The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection

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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.

TidsskriftFrontiers in Endocrinology
Antal sider14
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
LG is supported by the BRIDGE – Translational Excellence Programme ( at the Faculty of Health and Medical Sciences, University of Copenhagen, funded by the Novo Nordisk Foundation grant agreement no. NNF18SA0034956. AH would like to gratefully acknowledge funding from the Lundbeck Foundation (R278-2018-180). MR received funding from the Novo Nordisk Foundation (NNF21OC00671) and (NNF21OC0070347), from a donation from deceased Valter Alex Torbjørn Eichmuller (VAT Eichmuller)-2020-117043 and from Kirsten and Freddy Johansens Foundation (KFJ)-2017-112697.

Publisher Copyright:
Copyright © 2022 Lindquist, Gasbjerg, Mokrosinski, Holst, Hauser and Rosenkilde.

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