Mutation rate

In genetics, the mutation rate is the chance of a mutation occurring in an organism or gene in each generation (or, in the case of multicellular organisms, cell division). The mutation frequency is the number of individuals in a population with a particular mutation, and tends to be reported more often as it is easier to measure (for instance, there is no need to restrict the population to experiencing only one generation, as needed to measure mutation rate). This is important in fields such as evolutionary biology and oncology.

In evolutionary biology, mutations can have a neutral, favorable or unfavorable effect on the organism, with respect to the present environment. The effect of a low mutation rate on a population is that few variations are available to respond to sudden environmental change. This means the species is slower to adapt. A higher mutation rate damages more individuals, but by increasing variation in the population could increase the speed at which the population can adapt to changing circumstances. The majority of mutations in a multi-cellular organism's genome are neutral and do not harm the organism^[1]. Occasional mutations are unfavorable, and rarely a mutation will be favorable. As a result of natural selection, unfavorable mutations will typically be eliminated from a population while favorable and neutral changes accumulate. The rate of elimination or accumulation depends on how unfavorable or favorable the mutation is.

There appear to be limits on how advantageous a high mutation rate can be, and there is evidence that mutation rates (as determined by polymerase fidelity) are under selection to be neither too high, nor too low. An exciting extension of the idea that mutation rates can be too high is that drugs can be used to increase the mutation rates of pathogens to intolerable levels. 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^[2]. This is termed error catastrophe.

Species

Mutation rates differ between species and even between different regions of the genome of a single species. This should not be confused with the idea that mutations accumulate at different rates over longer periods of time than a generation. These different rates of nucleotide substitution are measured in substitutions (fixed mutations) per base pair per generation. For example, mutations in so-called Junk DNA which do not affect organism function 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.^[1][3]

In general, the mutation rate in eukaryotes and bacteria is roughly 10⁻⁸ per base pair per generation.^[4] The highest 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^[1]. 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 ^[6].

The rate for other forms of mutation also differs wildly from point mutations. An individual microsatellite locus often has a mutation rate on the order of 10⁻⁴, though this can differ wildly with length.^[7]

Mutational spectrum

Transitions (Alpha) and transversions (Beta).

There is a systematic difference in rates for transitions (Alpha) and transversions (Beta).

Evolution

There are three theories on what determines the evolution of mutation rate. The optimal mutation rate of organisms may be determined by a trade-off between costs of a high mutation rate, such as deleterious mutations, and the metabolic costs of maintaining systems to reduce the mutation rate, such as DNA repair enzymes.^[8] Additionally, 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.^[9] 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.^[10] Viruses that use RNA as their genetic material have rapid mutation rates,^[11] 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.^[12]

References

1. ^ ^{a b c} Estimate of the Mutation Rate per Nucleotide in Humans M. W. Nachman, S. L. Crowell, Genetics 156, 297-304, 2000
2. ^ RNA virus error catastrophe Crotty et al. PNAS 2001
3. ^ Mutation rates in mammalian genomes, S. Kumar, S. Subramanian, Proc. of the NAS 99, 803–808. 2002
4. ^ ^{a b} Rates of Spontaneous Mutation Drake et al. Genetics, 1998
5. ^ Estimation of Past Demographic Parameters From the Distribution of Pairwise Differences S. Schneider, L. Excoffier, 1999
6. ^ Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing Roach et al. Science, 2010
7. ^ http://www.genetics.org/content/164/2/781.full
8. ^ 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. 
9. ^ Orr, A. (2000). "The Rate of Adaptation in Asexuals". Genetics 115: 961–968. 
10. ^ Lynch, M. (2010). "Evolution of the mutation rate". Trends in Genetic 26 (8): 345–352. 
11. ^ 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. http://www.pnas.org/content/96/24/13910.long. 
12. ^ 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. 

See also

• Allele frequency
• Evolvability
• Luria–Delbrück experiment
• Mutation