H2020Индивидуална стипендия2020–2022

CODer · The molecular basis and genetic control of local gene co-expression and its impact in human disease

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2020-06-01 → 2022-05-31
Финансиране от ЕС: 203 149 €
Участници: 1
Схема: MSCA-IF-EF-ST

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Накратко на български

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Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

The molecular basis and genetic control of local gene co-expression and its impact in human disease

The genetic makeup intrinsic to each person shapes their particular traits, disease susceptibilities and treatment effectiveness, making understanding the functional impact of mutations one of the most pursued challenges in genetics research. The action “The molecular basis of local gene co-expression and its impact on human disease” attempted to address several ongoing questions in genetics pertaining to how genes are interconnected and linked to disease. Up until recently, the field has focused on associating individual genes to disease, yet, thousands of genes in the human genome are active in the same cell and thus should be taken together in analysis. Considering multiple genes together could help explain disease aetiology as well as disease comorbidity, driven by mutations affecting multiple co-active genes. Yet, the co-activity of genes that are nearby each other is currently understudied. Moreover, gene activity varies across human tissues which provides a challenge to its analysis. This project aimed to tackle these challenges and address several questions: - Determine the extent of nearby gene co-activity across tissues and its regulation by genetic variants - Discover the regulatory mechanisms and evolutionary reasons underlying gene co-activity - Evaluate the potential impact of nearby gene co-activity in human disease A key step of this project consisted in determining the co-activity of genes across all available human tissues and cell types. For this, the largest publicly available dataset of gene activity measurements across human tissues was exploited to identify maps of nearby gene co-activity. Producing these co-activity maps allowed the investigation of the molecular and evolutionary reasons for gene co-activity as well as identifying mutations predicted to affect the activity of not only one but multiple nearby genes. The project revealed thousands of mutations that are able to affect the activity of multiple nearby genes - due to the shared regulation of gene activity - and provided first evidence that such mutations may affect a higher number of human diseases and traits than mutations only affecting one gene. The project shed new light to the interpretation of genetic mutation results and provided the community with maps of gene co-activity and the elements involved in their co-regulation.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

The genetic makeup intrinsic to each person shapes their particular traits, disease susceptibilities and treatment effectiveness, making understanding the functional impact of genetic variants one of the most pursued challenges in genetics research. Genome-wide association studies (GWAS) have so far associated >10,000 genetic variants with disease, with expression quantitative trait loci (eQTL) studies adamant in linking some of these disease variants to causal genes. Yet, understanding a variant’s molecular link to disease is still a major challenge, given that most are found in the genome’s non-coding regions, act only in specific tissues and may affect several genes. Recent studies revealed that neighbouring genes are often co-expressed – forming co-expression domains (CODs) – potentially regulated by shared regulatory variants, yet, this has been ignored in eQTL and GWAS studies. This project aims to investigate how local gene co-expression is achieved and regulated by genetic variants, and their impact on human disease. For this, I propose a novel genome-wide framework to detect human CODs and their regulatory variants (cod-QTLs) using transcriptomic profiles across hundreds of genotyped individuals. The mechanisms through which variants affect the expression of several genes will be discovered through causality inference and molecular characterisation using state-of-the-art datasets (e.g. Hi-C, promoter-enhancer maps). Notably, CODs’ tissue-specificity will be studied using gene expression across 53 human tissues and the co-expression variation across 120 individuals will be assessed using a cutting-edge dataset of single-cell RNA-seq. The impact of cod-QTLs on dozens of societal-relevant diseases will be determined by colocalization analysis with GWAS hits from the UK Biobank. This project promises to clarify fundamental aspects of gene (co-)regulation and provide functional interpretation of eQTLs and GWAS findings, including revealing novel disease genes.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITE DE LAUSANNE · LAUSANNEКоординаторШвейцария