Tag Archives: Natural selection

The most interesting thing to an evolutionist is not that APOE4 increases the risk of Alzheimer’s disease

Neurologists were immensely excited by the discovery 25 years ago that the APOE4 variant of APOlipoprotein E increases the risk of Late Onset Alzheimer’s Disease (LOAD). 24,000 papers later (Google Scholar) we still don’t know how it does it. Should all this work have been done ? Of course ! !  Once we know the mechanism(s) by which APOE4 increases Alzheimer’s risk we’ll have new ideas to help us attack.

The APOE gene has 3 variants (alleles) APOE2, 3 and 4. The protein is average sized (299 amino acids). The 3 alleles differ at two positions (amino acids #112 and #158) where either cysteine or arginine can be found. The frequency of APOE4 is 14% in the adult white population, that of E3 is 78% and that of E2 is 8%.

Fascinating as this all is, it’s not what’s interesting from an evolutionary point of view.

[ Proc. Natl. Acad. Sci. vol. 113 pp. 17 – 18, 74 – 79 ’16 ] Postmenpausal longevity in females is not limited to humans. Humans, orcas and pilot whales are the only vertebrate species known to have prolonged postreproductive lifespans. Our fertility ends at about the same age that fertility ends in other female hominids (the great apes). However, apes rarely live into their 40s (even in captivity).

Unlike APOE4, APOE2 and APOE3 protect against late onset Alzheimer’s.

The fascinating point is that APOE2 and APOE3 aren’t found in the great apes. They are a human invention. Now LOAD occurs well past reproduction, so there should be no reason in terms of reproductive success for them to arise and be more common in human populations than the original APOE4.

Even more interesting is some work on another protein CD33, found on immune cells and glia in the brain [ Neuron vol. 78 pp. 575 – 577, 631 – 643 ’13 ] A minor allele (21% frequency in human populations) of CD33 (SNP rs 3865444) protects against Alzheimer’s. The allele is associated with reductions in CD33 expression in microglia, and also with reduction in levels of insoluble Abeta42 in (Alzheimer’s) brain. The numbers of CD33+ microglia correlate with insoluble Abeta42 levels and amyloid plaque burden. So decreasing (or inhibiting) CD33 function might help Alzheimer patients.

Again the protective allele is only found in man. The great apes don’t have it just the major (nonprotective) allele.

Again, there is no way that having the allele directly improves your reproductive success. By the time it is protecting you, you’re infertile.

What in the world is going on? Why did alleles protective against Alzheimer’s arise in two very different proteins in the course of human evolution?

“There is something fascinating about science. One gets such wholesale returns of conjecture out of such a trifling investment of fact.” — Mark Twain.

The reason these alleles probably arose gets us in to an ancient battle in evolutionary theory — what is the actual unit of selection? It may be the group rather than the individual. Face it, human infants and children are helpless for longer than other primates, and need others to care for them, for at least 5 years. Who better than grandma and grandpa? So the fact that with granny around more children survive to reproduce constitutes group selection (I think).

As Theodosius Dobzhansky said “Nothing in Biology Makes Sense Except in the Light of Evolution”


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).


Addendum 13 April

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


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.