Obvious! Yessss! It was obvious!

At this point, it seems that paternal age is a significant driver of the human mutation rate,  likely the main driver.   Obviously this implies that many medical problems are more common in the children of older fathers, which is known to be the case. Less obviously, it  implies that a population that has had high average paternal age for a long time will have a higher-than-average mutational load.  This may well explain preliminary results that seem to show such differences.

Observed differences in paternal age are large enough to generate the sort of differences that have been observed so far. For example, judging from the Decode study, the mutation rate in a population with an average paternal age of 34 would be > 20% higher than that in a population with an average paternal age of 28.

If paternal age had increased significantly in the last generation, the genetic impact would be simple.  The kinds of medical problems that are associated with high paternal age would increase.  Although even that isn’t quite as simple as you might think, because, in practice, only problems that exceed a certain threshold of practical importance are officially noticed. If a kid has schizophrenia, or a cleft palate, a medical problem is deemed to exist.  But suppose there was a mutation that dropped someone’s IQ by 1 pt: that would never be  noticed at the individual level. There is every reason to think that advanced paternal age also increases the rate of such small-effect mutations – and over many generations such effects can add up.  So, if a population had adopted late fatherhood 500 years ago, increasing the overall mutation rate by 50%, you would expect to see an elevated  level of large effect mutations, but also an elevated level of mutations with effects on the order of 5% or greater.  The  class of 1% mutation would only gone up ~10%.  If the pattern had  been around  for 5000 years, the class of 1% mutations would have increased by about 43%.

Moreover, although only a smallish fraction of kids suffer bad effects from having had an elderly father in a population in which this is generally rare, a long-term pattern of advanced paternal age must eventually result in the entire population having an unusually high level of medium- and small-effect deleterious alleles.  That burden would be roughly  Poissonian, and would vary between individuals, but there might not be much overlap in burden between populations.

A disease syndrome  caused by one large-effect mutation has a fair chance of being pleiotropic.  That is to say, it pushes the whole phenotype in a funny direction.  The victim might be  funny-looking, as well as retarded.  An unusually large number of small-effect deleterious mutations shouldn’t push the phenotype in any particular direction, other than reduced performance.

The poster-boy population for checking out the consequences of a long-term pattern of advanced paternal age has to be the Australian Aborigines.   They are not the only population of interest – there are other cultural patterns that change average paternal age.  Like polygamy.

Someone should have noticed this a long time ago.  Weinberg noticed increasing levels of trouble with parental age 100 years ago. Haldane had figured out that most mutations were contributed by males in 1947.  He also developed the theory of genetic load before 1960.  The atypical paternal age of Australian Aborigines has been well-documented for a long time.

Haldane should have noticed, and for all I know he did, but I’m not aware that he published anything about it.  Thinking about it, I’d bet the bastard knew. Anyhow, he died in 1964.  My guess is that relatively few people were simultaneously familiar with the evidence for male-biased mutation, paternal-age evidence in medicine, the theory of genetic load, and ethnographic reports of big differences in average paternal age.  Genetic load went out of fashion, as did population genetics generally, and of courser no sensible person pays any attention to anthropologists.

I said a few months ago that there was still plenty of low-hanging fruit in biomedicine. There still is.

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20 Responses to Obvious! Yessss! It was obvious!

  1. albatross says:

    How would the world look different if this were true?

    There’s been a lot of press about a big increase in some health problems over the last couple generations–asthma, food allergies, ADHD, autism-spectrum disorders. I imagine some of this is changes in diagnostic criteria (do we say you have Asbergers, or do we just say you’re a kind-of weird, awkward kid?), and some is probably environmental or driven by changes in gut flora or something, but I wonder if some of these might reflect this kind of change in mutation rate.

    For increased allergies/asthma, in terms of mechanisms, think of changes to MHC2 molecules that made you slightly more likely to present peptides from some common food allergens to T cells, or changes to whatever complicated signaling happens between T cells and B cells to get them to switch over to IgE production, or to whatever complicated signaling mechanisms in the gut mucosa that are supposed to induce tolerance to stuff you eat most of the time. Those changes would mostly be slightly deleterious (MHC2 molecules that had been selected out when their carriers tended to die of an asthma attack after eating some wheat start showing back up a little faster than they can be filtered out).

    In terms of autism and ADHD, it seems like the same sort of explanation would apply that applies to slightly-deleterious mutations that lower IQ. Would we also expect to see more homosexuality over time? A mutation that slightly bumps up the chance that you’ll lose interest in girls sure seems like it ought to be selected out over time, for kind of obvious reasons.

    Mutations that slightly increase the chance of an early death by cancer might be a good place to look for the effects of this, because it might be possible to get a good handle on the number of deaths of (say) women in their 40s from breast cancer, historically, alongside information about their parents’ age when they were born, and their grandparents’ age when their parents were born. It seems like proto-oncogenes ought to be a pretty good example of slightly deleterious mutations, since they usually don’t cause cancer at an early age.

    One creepy thought: there’s a lot of redundancy in biology, so you can have mutations that don’t have any detectable effect, because there are several alternative mechanisms that can handle the same function. (Probably that means they have a small deleterious effect, I guess, and so they get selected gradually back out when they arise.) But any system with a certain amount of fault tolerance also has a number of faults at which is falls apart. I wonder if several generations of higher mutation rate could push you to the point where some critical stuff just stops working. Autism spectrum stuff seems like a plausible place to start looking for this, since there is surely a big and complicated system that probably has a lot of redundancy.

  2. AC says:

    European populations have had high paternal age for some time, haven’t they? Should we see a rapid increase in mutational load over the past few centuries?

  3. bob says:

    Doesn’t Harpending have a teenage son? Does he look a little wonky? What’s with communicating in math code? That seems prodromal for something.

    • Yes, he is now 16. Not wonkier than other teenagers I have known but certainly not standard issue either. He took some kind of standardized test last year, came out at 60 percentile verbal and 99 percentile on math. The kid just takes to math like a duck to water. I called him a poseur but he did max out on the AP Calculus exam.

      Nerd certainly but he is also heavily into guns and hunting and fishing and stuff like that. Not very social but hard to tell because he and his buddies do all their socializing over Skype.

  4. t3 says:

    If you think of this post about old dads together with the recent posts on mutational load in Africa/Australia, you might get an idea that differences in load could be attributable to a culture with more old dads.

    Maybe cultures that have required monogamous mating over many generations have limited the old dad risk by tying men to one woman’s fertility, while cultures where powerful men get more women increase the load of their populations.

  5. Karl Narveson says:

    Here is a case for primogeniture: whatever else may be true of the heir apparent, at least we know his father was younger at his conception than at the conceptions of his younger brothers.

    • typal says:

      Going by studies of those living to be 100 years old the mothers age is important, but fathers age is not. The case for primogeniture is that we know the mother was younger.

  6. typal says:

    CH Waddington said those mutations get canalized out of expression in normal circumstances. Qualities as yet undreamt of lie dormant in mutations.

  7. MikeP says:

    Given this, shouldn’t we see selection for women that prefer comparatively younger men? The problem, of course, is that younger men tend to be associated with fewer resources so, from the perspective of a woman’s fitness, the ideal would be an older husband combined with affairs with younger men.

  8. J says:

    Isn’t it true that in polygamous societies, something on the order of 40% of men don’t reproduce? Wouldn’t the increased selection in polygamous societies counteract the increased mutational load from older fathers?

    • gcochran9 says:

      If we’re talking about mortality selection, most happens earlier in life. I could imagine that successfully polygamous men have higher genetic quality by some measure, so as to counteract their higher mutation rate – but I don’t know that the effects cancel out. Moreover, this would probably involve selection for different traits than in other populations. Then there are different kinds of polygamous societies. In some, wealth is the driver. In others, like West Africa, women were more or less self-supporting and multiple wives might actually increase male wealth.

      We know that the mutation rate goes up with age – we’re sure of that. As for hypothetical compensating effects – we don’t know.

  9. M. M. says:

    So we’re talking about dumb-dumb bullets expanding in the underbellies of polygamous societies?

  10. hbd chick says:

    Determinants of age at first marriage among Jews in Amsterdam, 1625-1724

    “This study provides evidence for relatively early marriage among Ashkenazi Jews compared to Sephardi Jews and Christians in seventeenth-century Western Europe.”

  11. Anonymous says:

    What to do, what to do…?

  12. RT says:

    Reading this made me think of the “Methuselah flies” experiment (I think I read about it in one of Matt Ridley’s books many years ago, perhaps “Genome”) where scientists produced flies that lived about three times longer than the average fly and remained more vigorous in old age by making them breed at later ages when many flies are unable to reproduce and repeating this process over numerous generations. If I remember correctly, Ridley reported that it is speculated that the delayed reproduction selected for genes associated with longevity and also speculated that this may have been one of the factors that selected for longer lifespans in humans than other primates. He also speculated that the current trend in Western societies towards older parents might produce an effect of the same nature in humans as the Methuselah flies experiment.

    This may be a silly question (my biology and chemistry education ended with AP classes in highschool), but is it correct to assume that mutation rates increase in flies as they age as happens in humans (at least for the paternal genetic contribution)? If so, wouldn’t this tend to have a deleterious effect on the health of the offspring of the flies made to breed at later ages? Is the increased lifespan resulting from the experiment due to the selection for greater lifespan through delayed reproduction being of much stronger effect than the negative health effects of higher mutation rates because the experiment is specifically targeting genes for longevity?

  13. alex says:

    just wondering, since you guys are anthropologists who dont seem to like much anthropology…what are classic anthro/ethnography books that are worthwhile? or a link to a course with a solid reading list would be appreciated.

    • harpend says:

      We love anthropology but are not so enamored of a lot of anthropologists. Starting in the 1960s anthropology more or less split into those who try to do science and those who try to do something like literature. Read about Clifford Geertz for example. Today there are anthropology departments that are essentially all talking twits and departments thare are rock solid.
      Greg sneers at anthropologists, whom he regards as lowlifes. But when I go down the list of people in our department at Utah, one by one, he claims they are serious and valuable but thinks they must all be exceptions.
      Your question is a good one. If cultural anthropology is where you want to read my suggestion for a start would be a chapter on cultural diversity that our editor cut out of our book: it is posted on the book website at http://the10000yearexplosion.com/human-cultural-diversity/ . Another strategy is to go to serious departments and look at their websites, where faculty often post or link to their course syllabi. At the risk of leaving out some of the best places to look, I would start with UC Davis, New Mexico, Arizona, Northwestern (for Human Biology), Harvard (the Human Evolutionary Biology department, NOT the Anthropology department, which is solid sillies), Missouri, Washington, Binghamton, UC London.
      We (and alex I am sure) would be grateful for further suggestions.

  14. gold account says:

    Stefánsson’s team scanned demographic records in Iceland for the average paternal age starting in 1650. From 1900 to 1980, as the Icelandic population transitioned from agricultural to industrial living, the average paternal age dropped from 34.9 to 27.9 years. In the subsequent 30 years, however, thanks to better education and higher contraception use, the average age has gone back up, to 33 years in 2011.

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