The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection
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The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection. / Lindquist, Peter; Gasbjerg, Lærke Smidt; Mokrosinski, Jacek; Holst, Jens Juul; Hauser, Alexander Sebastian; Rosenkilde, Mette Marie.
In: Frontiers in Endocrinology, Vol. 13, 891586, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection
AU - Lindquist, Peter
AU - Gasbjerg, Lærke Smidt
AU - Mokrosinski, Jacek
AU - Holst, Jens Juul
AU - Hauser, Alexander Sebastian
AU - Rosenkilde, Mette Marie
N1 - Publisher Copyright: Copyright © 2022 Lindquist, Gasbjerg, Mokrosinski, Holst, Hauser and Rosenkilde.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - GIP - glucose-dependent insulinotropic peptide
KW - GIPR
KW - GPCR (G protein coupled receptor)
KW - missense variants
KW - pharmacogenomics
KW - UK Biobank
U2 - 10.3389/fendo.2022.891586
DO - 10.3389/fendo.2022.891586
M3 - Journal article
C2 - 35846282
AN - SCOPUS:85134168265
VL - 13
JO - Frontiers in Endocrinology
JF - Frontiers in Endocrinology
SN - 1664-2392
M1 - 891586
ER -
ID: 314837894