The Phylogeny of NPC1: the Evolution of a Gene‐Diet Interaction

Short genetic variations in the Niemann‐Pick C1 (NPC1) gene have been associated with elevated risk of obesity and diabetes in multiple population studies. The ancestral risk variants (H215R, M642I, I858V) are present at a frequency of 53%, 67%, and 52%, respectively, among European populations. These major variants are thought to encode a protein which is less efficient in regulating the transport of cholesterol, contributing to a thrifty genotype. To understand the history of these risk variants, a protein phylogeny was created based on orthologous sequence homology. The phylogeny determined that one of the variants (M642I) became predominant at some point after the divergence of man and ape. Since these variants are in linkage disequilibrium, they are likely to have been under the same selective pressure. Despite this novel finding, the idea of a gene optimized for nutrient storage by the environment has been debated since the thrifty genotype hypothesis proposed by James Neel in 1962. The thrifty gene was thought to be the product of long term famine, although there is little evidence that early humans experienced such events. Here, we propose that the NPC1 gene was molded by the high energy expenditure of persistence hunting in early hominid development. The distinct advantage for obtaining prey represented by these major variants may now be a hindrance in our modern obesogenic environment. Evidence that the European diet has selected for minor alleles which are not associated with risk of obesity/diabetes is apparent in the fact that Europeans have a higher frequency of the minor, non‐risk variants than subjects from sub‐Saharan Africa.