Play the (genetic) hand you’ve been dealt but don’t spindle, fold or mutilate your cards

Back in the day, computers were programmed by inserting multiple punch cards https://en.wikipedia.org/wiki/Punched_card, each containing a machine instruction. At the bottom of the card it said “do not fold, spindle, or mutilate”. My wife used them back then when she expected to be a widow if and when I got sent to Vietnam.

So it is with you and the genetic hand of coronary artery disease risk you’ve been dealt. [ Cell vol. 167 p. 1431 ’16 ] refers to a recent New England Journal of Medicine article –2016;DOI:http://dx.doi.org/10.1056/NEJMoa1605086.

It’s a very good study, with large numbers of participants in three prospective cohorts — 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women’s Genome Health Study (WGHS), and 22,389 in the Malmö Diet and Cancer Study (MDCS) — plus 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. Adherence to a healthy lifestyle among the participants was also determined using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet (hardly complicated).

As you probably know, Genome Wide Association Studies have identified over 50 places in our genomes in which slight variations (the technical term is single nucleotide polymorphisms — SNPs ) are associated with increased risk of coronary artery disease. Since vascular disease is a generalized problem, these SNPs also increase the risk of other vascular problems, notably stroke. None of them increases the risk very much, and even together they don’t explain much of the genetic risk of vascular disease (which we know is there). However, they were all determined (at least in the 4260) and a genetic risk score was calculated. So there were people with high, low and medium degrees of risk.

In all risk groups, high, low, whatever, a simple healthy lifestyle (no smoking, not fat, some exercise, healthy diet) decreased the coronary event rate (heart attack, death) by nearly half. So how bad was high risk? Bad indeed, the event rate in the high risk group was nearly twice that of the low risk group.

Even better, healthy lifestyle decreased risk the most just where you’d want it — in the highest risk group. You can reduce your risk of being eaten by a bear by not going to Yellowstone by 99% or more but so what.

This work is to be believed, because the number of events is high enough –1230 coronary events were observed in the ARIC cohort (median follow-up, 18.8 years), 971 coronary events in the WGHS cohort (median follow-up, 20.5 years), and 2902 coronary events in the MDCS cohort (median follow-up, 19.4 years).

So as my late father said (who lived to 100) when asked what his secret was “I chose my parents very carefully”. Well, we can’t do that, but don’t spindle the cards.

Is natural selection disprovable?

One of the linchpins of evolutionary theory is that natural selection works by increased reproductive success of the ‘fittest’. Granted that this is Panglossian in its tautology — of course the fittest is what survives, so of course it has greater reproductive success.

So decreased reproductive success couldn’t be the result of natural selection could it? A recent paper http://www.sciencemag.org/content/348/6231/180.full.pdf says that is exactly what has happened, and in humans to boot, not in some obscure slime mold or the like.

The work comes from in vitro fertilization which the paper says is responsible for 2 -3 % of all children born in developed countries — seems high. Maternal genomes can be sequenced and the likelihood of successful conception correlated with a variety of variants. It was found that there is a strong association between change in just one nucleotide (e.g. a single nucleotide polymorphism or SNP) and reproductive success. The deleterious polymorphism (rs2305957) decreases reproductive success. This is based on 15,388 embryos from 2,998 mothers sampled at the day-5 blastocyst stage.

What is remarkable is that the polymorphism isn’t present in Neanderthals (from which modern humans diverged between 100,000 and 400,000 year ago). It is in an area of the genome which has the characteristics of a ‘selective sweep’. Here’s the skinny

A selective sweep is the reduction or elimination of variation among the nucleotides in neighbouring DNA of a mutation as the result of recent and strong positive natural selection.

A selective sweep can occur when a new mutation occurs that increases the fitness of the carrier relative to other members of the population. Natural selection will favour individuals that have a higher fitness and with time the newly mutated variant (allele) will increase in frequency relative to other alleles. As its prevalence increases, neutral and nearly neutral genetic variation linked to the new mutation will also become more prevalent. This phenomenon is called genetic hitchhiking. A strong selective sweep results in a region of the genome where the positively selected haplotype (the mutated allele and its neighbours) is essentially the only one that exists in the population, resulting in a large reduction of the total genetic variation in that chromosome region.

So here we have something that needs some serious explaining — something decreasing fecundity which is somehow ‘fitter’ (by the definition of fitness) because it spread in the human population. The authors gamely do their Panglossian best explaining “the mitotic-error phenotype (which causes decreased fecundity) may be maintained by conferring both a deleterious effect on maternal fecundity and a possible beneficial effect of obscured paternity via a reduction in the probability of successful pregnancy per intercourse. This hypothesis is based on the fact that humans possess a suite of traits (such as concealed ovulation and constant receptivity) that obscure paternity and may have evolved to increase paternal investment in offspring.

Nice try fellas, but this sort of thing is a body blow to the idea of natural selection as increased reproductive success.

There is a way out however, it is possible that what is being selected for is something controlled near to rs2305957 so useful, that it spread in our genome DESPITE decreased fecundity.

Don’t get me wrong, I’m not a creationist. The previous post https://luysii.wordpress.com/2015/04/07/one-reason-our-brain-is-3-times-that-of-a-chimpanzee/ described some of the best evidence we have in man for another pillar of evolutionary theory — descent with modification. Here duplication of a single gene since humans diverged from chimps causes a massive expansion of the gray matter of the brain (cerebral cortex).

Fascinating

Addendum 13 April

I thought the following comment was so interesting that it belongs in the main body of the text

Handles:

Mutations dont need to confer fitness in order to spread through the population. These days natural selection is considered a fairly minor part of evolution. Most changes become fixed as the result of random drift, and fitness is usually irrelevant. “Nearly neutral theory” explains how deleterious mutations can spread through a population, even without piggybacking on a beneficial mutation; no need for panglossian adaptive hypotheses.

Here’s my reply

Well, the authors of the paper didn’t take this line, but came up with a rather contorted argument to show why decreased fecundity might be a selective advantage, rather than just saying it was random drift. They also note genomic evidence for a ‘selective sweep’ — decreased genomic heterogeneity around the SNP.