Tuesday, September 8, 2015

One mutation may drive you insane or make you smarter

I like to say, "physicists don't care about the details, chemists say the details do matter, and biologists say the details are a matter of life and death."

Bill Parson recently told me about a striking example of how one mutation [substituting a single amino acid for a different one in a protein] can really change things, for better or for worse. I reproduce below the relevant paragraph from this paper.

Crystal Structures of Human 108V and 108M Catechol O-Methyltransferase 
K. Rutherford, I. Le Trong, R.E. Stenkamp, W.W. Parson

Human COMT contains a common polymorphism at residue 108, which can be either valine (V) or methionine (M).2223 and 24 Approximately 25% of U.S. and Northern European Caucasians are homozygous for the 108M allele, which is much less common in African and Asian populations.25 and 26 The 108M allele has been linked with increased risk for breast cancer,272829 and 30 obsessive–compulsive disorder,31 and 32 some manifestations of schizophrenia,33343536 and 37 and increased sensitivity to pain,38 and 39but it has also been linked with improved prefrontal cognitive function, especially in working memory.40 and 41 It appears to be linked particularly strongly to neuropsychiatric dysfunction in velocardiofacial syndrome, a chromosomal disorder resulting from the deletion of multiple contiguous genes, including COMT, from one copy of chromosome 22. 3742 and 43 A haplotype involving the 108V allele and two noncoding COMTpolymorphisms has been associated with increased risk for schizophrenia, possibly because it results in diminished mRNA expression or translation. 44454647 and 48

One might wonder about connections with VHL disease, which it has been suggested may play a role in the Hatfield-McCoy feud. I first learned about this famous family feud in the book Outliers.


  1. Interesting - this (does not prove but) is consistent with the lore that being very smart skirts the line to being socially challenged (to use term that's a bit more PC ...).

  2. Thanks for pointing that out. I had not thought of that angle.