Mutational load and purifying selection

Mutational load and purifying selection are two important concepts in genetics. While mutational load is somewhat intuitive, purifying selection can be quite confusing to the layman, once you start to think about it in some detail. Here’s how I think about mutational load and purifying selection, after spending a long walk thinking through my confusion.

As you well know, every child inherits a set of chromosomes from each of her parents. But these aren’t perfect copies, instead they will contain around 60 copying errors. These errors are strewn randomly into the genome and because random changes to a complicated machinery are very unlikely to be beneficial, almost all of them will either be neutral or have a negative effect.

Now this has been happening for generation after generation and the negative mutations accumulated in a creature or a gene pool are called mutational load. If there were no mechanism to get rid of mutational load, something called mutational meltdown would occur: A species becomes so riddled with mutations that its members are no longer functional and it goes extinct. This typically happens when population size falls under a critical threshold and it might have wiped out the Flores hobbit.

Purifying selection is the mechanism that is balancing these ever accumulating negative mutations. The idea is basically that creatures with more load are less fit in an evolutionary sense, so they have fewer offspring, while creatures with less load pass their relatively pristine chromosomes on to the next generation.

Of course the devil is in the detail. Imagine you look only at the individual with least mutational load in every generation. This magnificent creature might almost always pass on its genes, but remember, every time it’ll add new mutations. So the very top seems to be slipping inexorably downwards with every generation and the whole species must be sliding into the shredder.

Now people might come up with the idea that the very top is propped up by positive mutations, which do happen. While almost all offspring is worse off than their parents, some might strike lucky and get additional positive changes. Well, that might work for bacteria, for human beings, forget about it. Positive mutations are way too rare and the number of children is way too small.

Instead the correct way of looking at purifying selection is the following: Imagine the genomes of your mom and your dad are made of parts. These parts always exist in two versions and every part is either perfect or somewhat damaged, maybe even broken. Each parent gives you a copy of a randomly selected version of each part. Now you can see how you might beat the downward ratchet of mutation: If you get lucky and just happen to get most of the perfect parts from your mom and most of the perfect parts of your dad, you can easily end up with more perfect parts than either, even after some of the parts have been damaged in the copying process.

This is what purifying selection actually operates on: The number of perfect parts. The question remains, what are these parts? One part of the answer is chromosomes, but chromosomes are way too big. You can easily generalize the argument about the degenerating top creature to each particular chromosome type in a population. Instead the key is recombination. Recombination allows chromosomes to literally exchange parts. Two chromosomes neatly aligned to each other break at the same position and then are mended with the half of the other chromosome. So with just two recombinations you can exchange every subsequence in a chromosome with the corresponding subsequence in the other version. These subsequences are the parts and they can be any size from a few bases to a whole chromosome. This mechanism gives purifying selection its power and it’s probably one of the main reason for the existence of sex.

Purifying selection and negative mutations reach a balance that is determined by the mutation rate and the selection pressure. And the important thing to note is that this balance is nowhere near the top of the local optimum of the fitness landscape. Olfactory receptor genes might be a decent illustration of this: OR genes encode receptors for certain smells. If one of these receptor genes has no functional part in your genome, you wont be able to detect the respective smell, which is quite unlikely to be a positive thing. In humans, of around 1000 OR genes found in our genome, generally only about 400 are functional. The picture that presents itself is that having an acute sense of smell got less and less important in our recent evolutionary history which translated into reduced purifying selection and the number of functional receptors slowly dropped towards a new balance between selection and mutation which likely hasn’t even been reached yet. A balance that is obviously far away from an optimum of having a full 1000 functional receptors.

Most of the slightly negative mutations don’t have this kind of localized effect. Instead they just make some metabolic pathway slightly less efficient in every single cell of your body. Which leads us to the next important point.

When the Human Genome Project was in full swing there were many enthusiastic expectations about how finding “the gene for cancer” or finding “the gene for Alzheimer’s” was going to lead to medical breakthroughs. This optimism persisted for a couple of years after the completion to then slowly scurry into a corner and die. Of course there are a lot of diseases that are caused by a single damaged allele, the so called mendelian diseases. But these diseases aren’t the big scourges of mankind, because a single allele that is extremely negative is effectively purged by purifying selection and therefore rare. (The exception being stuff like sickle-cell anemia which gives some protection against malaria.).

Instead a lot of common diseases like autism, schizophrenia, diabetes have turned out to be massively polygenic, i.e. thousands of mutations contribute very slightly to the risk of getting the disease. Sounds familiar? And this is not just the case for diseases, many interesting traits like IQ or height have turned out to be highly polygenic as well. Now it could be the case that all these alleles are not net-negatives, but instead involve some kind of trade-off and that is probably part of the picture. But research has shown that IQ is largely determined by rare slightly negative alleles, whereas in a trade-off scenario you would expect something more like 50:50 between positive and negative contributions of rare alleles. Also, most positive traits seem to be correlated, which points to a common underlying cause. These observations fit the theory that most polygenic traits are heavily influenced by mutational load.

Now, the worrying conclusion from these observations is that currently our industrialized societies are sliding towards a lower balance between mutation and purifying selection, as selection has been massively relaxed with the help of medicine and social security nets and as the most capable people are having the least kids due to a very long education. How fast we slide is a topic of debate and how far we will fall is anybodies guess. The best way seems to be to avoid finding out what the new balance would mean for our collective health and IQ. The exiting part is that mutational load gives us an uncomplicated handle on the functioning of our massively complex genomes. Generally we don’t have much of a clue how our genes give rise to different phenotypes. Every non-trivial change made to our genome is a shot in the dark with usually incalculable risks. Mutational load on the other hand is easily determined by just counting how rare an allele is in the population. Basically every deviation from a consensus genome is exceedingly likely to be negative or at least non-positive. Some people think that Crispr/CAS9 will be used to purge mutations from our genomes and they might be correct. But at the moment it is completely unclear whether it will become possible to do genome editing without off-target effects on thousands of loci at the same time.

Instead a much more realistic pathway to reducing mutational load would be embryo selection. Currently in the case of IV fertilization up to ten embryos are created, because not all of them will be viable and the process of ovum extraction is not something you’d want to repeat. One of these embryos is implanted into the uterus and the only selection that is going on in the moment is for genetic diseases, mostly chromosome aberrations. Of course if you already have ten embryos anyway, you might as well select the one which is most likely to grow into a happy, healthy and intelligent human being.

The easiest way to do this is single cell sequencing from placental cells (this reduces the likelihood of damage to the embryo). Single cell sequencing doesn’t contain enough information to pinpoint the number of negative mutations directly, but it is more than enough to determine which parts of the parental chromosomes are present. The parental genomes can be sequenced with more depth and the mutational load determined with very high precision for each stretch of each chromosome, which ultimately allows us to sort embryos by mutational load.

For ten embryos, of which a number is not going to be viable anyway, this selection would lead to results that are statistically very relevant, but not necessarily noticeable on an individual basis. Given that embryo selection already happens on the basis of other medical diagnosis and morphological appearance and given that the selection is not explicitly based on IQ or other specific traits, it also wouldn’t be a paradigm shift towards eugenics and might meet relatively little public opposition.

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