The Wikipedia section on substitution rates (shown below) isn't clear to me. What's the precise definition and difference between mutation and substitution rates, and how do they relate to each other?

Substitution Rates

Many sites in an organism's genome may admit mutations with small 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.

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2 Answers 2


@Tyersome's answer is correct if you consider that the only mutations that occur will result in substitutions. This is false for biology, if true for how the subject is commonly talked about. (I realize that I'm in the uncomfortable position of saying that Rich Lenski is being imprecise about his evolutionary terminology). In fact probably a rather larger proportion of mutations will result in other kinds of DNA modifications.

For those unfamiliar with the different kinds of mutations, substitutions (also called point mutations) are only one class of mutation. Other kinds include transpositions, inversions, insertions, deletions, and many many more.

In other words, the "mutation rate" is probably >2X higher than the "substitution mutation rate", and I suppose since I'm getting very involved with my terminology, we could then say that there is an "accepted substitution rate" (the same as the "substitution rate" that people talk about) and an "accepted mutation rate" which includes all substitutions but then also all other kinds of mutations that are incorporated as laid out in the quote above. (I have made up all the terms other than "substitution rate" and "mutation rate" to emphasize that I think the usage of terminology from the Barrick and Lenski article is extremely misleading).

We tend to focus on substitutions because they are easy to understand and our math works well for them. Thus when people write about the "mutation" rate they have a tendency to use it to mean the "mutations that lead to substitutions" rate. But that's an approximation for mathematical convenience rather than reflecting real biology.

It's good to recall that when Hugo de Vries wrote "The Mutation Theory" >100 years ago the mutations he was talking about were not substitutions but changes in ploidy- those are absolutely mutations, but they have nothing to do with substitution. In plants changes in ploidy are among the most phenotypically dramatic class of mutation, but those are invisible to analysis of substitutions.

Of course, the approximation for mathematical convenience has more or less taken over the field, so from that perspective @Tyersome's answer is perfectly correct, and it does directly address your specific question. But I think that there are problems with how the field in general thinks about this.

(Forgive me for being pedantic, I wrote a review on the topic: https://www.cell.com/trends/genetics/fulltext/S0168-9525(19)30012-5)

  • $\begingroup$ Thanks Maximilian. Very helpful. I noticed you introduced several terms here that would be great to define more precisely (e.g. you mentioned "substitution mutation rate", "accepted substitution rate", and "accepted mutation rate", not sure if there are others). Perhaps this could be an answer with a preamble that describes the basic entities, mechanics and steps involved, followed by definitions with their corresponding Eqs. I would love to help if you can point me to the right info. This is a good time for people to learn more and become more interested inabout virology / genomics :). $\endgroup$ Commented Mar 21, 2020 at 18:50
  • $\begingroup$ updated answer to reflect that these are terms that I made up on the spot, to underline how Barrick and Lenski's "mutation rate" is actually just one way people use that term. $\endgroup$ Commented Mar 21, 2020 at 19:54
  • $\begingroup$ (I also clarify that "substitution" has a very specific meaning in terms of the kind of modification to DNA that occurs) $\endgroup$ Commented Mar 21, 2020 at 19:55
  • $\begingroup$ Ok thanks. That's helpful. I think I get it now. From what you are describing a substitution is just one type of change (a single point nucleotide change specifically). I somehow understood "substitution" to mean directly the "acceptance" (i.e. take over) of an entirely new chain, i.e. a whole new chain "substituting" (displacing) a chain (e.g. a viral strain) that is prevalent in a population. What you are saying makes sense, i.e. there many other types of changes that can take place in replication that don't need to be simple single nucleotide substitutions. $\endgroup$ Commented Mar 21, 2020 at 20:28
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    $\begingroup$ Ok, glad to have cleared that all up! I will take a look at the other question. $\endgroup$ Commented Mar 21, 2020 at 20:31

The mutation rate is the rate at which mutations happen — i.e. the rate at which "mistakes" are generated.

The substitution rate is the rate at which mutations are accepted — i.e. the rate at which "mistakes" become incorporated into a genome.

The difference is due to selection — if a mutation happens that results in an essential protein becoming non-functional that mutation will tend to be purged and thus won't be "accepted".

A relatively clear discussion of these differences:

Box 1

Mutation rates versus substitution rates

It is important to distinguish between the rate at which spontaneous mutations occur and the rate at which genetic changes accumulate in a surviving lineage. The MUTATION RATE reflects the probability of a change in genome sequence between a parent and its offspring. It is the compound result of unrepaired DNA damage, polymerase errors, intragenomic recombination events, movements of transposable elements, and other molecular processes that introduce errors during the transmission of genetic information. However, only those mutations in lineages that persist — typically in the face of selection — contribute to the SUBSTITUTION RATE measured by whole-genome sequencing. The failure to carefully distinguish between these two types of rates is a persistent cause of confusion and misconceptions about whether mutations are random. In the same vein, the frequency of a mutant allele in a population generally does not equal the rate at which the corresponding mutational event occurs.

From: Barrick, J. E., & Lenski, R. E. (2013). Genome dynamics during experimental evolution. Nature Reviews Genetics, 14(12), 827-839.

You may also find the following article to be of interest: Yi, S. (2013) Neutrality and Molecular Clocks. Nature Education Knowledge 4(2):3 .

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    $\begingroup$ When you say "accumulate", or "become incorporated into a genome", you obviously mean the genome of an entire population (e.g. species of virus in this case), not a single virion, right? $\endgroup$ Commented Mar 19, 2020 at 23:39
  • $\begingroup$ Also, is it fair to say that the substitution rate is the rate at which the mutation in question increases its population share (%) over the entire population? If so, what are the units for it? $\endgroup$ Commented Mar 19, 2020 at 23:48
  • $\begingroup$ 1) Yes, you could think mutations as being accepted in the "gene pool". 2) No, I don't think that is correct. These are measures of new mutations either being generated (mutation rate) or being accepted (substitution rate). {I'll change the wording in my post since I see that accumulation is open to misunderstanding.} $\endgroup$
    – tyersome
    Commented Mar 20, 2020 at 0:54
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    $\begingroup$ This answer is not accurate. Probably only a minority of mutations that occur in any given genome would result in a "substitution" if "accepted"- a much larger proportion consist of expansion and contractions of satellite DNA. There is a bit of an ascertainment bias in how we think about mutations because substitutions are easy to "see" using most sequencing technologies. $\endgroup$ Commented Mar 21, 2020 at 16:47
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    $\begingroup$ I downvoted this answer because I was feeling grouchy and it touched on a pet peeve of mine, but upon reflection I decided that I was wrong to do so. The time window for changing that has passed, nonetheless I wanted to comment a symbolic +1 back in. $\endgroup$ Commented Mar 21, 2020 at 17:38

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