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

Descripción del proyecto

La base molecular de la coexpresión genética local y su repercusión en enfermedades humanas

Los estudios de asociación de genoma completo han permitido relacionar hasta ahora más de diez mil variantes genéticas con enfermedades y han vinculado algunas de estas variantes de enfermedades con genes causales. Nuestra comprensión del vínculo molecular de una variante con la enfermedad sigue siendo todo un reto, ya que la mayoría se encuentran en las regiones no codificantes del genoma, actúan solo en tejidos específicos y pueden afectar a varios genes. Estudios recientes revelaron que los genes próximos a menudo se coexpresan —forman dominios de coexpresión (COD, ing. co-expression domain)— y que podrían estar controlados por variantes reguladoras compartidas. El objetivo del proyecto financiado con fondos europeos CODer es investigar cómo se logra y se regula la coexpresión genética local a través de variantes genéticas y estudiar sus repercusiones en enfermedades humanas mediante el empleo de conjuntos de datos punteros de secuenciación de ARN de molécula única.

Objetivo

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.

Régimen de financiación

MSCA-IF-EF-ST - Standard EF

Coordinador

UNIVERSITE DE LAUSANNE
Aportación neta de la UEn
€ 203 149,44
Dirección
QUARTIER UNIL CENTRE - BATIMENT UNICENTRE
1015 LAUSANNE
Suiza

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Región
Schweiz/Suisse/Svizzera Région lémanique Vaud
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 203 149,44