A puzzling finding from the search for selection in humans is the large number of apparently selected variants versus the apparent absence of high frequency selected regions and regions that have become fixed in our species. If there is indeed a lot of selection, why haven’t more sweeps completed, that is, gone to fixation? The authors of one of the first of the flood of papers told us that they could only identify about fifty regions that were candidates for having recently fixed and they were not convinced of any of them.
An excellent review of this “problem” came up with a number of scenarios that could explain the prevalence of incomplete sweeps and the lack of hard sweeps. For example a sweep of an advantageous new mutant could be slowed down by the appearance of equivalent mutations in the same gene. These phenocopies would then compete with each other and none would show evidence of having gone to fixation. Niemann-Pick disease in Ashkenazi Jews is caused by one of four different mutations that are all at similar frequencies. Greg Cochran has called this the “stooge effect” after the three stooges all trying to get through the door at the same time.
Cochran, John Hawks, and I were involved in some of this work, and we all thought immediately without any discussion that the intermediate frequency sweeps must reflect heterozygote advantage. This seemed so obvious as to be hardly worth talking about, but no one else in the trade seems to find it so obvious. If there would be an advantage to modulating the effect of a locus, an easy quick fix is to break an allele. The broken alleles would all show up in heterozygotes when they were rare. This is the case with the classical example of heterozygote advantage, sickling haemoglobin, but it is also the case with most of the known and understood sweeps. The malaria defense polymorphisms all seem to involve slightly dinged versions of the ancestral allele, lactase persistence is a dinged regulator, the Duffy negative allele in sub-Saharan Africa is a broken immune system receptor, EDAR is a broken pump, and so on. We know of many similar cases in domestic animals too. Do you want more beef from your steers or a faster whippet? Easy, give them a copy of broken myostatin and they muscle up like Schwarzenegger. Unfortunately, when that broken myostatin allele becomes common enough to appear in homozygotes the outcome is not so favorable. Such useful dinged genes could very well sweep rapidly, until homozygotes started appearing, at which point the sweep would grind to a halt. Sickling haemoglobin loses its advantage as it becomes common, and any sweep in tropical Africa must have stopped long ago. Broken Duffy in Africa seems to be a hopeful example of a sweep that has gone to fixation, but it must do some damage to individuals. For example it is known that broken Duffy by itself is responsible for low levels of circulating neutrophils, as shown in this paper.
Our ideas were strengthened by this paper, known in the trade as “The White Man’s Burden Paper”. A careful and elegantly done survey of “possible damaging” and “probably damaged” alleles in sequences of 20 Europeans and 15 Africans showed that Europeans had more, in accord with the findings from SNP surveys that there more apparent sweeps in Europeans. On the other hand the authors, in the spirit of the times I suppose, proposed a completely implausible bottleneck in the history of Europeans that led to the buildup of many deleterious mutations in the population by drift.
Hawks, Cochran, and I are hardly mainstream and so, we thought, we must be missing something obvious. We put together a short paper laying out our reasoning, then we all completely lost interest in it. There followed months of a three way exchange of cajoling and threats trying to get someone to actually write it up and submit it somewhere. Nothing happened, even though the level of persuasion became so intense at one point that “kneecap” was used as a verb.
Hoping that we can get interested folks to have a look at this devil’s manuscript I have posted it on my school website at http://harpending.humanevo.utah.edu/Documents/fisher-geometric-11-2011.pdf. We would all be grateful for any comments or suggestions.