The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection
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 seq...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.891586/full |
| _version_ | 1811332470072672256 |
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| author | Peter Lindquist Lærke Smidt Gasbjerg Jacek Mokrosinski Jens Juul Holst Jens Juul Holst Alexander Sebastian Hauser Mette Marie Rosenkilde |
| author_facet | Peter Lindquist Lærke Smidt Gasbjerg Jacek Mokrosinski Jens Juul Holst Jens Juul Holst Alexander Sebastian Hauser Mette Marie Rosenkilde |
| author_sort | Peter Lindquist |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T16:37:30Z |
| format | Article |
| id | doaj.art-bf18da93d2c844fc905f0c8e2a199121 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-13T16:37:30Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-bf18da93d2c844fc905f0c8e2a1991212022-12-22T02:39:23ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-06-011310.3389/fendo.2022.891586891586The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural SelectionPeter Lindquist0Lærke Smidt Gasbjerg1Jacek Mokrosinski2Jens Juul Holst3Jens Juul Holst4Alexander Sebastian Hauser5Mette Marie Rosenkilde6Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkLaboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkNovo Nordisk Research Center Indianapolis, Indianapolis, IN, United StatesDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkLaboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkThe 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.https://www.frontiersin.org/articles/10.3389/fendo.2022.891586/fullGIP - glucose-dependent insulinotropic peptidemissense variantspharmacogenomicsGIPRGPCR (G protein coupled receptor)UK Biobank |
| spellingShingle | Peter Lindquist Lærke Smidt Gasbjerg Jacek Mokrosinski Jens Juul Holst Jens Juul Holst Alexander Sebastian Hauser Mette Marie Rosenkilde The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection Frontiers in Endocrinology GIP - glucose-dependent insulinotropic peptide missense variants pharmacogenomics GIPR GPCR (G protein coupled receptor) UK Biobank |
| title | The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection |
| title_full | The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection |
| title_fullStr | The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection |
| title_full_unstemmed | The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection |
| title_short | The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection |
| title_sort | location of missense variants in the human gip gene is indicative for natural selection |
| topic | GIP - glucose-dependent insulinotropic peptide missense variants pharmacogenomics GIPR GPCR (G protein coupled receptor) UK Biobank |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.891586/full |
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