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.

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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]