The combination of such a large risk with such a high frequency is, fortunately, unique. "How can such a harmful mutation be so common?" asks Chris Tyler-Smith from The Wellcome Trust Sanger Institute, Hinxton, UK. "We might expect such a deleterious change to have 'died out'.
"We think that the mutation arose around 30,000 years ago in India, and has been able to spread because its effects usually develop only after people have had their children. A case of chance genetic drift: simply terribly bad luck for the carriers."
This is a 25-bp deletion in a muscle protein gene, MYBPC3. The current allele frequency in India is estimated to be 4 percent; it is estimated to be carried by 60 million people. The paper suggests that it originated 30,000 years ago. Carriers of the gene have a massive increase in their chance of cardiomyopathy.
Here’s the relevant passage from the paper:
The presence of a disease-associated variant at substantial frequency raises an evolutionary question: if it is disadvantageous, how did it become so common? In principle, it could be evolutionarily neutral, manifesting its disadvantages only late in life; alternatively, its disadvantages could be outweighed by advantages early in life, or in a different environment, so that it could have been positively selected. To address this question, we examined the haplotype structure surrounding the deletion. Using ?ve short tandem repeat (STR) markers, spanning ca. 3.4 Mb surrounding the deletion in 287 heterozygous individuals, we found similar high degrees of variation in the inferred haplotypes from chromosomes with and without the deletion (Supplementary Fig. 7 and Supplementary Table 6 online). We then used allele-speci?c ampli?cation to resequence ca. 10-kb haplotypes centered on the 25-bp deletion from nine heterozygous individuals (Supplementary Tables 7 and 8 online). The chromosomes carrying the 25-bp deletion showed ?ve closely related haplotypes (Supplementary Fig. 8 online). After excluding variants likely to have arisen by recombination, we estimated a time to most recent common ancestry (TMRCA) of ca. 33 23 thousand years for the deletion haplotypes (Supplementary Methods). This time slightly postdates the initial peopling of the subcontinent 30,00050,000 years ago and together with its restricted geographical distribution suggests that the deletion did not arrive with the ?rst modern human settlers from Africa [more than] 50,000 years ago, but arose subsequently within the subcontinent. Its occurrence in two populations from Southeast Asia can be explained by recent gene ?ow from India (Supplementary Note online). Collectively, these observations provide no evidence for rapid spread of a recent founder haplotype or any departure from neutral evolution (Dhandapany et al. 2009:4).
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.
People mainly die of cardiac problems after age 40. But human reproductive lives aren’t over until they’re done investing in their children. Further, a weakened heart may reduce work potential or health even if it kills slowly. The fitness cost of this deletion is smaller than if it gave people a chance at a fatal disease when they are 17, but a smaller fitness cost is still a fitness cost. In a large population, that small fitness cost is going to whittle away the frequency of the allele over time.
A thousand generations is a lot of potential whittling. Using some quick calculations, it looks like selection against the deletion as low as 0.001 to 0.0015 in heterozygotes should have been enough to cut the frequency down to around 1 percent, from an initial value of 4 percent. So even if drift increased the deletion early after its origin, it ought to be much rarer today. Meanwhile, drift looks even more unlikely, since the chances of a mutation growing from 1 copy to 4 percent against such selection are nil.
Did this deletion have a fitness cost as high as one in a thousand? It increases cardiomyopathy by 5-fold or more compared to the wild type. So it seems very plausible. But really, we don’t have any good estimates of the fitness costs of chronic diseases in pre-industrial populations.
If the deletion was favored by some selection, that would probably be antagonistic, that is, acting against the fitness cost of the deletion late in life. The authors briefly investigated this hypothesis, as described above. They found no evidence for a recent expansion of a single haplotype around the deletion. That means that if there was strong selection favoring this deletion, it must have happened early after its origin and then petered out. If the expansion had been late in South Asian history, it would show more LD around it, and most of the deletion-carrying chromosomes would share a single long-range haplotype. So this deletion has not been increasing rapidly in the past few thousand years.
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.
Dhandapany PS and 23 others. 2009. A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia. Nat Genet (online early) doi:10.1038/ng.309