Natural selection yes, but for what?

Groups across the political spectrum don’t like the idea that natural selection operates on us. The left because of the monstrosities produced by social Darwinism and eugenics. The devout because we have supposedly been formed by the creator in his image and further perfection is blasphemous.

Like it or not, there is excellent evidence for natural selection occurring in humans. One of the best is natural selection for the lactase gene.

People with lactose intolerance have nothing wrong with the gene for lactase which breaks down the sugar lactose found in milk.  Babies have no problem with breast milk.  The enzyme (lactase)  produced from the gene is quite normal in all of us; no mutations are found in the lactose protein.  However 10,000 years ago and earlier, cattle were not domesticated, so there was no dietary reason for a human weaned from the breast to make the enzyme.  In fact continuing to use energy to make the enzyme something it would never get to act on is wasteful. The genomes of our ancient ancestors had figured this out.   The control region (lactase enhancer) for the lactase gene is 14,000 nucleotides upstream from the gene itself, and back then it shut off after age 8.  After domestication of cattle 10,000 or so years ago, so that people could digest milk their entire lives a mutation arose changing cytosine to thymine in the enhancer. It spread like wildfire because back then our ancestors were in a semi-starved state most of the time, and carriers of the mutation had better nutrition.

Well that was the explanation until a recent paper [ Cell vol. 183 pp. 684 – 701 ’20 ]. It was thought that lacking the mutation you couldn’t use milk past age 8 or so. However sequencing of sites of the herdsmen of the steppes showed that they were using milk a lot (making cheese and yogurt) 8,000 years ago. Our best guess is that the mutation arose 4,000 years ago.

So possibly, the reason it spread wasn’t milk digestion, but something else. Nothing has changed the million nucleotide segment of our genome since the mutation arose — this implies that it was under strong positive natural selection. But for what?

Well, a million nucleotides codes for a lot of stuff, not just the lactase enzyme. Also there is evidence that people with the mutation is linked to metabolic abnormalities and diseases associated with decreased energy expenditure, such as obesity and type II diabetes, as well as abnormal blood metabolites and lipids.

The region codes for a microRNA (miR-128-1). Knocking it out in mice results in increases energy expenditure and improvement in high fat diet obesity. Glucose tolerance is also improved.

So it is quite possible that what was being selected for was the ‘thrifty gene’ miR-128-1 which would our semi-starved ancestors expend less energy and store whatever calories they met as fat.

In cattle a similar (syntenic) genomic region near miR-128-1 has also been under positive selection (by breeders) for feed efficiency and intramuscular fat.

So a mutation producing a selective advantage in one situation is harmful in another.

Another example — https://luysii.wordpress.com/2012/06/10/have-tibetans-illuminated-a-path-to-the-dark-matter-of-the-genome/

The mutation which allows Tibetans to adapt to high altitude causes a hereditary form of blindness (Leber’s optic atroxpy) in people living at sea level. 25% of Tibetans have the mutation. Another example of natural selection operating on man.

“A Troublesome Inheritance” – I

One of the joys of a deep understanding of chemistry, is the appreciation of the ways in which life is constructed from the most transient of materials. Presumably the characteristics of living things that we can see (the phenotype) will someday be traceable back to the proteins, nucleic acids,and small metabolites (lipids, sugars, etc..) making us up.

For the time being we must content ourselves with understanding the code (our genes) and how it instructs the development of a trillion celled organism from a fertilized egg. This brings us to Wade’s book, which has been attacked as racist, by anthropologists, sociologists and other lower forms of animal life.

Their position is that races are a social, not a biological construct and that differences between societies are due to the way they are structured, not by differences in the relative frequency of the gene variants (alleles) in the populations making them up. Essentially they are saying that evolution and its mechanism descent with modification under natural selection, does not apply to humanity in the last 50,000 years when the first modern humans left Africa.

Wade disagrees. His book is very rich in biologic detail and one post about it discussing it all would try anyone’s attention span. So I’m going to go through it, page by page, commenting on the material within (the way I’ve done for some chemistry textbooks), breaking it up in digestible chunks.

As might be expected, there will be a lot of molecular biology involved. For some background see the posts in https://luysii.wordpress.com/category/molecular-biology-survival-guide/. Start with https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/ and follow the links forward.

Wade won me over very quickly (on page 3), by his accurate and current citations to the current literature. He talks about how selection on a mitochondrial protein helped Tibetans to live at high altitude (while the same mutation those living at low altitudes leads to blindness). Some 25% Tibetans have the mutation while it is rare among those living at low altitudes.
Here’s my post of 10 June 2012 ago on the matter. That’s all for now

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