Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells.

The gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We find that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between and , which we have named . The variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, enables appropriate expression and splicing of genes in HSCs, most notably , in an SRSF2-dependent manner. Given the critical role of gene expression in some blood cancers, we also demonstrate that variation or deletion compromises -dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression.