Too Darn Hot?

Several recent papers  give me the impression that there is regional variation in mutational load.   One can slice this a number of ways. A recent Science article looked at mutations that knocked out genes – loss-of-function or LOF mutations.  Mutational load is the sum of all deleterious mutations – LOF mutations are a clear-cut subset of total mutational load.

Some of the LOF mutations they are found are common, and are presumably neutral, maybe even beneficial, but most are rare and likely deleterious.  The kicker is that they found significantly more LOF mutations in their African population sample than in their European and East Asian samples – 25% higher.  That was unexpected. Population history (and mutation rate) determine the variation you expect to find in neutral genes, but significantly deleterious mutations should be in mutation-selection balance.  A neutral variant might easily be a million years old, but a deleterious variant will last, on average, 1/s generations, when s is the decrease in fitness caused by that variant.  A mutation that decreases fitness by 1% should disappear in  100 generations or so, about 2500 years.  Ancient bottlenecks should not influence the frequency of such noticeably deleterious mutations.

Another related paper  looked at a large set of coding genes, sequencing many times (average depth of 111x)  for high accuracy. As in the LOF paper,  they found that the average person carries many probably-deleterious mutations, mutations which are individually rare.  Each person carried, on average, mutations expected to change function (almost always for the worse, although usually only a little for the worse)  in 313 genes (out of the 15,585 they studied.

They looked at African-Americans and Americans of European descent, about a thousand of each.  They saw what what was seen in the LOF paper did: there were significantly more probably-deleterious mutations in the 80%-African population.  When they used a loose definition of functional variation, about 20% more : with a more conservative definition,  which should have a higher fraction of truly deleterious genes, about 29% more.

This African excess is similar in every category they examined: in synonymous changes, in missense changes,  in mutations that affect splicing or that turn a protein into hash.  Synonymous changes are neutral (or close enough), and more neutral variants in Africans could be a consequence of population history (a generally larger population size over most of the last few tens of thousands of year).  But that kind of ancient population history can’t matter much when we’re talking mutations that drop fitness by 1% or more, so what’s going on?    The only simple explanation (that I can think of)  is a higher mutation rate.

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22 Responses to Too Darn Hot?

  1. j says:

    Firstly, you are right, it is darn too hot.

    Secondly, a defective or a less efficient genotype maintenance mechanism could produce the same result.

  2. Paul Jaminet says:

    My guess is this is simply driven by rates of mitochondrial uncoupling. Africans have less uncoupling, less dissipation of mitochondrial electrons in heat generation, therefore greater free radical generation. This makes mutations more likely, even in nuclear DNA. That it’s mitochondrial would explain why people of African descent living at higher latitudes have higher mutation rates — it’s not the environmental temperature, but mitochondrial adaptations to ancestral temperatures, that is the driving factor.

  3. Matt says:

    As I understand it, we only know a mutation is deleterious by the fact that its carriers tend to have lower Darwinian fitness (number of offspring) when we analyse a large population of carriers of the gene (thus controlling sufficiently for other genes).

    Otherwise it’s not deleterious. Loss of function and deleterious are quite different?

    What’s the African Darwinian fitness, present and historical again? If they carry a greater load of deleterious alleles, then they should have lower fitness. Otherwise, by definition, they do not.

    Unless I’m making some horrible sophomoric mistake here.

    Perhaps with more relevance, it might be interesting to compare populations in the Americas and East Asia (e.g. north to meso america and China to Philippines), given these people have low overall genetic distances and timedepth of differentiation but have been resident in climates with quite different mean temperatures for 1000s of years?

  4. Bert says:

    Steve Sailer often points out that the disease burden is high in Africa. If who gets to live long enough to procreate is determined largely by disease (or other “random” factors, such as accidents or violence), deleterious mutations might not be weeded out to as large an extent as otherwise.

    • billswift says:

      That suggests an alternative hypothesis; what if it is viral load? Could having large numbers of viruses, even those that don’t cause clinical disease, be a factor?

  5. Anonymous says:

    In an earlier post, you said:

    “If I’m right, this means that most IQ variation – what we might call the normal range – is caused by differences in the number of slightly deleterious mutations.”

    You were talking about within-population variance, but I am wondering if this would apply to differences in the mean between populations? Is it possible the higher number of deleterious mutations among certain groups can explain part of the IQ gaps that we see between them?

  6. jb says:

    I can see how local temperatures might have an impact on the mutation rate of mammals, because of the external testicles of the males. But don’t human males at all latitudes keep their testicles at more or less a tropical temperature through the use of clothing?

    BTW, it seems to me that temperature regulation through the use of clothing is one of the few cases — if not the only case — where the old idea that “humans don’t need to adapt biologically to new conditions, because they can adapt culturally” is actually true. Humans really can keep themselves warm with clothing, so there was never much reason for modern humans in northern latitudes to evolve a warm fur coat.

    The thing is, because this was the example that was always trotted out to make the general case for cultural over biological adaptation in modern humans, the fact that the argument made sense in this specific case made the general argument seem much more reasonable than it actually was! As soon as you stop thinking about the example of clothing, and start thinking about, let’s say, high density agricultural societies, the inevitability of some sort of biological adaption becomes much harder to deny.

  7. albatross says:

    Were there historically more viral diseases in Africa than in Asia and Europe? My intuition is that Africa has probably historically had more endemic diseases (especially insect borne), but probably no more epidemic disease, and maybe less, since it’s harder to get to sub-Saharan Africa from elsewhere. I wonder what the levels of loss of function mutations look like for Aboriginees and North/South American Indians.

    The explanations I can imagine for this (but I don’t claim much expertise):

    a. Higher rate of mutations (hotter, more inflamation, some common gene that provides another benefit in exchange for less error correction in DNA replication (this would track with higher cancer rates, but that doesn’t matter much when few people live past 60 anyway))?
    b. Less selective pressure to remove mutations (shorter lifespans, more randomness in who lives and who dies)?
    c. Some offsetting advantage of all the mutations?

    I gather a lot of mutations that provide some resistance to diseases are loss of function mutations, like the mutation in one of the receptors on macrophages that makes it much harder to catch HIV, or the sickle-cell mutation. Could the larger number of loss of function mutations be the result of many generations living with diseases that have human as their only or main host, so that as humans develop loss-of-function mutations that somehow block the disease at the same time they decrease some other level of function, the disease mutates around the humans’ mutation?

    It seems like the higher level of loss of function mutations would lead to shorter lifespans and worse health. And I gather this is true of blacks in the US, but I have no idea whether there’s any connection between the two.

  8. dave chamberlin says:

    What about other species, do they have a higher mutational load when living in hotter environments. Is this tendency part of the reason for the higher diversity in life forms near the equator. I have no opinion but just think these are questions that may lead to more complete answers than we now have.

  9. Here is a simple explanation: Higher inequality in the recent past:

    Aristocratic systems had very high inequality, and, contrary to common perception, reasonable social mobility. Arguably, they were about as hereditary as race horses. The ability to organize other people, and the ability to move a very large heavy sword around really fast, was apt to have very large consequences to a noble’s career. Nobles were children of nobles in substantial part for the reason that race horses tend to be children of race horses.

    In a highly unequal system near Malthusian equilibrium, deleterious mutations will be eliminated faster than in a more equal system near Malthusian equilibrium.

  10. xxxx@yahoo.com says:

    Is there any evidence that white australians or south africans have higher mutational loads than their European counterparts? Although only relatively recently separated, the relative lack of climatic adaption (melanin) might still mean comparing the two could be informative.

  11. Steve Sailer says:

    There’s the general pattern identified by Michael H. Hart where agricultural civilizations originate at a moderate latitude, then slowly move north, and the northerners eventually do very well civilizationally.

    A couple of exceptions are China, where the current civilization originated pretty far north but slowly moved south, and the southerners are currently doing well. India seems to be another similar case, although some of southern India is at an altitude (e.g., Bangalore, the software hub, is at 3600 feet), which mitigates the warmth.

    • Matt says:

      Mesoamerica seems another exception – civilization in the north never really overtook the South, nor moved northwards. Of course, the cool highland civilizations of the Andes are pretty nice.

      Likewise Africa – the Bantu expansions are north to south, from more tropical to less tropical regions, but the zenith of African civilization (such as it is) seem ensconced firmly in its original west-central African homeland.

  12. RKU says:

    Well, color me a little skeptical that temperature-induced mutational loads would be much of a factor in the evolution of local intelligence, at least at the time-scales seemingly under consideration.

    One difficulty with evaluating this hypothesis is that I think in most of the world there’s been considerable gene-flow over time, and e.g. a 10% admixture of some wandering barbarian tribe might tend to confuse the issue. Another difficulty is measuring intelligence before modern times. Were the Greeks really that much smarter than the Phoenicians—who can say?

    But if we look at the case of China, they’ve been nationally administering competitive exams for almost 1,500 years, over 10x longer than anywhere else. Also, external gene-flows have generally been pretty small, since the couple of time they’ve been conquered it’s been by relatively tiny nomadic tribes, and Chinese otherwise don’t move around that much.

    As it happens, the best exam results have traditionally come from the Southern provinces, especially a couple of them whose names I forget, to such an extent that a national system of quotas had to be implemented. So various Southerners seem to have stayed quite a bit smarter over the last 1,000+ years, or almost 50 Chinese generations. Don’t know the temperature-gradient across China…

    • Paul Jaminet says:

      One possible response to the gene-flow objection is that the dings to IQ come from recent mutations (last few generations), and the recent mutation rate is determined by mitochondrial genes which have reduced gene-flow (due to lack of mixing and reduced migration by women).

      The IQ gradient across China could be related to rice vs wheat consumption. In Japanese children, rice eaters are 4 IQ points smarter than wheat eaters. In China, rice is the staple in the south, wheat in large parts of the north.

    • RKU says:

      Interesting—didn’t know that about the wheat/rice difference in Japan. Certainly might be true in China as well.

      But it seems to me that’s one of the problems with this very slow/mild genetic-load argument based on something like temperature—it can so easily be swamped by almost any other larger/faster factor such as a random wandering tribe, whose impact occurs in years or decades rather than many generations.

  13. Mike says:

    Could a lot of stuff that correlates with IQ, correlate better with mutational load instead? Reaction time, longevity, height, you name it.

    (I wonder what the ballpark correlation between IQ and mutational load is?)

    • Mike says:

      I appear to be restating what GC covered (much more eloquently) in April. Oops.

      I am curious whether focusing on miscarriage rates specifically could help illuminate this issue. I recall a post by Razib about miscarriages (and low fertility) often being nature’s way of pruning mutational load…

  14. Pingback: Evidence for Cochran’s & Harpending’s Theory of Genetic Load: The Link Between IQ and Attractiveness | JayMan's Blog

  15. soren says:

    I was reading about Russian Cosmism on wikipedia and came upon this…

    http://en.wikipedia.org/wiki/Alexander_Chizhevsky#Sunspots_and_mass_excitability

  16. Pingback: Genes Dealt Made Asians Svelte | Science.xcuz.me

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