More to go wrong

About 1.5% of the genome codes for proteins, and we understand proteins (and the genetic code) well enough to analyze mutations in those coding regions.  About 70% of nucleotide changes in codons change the amino acid sequence. Most of those changes are deleterious.

According to Kryukov and coauthors [Kryukov et al 2007, AJHG ] , about 27% of those missense mutations are neutral,  while 20% cause a loss of protein function. The remaining 53% have slight deleterious effects – their estimate is that the selective disadvantage ranges from 0.001 to 0.003.

Note that loss-of-function mutations are typically more deleterious, but many still have smallish effects in single copy.  In fruit flies, the average recessive lethal only decreases fitness by 1 or 2 percent in heterozygotes.

This is all aimed at understanding the spectrum of fresh mutations. I would like to know what fraction decrease fitness by 50%, 20%, 10%, 5%, 1%, etc.  If some population adopted customs that resulted in increased paternal age, the numbers of mutations in those classes would all increase, but at different rates.  If the mutation rate went up by 50%, the number of dominant lethals would reach the new higher equilibrium in one generation, but it would take on the order of 100 generations for the 1% deleterious mutations to approach their new higher equilibrium, So, if we knew more about the mutational spectrum, we could better understand the impact in a population that had had high average paternal age for 100, 1000, or 10,000 years.   Most of the old-dad cultures I am reading about look (to me) as if they came into existence in farming cultures, so are probably not incredibly old.  The Australian aborigine pattern of gerontocratic polygyny could be well be older, but I  don’t know how archaeology could resolve that question.  Ancient Viagra bottles? Genetics might tell us: if the Australians have higher-than-usual numbers of deleterious mutations with small effects, more so than other populations, we would have to suspect that they’d been at it a long time.

One big problem is that most of the genome that does something significant and can thus mutate in ways that cause harm is noncoding.  We don’t understand that component as well.  Certainly I don’t.   A rough estimate would be that 1.5% of the genome makes proteins while another 3.5% does something else functional –  regulation of protein expression, regulation of other regulators, etc.  The effect size of such mutations is probably biased towards small numbers, since few genetic syndromes serious enough to be called Mendelian diseases are caused by changes in noncoding parts of the genome.  Such stretches of the genome are conserved enough that they’re obviously experiencing purifying selection, but most don’t cause flagrant disease when altered.  Think of it this way:  a loss-of-function mutation ruins the protein, but a regulatory mutation might just change the amount made or the timing of its expression.  Sounds less serious.

Of course, as the functional fraction of the genome increases, there are that many more things to go wrong.  Genetic load will be bigger.  If selection is relaxed – as it is today – the human race will deteriorate more rapidly.  It is not just that people in developed countries are experiencing selection for lower intelligence (as they are) – you have to think about mutational accumulation.   While anyone still can think at all.

In the same way, the larger the fraction of the genome that plays a functional role in a particular organ,  the more that organ’s efficiency will be compromised by genetic load.  That’s what we see with the one-generation effects of advanced paternal age – they mess up the brain, as Kondrashov has pointed out.

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21 Responses to More to go wrong

  1. It may be that Gattaca will happen in successive stages, where the first stage will be selection against obvious Mendelians, the second stage will be selection against more subtle mutation load, and only in third and later stages will we have the ability, and political atmosphere, to select *for* variations which are not “normal”, IE which deviate from reference sequence. All 3 stages overlapping, of course.

    If you were to speculate for a moment, how far do you think the second stage may take a single generation, in the specific realm of brain health, Cochran? Getting the best of mutaload worlds from each parent, and no other factors significantly changed, with parents about as genetically similar as today?

    Perhaps more significantly, do you think that highly genotype diverse, historically polygynous homo sapiens might have particularly rich gains to be made? To the extent that they can be persuaded to embryo select, that is, which is another matter.

  2. bob sykes says:

    I think that the idea that only 5% of the human genome has function is absurd. The functional fraction of the genome is probably at least 95% and maybe 100%. The fact that we don’t know the functions is our problem.

    • gcochran9 says:

      You’re wrong. Go read up on it.

      • bob says:

        What about the evidence for much higher levels of transcription coverage such as with the recent Encode study that gave a figure of 80%?

        • gcochran9 says:

          The key is whether a given chunk of the genome mutates freely or is conserved. If you notice that that chunk in question is substantially the same as it is in mice, natural selection must be purging mutated versions. Which means that this chunk influences fitness. If that chunk is not subject to purifying selection, it is irrelevant to fitness and doesn’t really matter.

          All indications are that the vast majority of the genome is not subject to purifying selection, therefore is not doing anything significant. Good thing too: if most of the genome was doing something important, I doubt if we could survive our high mutation rate.

          • saintonge235 says:

            All indications are that the vast majority of the genome is not subject to purifying selection, therefore is not doing anything significant. Good thing too: if most of the genome was doing something important, I doubt if we could survive our high mutation rate.

                    Hmm, that suggests a possible function: it’s protection from something that attacks nucleic acid generally.  Has anyone ever looked?

                    In any case, might be a good sf story there.

    • DK says:

      To the contrary, the idea that 95% of the genome is functional is absurd. Everything we know about biology strongly suggests that junk will always be made and will tend to accumulate because it is easier to tolerate it than develop mechanisms of its detection and elimination. Here is a picture of an organism with genome size 50 times bigger than human:

      And its genome is 600 larger than genome required to build this plant:

      600 more functional elements to make up more or less the same thing? Defective genes and viruses are functional?

  3. Anonymous says:

    Is there selection for lower intelligence?
    Or is it that the selection pressure for high intelligence has been reduced/removed?

    • ziel says:

      Have you thought about who, in developed countries, are reproducing and who aren’t?

      • albatross says:

        Yet, we see increasing raw IQ scores in those devveloped countries, despite several generations of somewhat dysgenic reproduction. That says that whatever is behind the Flynn effect (probably some overlap of nutrition, health, and intellectual stimulation) is actually pushing those raw scores up agaisnt a big headwind of dysgenic breeding. On the other hand, as the environment improves, less and less IQ variation is environmental and more and more is genetic. So maybe the dysgenic breeding of several generations ago was a lot less important (when there’s substantial malnutrition and parasitic disease in your society, a lot of variation in IQ has got to be environmental).

    • A Erickson Cornish says:

      Not sure what the distinction is: the global maximum on the rep. fitness vs. intelligence curve (and really the whole curve) has moved left.

  4. whatever says:

    *If selection is relaxed – as it is today *
    Is it? The selection pressure surely has changed its direction (more than once in the last 10 000 years) – as you have shown in your resent book. Right now we have both population collapse and population sink in Europe; we also have population replacement on a major scale in several countries; these events somehow might be considered demographics or even social in character; but had they happened 200 000 years ago, no one would have think of them in demographics terms, but in evolutionary. In my understanding of Darwin evolution never stops even when it seems that it takes breaks. Would not be the same to say that *gravity has relaxed*?
    There are things going on in therms of surviving offspring. Heard of a lady in NYC with more than 1500 living children, grandchildren and grand grand children; She must be a little nation. We spend first 30 years of our lives studying (or some of us) which is preparing to enter adulthood; by that age an evolutionary successful hunter gatherer from anywhere between now and 1 million years ago could be a patriarch; same for the pre-modern agrarian societies – and some modern societies too; while we seem to be in charge for the natural environment, diseases, energy, etc, we are not in charge at all for the cultural environment. A cultural trait can kill wonderfully – better than hurricane, 10 tigers or a year long starvation. An organism which lacks nervous system would not suffer from diseases of the nervous system; he is immune to it. My point is, there might be a reason why evolution seems to select against higher intelligence nowadays in the environment of western culture. Due to its continuous centuries-long sophistication culture might be becoming a Darwinian burden, since we have reached a point where we need to spend nearly half of our lives in absorbing it trough mandatory education, with assumption that this would make us more competitive – which is – would improve our fitness; In fact, it seems -that it is not exactly the case, since there is some negative correlation between years spent in studding and number of survived offspring, at least in the western world; logically, some of the groups (but not all) with higher IQ would be more prone to this particular Darwinian disease (delayed adulthood). But there are many others, too. It might be getting too expensive (in terms of reproduction) to have a big brain. There is a trap. I do not see a difference between natural environment and cultural habitus in therms of selection pressure – they both cause it. With the difference that we try to be in control of nature, but culture is in control of us, hence, stronger selection pressure from this direction.
    At the same time we still need to have an IQ of 70 in order to safely cross the street , so I guess the selection is still at work against IQ lower than this, which is somehow cheering.

  5. spandrell says:

    Mr. Cochran how old was your father?
    Just to check if I should hurry and have children in my 20s.

  6. Steve Sailer says:

    In most monogamous cultures before modern medicine, a sizable fractions of old dads will be widowers on a second or third wife. Are there any cultures where widowers were banned from remarrying, thus lowering average paternal age.

  7. Priceeqn says:

    No one living now that I’m aware of has 1500 children etc! Maybe 15 but even that seems to be pushing the envelope in any developed nation. The Russian noblewoman who supposed had 65 grandchildren was a woman who historians haven’t proven ever existed.
    Random: I wonder what we are being selected for nowadays. Some have suggested a sort of abstract reasoning ability. Not sure I buy it though. With the ascendance of a service economy mostly based on low-end service industry jobs and the consumption of worthless banking products and entertainment intangibles, it seems odd that people would be loudly proclaiming that the world is becoming smarter. I think if anything the dumber people are approaching the mean but the smartest people are likely no smarter than they were 50 years ago. Of course the educational system is vastly different now…

    • saintonge235 says:

      If a woman had twelve children, and each of them had twelve children, and each of them had twelve children, that’s 1885 people altogether. Hard to believe, but not impossible.

  8. j says:

    …if most of the genome was doing something important, I doubt if we could survive our high mutation rate.

    Supposing the human type has been more or less stable in the last 3000 years, and knowing the human mutation rate, the total number of our “important” genes could be calculated. Not that I could calculate that equilibrium.

  9. Holm says:

    Good old Dr. Bob Arnot claims you can offset the risk with a diet high in micronutrients…

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