Is that mutation significant?

Face it, our genomes are a real mess. A study of just the parts of the genome coding for amino acids (2% at most) in about 2,500 people found an average of 205 variants which change the amino acid coded for IN EACH PERSON. Each person also had an average of 3 termination codons in the 15,000+ protein coding sequences they studied. So they are wandering around with 3 abnormally short proteins. You can read more about it in this old post –

Here’s the problem — these people were healthy. Obviously, not a problem for them, but a big problem for physicians attempting to do genetic counseling. For how it affected epilepsy counseling see —

This brings us to Lynch syndrome (aka Hereditary NonPolyposis Colorectal Cancer — HNPCC). It is a familial cancer syndrome, and we now know what the problem is — mutations in any of four genes involved in a type of DNA mutation repair (there are many). The genes are called MSH2, MSH6, MLH1 and PMS2 (acronyms all whose names you don’t need to know) and the type of repair is called MisMatch Repair (MMR).

This isn’t academic at all. Suppose your aunt comes down with colon cancer and you get tested for mutations in one of the four, and a mutation is found. You’re fine now. The question before the house is — should you have your colon out? Colonoscopy won’t help because this kind of colon cancer doesn’t arise from polyps (which is what colonoscopy is looking for).

The problem is that the 4 genes are ‘peppered’ with missense variants (change the amino acid coded for). They are called VUS (Variants of Unknown Significance). The following paper [ Proc. Natl. Acad. Sci. vol. 113 pp. 3918 – 3820, 4128 – 4133 ’16 ] used a clever way to test a VUS for significance. This would have been impossible 5 years ago. What they did was use CRISPR to introduce the variant into the appropriate protein in mouse Embryonic Stem cells. Then they tested the manipulated stem cells for defects in MisMatch Repair. They tested 59 (yes fifty-nine) such VUSs and found that about 1/3 (19) produced MMR defects.

Fascinating time to be alive and reading about all this stuff.

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  • Bryan  On April 18, 2016 at 10:30 am

    CRISPR offers some really nice opportunities for testing VUS. However, it’s worth keeping in mind that mutations can have different effects in different genetic backgrounds (a phenomenon known as epistasis). A paper in Science a couple of years ago (Ishimura et al 2014 Science 345:455) looked at a strain of mice showing a neurodegeneration phenotype and identified a loss of function mutation in a ribosome rescue factor, GTBP2 in these mice. However, when they introduced this mutation into other strains of mice, they did not see the neurodegeneration phenotype. It turns out that the original strain of mice contains a mutation in one of its tRNA genes and loss of GTBP2 function causes neurodegeneration only when combined with the tRNA mutation. Similar genetic interactions will probably complicate many other VUS analyses.

  • luysii  On April 18, 2016 at 10:48 am

    Exactly — that’s what the second link was all about — “We’ve found . .. ” — although not explicitly stated in the post, epistasis must be involved.

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