Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
received:
31
03
2023
accepted:
19
10
2023
pubmed:
1
12
2023
medline:
1
12
2023
entrez:
30
11
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 38036787
doi: 10.1038/s41588-023-01586-6
pii: 10.1038/s41588-023-01586-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2255-2268Subventions
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : U01HG012009
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : UC2AR081023
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : R01AR063759
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : F30AI172238
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : T32GM144273
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : T32HG002295
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : T32AR007530
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : F30AI157385
Investigateurs
Jennifer Albrecht
(J)
William Apruzzese
(W)
Nirmal Banda
(N)
Jennifer L Barnas
(JL)
Joan M Bathon
(JM)
Ami Ben-Artzi
(A)
Brendan F Boyce
(BF)
David L Boyle
(DL)
S Louis Bridges
(SL)
Vivian P Bykerk
(VP)
Debbie Campbell
(D)
Hayley L Carr
(HL)
Arnold Ceponis
(A)
Adam Chicoine
(A)
Andrew Cordle
(A)
Michelle Curtis
(M)
Kevin D Deane
(KD)
Edward DiCarlo
(E)
Patrick Dunn
(P)
Andrew Filer
(A)
Gary S Firestein
(GS)
Lindsy Forbess
(L)
Laura Geraldino-Pardilla
(L)
Susan M Goodman
(SM)
Ellen M Gravallese
(EM)
Peter K Gregersen
(PK)
Joel M Guthridge
(JM)
V Michael Holers
(VM)
Diane Horowitz
(D)
Laura B Hughes
(LB)
Kazuyoshi Ishigaki
(K)
Lionel B Ivashkiv
(LB)
Judith A James
(JA)
Gregory Keras
(G)
Ilya Korsunsky
(I)
Amit Lakhanpal
(A)
James A Lederer
(JA)
Myles Lewis
(M)
Zhihan J Li
(ZJ)
Yuhong Li
(Y)
Katherine P Liao
(KP)
Arthur M Mandelin
(AM)
Ian Mantel
(I)
Kathryne E Marks
(KE)
Mark Maybury
(M)
Andrew McDavid
(A)
Mandy J McGeachy
(MJ)
Joseph Mears
(J)
Nida Meednu
(N)
Nghia Millard
(N)
Larry W Moreland
(LW)
Saba Nayar
(S)
Alessandra Nerviani
(A)
Dana E Orange
(DE)
Harris Perlman
(H)
Costantino Pitzalis
(C)
Javier Rangel-Moreno
(J)
Karim Raza
(K)
Yakir Reshef
(Y)
Christopher Ritchlin
(C)
Felice Rivellese
(F)
William H Robinson
(WH)
Ilfita Sahbudin
(I)
Anvita Singaraju
(A)
Jennifer A Seifert
(JA)
Kamil Slowikowski
(K)
Melanie H Smith
(MH)
Darren Tabechian
(D)
Dagmar Scheel-Toellner
(D)
Paul J Utz
(PJ)
Gerald F M Watts
(GFM)
Kevin Wei
(K)
Kathryn Weinand
(K)
Dana Weisenfeld
(D)
Michael H Weisman
(MH)
Aaron Wyse
(A)
Qian Xiao
(Q)
Zhu Zhu
(Z)
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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