What Is a Mutation?
Estimating the Human Mutation Rate: Biochemical Method
There are basically three ways to estimate the mutation rate in the human lineage. I refer to them as the Biochemical Method, the Phylogenetic Method, and the Direct Method1.
The phylogenetic method relies on a known phylogenetic tree to pick out close relatives and the approximate time to the last common ancestor. In the case of humans, we know that chimpanzees and bonobos are our closest cousins and we think that the homind line diverged from the chimp line about 5 million years ago.
If we count mutations in chimps and humans we can assume that these mutations have been accumulating since the time of the last common ancestor. This can be converted to a mutation rate if we know that the mutations are neutral. That's because, according to population genetics, the rate of fixation of neutral alleles by random genetic drift is equal to the mutation rate.
Many studies have been done to estimate the mutations rate in the hominid lineage. I'll just mention two to illustrate the principle.
Nachman and Crowell (2000) looked at silent mutations in eighteen pseudogenes common to chimps and humans. They found a total of 199 substitutions in 16,086 nucleotides. Converting this to a mutation rate requires several assumptions. If we assume that equal numbers of mutations occurred in each lineage (~100) then the mutation rate works out to ~2.5 × 10-8 mutations per nucleotide. This calculation depends on the time since divergence (~5 million years), the generation time (they assumed about 25 years), and to some extent the population size (about 10,000).
That mutation rate corresponds to 160 mutations per diploid genome per generation.
160 mutations per generation
You can also calculate a mutation rate from the total differences in the (almost) complete sequences of the human and chimpanzee genomes. The human genome is a finished genome so it's quite reliable. The chimp genome is less reliable but good enough to gives us a ballpark estimate. The differences (substitutions and small deletions only) amount to 1.4% of the genomes or 44.8 million mutations.
Assuming that equal numbers of mutations occurred in each lineage this gives 22.4 million mutations that have become fixed in the human lineage since diverging from our common ancestor with chimpanzees.2 If the species diverged 5 million years ago and the generation time is 25 years then this gives a mutation rate of 112 mutations per generation.
112 mutations per generation
These mutation rates depend on the time since divergence or the time of the last common ancestor. In the case of chimps and humans, the estimate of 5 My is roughly compatible with the fossil record but the date is not well established by fossils. There's still some controversy. Many scientists think that the date should be older. If the two lineages diverged 6 My ago, then the mutation rate would be 93 mutations per generation.
The rate also depends on estimates of generation time. Human generation times are consistently underestimated compared to the actual data on modern humans. The data indicate an average generation time of 30 years and that's consistent with genealogical studies (Langergraber et al., 2012).3 Chimpanzee generation time in the wild averages 25 years (Langergraber et al., 2012).
The longer the generation time the higher the mutation rate. But differences in the generation time between chimp and human lineages means that more mutations are fixed in the chimpanzee lineage that the human lineage and this reduces the calculated mutation rate.
Using the phylogenetic method, we may not be able to calculate a precise mutation rate for humans but most of the values seem likely to be in the range of 100-150 mutations per generation and that's similar to the mutation rate calculated from our knowledge of biochemistry and molecular biology.
[Image Credits: The phylogenetic tree is from Locke et al. (2011)]. The chimp photo is from Wikipedia]
1. The traditional estimates were based on the analysis of the frequency of new disease loci in human populations. The classic paper by Haldane (1949) is now available online. The problem with those classic estimates if that most of the mutations were in hot spots—that's why they occur so frequently. Recently Kondrashov (2002) estimated the mutation rate from 20 disease loci that appear to arise from "normal" mutation rates. His estimate is 115 mutations per generation a value that's consistent with both the biochemical rate and the phylogenetic rate.
2. There are probably fewer mutations in the human lineage because the generation times were a bit longer. Not all of the differences are due to mutations that have become fixed in the chimp and human populations but this is probably a small fraction of the 44.8 million differences.
3. My wife and I share a common ancestor who was born about 1350. We are 18th cousins and that gives a generation time of about 31 years.
Haldane, J.B.S. (1949) The rate of mutation of human genes. Hereditas 35(S1):267-273. [doi: 10.1111/j.1601-5223.1949.tb03339.x]
Kondrashov, A.S. (2002) Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Human mutation 21:12-27. [doi: 10.1002/humu.10147
Langergraber, K.E., et al. (2012) Generation times in wild chimpanzees and gorillas suggest earlier divergence times in great ape and human evolution. Proc. Natl. Acad. Sci. (USA) 109:15716-15721. [doi: 10.1073/pnas.1211740109]
Locke, D.P., et al. (2011) Comparative and demographic analysis of orang-utan genomes. Nature 469:529-533.
Nachman, M.W. and Crowell S.L. (2000) Estimate of the mutation rate per nucleotide in humans. Genetics 156:297-304.