Mutation rate: Difference between revisions
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==Background== |
==Background== |
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Different genetic variants within a species are referred to as alleles, and so a new mutation is said to 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 <ref name="Adam Eyre-Walker"> |
Different genetic variants within a species are referred to as alleles, and so a new mutation is said to 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 <ref name="Adam Eyre-Walker">{{cite journal |author=Eyre-Walker A, Keightley PD |title=The distribution of fitness effects of new mutations |journal=Nat. Rev. Genet. |volume=8 |issue=8 |pages=610–8 |date=August 2007 |pmid=17637733 |doi=10.1038/nrg2146 |url=http://www.nature.com/nrg/journal/v8/n8/abs/nrg2146.html}}</ref> 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. As a result of natural selection, unfavorable mutations will typically be eliminated from a population while favorable changes are quickly fixed, and neutral changes accumulate at the rate they are created by mutations. |
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==Measurement== |
==Measurement== |
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===Substitution Rates=== |
===Substitution Rates=== |
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Many sites in an organism's genome may not admit mutations with large fitness effects. These sites are typically called neutral sites. Theoretically mutations under no selection become [[Fixation (population genetics)|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, despite the fact that 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.<ref name="Wielgoss"> |
Many sites in an organism's genome may not admit mutations with large fitness effects. These sites are typically called neutral sites. Theoretically mutations under no selection become [[Fixation (population genetics)|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, despite the fact that 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.<ref name="Wielgoss">{{cite journal |author=Wielgoss S, Barrick JE, Tenaillon O, ''et al.'' |title=Mutation Rate Inferred From Synonymous Substitutions in a Long-Term Evolution Experiment With ''Escherichia coli'' |journal=G3 (Bethesda) |volume=1 |issue=3 |pages=183–6 |date=August 2011 |pmid=22207905 |pmc=3246271 |doi=10.1534/g3.111.000406 |url=http://www.g3journal.org/content/1/3/183.full}}</ref> |
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===Mutation Accumulation Lines=== |
===Mutation Accumulation Lines=== |
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A particularly labor-intensive way of characterizing the mutation rate is the mutation accumulation line. |
A particularly labor-intensive way of characterizing the mutation rate is the mutation accumulation line. |
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Mutation accumulation lines have been used to characterize mutation rates with the [[Bateman-Mukai Method]] and direct sequencing of intestinal bacteria, round-worms, yeast, fruit flies, small annual plants,<ref name="Lucas-Lledo">''The |
Mutation accumulation lines have been used to characterize mutation rates with the [[Bateman-Mukai Method]] and direct sequencing of intestinal bacteria, round-worms, yeast, fruit flies, small annual plants,<ref name="Lucas-Lledo">{{cite journal |author=Ossowski S, Schneeberger K, Lucas-Lledó JI, ''et al.'' |title=The rate and molecular spectrum of spontaneous mutations in ''Arabidopsis thaliana'' |journal=Science |volume=327 |issue=5961 |pages=92–4 |date=January 2010 |pmid=20044577 |pmc=3878865 |doi=10.1126/science.1180677 |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=20044577}}</ref> Paramecium, mutation accumulation lines. |
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==Variation in mutation rates== |
==Variation in mutation rates== |
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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.{{citation needed|date=March 2014}} |
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.{{citation needed|date=March 2014}} |
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In general, the mutation rate in unicellular [[eukaryotes]] and [[bacteria]] is roughly 0.003 mutations per genome per generation.<ref name="Genetics"> |
In general, the mutation rate in unicellular [[eukaryotes]] and [[bacteria]] is roughly 0.003 mutations per genome per generation.<ref name="Genetics">{{cite journal |author=Drake JW, Charlesworth B, Charlesworth D, Crow JF |title=Rates of spontaneous mutation |journal=Genetics |volume=148 |issue=4 |pages=1667–86 |date=April 1998 |pmid=9560386 |pmc=1460098 |url=http://www.genetics.org/cgi/content/full/148/4/1667 }}</ref> 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<sup>−6</sup> to 10<sup>−8</sup> mutations per base per generation, and RNA viruses have mutation rates between 10<sup>−3</sup> to 10<sup>−5</sup> per base per generation.<ref name="Genetics"/> Human mitochondrial DNA has been estimated to have mutation rates of ~3× or ~2.7×10<sup>−5</sup> per base per 20 year generation (depending on the method of estimation);<ref>{{cite journal |author=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=1079–89 |date=July 1999 |pmid=10388826 |pmc=1460660 |url=http://www.genetics.org/cgi/reprint/152/3/1079}}</ref> these rates are considered to be significantly higher than rates of human genomic mutation at ~2.5×10<sup>−8</sup> per base per generation.<ref name="Nachman">{{cite journal |author=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 |url=http://www.genetics.org/cgi/content/full/156/1/297}}</ref> Using data available from whole genome sequencing, the human genome mutation rate is similarly estimated to be ~1.1×10<sup>−8</sup> per site per generation.<ref name="Science">{{cite journal |author=Roach JC, Glusman G, Smit AF, ''et al.'' |title=Analysis of genetic inheritance in a family quartet by whole-genome sequencing |journal=Science |volume=328 |issue=5978 |pages=636–9 |date=April 2010 |pmid=20220176 |pmc=3037280 |doi=10.1126/science.1186802 |url=http://www.sciencemag.org/cgi/content/abstract/science.1186802}}</ref> |
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The rate for other forms of mutation also differs greatly from [[point mutations]]. An individual [[Microsatellite (genetics)|microsatellite]] locus often has a mutation rate on the order of 10<sup>−4</sup>, though this can differ greatly with length.<ref>http://www.genetics.org/content/164/2/781.full</ref> |
The rate for other forms of mutation also differs greatly from [[point mutations]]. An individual [[Microsatellite (genetics)|microsatellite]] locus often has a mutation rate on the order of 10<sup>−4</sup>, though this can differ greatly with length.<ref>{{cite journal |author=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=781–7 |date=June 2003 |pmid=12807796 |pmc=1462577 |url=http://www.genetics.org/content/164/2/781.full}}</ref> |
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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.<ref> |
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.<ref>{{cite web |first=Lauren |last=Gravtiz |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}}</ref> |
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==Mutational spectrum== |
==Mutational spectrum== |
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==Evolution== |
==Evolution== |
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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,<ref name=Altenberg>{{cite journal |author=Altenberg |
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,<ref name=Altenberg>{{cite journal |author=Altenberg L |title=An evolutionary reduction principle for mutation rates at multiple Loci |journal=Bull. Math. Biol. |volume=73 |issue=6 |pages=1227–70 |date=June 2011 |pmid=20737227 |doi=10.1007/s11538-010-9557-9 }}</ref> such as deleterious mutations, and the [[metabolism|metabolic]] costs of maintaining systems to reduce the mutation rate (such as increasing the expression of DNA repair enzymes.<ref name=Sniegowski>{{cite journal |author=Sniegowski P, Gerrish P, Johnson T, Shaver A |title=The evolution of mutation rates: separating causes from consequences |journal=Bioessays |volume=22 |issue=12 |pages=1057–66 |year=2000 |pmid=11084621 |doi=10.1002/1521-1878(200012)22:12<1057::AID-BIES3>3.0.CO;2-W |ref=harv}}</ref> or, as reviewed by Bernstein et al.<ref>{{cite journal |author=Bernstein H, Hopf FA, Michod RE |title=The molecular basis of the evolution of sex |journal=Adv. Genet. |volume=24 |pages=323–70, see p. 347 |year=1987 |pmid=3324702 }}</ref> having increased energy use for repair, coding for additional gene products and/or having slower replication). Second, 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.<ref name=Orr>{{cite journal |author=Orr HA |title=The rate of adaptation in asexuals |journal=Genetics |volume=155 |issue=2 |pages=961–8 |date=June 2000 |pmid=10835413 |pmc=1461099 |url=http://www.genetics.org/cgi/pmidlookup?view=long&pmid=10835413}}</ref> 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.<ref name=Lynch_1>{{cite journal |author=Lynch M |title=Evolution of the mutation rate |journal=Trends Genet. |volume=26 |issue=8 |pages=345–52 |date=August 2010 |pmid=20594608 |pmc=2910838 |doi=10.1016/j.tig.2010.05.003 |url=http://linkinghub.elsevier.com/retrieve/pii/S0168-9525(10)00103-4}}</ref> Viruses that use RNA as their genetic material have rapid mutation rates,<ref>{{cite journal |author=Drake JW, Holland JJ |title=Mutation rates among RNA viruses |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue=24 |pages=13910–3 |year=1999 |pmid=10570172 |pmc=24164 |url=http://www.pnas.org/content/96/24/13910.long |doi=10.1073/pnas.96.24.13910 |ref=harv}}</ref> which can be an advantage since these viruses will evolve constantly and rapidly, and thus evade the defensive responses of e.g. the human [[immune system]].<ref>{{cite journal |author=Holland J, Spindler K, Horodyski F, Grabau E, Nichol S, VandePol S |title=Rapid evolution of RNA genomes |journal=Science |volume=215 |issue=4540 |pages=1577–85 |year=1982 |pmid=7041255 |doi=10.1126/science.7041255 |ref=harv}}</ref> |
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Studies have shown that treating [[RNA virus]]es 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.<ref name="Crotty"> |
Studies have shown that treating [[RNA virus]]es 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.<ref name="Crotty">{{cite journal |author=Crotty S, Cameron CE, Andino R |title=RNA virus error catastrophe: direct molecular test by using ribavirin |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=98 |issue=12 |pages=6895–900 |date=June 2001 |pmid=11371613 |pmc=34449 |doi=10.1073/pnas.111085598 |url=http://www.pnas.org/cgi/content/full/98/12/6895}}</ref> This is termed [[error catastrophe]]. |
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==References== |
==References== |
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Revision as of 02:50, 1 November 2014
In genetics, the mutation rate is a measure of the rate at which various types of mutations occur over time. Mutation rates are typically given for a specific class of mutation, for instance point mutations, small or large scale insertions or deletions. The rate of substitutions can be further subdivided into a mutation spectrum which describes the influence of genetic context on the mutation rate.
There are several natural units of time for each of these rates, with rates being characterized either as mutations per base pair per cell division, per gene per generation, or per genome per generation. The mutation rate of an organism is an evolved characteristic and is strongly influenced by the genetics of each organism, in addition to strong influence from the environment. The upper and lower limits to which mutation rates can evolve is the subject of ongoing investigation.
Background
Different genetic variants within a species are referred to as alleles, and so a new mutation is said to 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 [1] 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. As a result of natural selection, unfavorable mutations will typically be eliminated from a population while favorable changes are quickly fixed, and neutral changes accumulate at the rate they are created by mutations.
Measurement
An organism's mutation rates can be measured by a number of techniques.
Substitution Rates
Many sites in an organism's genome may not admit mutations with large 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, despite the fact that 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.[2]
Mutation Accumulation Lines
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 intestinal bacteria, round-worms, yeast, fruit flies, small annual plants,[3] Paramecium, mutation accumulation lines.
Variation in mutation rates
Mutation rates differ between species and even between different regions of the genome of a single species. 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). In fact, 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.[citation needed]
In general, the mutation rate in unicellular eukaryotes and bacteria is roughly 0.003 mutations per genome per generation.[4] 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.[4] 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);[5] these rates are considered to be significantly higher than rates of human genomic mutation at ~2.5×10−8 per base per generation.[6] 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.[7]
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.[8]
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.[9]
Mutational spectrum
The mutation spectrum of an organism is the rate at which different mutations occur at different sites. Typically two sites are considered, each of which may have three mutations, resulting in six total rates for most mutation spectra. The two sites are the two correct pairs possible in DNA: A:T pairs and C:G pairs;
There is a systematic difference in rates for transitions (Alpha) and transversions (Beta).
Evolution
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,[10] 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.[11] or, as reviewed by Bernstein et al.[12] having increased energy use for repair, coding for additional gene products and/or having slower replication). Second, 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.[13] 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.[14] Viruses that use RNA as their genetic material have rapid mutation rates,[15] which can be an advantage since these viruses will evolve constantly and rapidly, and thus evade the defensive responses of e.g. the human immune system.[16]
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.[17] This is termed error catastrophe.
References
- ^ Eyre-Walker A, Keightley PD (August 2007). "The distribution of fitness effects of new mutations". Nat. Rev. Genet. 8 (8): 610–8. doi:10.1038/nrg2146. PMID 17637733.
- ^ Wielgoss S, Barrick JE, Tenaillon O; et al. (August 2011). "Mutation Rate Inferred From Synonymous Substitutions in a Long-Term Evolution Experiment With Escherichia coli". G3 (Bethesda). 1 (3): 183–6. doi:10.1534/g3.111.000406. PMC 3246271. PMID 22207905.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ Ossowski S, Schneeberger K, Lucas-Lledó JI; et al. (January 2010). "The rate and molecular spectrum of spontaneous mutations in Arabidopsis thaliana". Science. 327 (5961): 92–4. doi:10.1126/science.1180677. PMC 3878865. PMID 20044577.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ a b Drake JW, Charlesworth B, Charlesworth D, Crow JF (April 1998). "Rates of spontaneous mutation". Genetics. 148 (4): 1667–86. PMC 1460098. PMID 9560386.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Schneider S, Excoffier L (July 1999). "Estimation of past demographic parameters from the distribution of pairwise differences when the mutation rates vary among sites: application to human mitochondrial DNA". Genetics. 152 (3): 1079–89. PMC 1460660. PMID 10388826.
- ^ Nachman MW, Crowell SL (September 2000). "Estimate of the mutation rate per nucleotide in humans". Genetics. 156 (1): 297–304. PMC 1461236. PMID 10978293.
- ^ Roach JC, Glusman G, Smit AF; et al. (April 2010). "Analysis of genetic inheritance in a family quartet by whole-genome sequencing". Science. 328 (5978): 636–9. doi:10.1126/science.1186802. PMC 3037280. PMID 20220176.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ Whittaker JC, Harbord RM, Boxall N, Mackay I, Dawson G, Sibly RM (June 2003). "Likelihood-based estimation of microsatellite mutation rates". Genetics. 164 (2): 781–7. PMC 1462577. PMID 12807796.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Gravtiz, Lauren (28 June 2012). "Lack of DNA modification creates hotspots for mutations". Simons Foundation Autism Research Initiative.
- ^ Altenberg L (June 2011). "An evolutionary reduction principle for mutation rates at multiple Loci". Bull. Math. Biol. 73 (6): 1227–70. doi:10.1007/s11538-010-9557-9. PMID 20737227.
- ^ Sniegowski P, Gerrish P, Johnson T, Shaver A (2000). "The evolution of mutation rates: separating causes from consequences". Bioessays. 22 (12): 1057–66. doi:10.1002/1521-1878(200012)22:12<1057::AID-BIES3>3.0.CO;2-W. PMID 11084621.
{{cite journal}}: Invalid|ref=harv(help)CS1 maint: multiple names: authors list (link) - ^ Bernstein H, Hopf FA, Michod RE (1987). "The molecular basis of the evolution of sex". Adv. Genet. 24: 323–70, see p. 347. PMID 3324702.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Orr HA (June 2000). "The rate of adaptation in asexuals". Genetics. 155 (2): 961–8. PMC 1461099. PMID 10835413.
- ^ Lynch M (August 2010). "Evolution of the mutation rate". Trends Genet. 26 (8): 345–52. doi:10.1016/j.tig.2010.05.003. PMC 2910838. PMID 20594608.
- ^ Drake JW, Holland JJ (1999). "Mutation rates among RNA viruses". Proc. Natl. Acad. Sci. U.S.A. 96 (24): 13910–3. doi:10.1073/pnas.96.24.13910. PMC 24164. PMID 10570172.
{{cite journal}}: Invalid|ref=harv(help) - ^ Holland J, Spindler K, Horodyski F, Grabau E, Nichol S, VandePol S (1982). "Rapid evolution of RNA genomes". Science. 215 (4540): 1577–85. doi:10.1126/science.7041255. PMID 7041255.
{{cite journal}}: Invalid|ref=harv(help)CS1 maint: multiple names: authors list (link) - ^ Crotty S, Cameron CE, Andino R (June 2001). "RNA virus error catastrophe: direct molecular test by using ribavirin". Proc. Natl. Acad. Sci. U.S.A. 98 (12): 6895–900. doi:10.1073/pnas.111085598. PMC 34449. PMID 11371613.
{{cite journal}}: CS1 maint: multiple names: authors list (link)