Descripción del proyecto
La arquitectura del cromosoma surge en la variación poblacional
La cadena de ADN de cada célula eucariota, cuando se desenreda, mide 2 m. Plegada con precisión en el núcleo, su configuración tridimensional (3D) es crucial para mantener la correcta transcripción de los genes. Para determinar qué efecto tiene la variación unidimensional en la variación 3D del genoma, el equipo del proyecto financiado con fondos europeos POPARCH ha reunido un conjunto único de 100 pollos criados en un entorno controlado, el mayor estudio animal «in vivo» realizado hasta la fecha. Los investigadores elaborarán un catálogo de variantes de la secuencia del ADN para determinar cómo las variantes del ADN no codificante pueden controlar la estructura genómica 3D. Este estudio promete ser el modelo único para futuros estudios, incluido el ensayo de nuevos tratamientos farmacológicos en humanos sin la interferencia de otras variables.
Objetivo
The linear one-dimensional (1D) DNA fiber inside each Eukaryotic cell nucleus folds into a precise three-dimensional (3D) structure, whose structural preservation is vital for correct cell homeostasis and gene-regulatory mechanisms. Previous studies showed that if 3D structure is altered, aberrant phenotypes and diseases can arise. However, little is known on how 1D variation can affect 3D genome variation. Although recently developed technologies allow researchers to generate data to characterize the 3D structural patterns, as of yet no studies have systematically examined how this affects inter-individual 3D variation. I hypothesize a substantial fraction of 3D genome structural variation is controlled through 1D variation, affecting gene expression, and lastly phenotypes. I will test this by quantifying 1D and 3D genomic variation from 100 individuals selected from a chicken cohort my host raised under extremely well-controlled environmental conditions, making it the largest study of its kind up to today, and the first to use an in vivo animal model. Then, computationally I will develop an analytical framework and produce a catalog of DNA sequence variants that condition 3D genome structure. Upon executing my research, I expect to provide a new explanation on how non-coding DNA variants can exert their effect, thus offer new testable hypotheses to researchers interested in genotype-phenotype transitions. This is a proof-of-concept project and, should I be correct, will open a door to expansion in other species, including humans, with a large potential use in medical genomics, thus facilitating pharmacological interventions by disentangling causal intermediate processes. By combining my 3D genomics expertise with the host’s population-statistical genomics knowledge, on his unparalleled cohort of chickens, I will develop unique expertise to place me as the pioneer of a completely new, multidisciplinary field.
Ámbito científico
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
MSCA-PF - MSCA-PFCoordinador
1165 Kobenhavn
Dinamarca