Effect on fitness of mutations

Question

What is the distribution/probability density function (PDF) of impacts on fitness of new mutations?

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I very welcome any partial answer that does not give the whole PDF but just some information about the expected value or the variance of this distribution. Information of the kind: "If we consider only beneficial mutations, then the PDF is $P(X=x) = f(x)$" are also welcome.

When I say mutations, one might have want to reduce the concept of mutations only to indels and point mutations.

Of course the answer will depend on the species under consideration and from population to population but I welcome any answer that could give some insights. Eventually, some information according to what is generally assumed to be the PDF of effects on fitness of new mutations might be useful.

Here is a related question

Here is an article that assumes an exponential distribution of effects on fitness of beneficial mutations.

Answer 1

To a good first approximation $\overline{\Delta f} = 0$. Where $\overline{\Delta f}$ is the mean change in fitness down to any point or indel mutation. The reasons for this are as follows:

1. In the genome of higher organisms, most of the genome is non-functional ("junk") so most mutations will not have any effect regardless of the change made.
2. A substantial proportion of in-frame point mutations will be synonymous mutations that result in the same amino acid being coded for (actually this can have an effect on protein expression but I don't believe anyone has - yet - shown a fitness difference?)
3. Even where a mutation does alter an amino acid many amino acid changes have no measurable effect on the protein produced. Especially where the new amino acid has similar properties to the one it has replaced.
4. Even when a mutation does alter the protein function, or render the product non-functional, in many cases this will not impact fitness since fitness is conditional on the environment in which it is measured and not all genes impact all environments.

So the distribution, whatever it is, will have a large spike at 0. Probably this spike is several orders of magnitude higher than the next highest value. Further, we can be reasonably certain that $\overline{\Delta f} < 0$ since there are more possible ways to break a Gene through a point or indel mutation than there are to improve it. If this is the case, so that there is a large excess of mutations with a negative effect on fitness, we can conclude that the distribution of mutational changes in fitness will be non-normal (negative skew and spike at zero), and that the normal distribution will be a poor approximation.

Answer 2

[This is purely speculative]

Assumptions:

• impact on fitness is measured by survival chance
• impact is because of protein coding genes

Probability of a mutation at position $i$

$P(m=i\ |\ g)$

where $g$ is the genome with its annotations.

Probability that activity of some protein changes by X-fold given mutation at $i^{th}$ position(s) in the genome:

$\sum\limits_{i}\sum\limits_{gene} P(a_{gene}= X\ |\ m=i)$

sum over all genes that occupy that locus.

Probability that on a given selection pressure $S$ and protein activity change $X$, the individual survives the selection.

$\sum\limits_{i}\sum\limits_{gene}P(1\ |\ a_{gene}=X,S)$

I am not an expert at Bayesian modeling. But I guess this is one way to go about obtaining the PDF. Each step has to be expanded and combined to get an equation for PDF.

I am not sure if this is of any help at all.