Genetic variation exposes regulators of blood cell formation in vivo in humans

Informations projet

BloodVariome

N° de convention de subvention: 770992

DOI

10.3030/770992

Projet clôturé

Date de signature de la CE 7 Août 2018

Date de début 1 Octobre 2018

Date de fin 30 Septembre 2024

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 000 000,00

Contribution de l’UE

€ 2 000 000,00

Coordonné par

LUNDS UNIVERSITET
Sweden

Periodic Reporting for period 4 - BloodVariome (Genetic variation exposes regulators of blood cell formation in vivo in humans)

Période du rapport: 2023-04-01 au 2024-09-30

Résumé du contexte et des objectifs généraux du projet

The human hematopoietic system is a paradigmatic, stem cell-maintained organ with enormous cell turnover. Hundreds of billions of new blood cells are produced each day. The process is tightly regulated, and susceptible to perturbation due to genetic variation.

In this project, we will explore an innovative, population-genetic approach to find regulators of blood cell formation. Unlike traditional studies on hematopoiesis in vitro or in animal models, we will exploit natural genetic variation to identify DNA sequence variants and genes that influence blood cell formation in vivo in humans. Instead of inserting artificial mutations in mice, we will read out ripples from the experiments that nature has performed during evolution.

If successful, the project will identify novel regulators of blood cell formation, including regulators of stem and progenitor cells. Potentially, identifying such regulators could lead to the development of better therapies for blood disorders (e.g. leukemia).

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

In this project, we have performed blood and immune cell phenotyping of unprecedented depth and breadth. We analyzed peripheral blood from approximately 25,000 blood donors and primary care patients, plus umbilical cord blood from more than 3,000 newborns. To enable an effort of this scope and scale, we established a high-throughput platform for deep flow cytometry and pattern recognition methods to facilitate the analysis of the generated data sets. Using these data sets, we have identified more than 280 independent loci influencing blood and immune cell traits in adults, and about 40 independent loci influencing blood cell traits in cord blood. The data has also spawned a number of follow-up project, including functional characterization of identified loci and projects aimed at clinical translation. For example, we have identified PPM1H as a tentative new target for stem cell mobilization.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The project has generated significant new insight into how natural genetic variation influences blood and immune cell formation in adults and neonates. The resulting data provide a new resource ("BloodVariome") for the scientific community that we are currently making available online.

Project overview