Periodic Reporting for period 4 - BloodVariome (Genetic variation exposes regulators of blood cell formation in vivo in humans)
Período documentado: 2023-04-01 hasta 2024-09-30
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).
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).
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.
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.