An Evolutionary Analysis of Antigen Processing and Presentation across Different Timescales Reveals Pervasive Selection

The antigenic repertoire presented by MHC molecules is generated by the antigen processing and presentation (APP) pathway. We analyzed the evolutionary history of 45 genes involved in APP at the inter- and intra-species level. Results showed that 11 genes evolved adaptively in mammals. Several positively selected sites involve positions of fundamental importance to the protein function (e.g. the TAP1 peptide-binding domains, the sugar binding interface of langerin, and the CD1D trafficking signal region). In CYBB, all selected sites cluster in two loops protruding into the endosomal lumen; analysis of missense mutations responsible for chronic granulomatous disease (CGD) showed the action of different selective forces on the very same gene region, as most CGD substitutions involve aminoacid positions that are conserved in all mammals. As for ERAP2, different computational methods indicated that positive selection has driven the recurrent appearance of protein-destabilizing variants during mammalian evolution. Application of a population-genetics phylogenetics approach showed that purifying selection represented a major force acting on some APP components (e.g. immunoproteasome subunits and chaperones) and allowed identification of positive selection events in the human lineage. We also investigated the evolutionary history of APP genes in human populations by developing a new approach that uses several different tests to identify the selection target, and that integrates low-coverage whole-genome sequencing data with Sanger sequencing. This analysis revealed that 9 APP genes underwent local adaptation in human populations. Most positive selection targets are located within noncoding regions with regulatory function in myeloid cells or act as expression quantitative trait loci. Conversely, balancing selection targeted nonsynonymous variants in TAP1 and CD207 (langerin). Finally, we suggest that selected variants in PSMB10 and CD207 contribute to human phenotypes. Thus, we used evolutionary information to generate experimentally-testable hypotheses and to provide a list of sites to prioritize in follow-up analyses.

[1]  J. Akey,et al.  Selection and adaptation in the human genome. , 2013, Annual review of genomics and human genetics.

[2]  N. Bresolin,et al.  A 175 million year history of T cell regulatory molecules reveals widespread selection, with adaptive evolution of disease alleles. , 2013, Immunity.

[3]  H. Brandstetter,et al.  Mechanistic and structural studies on legumain explain its zymogenicity, distinct activation pathways, and regulation , 2013, Proceedings of the National Academy of Sciences.

[4]  Liming Liang,et al.  A cross-platform analysis of 14,177 expression quantitative trait loci derived from lymphoblastoid cell lines , 2013, Genome research.

[5]  Eric S. Lander,et al.  Identifying Recent Adaptations in Large-Scale Genomic Data , 2013, Cell.

[6]  A. Milillo,et al.  The putative role of endoplasmic reticulum aminopeptidases in autoimmunity: insights from genomic-wide association studies. , 2012, Autoimmunity reviews.

[7]  Michael Emerman,et al.  Evolution-guided identification of antiviral specificity determinants in the broadly acting interferon-induced innate immunity factor MxA. , 2012, Cell host & microbe.

[8]  M. Ressing,et al.  Hiding Lipid Presentation: Viral Interference with CD1d-Restricted Invariant Natural Killer T (iNKT) Cell Activation , 2012, Viruses.

[9]  Shane J. Neph,et al.  Personal and population genomics of human regulatory variation , 2012, Genome research.

[10]  L. Quintana-Murci,et al.  The evolutionary landscape of cytosolic microbial sensors in humans. , 2012, American journal of human genetics.

[11]  Sergei L. Kosakovsky Pond,et al.  Detecting Individual Sites Subject to Episodic Diversifying Selection , 2012, PLoS genetics.

[12]  M. Ressing,et al.  Viral interference with antigen presentation: trapping TAP. , 2012, Molecular immunology.

[13]  Renaud Vitalis,et al.  rehh: an R package to detect footprints of selection in genome-wide SNP data from haplotype structure , 2012, Bioinform..

[14]  Jennifer Mulle,et al.  A Genome-Wide Scan of Ashkenazi Jewish Crohn's Disease Suggests Novel Susceptibility Loci , 2012, PLoS genetics.

[15]  J. Casanova,et al.  Evolutionary genetic dissection of human interferons , 2011, The Journal of experimental medicine.

[16]  J. Neefjes,et al.  Towards a systems understanding of MHC class I and MHC class II antigen presentation , 2011, Nature Reviews Immunology.

[17]  Daniel J. Wilson,et al.  A Population Genetics-Phylogenetics Approach to Inferring Natural Selection in Coding Sequences , 2011, PLoS genetics.

[18]  Sergei L. Kosakovsky Pond,et al.  A random effects branch-site model for detecting episodic diversifying selection. , 2011, Molecular biology and evolution.

[19]  Edward L. Huttlin,et al.  Systematic and quantitative assessment of the ubiquitin-modified proteome. , 2011, Molecular cell.

[20]  N. Bresolin,et al.  Balancing selection is common in the extended MHC region but most alleles with opposite risk profile for autoimmune diseases are neutrally evolving , 2011, BMC Evolutionary Biology.

[21]  M. Rooman,et al.  PoPMuSiC 2.1: a web server for the estimation of protein stability changes upon mutation and sequence optimality , 2011, BMC Bioinformatics.

[22]  Matteo Cereda,et al.  GeCo++: a C++ library for genomic features computation and annotation in the presence of variants , 2011, Bioinform..

[23]  R. Cherny,et al.  Regulation of insulin-regulated membrane aminopeptidase activity by its C-terminal domain. , 2011, Biochemistry.

[24]  J. Casanova,et al.  Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease , 2011, Nature Immunology.

[25]  P. Voulgari,et al.  Cutting Edge: Coding Single Nucleotide Polymorphisms of Endoplasmic Reticulum Aminopeptidase 1 Can Affect Antigenic Peptide Generation In Vitro by Influencing Basic Enzymatic Properties of the Enzyme , 2011, The Journal of Immunology.

[26]  W. Weis,et al.  Structural Basis for Langerin Recognition of Diverse Pathogen and Mammalian Glycans through a Single Binding Site , 2011, Journal of molecular biology.

[27]  N. Bresolin,et al.  Genetic diversity at endoplasmic reticulum aminopeptidases is maintained by balancing selection and is associated with natural resistance to HIV-1 infection. , 2010, Human molecular genetics.

[28]  Sergei L. Kosakovsky Pond,et al.  Datamonkey 2010: a suite of phylogenetic analysis tools for evolutionary biology , 2010, Bioinform..

[29]  Warren W. Kretzschmar,et al.  Balancing Selection Maintains a Form of ERAP2 that Undergoes Nonsense-Mediated Decay and Affects Antigen Presentation , 2010, PLoS genetics.

[30]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[31]  W. Weis,et al.  Trimeric Structure of Langerin , 2010, The Journal of Biological Chemistry.

[32]  Or Zuk,et al.  A Composite of Multiple Signals Distinguishes Causal Variants in Regions of Positive Selection , 2010, Science.

[33]  N. Hayatsu,et al.  Dual Specificity of Langerin to Sulfated and Mannosylated Glycans via a Single C-type Carbohydrate Recognition Domain* , 2009, The Journal of Biological Chemistry.

[34]  Jeremiah D. Degenhardt,et al.  Targets of balancing selection in the human genome. , 2009, Molecular biology and evolution.

[35]  Eunkyung Kim,et al.  Cytosolic Aminopeptidases Influence MHC Class I-Mediated Antigen Presentation in an Allele-Dependent Manner1 , 2009, The Journal of Immunology.

[36]  M. Mann,et al.  Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions , 2009, Science.

[37]  M. Bouvier,et al.  MHC class I antigen presentation: learning from viral evasion strategies , 2009, Nature Reviews Immunology.

[38]  Joseph K. Pickrell,et al.  Evolutionary Dynamics of Human Toll-Like Receptors and Their Different Contributions to Host Defense , 2009, PLoS genetics.

[39]  Jianyun Liu,et al.  A Threonine-Based Targeting Signal in the Human CD1d Cytoplasmic Tail Controls Its Functional Expression , 2009, The Journal of Immunology.

[40]  S. Levy,et al.  NA-Seq: a discovery tool for the analysis of chromatin structure and dynamics during differentiation. , 2009, Developmental cell.

[41]  Karin M Reinisch,et al.  Insights into MHC class I peptide loading from the structure of the tapasin-ERp57 thiol oxidoreductase heterodimer. , 2009, Immunity.

[42]  R. Detels.  The 'immunologic advantage' of HIV-exposed seronegative individuals , 2009 .

[43]  J. Murray-Rust,et al.  Structure of a Conserved Dimerization Domain within the F-box Protein Fbxo7 and the PI31 Proteasome Inhibitor* , 2008, Journal of Biological Chemistry.

[44]  R. Nielsen,et al.  Patterns of Positive Selection in Six Mammalian Genomes , 2008, PLoS genetics.

[45]  M. Kolbe,et al.  Single residue determines the specificity of neutrophil elastase for Shigella virulence factors. , 2008, Journal of molecular biology.

[46]  L. Quintana-Murci,et al.  Natural selection has driven population differentiation in modern humans , 2008, Nature Genetics.

[47]  Pardis C Sabeti,et al.  Genome-wide detection and characterization of positive selection in human populations , 2007, Nature.

[48]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[49]  Ziheng Yang.  PAML 4: phylogenetic analysis by maximum likelihood. , 2007, Molecular biology and evolution.

[50]  Narayanaswamy Srinivasan,et al.  Nucleic Acids Research Advance Access published June 21, 2007 PIC: Protein Interactions Calculator , 2007 .

[51]  Kevin R. Thornton,et al.  A New Approach for Using Genome Scans to Detect Recent Positive Selection in the Human Genome , 2007, PLoS biology.

[52]  Maria Anisimova,et al.  Multiple hypothesis testing to detect lineages under positive selection that affects only a few sites. , 2007, Molecular biology and evolution.

[53]  Carlos D Bustamante,et al.  Localizing Recent Adaptive Evolution in the Human Genome , 2007, PLoS genetics.

[54]  A. Fujimoto,et al.  A Practical Genome Scan for Population-Specific Strong Selective Sweeps That Have Reached Fixation , 2007, PloS one.

[55]  Y. Kooyk,et al.  Langerin is a natural barrier to HIV-1 transmission by Langerhans cells , 2007, Nature Medicine.

[56]  David A. Williams,et al.  Rac1 and a GTPase-activating protein, MgcRacGAP, are required for nuclear translocation of STAT transcription factors , 2006, The Journal of cell biology.

[57]  Kai Zeng,et al.  Statistical Tests for Detecting Positive Selection by Utilizing High-Frequency Variants , 2006, Genetics.

[58]  David Posada,et al.  Automated phylogenetic detection of recombination using a genetic algorithm. , 2006, Molecular biology and evolution.

[59]  Michael F. Hammer,et al.  Reconstructing human origins in the genomic era , 2006, Nature Reviews Genetics.

[60]  Joshua M Akey,et al.  Genomic signatures of positive selection in humans and the limits of outlier approaches. , 2006, Genome research.

[61]  G. Raposo,et al.  NOX2 Controls Phagosomal pH to Regulate Antigen Processing during Crosspresentation by Dendritic Cells , 2006, Cell.

[62]  Pardis C Sabeti,et al.  Positive Natural Selection in the Human Lineage , 2006, Science.

[63]  Maureen E. Taylor,et al.  Polymorphisms in Human Langerin Affect Stability and Sugar Binding Activity* , 2006, Journal of Biological Chemistry.

[64]  D. Charlesworth.  Balancing Selection and Its Effects on Sequences in Nearby Genome Regions , 2006, PLoS genetics.

[65]  R. Tampé,et al.  Membrane Topology of the Transporter Associated with Antigen Processing (TAP1) within an Assembled Functional Peptide-loading Complex* , 2006, Journal of Biological Chemistry.

[66]  J. Pritchard,et al.  A Map of Recent Positive Selection in the Human Genome , 2006, PLoS biology.

[67]  R. Nielsen,et al.  Evaluation of an improved branch-site likelihood method for detecting positive selection at the molecular level. , 2005, Molecular biology and evolution.

[68]  Deborah A Nickerson,et al.  Genomic regions exhibiting positive selection identified from dense genotype data. , 2005, Genome research.

[69]  S. Gabriel,et al.  Calibrating a coalescent simulation of human genome sequence variation. , 2005, Genome research.

[70]  Patrick D. Evans,et al.  Microcephalin, a Gene Regulating Brain Size, Continues to Evolve Adaptively in Humans , 2005, Science.

[71]  F. Ginhoux,et al.  Direct recognition by alphabeta cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[72]  François Stricher,et al.  The FoldX web server: an online force field , 2005, Nucleic Acids Res..

[73]  Piero Fariselli,et al.  I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure , 2005, Nucleic Acids Res..

[74]  Jacqueline K. Wittke-Thompson,et al.  Rational inferences about departures from Hardy-Weinberg equilibrium. , 2005, American journal of human genetics.

[75]  Narayanasami Sukumar,et al.  A Novel, Potent Dual Inhibitor of the Leukocyte Proteases Cathepsin G and Chymase , 2005, Journal of Biological Chemistry.

[76]  Timothy B Sackton,et al.  A Scan for Positively Selected Genes in the Genomes of Humans and Chimpanzees , 2005, PLoS biology.

[77]  Sergei L. Kosakovsky Pond,et al.  Not so different after all: a comparison of methods for detecting amino acid sites under selection. , 2005, Molecular biology and evolution.

[78]  W. Wong,et al.  Bayes empirical bayes inference of amino acid sites under positive selection. , 2005, Molecular biology and evolution.

[79]  A. Mulder,et al.  A lack of Birbeck granules in Langerhans cells is associated with a naturally occurring point mutation in the human Langerin gene. , 2005, The Journal of investigative dermatology.

[80]  M. Stephens,et al.  Accounting for Decay of Linkage Disequilibrium in Haplotype Inference and Missing-data Imputation , 2022 .

[81]  B. Charlesworth,et al.  The HKA Test Revisited , 2004, Genetics.

[82]  M. Dagher,et al.  Localization of Nox2 N-terminus using polyclonal antipeptide antibodies. , 2004, The Biochemical journal.

[83]  D. Rodgers,et al.  Crystal Structure of Human Thimet Oligopeptidase Provides Insight into Substrate Recognition, Regulation, and Localization* , 2004, Journal of Biological Chemistry.

[84]  R. Tampé,et al.  Functional Dissection of the Transmembrane Domains of the Transporter Associated with Antigen Processing (TAP)* , 2004, Journal of Biological Chemistry.

[85]  J. Lambeth.  NOX enzymes and the biology of reactive oxygen , 2004, Nature Reviews Immunology.

[86]  Kevin Thornton,et al.  libsequence: a C++ class library for evolutionary genetic analysis , 2003, Bioinform..

[87]  C. Watts,et al.  Multistep Autoactivation of Asparaginyl Endopeptidase in Vitro and in Vivo* , 2003, Journal of Biological Chemistry.

[88]  Anders Gorm Pedersen,et al.  RevTrans: multiple alignment of coding DNA from aligned amino acid sequences , 2003, Nucleic Acids Res..

[89]  R. Nielsen,et al.  Effect of recombination on the accuracy of the likelihood method for detecting positive selection at amino acid sites. , 2003, Genetics.

[90]  G. Glazko,et al.  Estimation of divergence times for major lineages of primate species. , 2003, Molecular biology and evolution.

[91]  Peter D. Kwong,et al.  The Mannose-Dependent Epitope for Neutralizing Antibody 2G12 on Human Immunodeficiency Virus Type 1 Glycoprotein gp120 , 2002, Journal of Virology.

[92]  Joseph P Bielawski,et al.  Accuracy and power of bayes prediction of amino acid sites under positive selection. , 2002, Molecular biology and evolution.

[93]  Giorgio Gabella,et al.  Killing activity of neutrophils is mediated through activation of proteases by K+ flux , 2002, Nature.

[94]  R. Hudson.  Two-locus sampling distributions and their application. , 2001, Genetics.

[95]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[96]  Justin C. Fay,et al.  Hitchhiking under positive Darwinian selection. , 2000, Genetics.

[97]  M W Feldman,et al.  Recent common ancestry of human Y chromosomes: evidence from DNA sequence data. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[98]  F. Plummer,et al.  Resistance to HIV-1 infection among highly exposed sex workers in Nairobi: what mediates protection and why does it develop? , 1999, Immunology letters.

[99]  A. Segal,et al.  Analysis of glycosylation sites on gp91phox, the flavocytochrome of the NADPH oxidase, by site-directed mutagenesis and translation in vitro. , 1997, The Biochemical journal.

[100]  M. Nijenhuis,et al.  Multiple regions of the transporter associated with antigen processing (TAP) contribute to its peptide binding site. , 1996, Journal of immunology.

[101]  N. Nagelkerke,et al.  Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya , 1996, The Lancet.

[102]  Marc Parmentier,et al.  Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene , 1996, Nature.

[103]  S. Tavaré,et al.  Unrooted genealogical tree probabilities in the infinitely-many-sites model. , 1995, Mathematical biosciences.

[104]  Günter J. Hämmerling,et al.  Selectivity of MHC-encoded peptide transporters from human, mouse and rat , 1994, Nature.

[105]  C. Enenkel,et al.  BLH1 codes for a yeast thiol aminopeptidase, the equivalent of mammalian bleomycin hydrolase. , 1993, The Journal of biological chemistry.

[106]  W. Li,et al.  Statistical tests of neutrality of mutations. , 1993, Genetics.

[107]  F. Tajima.  Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. , 1989, Genetics.

[108]  A. Monaco,et al.  Cloning the gene for an inherited human disorder—chronic granulomatous disease—on the basis of its chromosomal location , 1986, Nature.

[109]  M. Nei,et al.  Mathematical model for studying genetic variation in terms of restriction endonucleases. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[110]  G. A. Watterson.  On the number of segregating sites in genetical models without recombination. , 1975, Theoretical population biology.

[111]  S WRIGHT,et al.  Genetical Structure of Populations , 1950, British medical journal.

[112]  P. Kloetzel,et al.  Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes , 2011, Nature Immunology.

[113]  R. Detels.  The 'immunologic advantage' of HIV-exposed seronegative individuals. , 2009, AIDS.

[114]  Albert J. Vilella,et al.  EnsemblCompara GeneTrees: Complete, duplication-aware phylogenetic trees in vertebrates. , 2009, Genome research.

[115]  N. Bresolin,et al.  Widespread balancing selection and pathogen-driven selection at blood group antigen genes. , 2009, Genome research.

[116]  Pardis C Sabeti,et al.  Positive Natural Selection in the Human , 2006 .

[117]  S..  Sampling theory for neutral alleles in a varying environment , 2003 .

[118]  H. Bandelt,et al.  Median-joining networks for inferring intraspecific phylogenies. , 1999, Molecular biology and evolution.

[119]  A. Hughes,et al.  Natural selection at major histocompatibility complex loci of vertebrates. , 1998, Annual review of genetics.