Mutation
-definition
-mutation types
-mutation rates
-phylogeny
-controversies
There are three ways of estimating the human mutation rate. The Biochemical Method is based on the known error rate of DNA replication and the average number of cell divisions between generations. It gives a rate of about 130 mutations per generation.
The Phylogenetic Method assumes that a large fraction of mammalian genomes is evolving at the neutral rate because it is junk DNA. Since we know that the rate of fixation of neutral alleles is equal to the mutation rate, we can estimate the mutation rate if we know the total number of nucleotide difference between two species (e.g. humans and chimpanzees) and the approximate time of divergence from a common ancestor. This gives an estimate of about 112 mutations per generation.
The third method is to sequence the genomes of a mother, a father, and a child and count the new mutations that show up in the child. This is the Direct Method and it yields values of 60-100 mutations per generation. The direct method would seem to be the best method but it turns out to be very difficult to identify true de novo mutations from sequencing errors and somatic mutations. There's reason to believe that the direct method underestimates the real mutation rate so the most common mutation rate is often taken to be about 100 mutations per generation.
This value (100 mutations per generation) is likely to be reasonably accurate but there's still considerable controversy surrounding these estimates [Human mutation rates] [Human mutation rates - what's the right number?].
The latest attempt at a direct method has recently been published in Nature (Porubsky et al., 2025). The authors looked at 28 members of a four-generation family and sequenced their genomes using the latest technology. This yielded genome sequences that include highly repetitive regions such as centromeres. The results showed an average of 82 single nucleotide mutations and small indels (insertions and deletions) in the unique sequence part of the genome. This is consistent with earlier estimates using just trios (mother, father, child) and older technology.
The new finding is that there are about 65 additional indels and structural variants in the tandem repeat regions of the genome. The authors are convinced that these are true de novo mutations but as far as I can tell the result is highly dependent on the software used to align the sequences and identify differing numbers of repeats. The final tally reported by the authors is between 98 and 206 de novo mutations per generation with an average of 152 mutations per generation.
I still think we can use 100 mutations per generation as a reasonable approximation of the mutation rate in humans.
The press release from the University of Utah is full of the usual hype: Our DNA May Evolve Much Faster Than Previously Thought.
Scientists from University of Utah Health, the University of Washington, PacBio, and other institutions have used advanced DNA sequencing technologies to create the most detailed map of genetic change across generations. Their study revealed that certain parts of the human genome change far more rapidly than previously believed, opening the door to deeper insights into the origins of human disease and evolution.
... The researchers estimate that every human has nearly 200 new genetic changes that are different from either parent. Many of these changes occur in regions of DNA that are especially difficult to study.
Porubsky, D., Dashnow, H., Sasani, T.A., Logsdon, G.A., Hallast, P., Noyes, M.D., Kronenberg, Z.N., Mokveld, T., Koundinya, N., Nolan, C. et al. (2025) Human de novo mutation rates from a four-generation pedigree reference. Nature: online [doi: 10.1038/s41586-025-08922-2]
Understanding the human de novo mutation (DNM) rate requires complete sequence information1. Here using five complementary short-read and long-read sequencing technologies, we phased and assembled more than 95% of each diploid human genome in a four-generation, twenty-eight-member family (CEPH 1463). We estimate 98–206 DNMs per transmission, including 74.5 de novo single-nucleotide variants, 7.4 non-tandem repeat indels, 65.3 de novo indels or structural variants originating from tandem repeats, and 4.4 centromeric DNMs. Among male individuals, we find 12.4 de novo Y chromosome events per generation. Short tandem repeats and variable-number tandem repeats are the most mutable, with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length and sequence identity. We show a strong paternal bias (75–81%) for all forms of germline DNM, yet we estimate that 16% of de novo single-nucleotide variants are postzygotic in origin with no paternal bias, including early germline mosaic mutations. We place all this variation in the context of a high-resolution recombination map (~3.4 kb breakpoint resolution) and find no correlation between meiotic crossover and de novo structural variants. These near-telomere-to-telomere familial genomes provide a truth set to understand the most fundamental processes underlying human genetic variation.
14 comments :
random Mutation are always deleterious, they always show deteriorating effects, they always degrade the informational contents of the genome ... There are no such a thing as neutral mutation. As an software engineer would never be lives that random noises can generate a new code of non-deterimetal impact. That is the nature of information. Information can never tolerate random noise
Literally every single sentence you wrote is known to be false and you should feel shame for having been brainwashed to write something so fantastically stupid.
Pretty sure that was Byers. No brain to wash.
I have a basic question (and I am NOT the other anonymous). It was said that the rate of fixation of neutral alleles should equal the rate of mutation. But I would expect that the rate of fixation would be 1/2 of the rate of mutation, since 1/2 could be fixed by drift and the other 1/2 could go to extinction by drift.
@Anonymous You may be correct that the rate of fixation is one half the mutation rate of 100 mutations per individual per generation but not for the reasons you suggest.
I'm consulting an expert to see if I've made an error by counting the number of mutations per diploid individual instead of the number of mutations per locus.
OK, the probability of fixation of a neutral mutation is its frequency, which for a new mutation is 1/2Ne, and the number of such mutations per generation is 2Neµ, so just do the math. The number fixed per generation is just µ.
@John Harshman Let's assume that there are 100 new mutations in a newborn baby. Since there are N babies per generation this means that there are 100N new mutations introduced into the population per generation.
Assuming that all these mutations are neutral, the probability of fixation for each one is 1/2N. Do the math. There are 50 neutral mutations fixed in the population each generation.
The textbook calculations define the mutation rate (µ) as the rate of mutation per gene or per locus. Since there are two loci in a diploid organism, this means that there are 2Nµ new mutations per generation. This is why the rate of fixation in the population is µ per generation using that definition of mutation rate.
My value of 100 new mutations per INDIVIDUAL already takes diploidy into account since I'm adding the mutations from egg and sperm. This is why I think I've been overestimating the rate of fixation by a factor of 2.
Larry, I think you may be mixing two incompatible definitions of µ here. Under your definition, mutations per individual, the initial frequency of a mutation is 1/N, and population size still cancels out, leaving us with 100 fixations in the population per generation.
@John Harshman I don't think that's right. There are 100 new mutations per individual but these are all single mutations at a single locus. There are still 2N loci in the population and all of them have to be changed to the new allele if it's going to be fixed in the population.
You could make the entire population heterozygous for the new allele so that every single individual carried a single copy but it still wouldn't be fixed in the population.
But you are right about one thing. There are, indeed, two incompatible definitions of mutation rate and that's the problem.
I am unclear as to whether the issue here is the neutral substitution rate implied, or the mutational load implied. For the former, if there are L "loci", in a diploid population of N individuals, the substitution rate per (neutrally mutating) locus will be the per-copy mutation rate µ. Then with 100 mutations per individual, at 2L copies, the per-copy mutation rate will be 100/(2L). The L loci will then each have 100/(2L) mutations per locus, so 100/2 substitutions per generation if all these mutations are neutral.
@Joe Felsenstein I agree. There will be 50 (100/2) substitutions per generation. I've been incorrectly using 100 substitutions per generation.
Yeah, I guess so. It's simpler to forget µ by any definition and just consider the 100 mutations per individual, 100N in the population, each with a probability of 1/2N of becoming fixed. So the mean number in a generation that will become fixed is 100N/2N, or 50.
Another way to see that the rate of neutral substitution is the mutation rate per copy is to consider a copy of a gene in you, and then think about its ancestor copy in one of your parents, the ancestor of that in one of their parents, and so on back, say 1,000,000 years. How many (neutral) substitutions will your gene and the copy in that ancestor have undergone? Clearly it will be the rate of mutation per copy per generation, times the number of generations. Or, if more relevant, the rate of mutation per copy per year times the number of years.
I should have said "How many (neutral) substitutions will your gene have undergone since the copy in that ancestor?"
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