Impact of genomic polymorphisms on the repertoire of human MHC class I-associated peptides

Abstract

For decades, the global impact of genomic polymorphisms on the repertoire of peptides presented by major histocompatibility complex (MHC) has remained a matter of speculation. Here we present a novel approach that enables high-throughput discovery of polymorphic MHC class I-associated peptides (MIPs), which play a major role in allorecognition. On the basis of comprehensive analyses of the genomic landscape of MIPs eluted from B lymphoblasts of two MHC-identical siblings, we show that 0.5% of non-synonymous single nucleotide variations are represented in the MIP repertoire. The 34 polymorphic MIPs found in our subjects are encoded by bi-allelic loci with dominant and recessive alleles. Our analyses show that, at the population level, 12% of the MIP-coding exome is polymorphic. Our method provides fundamental insights into the relationship between the genomic self and the immune self and accelerates the discovery of polymorphic MIPs (also known as minor histocompatibility antigens).

Analysis of Major Histocompatibility Complex (MHC) Immunopeptidomes Using Mass Spectrometry*

“…By integrating exome sequencing, MHC peptide ligand prediction algorithms and targeted MS, Gubin et al recently identified tumor-specific mutant MHC class I peptides as targets of this form of immunotherapy (88). Proteogenomics approaches (139, 140) using DDA MS were also recently used for the identification of mutant as well as polymorphic MHC class I peptides (5,51,(141)(142)(143)(144). Notably, the detection of tumor-specific mutant MHC peptides has not been achieved yet using DIA MS.…”

“…We also highlight selected biological applications and discuss important current technical limitations that need to be solved to accelerate the development of this field. The immunopeptidome is referred to as the collection of peptides associated with and presented by major histocompatibility complex (MHC) molecules (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). MHC-associated peptides are recognized by T lymphocytes that are in turn activated to eliminate abnormal cells such as pathogen-infected and cancer cells.…”

“…Until recently, MAE was used to isolate MHC class I peptides from various cell lines, bone-marrow-derived dendritic cells, and primary thymocytes (5,38,39,48,50). The MAE approach is cell-surface-specific and can be repeated over time from the same cell population, e.g.…”

pyGeno: A Python package for precision medicine and proteogenomics

“…Personalized genomes are a powerful tool that can go beyond the definition of patient-specific genomes. For instance, we recently used this tool to combine the results of both RNAand DNA-seq data and create more robust personalized genomes that were used to identify protein-derived peptides by mass spectrometry 3 . Furthermore because pyGeno loads the necessary parts of a given reference genome only once, a pyGeno application can handle several personalized genomes without significantly increasing its memory consumption.…”

“…For instance, a significant part of precision medicine research revolves around the identification of relevant single nucleotide polymorphisms (SNPs) and insertions/deletions (INDELS) and the study of their context 1 . Furthermore recent studies in proteogenomics show that replacing traditional reference databases such as Uniprot 2 by customized databases that integrate the subject's genomic polymorphisms, can significantly improve the identification of peptides or proteins using mass spectrometry [3][4][5][6] . These applications usually require the integration of reference sequences, reference genome annotations, specific SNPs and INDELs along with an external SNP database such as dbSNP 7 for validation.…”