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If a person has a specific mutation in a gene (2281 del/ins in a single copy of the Bloom BLM gene), is he more likely than the general population to have other types of mutations in the same gene?

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A priori, no! Why would it? Do you have any specific hypothesis in mind you would like to discuss?

Below are some expectations from a simple model and possible reasons for why this expectation may break down under more complicated models.

Simple model

Under a simple model (panmictic population and a few other simple assumptions), the number of mutations a given individual has in any sequence considered follows a poisson distribution. Assuming that all mutations occuring have a constance selection coefficient $s$, a constant dominance coefficient $h$ and that the mutation rate for the sequence of interest is $U$, then the number of mutations an individual carry comes from a Poisson distribution with mean $\frac{U}{2hs}$ (Crow 1970).

This model is simple but is probably a pretty good approximation to reality. Below are three assumptions that are not necessarily true and that would yield to a higher variance in the number of mutations (that is a higher probability for an individual that already carry a mutation to get a second mutation).

Population structure

In reality, populations are often not panmictic. As the genetic load depends upon the population size. More specifically, the smaller the population, the higher the genetic load (or the higher the number of mutants alleles present in the population) (Kimura et al. 1963).

Past evolutionary and demographic history

Populations are not stable through time. Some population have recently gone through a bottleneck, others a quickly expanding, some are shrinking, some have recently suffered from a plague, etc... Such processes can all cause populations to differ in the number of mutations they carry and therefore would increase the variance in the distribution of number of mutations individuals carry.

Within a specific short enough sequence, physical linkage associated with specific past evolutionary process will create a relatively long lasting linkage disequilibrium.

Condition-dependent mutation rate

It has been shown in Drosophila melanogaster that individuals with poor genotype tend to have a higher mutation rate causing their lineage to accumulate even more mutations (Sharp and Agrawal 2012).

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    $\begingroup$ I would add that there are mutations in certain genes that increase the likelyhood of mutations in general or genomic instability. But i agree that mutation in one gene is not likely to increase mutations in that gene. ncbi.nlm.nih.gov/pubmed/16020738 $\endgroup$ – JustGettinStarted Feb 15 '17 at 0:39
  • $\begingroup$ I agree theoretically it's unlikely, I wonder though if there is empirical data to support this from the 1000 genomes project. $\endgroup$ – Artem Feb 15 '17 at 1:12
  • $\begingroup$ thanks! so, correct me if I'm wrong, but all 3 arguments are supporting higher variance in the total number of mutations for an individual, NOT for a higher variance in the number of mutations of the SAME gene, correct? $\endgroup$ – ihadanny Feb 15 '17 at 6:25
  • $\begingroup$ Yes, you are right. However, higher variance in the total number of mutations also increases the variance in the number of mutations for any sequence of interest, including a specific gene. $\endgroup$ – Remi.b Feb 15 '17 at 15:31
  • $\begingroup$ I think you're missing the most important factor: variation in coalescence time across the genome. The fact that the individual has one polymorphism in the gene means that the coalescence time of their two copies is not very short, and so they are more likely than average to have additional polymorphisms in the gene. $\endgroup$ – Daniel Weissman Feb 16 '17 at 18:15
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Bear in mind that the average mutation rate of DNA polymerase is about 1 error for every 1 x 10^6 bases. So the probability of mutation is independent at each base pair, but low - there's nothing that would prevent another mutation, but there also is nothing that says it is demanded.

There is, however, a phenomenon known as compensating mutations - a second mutation that compensates for a detrimental effect of an earlier mutation. For example, if I have a mutation in a gene that codes for a protein, and that mutation changes an amino acid that is a contact point for protein folding (or a similar structural component), the protein may not fold correctly until there is a compensating mutation in the region of sequence coding for the residue that interacts with that first amino acid. Compensating mutations would tend to be positively selected if the protein function is significantly affected....

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  • $\begingroup$ Any sources you could add? $\endgroup$ – AliceD Feb 16 '17 at 20:19
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The answer of course depends some on the details (e.g., whether or not the mutation is neutral), but in general, yes, polymorphisms should cluster along the genome. Roughly speaking, the presence of one polymorphism indicates that the most recent common ancestor of this individual's two copies of the gene probably lived pretty far in the past, so there's been a lot of time for them to accumulate additional mutations.

I'm being a little sloppy here about polymorphisms within an individual vs differences from the reference genome, but the logic is the same.

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