Is there evidence for selection in functional pathways across chromosomes?

 Cases of hypercholesterolemia are often associated with fat- and cholesterol-rich diets; in spite of this, the Maasai people of East Africa live on a diet consisting mainly of milk, meat and blood and yet, largely avoid hypercholesterolemia and arteriosclerosis, do not suffer from gallstones, have low blood pressures and low rates of cardiac incidents. In the 1970s, radioactively labeled diet studies identified a negative feedback mechanism in the Maasai which maintained cholesterol homeostasis by co-regulating endogenous cholesterol synthesis and dietary cholesterol absorption. These studies suggested, but did not prove, a genetic origin for this phenomenon. The Maasai were also found to have high serum levels of IgA as compared to Caucasians; selected perhaps on account of the pressure to survive in a highly pathogenic environment. Using a number of association significance tests on the recently released HapMap III data, we identified 5,173 polymorphisms that are significantly associated with the Maasai (MKK) samples in the HapMap III dataset compared to all other samples/populations (p-value <10-12). Compared to the distribution of randomly selected polymorphisms in MKK, we found that a subset of 697 polymorphisms formed a clique across all MKK founders with highly significant pair-wise correlation (r2>0.95, Wilcoxon p-value<10-16). A large number of the 5,173 polymorphisms are within or near genes known to be associated with the lipid metabolism pathway. Many are in or close to genes whose dysfunction is known to be associated with arteriosclerosis, coronary artery disease, hypercholesterolemia, hyperlipidemia, hyperlipoprotemia, hypertriglyceridemia, and cardiovascular and metabolic disorders. Many of the other polymorphisms are in regions involving immune system genes. 120 of the 5,173 and 8 of the 697 polymorphisms are located in the human orthologous regions of the "Diet1" locus in mouse strain C57BL/6ByJ (B6By), where polymorphisms are known to induce resistance to diet-induced hypercholesterolemia. Our results strongly suggest that the Maasai have specific genetic alterations compared to other populations in genes involved in metabolic and immune regulation pathways that protect them against hypercholesterolemia and from pathogenic organisms. Such strong selection presumably derives from inbreeding, a relatively small population size, a fat-rich diet, long exposure to a steady but hostile environment, and unusual social customs.