Have Tibetans illuminated a path to the dark matter (of the genome)?

I speak not of the Dalai Lama’s path to enlightenment (despite the title).  Tall people tend to have tall kids. Eye color and hair color is also hereditary to some extent.  Pitched battles have been fought over just how much of intelligence (assuming one can measure it) is heritable.  Now that genome sequencing is approaching a price of $1,000/genome, people have started to look at variants in the genome to help them find the genetic contribution to various diseases, in the hopes of understanding andtreating them better.

Frankly, it’s been pretty much of a bust.  Height is something which is 80% heritable, yet the 20 leading candidate variants picked up by genome wide association studies (GWAS) account for 3% of the variance [ Nature vol. 461 pp. 458 – 459 ’09 ].  This has happened again and again particularly with diseases.  A candidate gene (or region of the genome), say for schizophrenia, or autism,  is described in one study, only to be shot down by the next.   This is likely due to the fact that many different genetic defects can be associated with schizophrenia — there are a lot of ways the brain cannot work well.  For details — see https://luysii.wordpress.com/2010/04/25/tolstoy-was-right-about-hereditary-diseases-imagine-that/. or see https://luysii.wordpress.com/2010/07/29/tolstoy-rides-again-autism-spectrum-disorder/.

Typically, even when an  association of a disease with a genetic variant is found, the variant only increases the risk of the disorder by 2% or less.  The bad thing is that when you lump them all of the variants you’ve discovered together (for something like height) and add up the risk, you never account for over 50% of the heredity.  It isn’t for want of looking as by 2010 some 600 human GWAS studies had been published  [ Neuron vol. 68 p. 182 ’10 ].  Yet lots of the studies have shown various disease to have a degree of heritability (particularly schizophrenia).  The fact that we’ve been unable to find the DNA variants causing the heritability was totally unexpected.  Like the dark matter in galaxies, which we know is there by the way the stars spin around the galactic center, this missing heritability has been called the  dark matter of the genome.

Which brings us to Proc. Natl. Acad. Sci. vol. 109 pp. 7391 – 7396 ’12.  It concerns an awful disease causing blindness in kids called Leber’s hereditary optic neuropathy.  The ’cause’ has been found. It is a change of 1 base from thymine to cytosine in the gene for a protein (NADH dehydrogenase subunit 1) causing a change at amino acid #30 from tyrosine to histidine.  The mutation is found in mitochondrial DNA not nuclear DNA, making it easier to find (it occurs at position 3394 of the 16,569 nucleotide mitochondrial DNA).

Mitochondria in animal cells, and chloroplasts in plant cells, are remnants of bacteria which moved inside cells as we know them today (rest in peace Lynn Margulis).

Some 25% of Tibetans have the 3394 T–>C mutations, but they see just fine.  It appears to be an adaptation to altitude, because the same mutation is found in nonTibetans on the Indian subcontinent living about 1500 meters (about as high as Denver).  However, if you have the same genetic change living below this altitude you get Lebers.

This is a spectacular demonstration of the influence of environment on heredity.  Granted that the altitude you live at is a fairly impressive environmental change, but it’s at least possible that more subtle changes (temperature, humidity, air conditions etc. etc.) might also influence disease susceptibility to the same genetic variant.  This certainly is one possible explanation for the failure of GWAS to turn up much.  The authors make no mention of this in their paper, so these ideas may actually be (drumroll please) original.

If such environmental influences on the phenotypic expression of genetic changes are common, it might be yet another explanation for why drug discovery is so hard.  Consider CETP (Cholesterol Ester Transfer Protein) and the very expensive failure of drugs inhibiting it. Torcetrapib was associated with increased deaths in a trial of 15,000 people for 18 – 20 months.  Perhaps those dying somehow lived in a different environment.  Perhaps others were actually helped by the drug

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