Hacking hematopoiesis - emerging tools for examining variant effects.

Hematopoiesis is a continuous process of blood and immune cell production. It is orchestrated by thousands of gene products that respond to extracellular signals by guiding cell fate decisions to meet the needs of the organism. Although much of our knowledge of this process comes from work in model systems, we have learned a great deal from studies on human genetic variation. Considerable insight has emerged from studies on presumed monogenic blood disorders, which continue to provide key insights into the mechanisms critical for hematopoiesis. Furthermore, the emergence of large-scale biobanks and cohorts has uncovered thousands of genomic loci associated with blood cell traits and diseases. Some of these blood cell trait-associated loci act as modifiers of what were once thought to be monogenic blood diseases. However, most of these loci await functional validation. Here, we discuss the validation bottleneck and emerging methods to more effectively connect variant to function. In particular, we highlight recent innovations in genome editing, which have paved the path forward for high-throughput functional assessment of loci. Finally, we discuss existing barriers to progress, including challenges in manipulating the genomes of primary hematopoietic cells.