) is roughly 0.003 mutations per genome per cell generation. However, some species, especially the ciliate of the genus Paramecium have an unusually low mutation rate. For instance, Paramecium tetraurelia has a base-substitution mutation rate of ~2 × 10⁻¹¹ per site per cell division. This is the lowest mutation rate observed in nature so far, being about 75× lower than in other eukaryotes with a similar genome size, and even 10× lower than in most prokaryotes. The low mutation rate in Paramecium has been explained by its transcriptionally silent germ-line nucleus, consistent with the hypothesis that replication fidelity is higher at lower gene expression levels.{{cite journal | vauthors = Sung W, Tucker AE, Doak TG, Choi E, Thomas WK, Lynch M | title = Extraordinary genome stability in the ciliate Paramecium tetraurelia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 47 | pages = 19339–19344 | date = November 2012 | pmid = 23129619 | pmc = 3511141 | doi = 10.1073/pnas.1210663109 | doi-access = free | bibcode = 2012PNAS..10919339S }}

The highest per base pair per generation mutation rates are found in viruses, which can have either RNA or DNA genomes. DNA viruses have mutation rates between 10⁻⁶ to 10⁻⁸ mutations per base per generation, and RNA viruses have mutation rates between 10⁻³ to 10⁻⁵ per base per generation.

A mutation spectrum is a distribution of rates or frequencies for the mutations relevant in some context, based on the recognition that rates of occurrence are not all the same. In any context, the mutation spectrum reflects the details of mutagenesis and is affected by conditions such as the presence of chemical mutagens or genetic backgrounds with mutator alleles or damaged DNA repair systems. The most fundamental and expansive concept of a mutation spectrum is the distribution of rates for all individual mutations that might happen in a genome (e.g., {{cite journal | vauthors = López-Cortegano E, Craig RJ, Chebib J, Balogun EJ, Keightley PD | title = Rates and spectra of de novo structural mutations in Chlamydomonas reinhardtii | journal = Genome Research | volume = 33 | issue = 1 | pages = 45–60 | date = January 2023 | pmid = 36617667 | pmc = 9977147 | doi = 10.1101/gr.276957.122 }}). From this full de novo spectrum, for instance, one may calculate the relative rate of mutation in coding vs non-coding regions. Typically the concept of a spectrum of mutation rates is simplified to cover broad classes such as transitions and transversions (figure), i.e., different mutational conversions across the genome are aggregated into classes, and there is an aggregate rate for each class.

In many contexts, a mutation spectrum is defined as the observed frequencies of mutations identified by some selection criterion, e.g., the distribution of mutations associated clinically with a particular type of cancer,{{cite journal | vauthors = Cao W, Wang X, Li JC | title = Hereditary breast cancer in the Han Chinese population | journal = Journal of Epidemiology | volume = 23 | issue = 2 | pages = 75–84 | year = 2013 | pmid = 23318652 | pmc = 3700245 | doi = 10.2188/jea.je20120043 }} or the distribution of adaptive changes in a particular context such as antibiotic resistance (e.g.,

{{cite journal | vauthors = Levy DD, Sharma B, Cebula TA | title = Single-nucleotide polymorphism mutation spectra and resistance to quinolones in Salmonella enterica serovar Enteritidis with a mutator phenotype | journal = Antimicrobial Agents and Chemotherapy | volume = 48 | issue = 7 | pages = 2355–2363 | date = July 2004 | pmid = 15215081 | pmc = 434170 | doi = 10.1128/AAC.48.7.2355-2363.2004 }}

).

Whereas the spectrum of de novo mutation rates reflects mutagenesis alone, this kind of spectrum may also reflect effects of selection and ascertainment biases (e.g., both kinds of spectrum are used in {{cite journal | vauthors = Cano AV, Rozhoňová H, Stoltzfus A, McCandlish DM, Payne JL | title = Mutation bias shapes the spectrum of adaptive substitutions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 119 | issue = 7 | date = February 2022 | pmid = 35145034 | pmc = 8851560 | doi = 10.1073/pnas.2119720119 | bibcode = 2022PNAS..11919720C | doi-access = free }}).

File:TsTvMutation.jpgs (Alpha) and transversions (Beta).]]

The theory on the evolution of mutation rates identifies three principal forces involved: the generation of more deleterious mutations with higher mutation, the generation of more advantageous mutations with higher mutation, and the metabolic costs and reduced replication rates that are required to prevent mutations. Different conclusions are reached based on the relative importance attributed to each force. The optimal mutation rate of organisms may be determined by a trade-off between costs of a high mutation rate,{{cite journal | vauthors = Altenberg L | title = An evolutionary reduction principle for mutation rates at multiple Loci | journal = Bulletin of Mathematical Biology | volume = 73 | issue = 6 | pages = 1227–1270 | date = June 2011 | pmid = 20737227 | doi = 10.1007/s11538-010-9557-9 | arxiv = 0909.2454 | s2cid = 15027684 }} such as deleterious mutations, and the metabolic costs of maintaining systems to reduce the mutation rate (such as increasing the expression of DNA repair enzymes.{{cite journal | vauthors = Sniegowski PD, Gerrish PJ, Johnson T, Shaver A | title = The evolution of mutation rates: separating causes from consequences | journal = BioEssays | volume = 22 | issue = 12 | pages = 1057–1066 | date = December 2000 | pmid = 11084621 | doi = 10.1002/1521-1878(200012)22:12<1057::AID-BIES3>3.0.CO;2-W | s2cid = 36771934 }} or, as reviewed by Bernstein et al.{{cite book |vauthors=Bernstein H, Hopf FA, Michod RE |title=Molecular Genetics of Development |chapter=The molecular basis of the evolution of sex |series=Advances in Genetics |volume=24 |pages=323–70 |year=1987 |pmid=3324702 |doi=10.1016/s0065-2660(08)60012-7 |isbn=9780120176243}} having increased energy use for repair, coding for additional gene products and/or having slower replication). Secondly, higher mutation rates increase the rate of beneficial mutations, and evolution may prevent a lowering of the mutation rate in order to maintain optimal rates of adaptation.{{cite journal | vauthors = Orr HA | title = The rate of adaptation in asexuals | journal = Genetics | volume = 155 | issue = 2 | pages = 961–968 | date = June 2000 | pmid = 10835413 | pmc = 1461099 | doi = 10.1093/genetics/155.2.961 | url = http://www.genetics.org/cgi/pmidlookup?view=long&pmid=10835413 | access-date = 2014-11-01 | url-status = live | archive-url = https://web.archive.org/web/20220625052242/https://academic.oup.com/genetics | archive-date = 2022-06-25 }}{{Cite journal |last1=Wielgoss |first1=S |last2=Barrick |first2=JE |last3=Tenaillon |first3=O |last4=Wiser |first4=MJ |last5=Dittmar |first5=WJ |last6=Cruvellier |first6=S |last7=Chane-Moon-Wing |first7=B |last8=Médigue |first8=C |last9=Lenski |first9=RE |last10=Schneider |first10=D |date=November 13, 2012 |title=Mutation rate dynamics in a bacterial population reflect tension between adaptation and genetic load |url=https://www.pnas.org/doi/abs/10.1073/pnas.1219574110 |journal=Proceedings of the National Academy of Sciences, USA |volume=110 |pages=222–227 |doi=10.1073/pnas.12195741|doi-broken-date=1 November 2024 |doi-access=free }} As such, hypermutation enables some cells to rapidly adapt to changing conditions in order to avoid the entire population from becoming extinct.{{cite journal | vauthors = Swings T, Van den Bergh B, Wuyts S, Oeyen E, Voordeckers K, Verstrepen KJ, Fauvart M, Verstraeten N, Michiels J | title = Adaptive tuning of mutation rates allows fast response to lethal stress in Escherichia coli | journal = eLife | volume = 6 | date = May 2017 | pmid = 28460660 | pmc = 5429094 | doi = 10.7554/eLife.22939 | doi-access = free }} Finally, natural selection may fail to optimize the mutation rate because of the relatively minor benefits of lowering the mutation rate, and thus the observed mutation rate is the product of neutral processes.{{cite journal | vauthors = Lynch M | title = Evolution of the mutation rate | journal = Trends in Genetics | volume = 26 | issue = 8 | pages = 345–352 | date = August 2010 | pmid = 20594608 | pmc = 2910838 | doi = 10.1016/j.tig.2010.05.003 }}{{cite journal | vauthors = Sung W, Ackerman MS, Miller SF, Doak TG, Lynch M | title = Drift-barrier hypothesis and mutation-rate evolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 45 | pages = 18488–18492 | date = November 2012 | pmid = 23077252 | pmc = 3494944 | doi = 10.1073/pnas.1216223109 | doi-access = free | bibcode = 2012PNAS..10918488S }}

Studies have shown that treating RNA viruses such as poliovirus with ribavirin produce results consistent with the idea that the viruses mutated too frequently to maintain the integrity of the information in their genomes.{{cite journal | vauthors = Crotty S, Cameron CE, Andino R | title = RNA virus error catastrophe: direct molecular test by using ribavirin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 12 | pages = 6895–6900 | date = June 2001 | pmid = 11371613 | pmc = 34449 | doi = 10.1073/pnas.111085598 | doi-access = free | bibcode = 2001PNAS...98.6895C }} This is termed error catastrophe.

The characteristically high mutation rate of HIV (Human Immunodeficiency Virus) of 3 x 10⁻⁵ per base and generation, coupled with its short replication cycle leads to a high antigen variability, allowing it to evade the immune system.{{cite journal | vauthors = Rambaut A, Posada D, Crandall KA, Holmes EC | title = The causes and consequences of HIV evolution | journal = Nature Reviews. Genetics | volume = 5 | issue = 1 | pages = 52–61 | date = January 2004 | pmid = 14708016 | doi = 10.1038/nrg1246 | url = http://tree.bio.ed.ac.uk/downloadPaper.php?id=242 | access-date = 2019-05-28 | url-status = live | s2cid = 5790569 | doi-access = free | archive-url = https://web.archive.org/web/20191109035127/http://tree.bio.ed.ac.uk/downloadPaper.php?id=242 | archive-date = 2019-11-09 }}

• Mutation
• Critical mutation rate
• Mutation frequency
• Dysgenics
• Allele frequency
• Rate of evolution
• Genetics
• Cancer

{{Reflist|2}}

• {{Commons category-inline|Mutation rate}}

{{DEFAULTSORT:Mutation Rate}}

Category:Mutation

Category:Evolutionary biology

Category:Temporal rates