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Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution

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 co...

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Detalles Bibliográficos
Autores principales: Kang, Joyce B., Shen, Amber Z., Sakaue, Saori, Luo, Yang, Gurajala, Saisriram, Nathan, Aparna, Rumker, Laurie, Aguiar, Vitor R. C., Valencia, Cristian, Lagattuta, Kaitlyn, Zhang, Fan, Jonsson, Anna Helena, Yazar, Seyhan, Alquicira-Hernandez, Jose, Khalili, Hamed, Ananthakrishnan, Ashwin N., Jagadeesh, Karthik, Dey, Kushal, Daly, Mark J., Xavier, Ramnik J., Donlin, Laura T., Anolik, Jennifer H., Powell, Joseph E., Rao, Deepak A., Brenner, Michael B., Gutierrez-Arcelus, Maria, Raychaudhuri, Soumya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055604/
https://www.ncbi.nlm.nih.gov/pubmed/36993194
http://dx.doi.org/10.1101/2023.03.14.23287257
Descripción
Sumario: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.