Mapping the dynamic genetic regulatory architecture ofHLAgenes at single-cell resolution

Abstract

AbstractThe human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation, and cancer. While coding variation inHLAgenes has been extensively documented, regulatory genetic variation modulatingHLAexpression levels has not been comprehensively investigated. Here, we mapped expression quantitative trait loci (eQTLs) for classicalHLAgenes across 1,073 individuals and 1,131,414 single cells from three tissues, using personalized reference genomes to mitigate technical confounding. We identified cell-type-specificcis-eQTLs for every classicalHLAgene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type.HLA-DQgenes exhibit particularly cell-state-dependent effects within myeloid, B, and T cells. DynamicHLAregulation may underlie important interindividual variability in immune responses.