Adaptive selection of an incretin gene in Eurasian populations

  1. Sheau Yu Teddy Hsu7,8
  1. 1 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan 333, Taiwan;
  2. 2 Department of Biology, Stanford University, Stanford, California 94305, USA;
  3. 3 Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77840, USA;
  4. 4 Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom;
  5. 5 Genomic Medicine Group, University of Santiago de Compostela, CIBERER, Santiago de Compostela 15706, Spain;
  6. 6 Hormone Research Center and School of Biological Sciences and Technology, Chonnam National University, Kwangju 500-712, Republic of Korea;
  7. 7 Reproductive Biology and Stem Cell Research Program, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317, USA

    Abstract

    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). 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 compared with GIP55S, which is derived from the ancestral allele. Haplotype structure analysis suggests that the derived allele at rs2291725 arose to dominance in East Asians ∼8100 yr ago due to positive selection. 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 the 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.

    Footnotes

    • Received May 17, 2010.
    • Accepted October 22, 2010.
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