Monday, January 19, 2009

John Hawks doesn't like random genetic drift

 
The human MYBPC3 gene encodes a muscle protein. A 25 bp deletion in that gene is associated with a large increase the risk of cardiomyopathy ("heart muscle disease"). The most severe problems appear when carriers reach the age of 40.

According to a recent paper by Dhandapany et al. (2009), the overall frequency of the deletion allele is about 4% in India but it ranges from 0% to 7% in different parts of the country. The allele is not present in most other populations outside of India.

The authors conclude that the allele has reached this frequency by random genetic drift beginning with an initial mutation about 30,000 years ago. This increase has occurred in spite of the fact that the allele is deleterious and should decrease overall fitness.

John Hawks disagrees: Could genetic drift really break your heart?.
The issue is not really whether a gene could go from 1 copy to 4 percent in 1200 generations by chance. That wouldn't be so terribly unlikely in Pleistocene humans -- in fact, the mean time for a mutation to go from 1 copy to 4 percent by drift in a population of effective size 10,000 individuals is not 30,000 years, but only around 20,000 years. On the other hand, mtDNA variation today suggests that South Asia experienced early and rapid population growth -- so we're not likely talking about a population of 10,000, but more like a minimum of 100,000 effective individuals through the past 30,000 years at least. It would take genetic drift at least 10 times longer to accomplish the requisite frequency change given that demographic history. Still, a single allele at a single gene locus might be exceptional.

But that scenario, however unlikely, is simply not the situation we have here. Here we have a deletion that must have some disadvantage, because it gives people a fatal disease. This disadvantage is apparently dominant in effect, based on the case-control study. Yet the deletion has managed to persist within the large South Asian populations of the last 10,000 years so that today it is still around 4 percent.
John is an expert on evolution within human populations but he seems to be basing all of his calculations on the idea that the mutation arose in a population of 100,000 individuals and that this population was the effective population (e.g. they all freely interbred). I don't think this is very likely.

The fact that the allele frequency varies within India suggests that there are many subpopulations. Some of them might have been as small as 1000 individuals at vary time over the course of the last 30,000 years. As I'm sure John knows, the populations dynamics of human groups is extremely complex. We only have to think about the allele frequency differences in the Pennsylvania Amish communities or French Canadians to recognize this fact.

And let's not forget that the frequency of Huntington's disease is high around Lake Maracaibo in Venezuela. Over a period of 200 years a single individual with the Huntington's disease allele has left 18,000 descendants.

When we look at modern allele frequencies we don't only think about average rates of change due to random genetic drift in panmitic populations. We also have to consider the unusual events that occur from time to time. These include founder effects, natural disasters, etc. etc. The MYBPC3 is a lottery winner. You can't dismiss evolution by accident just because the probability of any one event is low.

This is why John says that, "Still, a single allele at a single gene locus might be exceptional." But John seems to think that in this case the result is not just "exceptional" but extraordinarily exceptional. He suggests that the deleterious effects of the allele are a recent phenomenon and that explains why it survived in early populations.
I would hypothesize that the disadvantages of the deletion have actually increased over time. The average lifespan increased into the Upper Paleolithic and probably later as well. Meanwhile, as the population grew, larger completed family sizes became more important to fitness. As people became more sedentary, the accumulation and inheritance of possessions and land became an important means of investing in children. The increasing importance of later survival and investment in children should have raised the fitness cost of chronic disease. That would explain a pattern of evolution in which this deletion increased in frequency early in its history, but later remained static or declined.

So, I don't suppose I can say people are crazy for thinking genetic drift could explain this deletion's current high frequency. But considering the powerful effect of weak selection over the many generations involved here, and the very large size of the South Asian population during most of that time, genetic drift seems pretty unlikely.
This makes sense to me. It's consistent with John's idea that the rate of human evolution has changed substantially over the past 30,000 years but I don't see why he objects so much to a random genetic drift explanation. Why does he suggest the the authors of the paper are crazy to suggest drift as an explanation?

It seems to me that his explanation is consistent with an increase in allele frequency due to random genetic drift just as the authors claim.


Dhandapany, P.S., Sadayappan, S., Xue, Y., Powell, G.T., Rani, D.S., Nallari, P., Rai, T.S., Khullar, M., Soares, P., Bahl, A., Tharkan, J.M., Vaideeswar, P., Rathinavel, A., Narasimhan, C., Ayapati, D.R., Ayub, Q., Mehdi, S.Q., Oppenheimer1, S., Richards, M.B., Price, A.L., Patterson, N., Reich, D., Singh, L., Tyler-Smith, C., and Thangaraj, K. (2009) A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia. Nature Genetics, Published online: 18 January 2009 [doi:10.1038/ng.309]

4 comments :

  1. You might find this new paper interesting Larry:

    Keinan, A. et al. (2008) Accelerated genetic drift on chromosome X during the human dispersal out of Africa. Nature Genetics, 41, 66 - 70.

    Comparisons of chromosome X and the autosomes can illuminate differences in the histories of males and females as well as shed light on the forces of natural selection. We compared the patterns of variation in these parts of the genome using two datasets that we assembled for this study that are both genomic in scale. Three independent analyses show that around the time of the dispersal of modern humans out of Africa, chromosome X experienced much more genetic drift than is expected from the pattern on the autosomes. This is not predicted by known episodes of demographic history, and we found no similar patterns associated with the dispersals into East Asia and Europe. We conclude that a sex-biased process that reduced the female effective population size, or an episode of natural selection unusually affecting chromosome X, was associated with the founding of non-African populations.

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  2. Tribal/village life would mean that a total population of 100,000 would be split into a large number of discrete sub populations with limited interaction, as you suggest.

    Also the deletrious impact appears to occur around age 40. By that time most of the heavy lifting, with regard to reproduction, would have been done, so the gene would have minimal impact on reproductive success.

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  3. Sorry I showed up late --

    The division of the regional population into smaller partially isolated groups will make genetic drift weaker not stronger, when considering the region as a whole (as we are here).

    I like genetic drift. It's a testable hypothesis. In this instance, I think it fails the test, because our knowledge of South Asian demography (from other genetic loci, as well as history) puts the effective population size at a much larger value.

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  4. John Hawks said:
    The division of the regional population into smaller partially isolated groups will make genetic drift weaker not stronger, when considering the region as a whole (as we are here).

    Maybe not. If the gene became fixed in one or two populations and than was introduced as part of the limited exchange between populations, it would stand a chance of becoming fixed in those populations.

    The map appears to show the highest concentrations roughly around the coastal areas. These populations would be the most likely to have limited inter-population exchange.

    Besides, while the gene may be deleterious to the individual, it may not be to the community.

    Family elders, once they reached 40 would have done most of their reproductive heavy lifting, and so from an evolutionary perspective, removing them will not matter much, and may help as resources can be allocated to other family members.

    Also number one offspring gets a bonus. Instead of plowing the family plot, or tending the family cow, the offspring would be amongst the few in their generation to legitimately use the chat-up line "Wanna come back to my place and see my cow"!

    Cashed up (or at least cowed-up) youth would be a prize catch which, in turn improves the chances of reproductive success.

    So the gene may be advantageous.

    I may try this adaptationist lark. It's easier than working.

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