Genome Res. 2010 Oct 26. [Epub ahead of print]

Chang CL, Cai JJ, Lo C, Amigo J, Park JI, Hsu SY.

Diversities in human physiology have been partially shaped by adaptation to natural environments and changing cultures. Recent genomic analyses have revealed single nucleotide polymorphisms (SNPs) that are associated with adaptations in immune responses, obvious changes in human body forms, or adaptations to extreme climates in select human populations. Here, we report that the human GIP locus was differentially selected among human populations based on the analysis of a nonsynonymous SNP (rs2291725). Haplotype structure analysis suggests that, owing to positive selection, the derived allele at 2291725 arose to dominance in East Asians ~8.1 thousand years ago. In addition, comparative and functional analyses showed that the human GIP gene encodes a cryptic glucose-dependent insulinotropic polypeptide (GIP) isoform (GIP55S or GIP55G) that encompasses the SNP and is resistant to serum degradation relative to the known mature GIP peptide. Importantly, we found that GIP55G, which is encoded by the derived allele, exhibits a higher bioactivity as compared to GIP55S, which is derived from the ancestral allele. The combined results suggested that rs2291725 represents a functional mutation and may contribute to the population genetics observation. Given that GIP signaling plays a critical role in homeostasis regulation at both enteroinsular and enteroadipocyte axes, our study highlights the importance of understanding adaptations in energy-balance regulation in the face of the emerging diabetes and obesity epidemics.

PMID: 20978139 [PubMed - as supplied by publisher]