The genetics of human hematopoiesis and its disruption in disease

Abstract

Hematopoiesis, or the process of blood cell production, is a paradigm of multi-lineage cellular differentiation that has been extensively studied, yet in many aspects remains incompletely understood. Nearly all clinically measured hematopoietic traits exhibit extensive variation and are highly heritable, underscoring the importance of genetic variation in these processes. This review explores how human genetics have illuminated our understanding of hematopoiesis in health and disease. The study of rare mutations in blood and immune disorders has elucidated novel roles for regulators of hematopoiesis and uncovered numerous important molecular pathways, as seen through examples such as Diamond-Blackfan anemia and the GATA2 deficiency syndromes. Additionally, population studies of common genetic variation have revealed mechanisms by which human hematopoiesis can be modulated. We discuss advances in functionally characterizing common variants associated with blood cell traits and discuss therapeutic insights, such as the discovery of BCL11A as a modulator of fetal hemoglobin expression. Finally, as genetic techniques continue to evolve, we discuss the prospects, challenges, and unanswered questions that lie ahead in this burgeoning field.

Keywords: blood disorders; genetics; genome-wide association studies; hematopoiesis.

Figure 1. Overview of hematopoiesis

(A) Schematic of the human hematopoietic hierarchy. Dashed lines indicate recently discovered differentiation paths. mono, monocyte; gran, granulocyte; ery, erythroid; mega, megakaryocyte; CD4, CD4⁺ T cell; CD8, CD8⁺ T cell; B, B cell; NK, natural killer cell; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; MPP, multipotent progenitor; LMPP, lymphoid‐primed multipotent progenitor; CMP, common myeloid progenitor; CLP, common lymphoid progenitor; GMP, granulocyte–macrophage progenitor; MEP, megakaryocyte–erythroid progenitor. Figure adapted from Corces et al (2016). (B) Quantitative depiction of hematopoietic hierarchy, in which erythroid commitment is the predominant and default pathway of differentiation. Figure adapted from Boyer et al (2019). (C) Visualization of hematopoietic hierarchy in which lineage commitment occurs on a continuum rather than in punctuated stages, a perspective motivated by recent single‐cell transcriptomic studies. Figure adapted from Grootens et al (2019).

Figure 2. Trends in genome‐wide association studies (GWAS) of blood traits

(A) Sample size of GWAS for commonly measured hematopoietic traits, including red cell, platelet, and leukocyte traits, over time. (B) Number of independent genome‐wide significant loci discovered for the hemoglobin trait as a function of study sample size. In both panels, the colors of lines and points indicate the ancestry of the study population. The text labels denote the first author of each study.

Figure 3. Discovery of association signals across the allelic frequency spectrum

(A) Traditional depiction of variant discovery power by genetic association studies, as a function of variant effect size and allele frequency. Figure adapted from Manolio et al (2009). (B) Revised schematic that illustrates the 3‐way relationship between (i) sample size of the study, (ii) effect size of a genetic variant, (iii) and allele frequency of the variant on discovery power. The dashed triangular plane indicates the sample size threshold above which studies are sufficiently powered to detect variants at any given coordinate of allele frequency and effect size. The labeled circles depict categories of variants which are most often studied by the analytical methods listed next to them: common variant association studies (CVAS) and/or rare variant association studies (RVAS).

Figure 4. Schematic of moving from variant to function in human genetics research

Blue boxes indicate key areas involved in characterizing and applying the biological mechanisms of genetic associations.