Descrizione del progetto
Decodificare la variazione genetica umana
Gli studi di associazione genomica sono stati fondamentali per identificare le varianti genetiche associate a diverse malattie. È interessante notare che questi studi hanno dimostrato che una percentuale sostanziale di loci associati alla malattia si trova in regioni intergeniche inizialmente ritenute non funzionali. Tuttavia, determinare l’impatto delle varianti di un singolo allele sull’espressione genica è difficile a causa delle informazioni limitate sulle combinazioni di varianti genetiche ereditate insieme sullo stesso cromosoma. Il progetto HAP-PHEN, finanziato dal Consiglio europeo della ricerca, intende identificare le varianti genetiche che influenzano l’espressione genica nel cancro al seno e in altri tipi di cancro. L’obiettivo generale è quello di perfezionare la valutazione del rischio di cancro e di fornire una migliore comprensione dei complessi meccanismi di regolazione genica.
Obiettivo
High-throughput sequencing methods are breaching the barrier of $1000 per genome. This means that it will become feasible to sequence the genomes of many individual and create a deep catalog of the bulk of human genetic variation. A great task will lie in assigning function to all this genetic variation. Genome wide association studies have already shown that 40% of all loci significantly associated with disease are found in intergenic, supposedly regulatory regions. One of the current challenges in human genetics is that variants that affect expression on a single allele cannot be directly linked, because only have genotype information, rather then haplotype information. The overarching aim of the project is to resolve haplotypes in order to identify genetic variants that affect gene expression. We will do this in three sub-projects. In the first main project we will use 3D genome information gathered from Hi-C experiments to haplotype the genomes of six lymphoblastoid cell lines. We will integrate these data with chromatin profiling and RNAseq data in order to build integrative models for the prediction of gene expression and the effect of genetic variation on gene expression. In the second project we will perform haplotyping the breast cancer genes BRCA1/2 in a large cohort of individuals that come from families with a high-risk of hereditary breast cancer. Allelic imbalance in BRCA1/2 expression levels are known to be associated with an increased risk for breast cancer. We will aim to find genetic variants that are associated with a decreased allelic expression of BRCA1/2 to improve breast cancer risk assessment. Finally, we will develop a novel tool to study 3D genome organization of single alleles, which will allow us to identify how individual alleles are organized in the nucleus and identify multi-way interactions (i.e. involving more than two genomic loci). With this we hope to better understand how complex 3D organization contributes to gene regulation.
Campo scientifico
- medical and health sciencesclinical medicineoncologybreast cancer
- medical and health sciencesclinical medicinecardiologycardiovascular diseases
- natural sciencesbiological sciencesgeneticsnucleotides
- medical and health sciencesbasic medicinemedical genetics
- natural sciencesbiological sciencesgeneticsgenomes
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
1066 CX Amsterdam
Paesi Bassi