Descrizione del progetto
La base molecolare della co-espressione genica locale e il suo impatto sulle malattie umane
Fino ad ora, gli studi di associazione sull’intero genoma (GWAS, Genome-Wide Association Studies) hanno associato >10 000 varianti genetiche alla malattia e collegato alcune di queste varianti delle malattie ai geni che le provocano. La nostra comprensione relativa a un collegamento molecolare della variante alla malattia rappresenta ancora una grande sfida, poiché la maggior parte dei collegamenti viene trovata nelle regioni non codificanti del genoma, agisce solo in particolari tessuti e potrebbe influire su diversi geni. Studi recenti hanno dimostrato che i geni limitrofi sono spesso co-espressi – formano domini di co-espressione (COD, Co-expression Domains) – e potrebbero essere regolati da varianti di regolazione condivise. Il progetto CODer, finanziato dall’UE, si propone di approfondire il modo in cui la co-espressione genica locale viene raggiunta e regolata dalle varianti genetiche e di studiare il loro impatto sulla malattia umana, utilizzando set di dati all’avanguardia del sequenziamento di RNA a singola cellula.
Obiettivo
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.
Campo scientifico
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Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
1015 LAUSANNE
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