DHCR7 mutations linked to higher vitamin D status allowed early human migration to Northern latitudes

BACKGROUND: Vitamin D is essential for a wide range of physiological processes including immune function and calcium homeostasis. Recent investigations have identified candidate genes which are strongly linked to concentrations of 25-hydroxyvitamin D. Since there is insufficient UVB radiation to induce year-round cutaneous synthesis of vitamin D at latitudes distant from the equator it is likely that these genes were subject to forces of natural selection. We used the fixation index (F(ST)) to measure differences in allele frequencies in 993 individuals from ten populations to identify the presence of evolutionary selection in genes in the vitamin D pathway. We then explored the length of haplotypes in chromosomes to confirm recent positive selection. RESULTS: We find evidence of positive selection for DHCR7, which governs availability of 7-dehydrocholesterol for conversion to vitamin D(3) by the action of sunlight on the skin. We show that extended haplotypes related to vitamin D status are highly prevalent at Northern latitudes (Europe 0.72, Northeast Asia 0.41). The common DHCR7 haplotype underwent a recent selective sweep in Northeast Asia, with relative extended haplotype homozygosity of 5.03 (99th percentile). In contrast, CYP2R1, which 25-hydroxylates vitamin D, is under balancing selection and we found no evidence of recent selection pressure on GC, which is responsible for vitamin D transport. CONCLUSIONS: Our results suggest that genetic variation in DHCR7 is the major adaptation affecting vitamin D metabolism in recent evolutionary history which helped early humans to avoid severe vitamin D deficiency and enabled them to inhabit areas further from the equator.