Adaptive selection of an incretin gene in Eurasian populations

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.

Identification of Metabolic Modifiers That Underlie Phenotypic Variations in Energy-Balance Regulation

“…The selection of GIP variants was inferred after we focused the analysis on local genomic regions and assessed the significance of integrated haplotype score using coalescent simulations (22). Therefore, our investigation provided a proof-of-concept study for identifying causal mutations that underlie phenotypic variation of complex disease-related traits.…”

“…It is also important to note that the selection of GIP variants represents a unique example in which the selection process involves regulatory variants that alter the glucose-induced GIP response as well as a nonsynonymous variant that affects peptide bioactivity (22). Thus, the GIP signaling pathway could represent a hotspot for selection in recent human history and play an important role in the manifestation of phenotypic variation in energy-balance regulation among individuals.…”

“…Among these variants, those in GIP are of particular interest because they are highly linked to each other as well as to a functional nonsynonymous mutation (rs2291725) in exon 4 of GIP ; that is, in a high linkage-disequilibrium (LD) block (22). …”

Adaptive Human CDKAL1 Variants Underlie Hormonal Response Variations at the Enteroinsular Axis

“…In a recent investigation, we documented the strong selection of a cluster of GIP variants in East Asians ∼8,100 (11,800 to 2,000) years ago [5], [6]. It is surprising to find that the selection of rs7754840 in CDKAL1 occurred in the same population at approximately the same time period (i.e., ∼6,900 years ago).…”

The Nutrigenome and Gut Microbiome: Chronic Disease Prevention with Crop Phytochemical Diversity

“…GIP is resistant to serum degradation, and exhibits a higher bioactivity May have been beneficial for individuals who had unconstrained access to the food supply in agricultural societies by preventing hyperglycemia (Chang et al, 2011) ADH1B Alcohol Dehydrogenase 1B (class 1), beta polypeptide…”