I've been bandying a particular hypothesis about lately in terms of human evolution: strong recent selection for adaptive alleles will result in a fitness drag due to pleiotropic effects. In short, I'm working with the assumption that a new mutant which has significant positive benefits because of a phenotypic change is also liable to foul up other functional pathways. Sickle cell as an adaptation to malaria is a classic case of this; the fitness benefits of heterozygosity are great enough to outweigh the drag of a proportion of anemic homozygotes (this is a case of balancing selection via overdominance). Yesterday I commented on copy number variation in the gene responsible for amylase, AMY1. Last month I covered lactase persistence. The rise in frequency of lactase persistence and the emergence of sickle cell are recent, within the last 10,000 years. It also seems likely that some of the copy number variation selection was also relatively recent. We don't know of any downsides to lactase persistence and increased copy number for AMY1, though it seems plausible in both of these cases there is some metabolic cost simply from producing greater quantities of the enzymes in question. But in any case, my conjecture is that given enough time these sorts of traits lose their fitness drag as modifier alleles emerge at other loci to mask their deleterious impact. I am basically describing the ascension of the adaptive peak through mutants of small effect after the initial "overshoot."
That is why I was rather interested in this paper, Two routes to functional adaptation: Tibetan and Andean high-altitude natives:
Populations native to the Tibetan and Andean Plateaus are descended from colonizers who arrived perhaps 25,000 and 11,000 years ago, respectively. Both have been exposed to the opportunity for natural selection for traits that offset the unavoidable environmental stress of severe lifelong high-altitude hypoxia. This paper presents evidence that Tibetan and Andean high-altitude natives have adapted differently, as indicated by large quantitative differences in numerous physiological traits comprising the oxygen delivery process. These findings suggest the hypothesis that evolutionary processes have tinkered differently on the two founding populations and their descendents, with the result that the two followed different routes to the same functional outcome of successful oxygen delivery, long-term persistence and high function. Assessed on the basis of basal and maximal oxygen consumption, both populations avail themselves of essentially the full range of oxygen-using metabolism as populations at sea level, in contrast with the curtailed range available to visitors at high altitudes. Efforts to identify the genetic bases of these traits have included quantitative genetics, genetic admixture, and candidate gene approaches. These reveal generally more genetic variance in the Tibetan population and more potential for natural selection. There is evidence that natural selection is ongoing in the Tibetan population, where women estimated to have genotypes for high oxygen saturation of hemoglobin (and less physiological stress) have higher offspring survival. Identifying the genetic bases of these traits is crucial to discovering the steps along the Tibetan and Andean routes to functional adaptation.
It is an open access article. You are free to read it closely. Here is my own impression: the Andeans have more clunky "brute force" adaptations to high altitudes, while the Tibetans have some more subtle characteristics which are more difficult to smoke out physiologically (obviously your impression may differ). I suspect that the Andean physiological response is so easy to detect because it is not seamlessly integrated into the rest of their functionality. Evolution has had less time to work with the Andeans to streamline their adaptation so as to induce less stress in their system. Modern humans have been resident in Tibet for 2.5 times as long as in the Andes. Additionally, pre-sapient species likely had their own adaptations which could plausibly have jumped through introgression. And there is a final piece of the puzzle: I am to understand that the adaptations of the Ethiopians are even more cryptic than those of the Tibetans! This is what one would expect, as humans have been resident at high altitudes in the Horn of Africa for an order of magnitude longer than they have in Tibet.