Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.
Joyce B KangAmber Z ShenSaori SakaueYang LuoSaisriram GurajalaAparna NathanLaurie RumkerVitor R C AguiarCristian ValenciaKaitlyn LagattutaFan ZhangAnna Helena JonssonSeyhan YazarJose Alquicira HernandezHamed KhaliliAshwin N AnanthakrishnanKarthik JagadeeshKushal Deynull nullMark J DalyRamnik J XavierLaura T DonlinJennifer H AnolikJoseph E PowellDeepak A RaoMichael B BrennerMaria Gutierrez-ArcelusSoumya RaychaudhuriPublished in: medRxiv : the preprint server for health sciences (2023)
The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation, and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here, we mapped expression quantitative trait loci (eQTLs) for classical HLA genes 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-specific cis- eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B, and T cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.
Keyphrases
- genome wide
- single cell
- immune response
- rna seq
- dna methylation
- poor prognosis
- genome wide identification
- infectious diseases
- high throughput
- gene expression
- transcription factor
- high resolution
- cell therapy
- copy number
- bioinformatics analysis
- multidrug resistant
- bone marrow
- endothelial cells
- acute myeloid leukemia
- single molecule
- squamous cell carcinoma
- young adults
- dendritic cells
- toll like receptor
- signaling pathway
- stem cells
- binding protein
- drug induced
- induced pluripotent stem cells