From prioritisation to understanding: mechanistic predictions of variant effects

Slodkowicz, Greg; Babu, M. Madan

doi:10.15252/msb.20188741

Cited by 2 publications

(2 citation statements)

References 12 publications

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“…Nevertheless, more progress is required in the development of new data analysis interfaces that facilitate the integration of OR information with structural knowledge. Taking into account the increasing need for tools providing accurate predictions of functional consequences of natural variants identified in genomic studies [ 63 ]; evolutionary conservation and structural context were considered as key elements in the estimation of the functional role of the natural variations identified. It is worth stressing that, in many cases, the structural framework of the mutated sites (intimately linked to the stability, function, and interactions) is often overlooked due to a limited structural knowledge [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

The mutational landscape of human olfactory G protein-coupled receptors

et al. 2021

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Background Olfactory receptors (ORs) constitute a large family of sensory proteins that enable us to recognize a wide range of chemical volatiles in the environment. By contrast to the extensive information about human olfactory thresholds for thousands of odorants, studies of the genetic influence on olfaction are limited to a few examples. To annotate on a broad scale the impact of mutations at the structural level, here we analyzed a compendium of 119,069 natural variants in human ORs collected from the public domain. Results OR mutations were categorized depending on their genomic and protein contexts, as well as their frequency of occurrence in several human populations. Functional interpretation of the natural changes was estimated from the increasing knowledge of the structure and function of the G protein-coupled receptor (GPCR) family, to which ORs belong. Our analysis reveals an extraordinary diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a significant number of changes occurring at the structurally conserved regions. A particular attention is paid to mutations in positions linked to the conserved GPCR activation mechanism that could imply phenotypic variation in the olfactory perception. An interactive web application (hORMdb, Human Olfactory Receptor Mutation Database) was developed for the management and visualization of this mutational dataset. Conclusion We performed topological annotations and population analysis of natural variants of human olfactory receptors and provide an interactive application to explore human OR mutation data. We envisage that the utility of this information will increase as the amount of available pharmacological data for these receptors grow. This effort, together with ongoing research in the study of genetic changes in other sensory receptors could shape an emerging sensegenomics field of knowledge, which should be considered by food and cosmetic consumer product manufacturers for the benefit of the general population.

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Section: Discussionmentioning

confidence: 99%

The mutational landscape of human olfactory G protein-coupled receptors

et al. 2021

View full text Add to dashboard Cite

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“…Taking into account the increasing need of tools providing accurate predictions of functional consequences of natural variants identified in genomic studies [61]; evolutionary conservation and structural context were considered as key elements in the estimation of functional role of the natural variations identified. It is worth stressing that, in many cases, the structural framework of the mutated sites (intimately linked to the stability, function and interactions) is often overlooked due to a limited structural knowledge [62].…”

Section: Discussionmentioning

confidence: 99%

The mutational landscape of human olfactory G protein-coupled receptors

Jiménez

Casajuana-Martín

García-Recio

et al. 2020

Preprint

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Olfactory receptors (ORs) constitute a large family of sensory proteins that enable us to recognize a wide range of chemical volatiles in the environment. By contrast to the extensive information about human olfactory thresholds for thousands of odorants, studies of the genetic influence on olfaction are limited to a few examples. Here, we analyzed a compendium of 118,057 natural variants in human ORs collected from the public domain. OR mutations were categorized depending on their genomic and protein contexts, as well as their frequency of occurrence in several human populations. Functional interpretation of the natural changes was estimated from the increasing knowledge of the structure and function of the G protein-coupled receptor (GPCR) family, to which ORs belong. Our analysis reveals an extraordinary diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a significant number of changes occurring at structural conserved regions. A particular attention is paid to mutations in positions linked to the conserved GPCR activation mechanism that could imply phenotypic variation in the olfactory perception. An interactive web application (available at http://lmc.uab.cat/hORMdb) was developed for the management and visualization of this mutational dataset.

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From prioritisation to understanding: mechanistic predictions of variant effects

Cited by 2 publications

References 12 publications

The mutational landscape of human olfactory G protein-coupled receptors

The mutational landscape of human olfactory G protein-coupled receptors

The mutational landscape of human olfactory G protein-coupled receptors

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