Mutation rate refers to the frequency of new mutations per generation in an organism or a population. Mutation rates can be determined fairly precisely in experimental organisms with short generation times, such as bacteria or fruit flies. Human mutation rates are more difficult to determine accurately. Mutation rates can be used as a "molecular clock" to determine the time since two species diverged during their evolution.
Measurements of Mutation Rate
Mutation rate is often difficult to measure. The frequency of existing mutations in a population is not a good indication of the mutation rate, since a single mutation may be passed on to many offspring. In addition, there are often selective pressures that increase or decrease the frequency of a mutation in a population.
Mutation rates differ widely from one gene to another within an organism and between organisms. Generally mutation rates in bacteria are about one mutation per one hundred million genes per generation. While this sounds quite low, consider that the Escherichia coli bacteria in our intestines produce more than 20 billion new bacteria every day, each of which has approximately four thousand genes. This works out to about ten million new mutations in the population every day. In mice, the rate is about one mutation per ten thousand genes per generation. While this is much larger than the rate for bacteria, the mouse generation time is also much greater.
Human Mutation Rates
The appearance of rare dominant genetic diseases, such as retinoblastoma, have been used to estimate the mutation rate in the human population. Retinoblastoma is a childhood cancer of the eye and was a lethal condition until recently. Hence almost every case represented a new mutation (because individuals with the condition did not survive to reproduce and pass the genetic propensity for the disease along to their offspring), and the mutation rate could thus be readily estimated. Modern methods indicate that the mutation rate is roughly one mutation per 10,000 genes per generation. With at least 30,000 genes, this means that each person harbors about three new mutations, although this estimate may be off by a factor of ten. There are many more mutations in non-coding portions of DNA, but these are fairly difficult to study because they have no effect on the phenotype of the person.
About 90 percent of human mutations arise in the father rather than the mother. This may be related to the difference in the number of cell divisions required to produce a sperm versus an egg; sperm are produced late in a male's development, compared to eggs, which are produced quite early in the development of a female. Older parents pass on more mutations, and these may be either mutations within a gene or chromosomal aberrations, which are deletions or rearrangements of the chromosomes and involve many genes. Human mutation rates are generally quite similar worldwide. The exception is in local populations that have been exposed to radioactivity from nuclear testing or other sources.
Factors Influencing the Mutation Rate
Within a single organism, the mutation rate of two genes can differ by a thousandfold or more, so within a species some mutations may be very rare and others quite common. Exposures to very high doses of very potent mutagens can increase the mutation rate per generation by more than a hundredfold.
Both the nature of the gene and its environment can influence the mutation rate. The size of the gene, its base composition, its position in the genome, and whether or not it is being actively transcribed influence its mutation rate. The dystrophin gene, mutated in Duchenne muscular dystrophy, is thought to have a mutation rate of one in every ten thousand births, while the gene, mutated in Huntington's disease, has a mutation rate of closer to one in one million. The explanation for this difference is, at least in part, gene size: The dystrophin gene is one of the largest known. Genes whose promoter regions have been silenced by methylation (the addition of-CH3 units to cytosine bases) are more likely to be mutated, since methylcytosine is easily converted to a base that resembles thymine.
In addition, the repair capacity of the organism can be important in determining how many mutations ultimately remain in the genome. For example, Bloom syndrome, a human cancer-causing condition, causes a decreased ability to repair DNA damage and an elevated mutation rate. Exposure to environmental mutagens or to protective agents, possibly dietary, can alter the mutation rate. Since the mutation rate is partly under genetic control, it is a selected characteristic of an organism, with the burden of detrimental mutations being balanced by the benefit of rare favorable mutations that are adaptive and permit evolution of the species.
One important factor influencing observed mutation rates is the means by which mutations are detected, as some methods may detect a changes at only one or two base pairs of a specific gene, leaving others undetected. Obviously the mutation rate observed by such methods will be lower than if more altered bases could be detected.
Mutations can also change a mutated gene back to the normal, wild-type form of the gene. Such "back" mutations are typically much rarer than "forward" mutations. This is because the number of ways to inactivate a gene is much greater than the number of ways to fix it. Imagine there are 1,000 bases that could be changed to produce a forward mutation. To reverse one of these mutations, it is necessary to change the one specific base pair that has mutated, and to change it back to the base it was before, rather than to a different one. Therefore, a back mutation rate of less than 1 one-thousandth of the forward rate would be expected.
The Origin of Spontaneous Mutations
The causes of most spontaneous mutations is not known, so the main factors affecting the spontaneous mutation rates are obscure. It is likely that the methylation of cytosine in the DNA is important for many spontaneous mutations, because many are found at sites in the genes where cytosine is methylated. Ionizing radiations, such as cosmic rays, probably account for less than 10 percent of spontaneous mutations. Other factors are errors made during replication of the DNA; exposure to mutagens produced by cells during their normal metabolic activity, with reactive oxygen species being the common suspect; spontaneous breakdown of DNA at body temperatures; and exposure to environmental agents. Many mutations are made when the mechanisms that repair DNA make mistakes, and many error-prone DNA repair enzymes are known.
While it may seem unlikely, it is believed that the overall mutation rate within a species does not vary much over long periods of time. This means that the mutation rate serves as a "molecular clock." The clock can be used to determine the time since the evolutionary divergence of two species. Two organisms with very few DNA sequence differences between them diverged more recently than two that display more accumulated differences. The absolute amount of time for these divergences can be determined if the clock is calibrated, that is, if a known number of sequence differences can be correlated with a known time since divergence. This is done by comparing sequence data with data from the fossil record.
Early work in this field concentrated on a small handful of genes and gave conflicting results. Because mutation rates vary among genes, the best results come from analyzing changes in many genes. A 1998 study of the evolution of mammals analyzed 658 nuclear genes from 207 vertebrate species. It showed that the ancestors of most contemporary mammals arose more than 80 to 110 million years ago, long before the extinction of dinosaurs, and demonstrated that the fossil record from that time has some very large gaps in it.
see also Carcinogens; DNA Repair; Gene; Methylation; Molecular Anthropology; Muscular Dystrophy; Mutagen; Mutation.
Crow, J. F. "The High Spontaneous Mutation Rate: Is It a Health Risk?" Proceedings of the National Academy of Science 94 (1997): 8380-8386.
Griffiths, Anthony J. F., et al. An Introduction to Genetic Analysis. New York: W. H.Freeman, 2000.
Kumar, Sudhir, and S. Blair Hedges. "A Molecular Timescale for Vertebrate Evolution." Nature 392 (1998): 917-920.