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

2023; Nature Portfolio; Volume: 55; Issue: 12 Linguagem: Inglês

10.1038/s41588-023-01586-6

1546-1718

Joyce B. Kang, Amber Shen, Saisriram Gurajala, Aparna Nathan, Laurie Rumker, Vitor R. C. Aguiar, Cristian Valencia, Kaitlyn A. Lagattuta, Fan Zhang, A. Helena Jonsson, Seyhan Yazar, José Alquicira-Hernández, Hamed Khalili, Ashwin N. Ananthakrishnan, Karthik A. Jagadeesh, Kushal K. Dey, Jennifer S. Albrecht, William Apruzzese, Nirmal K. Banda, Jennifer L. Barnas, Joan M. Bathon, Ami Ben‐Artzi, Brendan F. Boyce, David L. Boyle, S. Louis Bridges, Vivian P. Bykerk, Debbie Campbell, Hayley L. Carr, Arnold Ceponis, Adam Chicoine, Andrew Cordle, Michelle Curtis, Kevin D. Deane, Edward F. DiCarlo, Patrick Dunn, Andrew Filer, Gary S. Firestein, Lindsy Forbess, Laura Geraldino‐Pardilla, Susan M. Goodman, Ellen M. Gravallese, Peter K. Gregersen, Joel M. Guthridge, V. Michael Holers, Diane Horowitz, Laura B. Hughes, Kazuyoshi Ishigaki, Lionel B. Ivashkiv, Judith A. James, Gregory Keras, Ilya Korsunsky, Amit Lakhanpal, James A. Lederer, Myles Lewis, Zhihan J. Li, Yuhong Li, Katherine P. Liao, Arthur M. Mandelin, Ian Mantel, Kathryne E. Marks, Mark Maybury, Andrew McDavid, Mandy J. McGeachy, Joseph Mears, Nida Meednu, Nghia Millard, Larry W. Moreland, Saba Nayar, Alessandra Nerviani, Dana E. Orange, Harris Perlman, Costantino Pitzalis, Javier Rangel‐Moreno, Karim Raza, Yakir Reshef, Christopher T. Ritchlin, Felice Rivellese, William H. Robinson, Ilfita Sahbudin, Anvita Singaraju, Jennifer Seifert, Kamil Slowikowski, Melanie H. Smith, Darren Tabechian, Dagmar Scheel‐Toellner, Paul J. Utz, Gerald F. Watts, Kevin Wei, Kathryn Weinand, Dana Weisenfeld, Michael H. Weisman, Aaron Wyse, Qian Xiao, Zhu Zhu, Mark J. Daly, Ramnik J. Xavier, Laura T. Donlin, Jennifer H. Anolik, Joseph E. Powell, Deepak A. Rao, Michael B. Brenner, María Gutiérrez‐Arcelus, Yang Luo, Saori Sakaue, Soumya Raychaudhuri,

Immune Cell Function and Interaction

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. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. 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. For example, a T cell HLA-DQA1 eQTL ( rs3104371 ) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.