Table_3_The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection.xlsx

The intestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is involved in important physiological functions, including postprandial blood glucose homeostasis, bone remodeling, and lipid metabolism. While mutations leading to physiological changes can be identified in large-scale sequencing, no systematic investigation of GIP missense variants has been performed. Here, we identified 168 naturally occurring missense variants in the human GIP genes from three independent cohorts comprising ~720,000 individuals. We examined amino acid changing variants scattered across the pre-pro-GIP peptide using in silico effect predictions, which revealed that the sequence of the fully processed GIP hormone is more protected against mutations than the rest of the precursor protein. Thus, we observed a highly species-orthologous and population-specific conservation of the GIP peptide sequence, suggestive of evolutionary constraints to preserve the GIP peptide sequence. Elucidating the mutational landscape of GIP variants and how they affect the structural and functional architecture of GIP can aid future biological characterization and clinical translation.

肠道激素葡萄糖依赖性促胰岛素多肽（glucose-dependent insulinotropic polypeptide, GIP）参与诸多重要生理功能，包括餐后血糖稳态、骨重塑以及脂质代谢。尽管通过大规模测序可识别出引发生理改变的突变，但目前尚未针对GIP错义变异（missense variants）开展系统性研究。本研究从包含约72万名个体的三个独立队列中，共鉴定出人类GIP基因的168种自然发生的错义变异。我们采用计算机模拟效应预测（in silico effect predictions）方法，对分布于前原GIP（pre-pro-GIP）肽段的氨基酸替换变异进行了分析，结果显示，与前体蛋白的其余区域相比，完全加工成熟的GIP激素的序列更受突变保护。据此，我们发现GIP肽段序列具有高度的物种同源性与群体特异性保守性，这提示存在进化约束以维持GIP肽段的序列稳定性。阐明GIP变异的突变图谱及其对GIP结构与功能架构的影响，将为后续的生物学功能表征及临床转化研究提供助力。