Adaptive selection of an incretin gene in Eurasian populations.
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.
Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan 333, Taiwan.
Chia Lin
CL
Chang
James J
JJ
Cai
Chiening
C
Lo
Jorge
J
Amigo
Jae-Il
JI
Park
Sheau Yu Teddy
SY
Hsu
D000222:Adaptation, Physiological; D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People / Q000235:genetics*; D002415:Cats; D002417:Cattle; D002460:Cell Line; D004285:Dogs; D019143:Evolution, Molecular; D005202:Asia, Eastern; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics*; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D054795:Incretins / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012641:Selection, Genetic
D054795:Incretins; D020033:Protein Isoforms; D005749:Gastric Inhibitory Polypeptide