Genetic variation in MHC proteins is associated with T cell receptor expression biases

Jonathan Pritchard, Christopher Garcia and colleagues examine associations between different T cell receptor V genes and MHC alleles by eQTL mapping. They find that there are strong associations between MHC variation and T cell receptor gene usage and map these signals to specific MHC amino acids, m...

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Bibliographic Details
Published in:Nature genetics Vol. 48; no. 9; pp. 995 - 1002
Main Authors: Sharon, Eilon, Sibener, Leah V, Battle, Alexis, Fraser, Hunter B, Garcia, K Christopher, Pritchard, Jonathan K
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.09.2016
Nature Publishing Group
Subjects:
38/39
38/43
45/91
631/208/199
631/208/205/2138
631/208/248
631/250/248
Agriculture
Amino acids
Analysis
Animal Genetics and Genomics
Bias
Biomedicine
Cancer Research
Cohort Studies
Gene expression
Gene Function
Gene mapping
Genes
Genetic diversity
Genetic variation
Genetic Variation - genetics
Genomes
Genotype & phenotype
Health aspects
High-Throughput Nucleotide Sequencing
Human Genetics
Humans
Identification and classification
Immunoglobulin Variable Region - genetics
Immunoglobulin Variable Region - metabolism
Lymphocytes
Major Histocompatibility Complex - physiology
Membrane proteins
Peptides
Properties
Proteins
Quantitative Trait Loci
Receptors, Antigen, T-Cell - genetics
Receptors, Antigen, T-Cell - metabolism
Scholarships & fellowships
T cell receptors
ISSN:1061-4036, 1546-1718, 1546-1718
Online Access:Get full text
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Summary:Jonathan Pritchard, Christopher Garcia and colleagues examine associations between different T cell receptor V genes and MHC alleles by eQTL mapping. They find that there are strong associations between MHC variation and T cell receptor gene usage and map these signals to specific MHC amino acids, many of which physically interact with germline-encoded amino acids on the T cell receptor. In each individual, a highly diverse T cell receptor (TCR) repertoire interacts with peptides presented by major histocompatibility complex (MHC) molecules. Despite extensive research, it remains controversial whether germline-encoded TCR–MHC contacts promote TCR–MHC specificity and, if so, whether differences exist in TCR V gene compatibilities with different MHC alleles. We applied expression quantitative trait locus (eQTL) mapping to test for associations between genetic variation and TCR V gene usage in a large human cohort. We report strong trans associations between variation in the MHC locus and TCR V gene usage. Fine-mapping of the association signals identifies specific amino acids from MHC genes that bias V gene usage, many of which contact or are spatially proximal to the TCR or peptide in the TCR–peptide–MHC complex. Hence, these MHC variants, several of which are linked to autoimmune diseases, can directly affect TCR–MHC interaction. These results provide the first examples of trans -QTL effects mediated by protein–protein interactions and are consistent with intrinsic TCR–MHC specificity.
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These authors contributed equally to this work.
ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/ng.3625