Literature DB >> 35327572

IMGT®Homo sapiens IG and TR Loci, Gene Order, CNV and Haplotypes: New Concepts as a Paradigm for Jawed Vertebrates Genome Assemblies.

Marie-Paule Lefranc1, Gérard Lefranc1.   

Abstract

IMGT®, the international ImMunoGeneTics information system®, created in 1989, by Marie-Paule Lefranc (Université de Montpellier and CNRS), marked the advent of immunoinformatics, a new science which emerged at the interface between immunogenetics and bioinformatics for the study of the adaptive immune responses. IMGT® is based on a standardized nomenclature of the immunoglobulin (IG) and T cell receptor (TR) genes and alleles from fish to humans and on the IMGT unique numbering for the variable (V) and constant (C) domains of the immunoglobulin superfamily (IgSF) of vertebrates and invertebrates, and for the groove (G) domain of the major histocompatibility (MH) and MH superfamily (MhSF) proteins. IMGT® comprises 7 databases, 17 tools and more than 25,000 pages of web resources for sequences, genes and structures, based on the IMGT Scientific chart rules generated from the IMGT-ONTOLOGY axioms and concepts. IMGT® reference directories are used for the analysis of the NGS high-throughput expressed IG and TR repertoires (natural, synthetic and/or bioengineered) and for bridging sequences, two-dimensional (2D) and three-dimensional (3D) structures. This manuscript focuses on the IMGT®Homo sapiens IG and TR loci, gene order, copy number variation (CNV) and haplotypes new concepts, as a paradigm for jawed vertebrates genome assemblies.

Entities:  

Keywords:  IMGT; T cell receptor (TR); antibody; bioengineering; copy number variation (CNV); haplotype; immunogenetics; immunoglobulin (IG); immunoinformatics; system biology

Mesh：

Substances：

Year:  2022        PMID： 35327572      PMCID： PMC8945572          DOI： 10.3390/biom12030381

Source DB:  PubMed          Journal:  Biomolecules        ISSN： 2218-273X


1. Introduction

The adaptive immune response of the jawed vertebrates (or gnathostomata), which appeared in evolution about 450 million years ago is characterized by a remarkable immune specificity and memory, which are the properties of the B and T cells owing to an extreme diversity of their antigen receptors, the immunoglobulins (IG) or antibodies and the T cell receptors (TR), respectively [1]. In humans and other mammals, an IG consists of two identical light chains (kappa (IGK) or lambda (IGL)) and two identical heavy chains (IGH) [2], while a TR consists of two chains, either alpha (TRA) and beta (TRB), or gamma (TRG) and delta (TRD) [3]. Each IG and TR chain comprises a variable domain (V-DOMAIN) which determines the specificity for the antigen, and a constant region (C-REGION) composed of one, three or four constant domains (C-DOMAIN) depending on the chain type [4,5]. The V-DOMAIN results from the genomic rearrangement of variable (V), diversity (D) and joining (J) genes for IGH, TRB and TRD chains (encoding a V-D-J-REGION) and of V and J genes for IGK, IGL, TRA and TRG chains (encoding a V-J-REGION) [1,2,3,4,5]. Additional mechanisms occurring during the rearrangements (N diversity, somatic hypermutations for the IG [5]) contribute to the extreme diversity of the IG and TR (theoretically 1012 IG and TR per individual, which is only limited by the number of the B and T cells that an organism is genetically programmed to produce) [1]. IMGT®, the international ImMunoGeneTics information system® (http://www.imgt.org) (accessed on 22 February 2022) (Figure 1) [1,2,3,4,5], was created in 1989 by Marie-Paule Lefranc (Université de Montpellier and CNRS) in order to characterize the genes and alleles involved in the IG and TR synthesis of vertebrate species from fish to human, and to standardize and manage the huge and complex diversity of IG and TR sequences and structures. The founding of IMGT® marked the birth of immunoinformatics [1], a new science, which emerged at the interface between immunogenetics and bioinformatics. For the first time, IG and TR genes (V, D, J and C) were officially recognized as “genes” as well as were the conventional genes [2,3,6,7]. This major breakthrough allowed genes and data of the complex and highly diversified adaptive immune responses to be managed in genomic databases and tools [1]. IMGT®, the international ImMunoGenetics information system® has been online since 1995 (the first Internet connexion of IMGT/LIGM-DB occurred at the 9th International Congress of Immunology (ICI) in San Francisco, CA, USA), 23–29 July 1995), marking the 7-year anniversary of the first Internet France-USA connexion of 28 July 1988). The IG and TR nomenclature [1,2,3,4,5,6,7], based on the internationally acknowledged expertise of the Laboratoire d’ImmunoGénétique Moléculaire (LIGM), has been endorsed since 1992 by the World Health Organization—International Union of Immunological Societies (WHO-IUIS) [8,9], making IMGT®, the global reference in immunogenetics and immunoinformatics.
Figure 1

IMGT®, the international ImMunoGenetics information system®, http://www.imgt.org (accessed on 22 February 2022) [1,5]. IMGT® comprises seven IMGT databases (shown as cylinders), seventeen online IMGT tools (shown as rectangles) and the IMGT Web resources (more than 25,000 pages, the ‘IMGT Marie-Paule page’) (not shown), for genes (in yellow), sequences (in green) and structures (in blue), all available from the IMGT® Home page. IMGT/mAb-DB has been online since 4 December 2009. IMGT/HighV-QUEST for next-generation sequencing (NGS) high-throughput sequence analysis, created in October 2010, has been available on the web since 22 November 2010. (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org) (accessed on 22 February 2022).

IMGT® is an integrated knowledge system for sequences, genes and structures of the IG or antibodies, TR and major histocompatibility (MH) proteins of the adaptive immune responses of the jawed vertebrates, as well as of other proteins of the IG superfamily (IgSF) and MH superfamily (MhSF) of vertebrates and invertebrates and of related proteins of immunological interest (RPI) [1,2,3,4,5]. The strength of the system is to have been built on the scientific rules (standardized keywords, standardized labels, standardized gene and allele names, a unique numbering for domains) elaborated by LIGM, with the goal to bridge genes, nucleotide and amino acid sequences and structures for analyzing their diversity and understanding biological functions. The first nucleotide sequences database for the genes of the adaptive immune responses in immunology, LIGM-DB/IMGT [10,11], became rapidly international [12,13,14], with a systematized approach for data coherence and distribution [15,16,17,18,19,20] and the building of an information system for comparative immunogenetics and immunology [21,22,23]. In 2003, IMGT was acknowledged as the global reference in immunoinformatics [24,25] with high-quality databases, tools and web resources, publicly available for IG and TR sequence analysis and antibody engineering [26]. At the research level, it was the demonstration that an ontology (formalization of the LIGM standardized rules in IMGT-ONTOLOGY [27,28,29]) and a system (implementation of IMGT-Choreography for genomics, genetics and structural approaches [30,31,32,33,34,35,36,37,38]) have bridged biological and computational spheres in bioinformatics [39,40]. As examples, IMGT® databases, tools and web resources are used for genome diversity and evolution studies, immune repertoire analysis, in medical research (repertoire in autoimmune diseases, AIDS, leukemia and lymphoma) and therapeutic antibody engineering and humanization [23,41,42,43,44,45,46,47,48,49,50,51]. IMGT® comprises seven IMGT databases, seventeen online IMGT tools (Figure 1) and the IMGT Web resources (more than 25,000 pages, the ‘IMGT Marie-Paule page’), all available from the IMGT Home page (http://www.imgt.org) (accessed on 22 February 2022) [1,2,3,4,5]. IMGT® databases are specialized in sequences (IMGT/LIGM-DB [52], IMGT/PRIMER-DB [53,54], IMGT/CLL-DB [55]), genes and alleles (IMGT/GENE-DB [56]), two-dimensional (2D) and three-dimensional (3D) structures (IMGT/2Dstructure-DB, IMGT/3Dstructure-DB) [57,58,59]. IMGT/2Dstructure-DB and IMGT/3Dstructure-DB use the same computing frame and provide gene and allele identification and molecular characterization of the amino sequences of the IG and TR receptors, chains and domains [1,2,3,4,5,60]. In addition, IMGT/3Dstructure-DB provides contact analysis between domains, standardized pMH contact sites, and amino acid characterization of paratope [61] and epitope [62] in IG/Ligand and TR/peptide/MH complexes [63,64]. IMGT/mAb-DB [1,65], the IMGT database and interface for therapeutic adaptive immune responses proteins (IG such as monoclonal antibodies (mAb), antibody–drug conjugates (ADC) or chimeric antigen receptors (CAR T), and TR), fusion proteins for immune applications (FPIA) and composite proteins for clinical applications (CPCA), has been online since 4 December 2009. IMGT/mAb-DB has reciprocal links with the IMGT/2Dstructure-DB (and IMGT/3Dstructure-DB, if 3D structures are available) and allows query on the International Nonproprietary Names (INN) of the World Health Organization (WHO) [66,67]. It also provides links to the lists and definitions published twice a year by the WHO INN programme and to the USA Food and Drug Administration (FDA) approvals. IMGT® tools for nucleotide sequence analysis comprise IMGT/V-QUEST [68,69,70,71,72,73] which implements IMGT/JunctionAnalysis [74,75,76,77] and IMGT/Automat [78,79], and IMGT/HighV-QUEST [73,80,81,82,83], its high-throughput version for next-generation sequencing (NGS). Created in October 2010 and available on the web since 22 November 2010, IMGT/HighV-QUEST uses the same algorithm and IMGT reference directories and provides the same functionalities as IMGT/V-QUEST. It includes, as an option, a statistical module for the characterization of IMGT (AA) clonotypes [82]. Pairwise comparisons of the diversity and expression of the IMGT (AA) clonotypes can be performed using IMGT/StatClonotype [84,85], a package downloadable from the website. IMGT/DomainGapAlign [58,86,87] is the IMGT® tool for amino acid sequence analysis widely used for domain antibody engineering and humanization. IMGT tools for genomic analysis include IMGT/LIGMotif [88] used for genomic annotations and a set of tools for visualization and analysis, IMGT/LocusView, IMGT/GeneView, IMGT/GeneSearch, IMGT/CloneSearch, IMGT/GeneFrequency, IMGT/AlleleAlign, IMGT/PhyloGene [89], IMGT/GeneInfo [90,91]. The IMGT® Web resources (the ‘IMGT Marie-Paule page’) comprise IMGT Repertoire (IG and TR, MH, and RPI), IMGT Scientific chart, IMGT Index, IMGT Bloc-notes, IMGT Education, IMGT Posters and diaporama, The IMGT Medical page, The IMGT Veterinary page, The IMGT Biotechnology page (Antibody engineering) and The IMGT Immunoinformatics page [1]. The accuracy and the consistency of the IMGT data through the IMGT information system [1,2,3,4,5] are based on IMGT-ONTOLOGY [92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113], the first ontology for immunogenetics and immunoinformatics, and on the IMGT Scientific chart rules generated from its axioms and concepts [1]. They include the controlled vocabulary and annotation rules that comprise the IMGT® standardized keywords (IDENTIFICATION axiom) [96], the IMGT® standardized labels (DESCRIPTION axiom) [97], the IMGT® gene and allele nomenclature (CLASSIFICATION axiom) [98], the IMGT® unique numbering [99,100,101,102,103,104,105,106] for variable V [101], constant C [102] and groove G [103] domains, and IMGT® Colliers de Perles [107,108,109,110,111,112] (NUMEROTATION axiom), with standardized IMGT physicochemical classes of the 20 common amino acids [113]. Links to biocurated data of IG and TR genes and alleles from fish to humans are provided in IMGT® Creations and updates (http://www.imgt.org/IMGTinformation/creations/) (access in ‘References and News’ on the IMGT® Home page) (accessed on 22 February 2022), online since October 1998. IG and TR nomenclature (genes and alleles names) and IMGT unique numbering of the IMGT® Creations and updates are validated by the International Union of Immunological Societies (IUIS) Nomenclature Committee (NOM) Immunoglobulins (IG), T cell receptors (TR) and major histocompatibility (MH) Sub-Committee (IMGT-NC) [114]. A primary axis of research and development in immunogenetics and immunoinformatics consists in deciphering the genomic organization of the IG and TR loci in jawed vertebrates. Indeed, new IMGT genes and alleles, described with the IMGT nomenclature, IMGT unique numbering and IMGT standardized keywords and labels [1], enrich the IMGT® databases, tool reference directories and web resources for a better knowledge of natural IG and TR repertoires. These data are used for the analysis of the next generation sequencing (NGS) high-throughput expressed IG and TR repertoires (natural, synthetic and/or bioengineered) and for bridging sequences and two-dimensional (2D) and three-dimensional (3D) structures. This manuscript focuses on the Homo sapiens IG and TR loci, gene order, CNV and haplotypes new concepts, as a paradigm for jawed vertebrates genome assemblies.

2. IG and TR Genes and Alleles Paradigm

2.1. Advent of Immunoinformatics

The V, D, J, and C genes which code the antigen receptors were officially recognized as ‘genes’, as were the conventional genes, at the 10th Human Genome Mapping (HGM10) Workshop, in New Haven in 1989, marking the creation of IMGT® and the advent of immunoinformatics [1]. The Homo sapiens TRG locus [115] was the first complete antigen receptor locus officially approved in 1989 for entry in the HGM database [116,117]. In 1992, the Homo sapiens IMGT genes and alleles names were endorsed by the WHO—IUIS NOM (https://iuis.org/committees/nom/) (accessed on 22 February 2022). IMGT-NC became the first IUIS Nomenclature Sub-Committee for immunoglobulins and T cell receptors [114] in charge of providing the IG and TR genes and alleles names and promoting IMGT standards [118,119,120,121]. The human (Homo sapiens) IG and TR IMGT gene names [6,7] were approved by the Human Genome Organization (HUGO) Nomenclature Committee (HGNC) in 1999 [122] and entered in the NCBI gene database (first LocusLink, then EntrezGene, superseded by Gene).

2.2. Homo sapiens Locus, Genes and Alleles

The IG and TR genes are classified in groups defined by the gene type (V, D, J or C) and by the locus to which they belong [1,2,3,4,5,6,7,8,9]. The seven major loci, three for IG (IGH, IGK and IGL) [2,4,5] and four for TR (TRA, TRB, TRD and TRG) [3], are located on different chromosomes, with the particularity of the TRD locus being nestled inside the TRA locus in higher vertebrates [3]. The princeps LIGM publications on the IG and TR loci, genes and alleles of the seven human (Homo sapiens) loci are the two FactsBooks published in 2001 [2,3]. They comprised for the IG, 203 functional and open reading frame (ORF) genes corresponding to 459 alleles, for a total of 837 sequences [2], and for the TR, 168 functional and ORF genes [3]. Entries of the FactsBooks [2,3] provide information on assignment to subgroups and nomenclature, gene definition and functionality, gene location, allelic polymorphism, standardized sequence alignment with protein translation, framework and complementarity determining region (CDR-IMGT) lengths, two-dimensional representations (or Colliers de Perles), IMGT/LIGM-DB and EMBL/GenBank accession numbers, genome database accession numbers (GDB, LocusLink) and key references [2,3]. This information has served as templates for the IMGT Repertoire (IG and TR) sections on the IMGT website, in the IMGT Web resources (the ‘IMGT Marie-Paule page’) (IMGT® http://www.imgt.org (accessed on 22 February 2022), IMGT Repertoire (IG and TR) (1). Locus and genes; (2). Proteins and alleles; (3). 2D and 3D structures; (4). Probes and RFLP; (5). Taxonomy; (6). Gene regulation and expression; (7). Genes and clinical entities). Basic IMGT Web resources include Gene tables, Alignment of alleles, Protein displays, Colliers de Perles, Locus representations, Potential germline repertoire with CDR-IMGT lengths, Locus gene order, copy number variations (CNV) and haplotypes) [5]. This detailed identification, description and classification of the human IG and TR loci, genes and alleles [2,3], using the IMGT Scientific chart rules, is the result of a huge work of annotation and expert analysis, by LIGM, of tens of thousands of nucleotide sequences from phages, cosmids or contigs submitted by the authors to the generalist nucleotide databases (EMBL database, now European Nucleotide Archive (ENA) [123], GenBank [124] and DNA Databank of Japan (DDBJ) [125]. The annotated sequences were integrated into the newly created IMGT/LIGM-DB [10,11], using the EMBL/GenBank/DDBJ accession numbers in order to facilitate interoperability with the generalist nucleotide databases. The Nature and Science papers on the human genome sequencing [126,127], published in 2001, contain limited information on the genes of the adaptive immune responses. However a careful analysis of the maps published in these papers allowed us to confirm the chromosomal localizations of the seven main loci: IGH, IGK and IGH (for the immunoglobulins), TRA, TRB, TRG and TRD (for the T cell receptors), described in 2001, in the Immunoglobulin FactsBook [2] and T cell receptor FactsBook [3], respectively, and determined by an analysis of translocations involving the IG and/or TR loci in leukemia and lymphoma (http://www.imgt.org/IMGTrepertoire/GenesClinical/translocation/human/overview/Hu_overviewpart1.html) (accessed on 22 February 2022).

2.3. Extension to Mus musculus and Fish (Chondrichtyes and Teleostei)

Based on this paradigm of the human loci (IMGT nomenclature, IMGT unique numbering, IMGT standardized keywords and labels), the seven mouse (Mus musculus) loci with a total of 625 genes (377 IG and 248 TR) [128,129,130,131] were characterized and presented at the 19th International Mouse Genome Conference (IMGC) in 2005 ((http://www.imgt.org/IMGTposters/IMGC_IG.html) (accessed on 22 February 2022) and (http://www.imgt.org/IMGTposters/IMGC_TR.html) (accessed on 22 February 2022)), and entered in NCBI Gene, with reciprocal links to IMGT/GENE-DB and in Mouse Genome Informatics (MGI). The analysis of IG genes of four Chondrichthyes and twenty-two Teleostei different species confirmed that the IG and TR paradigm was applicable for fish, however, most sequences were at that time unmapped and were assigned a provisional nomenclature with the letter S [132,133]. The Chondrichthyes and Teleostei light chain which is neither kappa nor lambda was defined as ‘iota’ encoded by genes of the IG iota (IGI) locus which includes IGIV, IGIJ and IGIC groups (http://www.imgt.org/IMGTrepertoire/LocusGenes/genetable/Teleostei/#IGIV) (accessed on 22 February 2022).

2.4. Homo sapiens and Mus musculus Data Availability Online

Since 1998, novel Homo sapiens and Mus musculus genes and alleles have been announced in ‘IMGT® Creations and updates’ and validated by the IUIS NOM IMGT-NC [114]. Since 2003, IMGT/GENE-DB provides direct links (access from the Query page) which allow the most frequent requests to be encoded in the form of URL: (i) for a given gene {(1). IMGT/GENE-DB entry, (2). IMGT/GENE-DB reference sequences of alleles of a given gene in FASTA format, (3). IMGT/LIGM-DB label sequences in FASTA format, (4). Tables of known IMGT/LIGM-DB cDNA or rearranged gDNA sequences or known IMGT/3Dstructure-DB entries}, or (ii) for genes of a group {(1). IMGT/GENE-DB reference sequences of genes of a group in FASTA format, (2). IMGT/LIGM-DB label sequences in FASTA format}. There are also direct links to IMGT/GENE-DB and generalist genomic databases entries in two formats, HTML tables and CSV format. On 25 November 2021, IMGT/GENE-DB data include 732 Homo sapiens IG and TR genes (with links to HGNC, NCBI Gene, Ensembl, GenAtlas, GeneCards and UniProt) and 916 Mus musculus IG and TR genes (with links to MGI and NCBI Gene). The information, for each IMGT/GENE-DB entry, include: IMGT gene functionality, IMGT gene definition (for Homo sapiens and Mus musculus IG and TR), the HGNC gene definition (identical to the IMGT gene definition), number of alleles, chromosomal localization and IMGT/LIGM-DB reference sequence(s) for allele *01. IMGT/GENE-DB is updated weekly, with downloads available in different formats, in the “IMGT downloads” section.

3. IUIS NOM IMGT-NC Reports for New IG and TR Loci Gene and Allele Names

With the increase in genome sequencing and assembly, the starting point for IG and TR gene identification, description and classification has moved from individual sequences (researchers’ submission to generalist databases) to the IG and TR locus identification in NCBI Whole Genome Assemblies (WGS) (submitted by sequencing groups and analyzed by researchers). In order to allow researchers to go ahead with expression studies and to publish their data with IMGT gene names even if the loci are not yet been annotated in IMGT® or in other specialist databases, the IUIS NOM Sub-Committee [114] has created the IUIS NOM IMGT-NC Reports. That initiative allows scientists to propose IMGT gene names for new IG and TR variable (V), diversity (D), joining (J) and constant (C) genes and alleles, for a given locus of a given species, to the IUIS Sub-Committee for approval, based on the IMGT Scientific chart rules and the IMGT-ONTOLOGY concepts of classification (CLASSIFICATION axiom). The submission for an IUIS NOM IMGT-NC Report requires that each gene sequence has an accession number in a generalist database (with localization if large original sequence) and that each V, D, J or C gene sequence has been mapped (cloned from bacterial artificial chromosome (BAC), fosmid, cosmid or phage, or extracted from a referenced genome assembly) (Figure 2).
Figure 2

Prototypes with IMGT standardized labels. (A) L-V-GENE-UNIT. This label describes gDNA of an IG or TR V-GENE unit, in germline configuration, that comprises L-PART1, V-INTRON, V-EXON and V-RS. (B) D-GENE-UNIT. This label describes gDNA of an IG or TR D-GENE unit, in germline configuration, that comprises 5′D-RS, D-REGION and 3′D-RS. (C) J-GENE-UNIT. This label describes gDNA of an IG or TR J-GENE unit, in germline configuration, that comprises 5′J-RS and J-REGION. Definitions of the IMGT standardized labels are available at https://www.imgt.org/ligmdb/label# (accessed on 22 February 2022). Abbreviations: L: leader, RS: recombination signal (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®).

For a new V gene and allele, the submitted sequence is that of the L-V-GENE-UNIT: a complete germline genomic sequence (germline gDNA) from the atg (INIT-CODON) of L-PART1 to the V-RS included (http://www.imgt.org/IMGTScientificChart/SequenceDescription/displayimage.php?id=19) (accessed on 22 February 2022) (Figure 2A). For a new D gene and allele, the submitted sequence is that of the D-GENE-UNIT: a complete germline genomic sequence (germline gDNA) from the 5′D-RS to the 3′D-RS included (http://www.imgt.org/IMGTScientificChart/SequenceDescription/displayimage.php?id=2) (accessed on 22 February 2022) (Figure 2B). For a new J gene and allele, the submitted sequence is that of the J-GENE-UNIT plus DONOR-SPLICE: a complete germline genomic sequence (germline gDNA) from the J-RS to the DONOR-SPLICE included (http://www.imgt.org/IMGTScientificChart/SequenceDescription/displayimage.php?id=9) (accessed on 22 February 2022) (Figure 2C). For a new C gene and allele, the submitted sequence is that of the C-GENE-UNIT: a complete genomic sequence (gDNA) from the first codon of the first exon (EX1) to the STOP-CODON included (this requirement has become effective from 1 January 2018), plus the individual exons, if several (http://www.imgt.org/IMGTScientificChart/SequenceDescription/displayimage.php?id=6) (accessed on 22 February 2022). The label C-GENE-UNIT describes gDNA of an IG or TR C-GENE unit, in undefined configuration, that comprises exon(s) (EXON), coding the C-REGION, and intron(s) (INTRON) if present, from the first nucleotide of the first exon to the STOP-CODON (included) after the last exon. Recent examples of veterinary IG and TR loci from genome assemblies, analyzed by scientists using gene and allele names validated by the IUIS NOM IMGT-NC [114], include: dog (Canis lupus familiaris) [134], the first veterinary species with the seven loci identified, cat (Felis catus) TR loci [135], rabbit (Oryctolagus cuniculus) TRA locus [136], dolphin (Tursiops truncatus) [137], Salmonid including salmon (Salmo salar) and trout (Oncorhynchus mykiss) IGH duplicated loci [138,139] and TRA/TRD locus [140]. These examples of different species and loci have been key elements in the setting of the submission criteria and steps of the now well established IUIS NOM IMGT-NC Reports [114]. They also confirm the necessity for databases using these data (for analysis or biocuration) to cite and link to the original IUIS report to guarantee interoperability. This is illustrated by the links made to the IUIS reports, in IMGT® Creations and updates (http://www.imgt.org/IMGTinformation/creations/) (accessed on 20 February 2022), following data annotation by the IMGT biocurators for data entry in IMGT®, as described in Section 6.

4. IMGT New Concepts for IG and TR Loci of Jawed Vertebrates Genome Assemblies

4.1. Locus in Genome Assembly

Before starting IMGT biocuration of a new IG or TR locus of a veterinary species, information is collected in ‘Locus in genome assembly’ (Figure 3). For an easier comparison between loci of different species, and/or between loci of different genomes assemblies (or of different haplotypes, including CNV), the IDENTIFICATION axiom has been enriched by the implementation of ‘IMGT locus ID’ and ‘IMGT/LIGM-DB locus reference sequence (ID)’ (Figure 3).
Figure 3

Locus in genome assembly: Rhesus monkey (Macaca mulatta) IGL IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Web resources > IMGT Repertoire (IG and TR) 1. Locus and genes. >3. Locus descriptions > Locus in genome assembly > IGL: Rhesus monkey http://www.imgt.org/IMGTrepertoire/index.php?section=LocusGenes&repertoire=locusAssembly&species=rhesus_monkey&group=IGL (accessed on 20 February 2022) Only the last annotated locus in genome assembly is shown in the figure, annotated loci of previous assemblies are available online on the right of the displayed locus. (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org) (accessed on 20 February 2022).

4.2. IMGT Locus ID and IMGT/LIGM-DB Locus Reference Sequence

An ‘IMGT locus ID’ comprises the 6-letter (or 9-letter) code from the genus and species (or subspecies) Latin names (IMGT taxon abbreviations), the locus type and a chronological increasing number, separated by underscores, for example, Macmul_IGL_2 (Figure 3). An ‘IMGT/LIGM-DB locus reference sequence’ is an IMGT accession number (‘IMGT’ followed by 6 digits) which identifies the IMGT/LIGM-DB flat files containing an IG or TR locus (or part of it) extracted from an NCBI genome assembly and presented in its own 5′ to 3′ locus orientation. As a locus may have, on the chromosome, a forward (or ‘Watson’) (FWD) or a reverse (REV) orientation (IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Web resources > IMGT Index > Genomic orientation), the sequence orientation in the IMGT accession number flat file is either unchanged (direct) relative to the sequence on the chromosome for an FWD locus, or reverse complemented for a REV locus. For example, the rhesus macaque (Macaca mulatta) IGL locus orientation on chromosome 10 is reverse (REV) and the IMGT/LIGM-DB locus reference sequence in IMGT000062 is reverse-complement relative to the sequence on chromosome 10. The information from ‘Locus in genome assembly’ (Figure 3) is reported in the definition lines (DE) of the IMGT/LIGM-DB locus reference accession number. For IMGT000062 it includes: Macaca mulatta (Rhesus monkey), taxon:9544, isolate: AG07107 single Indian origin rhesus female, assembly Mmul_10, 2345051 [UID], GenBank assembly ID: GCA_003339765.3, Refseq assembly ID: GCF_003339765.1, chromosome 10: CM014345.1 (29621424-30922134, complement), IMGT locus ID: Macmul_IGL_2.

4.3. IMGT LOCUS-UNIT Label and Qualifiers

The label IMGT-LOCUS-UNIT (DESCRIPTION axiom) was created to describe a locus, isolated from a genome assembly, in an IMGT accession number flat file. The definition of the IMGT-LOCUS-UNIT and its qualifiers are given in Table 1.
Table 1

The IMGT-LOCUS-UNIT label and its associated qualifiers and definitions.

IMGT New Label and Associated QualifiersDefinition
IMGT label aIMGT-LOCUS-UNITgDNA of an immunoglobulin (IG) or T cell receptor (TR) IMGT locus unit from chromosome genomic assembly, that starts at the 5 prime (5′) end of the most 5′ IG or TR GENE-UNIT in the IMGT-LOCUS-UNIT and ends at the 3 prime (3′) end of the most 3′ IG or TR GENE-UNIT in the locus
IMGT qualifiers bIMGT_locus_3prime_borne cName of the gene identified as the 3 prime (3′) borne of an IMGT-LOCUS-UNIT
IMGT_locus_3prime_geneIMGT gene name of the most 3 prime (3′) IG or TR GENE-UNIT of an IMGT-LOCUS-UNIT
IMGT_locus_5prime_borne cName of the gene identified as the 5 prime (5′) borne of an IMGT-LOCUS-UNIT
IMGT_locus_5prime_geneIMGT gene name of the most 5 prime (5′) IG or TR GENE-UNIT of an IMGT-LOCUS-UNIT
IMGT_locus_IDIdentifier of an IMGT-LOCUS-UNIT comprising the IMGT_locus_name and a chronological number, separated with underscores
IMGT_locus_chromosomeChromosome identifier (with band or section if known)
IMGT_locus_lengthLength of an IMGT-LOCUS-UNIT in base pairs (bp) in the sequence
IMGT_locus_nameName of an IMGT-LOCUS-UNIT, that includes the genus and species Latin names and the IMGT locus type
(i.e., in higher vertebrates: IGH, IGK, IGL, TRA, TRB, TRG, TRD)
IMGT_locus_orientationOrientation of an IMGT-LOCUS-UNIT on a chromosome, is either “forward (FWD)” or “reverse (REV)”
IMGT_locus_positionsNCBI chromosome sequence accession with positions of the IMGT-LOCUS-UNIT

a IMGT/LIGM-DB labels: http://www.imgt.org/ligmdb/label# (accessed on 20 February 2022). b IMGT/LIGM-DB qualifiers: http://www.imgt.org/ligmdb/qualifier (accessed on 20 February 2022). c IMGT Borne: http://www.imgt.org/IMGTindex/IMGTborne.php (accessed on 20 February 2022).

Three IMGT/LIGM-DB locus reference sequences for the Macaca mulatta (rhesus monkey) IGH (IMGT000064), IGL (IMGT000062) and IGK (IMGT000063) have recently been created and annotated for the Mmul_10 assembly (GCF_003339765.1). As an example, the IMGT000062 qualifiers for the IMGT-LOCUS-UNIT (1..1300711) of the Macmul_IGL_2 (IMGT_locus_ID) are the following: FT IMGT-LOCUS-UNIT 1..1300711 FT /IMGT_locus_3prime_borne=“RSPH14” FT /IMGT_locus_3prime_gene=“IGLC7” FT /IMGT_locus_5prime_borne=“TOP3B” FT /IMGT_locus_5prime_gene=“IGLV(IV)-127” FT /IMGT_locus_ID=”Macmul_IGL_2” FT /IMGT_locus_chromosome=”10” FT /IMGT_locus_length=“1300711 bp” FT /IMGT_locus_name=“Macaca mulatta IGL” FT /IMGT_locus_orientation=“reverse (REV)” FT /IMGT_locus_positions=“CM014345.1 FT (29621424-30922134 complement)”

4.4. IMGT Locus 5′ and 3′ Bornes

The IMGT Locus 5′ borne (IMGT_locus_5prime_borne) and the IMGT Locus 3′ borne (IMGT_locus_3prime_borne) (Table 2) are defined for a standardized comparison of the IG and TR locus delimitation across species. The IMGT bornes are genes coding for a protein (other than IG or TR), conserved between species, located upstream of the first gene (for the IMGT 5′ borne) or downstream of the last gene (for the IMGT 3′ borne) of an IG or TR locus (IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Web resources > IMGT Repertoire (IG and TR) > 1. Locus and genes > 3. Locus descriptions > Locus bornes: IGH, IGK, IGL, TRA, TRB, TRG, TRD). If IMGT bornes are not yet identified or are too distant to be included in the locus sequence, a minimal 10 kb sequence is added upstream of the first IG or TR gene in 5′ and/or downstream from the last IG or TR gene in 3′. A preliminary overview of the locus IG and TR 5′ and 3′ bornes is shown in Table 2.
Table 2

IMGT Locus 5′ and 3′ bornes of the IG and TR loci.

IMGT Locus 5′ BorneIMGT Locus 3′ Borne
Gene NameOccurrenceGene Name Occurrence
/Nb of Species/Nb of Species
IGHN.d. a,b 6/6 N.d. a,b 6/6
IGKPAX8 bpaired box 86/10RPIA bribose 5-phosphate isomerase A10/10
N.d. a 4/10
IGLTOP3B b DNA topoisomerase III4/9RSPH14 bradial spoke head 14 homolog5/9
SLC5A1solute carrier family 5 member 12/9VPREB3V-set pre-B cell surrogate light chain 33/9
N.d. a 3/9N.d. a 1/9
TRA/TRDOR10G3 bolfactory receptor 10G36/9DAD1 bdefender against cell death9/9
N.d. a 3/9
TRBMOXD2 bmonooxygenase DBH-like 210/10EPHB6 bEPH receptor B610/10
TRGAMPH bamphiphysin8/8STARD3NLSTARD3 N-terminal like8/8

a N.d.: Not defined; b Macaca mulatta, included in the occurrence/Nb of species.

4.5. IMGT/GENE-DB Localization in Genome Assemblies

The section “LOCALIZATION IN GENOME ASSEMBLIES” (Figure 4) integrated in 2015 in IMGT/GENE-DB, allows, for a given species and a given locus, to query the IMGT IG or TR genes of a given genome assembly. The query Species: Macaca mulatta|AG07107 (AG07107 is the isolate) and Locus: IGH locus shows the availability of IMGT/GENE-DB biocurated genes for the assembly ‘Mmul_10, NCBI’, ‘Primary Assembly’ ‘Full chromosome 7′ (Figure 4A).
Figure 4

IMGT/GENE-DB Localization in genome assemblies. (A) Query for Macaca mulatta|AG07107 (Species, AG07107 isolate) and IGH (Locus) showing the availability of IMGT/GENE-DB biocurated genes for the assembly ‘Mmul_10, NCBI’. (B) Top of the results page for the query. IMGT alleles of a given gene are defined by the number which follows the asterisk (i.e., *01) (With permission from M–P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org) (accessed on 20 February 2022).

The results page for the query Species: Macaca mulatta|AG07107 (Rhesus monkey) Locus: IGH (Figure 4B) provides at the top the chromosome localization: ‘chrom 7′, the locus orientation on chromosome ‘REV’, the number of genes in Mmul_10 (NCBI) (IMGT/GENE-DB annotated genes) ‘265′ and the number of labels ‘437′. For each gene, the information comprises IMGT gene name, IMGT gene order, IMGT gene orientation (direct (5′ > 3′) or opposite (3′ > 5′) in the locus), IMGT allele name and Functionality (F, ORF or P), IMGT/LIGM-DB accession number, IMGT labels (L-V-GENE-UNIT and V-REGION for a V gene, D-GENE-UNIT and D-REGION for a D gene, J-GENE-UNIT and J-REGION for a J gene, C-GENE-UNIT and C-REGION or the different individual exons for a C gene), IMGT label positions in the IMGT/LIGM-DB accession number, HGNC gene ID (for Homo sapiens), NCBI gene ID (if available), NCBI Mmul_10 Primary Assembly Chromosome (NC) accession number and IMGT label positions in the NC sequence. The list of genes known to belong to the locus but not localized (NL) in the assembly is also provided in this section as this may correspond to polymorphism by copy number variation, insertion/deletion, or gaps in the assembly.

5. Immunoglobulin IMGT Copy Number Variations (CNV) and Haplotypes

5.1. Homo sapiens IGH Locus

5.1.1. IGH Locus Representation

The Homo sapiens IGH locus is located on chromosome 14, at the telomeric extremity of the long arm, at band 14q32.33 [2]. The orientation of the locus reverse (REV) on the chromosome has been determined by the analysis of translocations, involving the IGH locus, in leukemia and lymphoma. The Homo sapiens IGH locus spans 1250 kb [2,5] (Figure 5). The human IGH locus consists of 123 to 129 IGHV genes depending on the haplotypes, 27 IGHD genes belonging to seven subgroups, nine IGHJ genes and, in the most frequent haplotype, 11 IGHC genes [2,5]. Eighty-two to 89 IGHV genes belong to seven subgroups, whereas 43 pseudogenes, which are too divergent to be assigned to subgroups, have been assigned to the clans [2,5] (Figure 5).
Figure 5

Representation of the human IGH locus at 14q32.33 (REV orientation on the chromosome) [2,5]. The boxes representing the genes are not to scale. Exons are not shown. Switch sequences are represented by a filled circle upstream of the IGHC genes. Pseudogenes that could not be assigned to subgroups with functional genes are designated by a Roman numeral between parentheses, corresponding to the clans, followed by a hyphen, and a number for the localization from 3′ to 5′ in the locus [2]. IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Repertoire (IG and TR) 1. Locus and genes > 2. Locus representations > IGH: Human (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org) (accessed on 20 February 2022).

IGH Locus Gene order

5.1.2. IGH Locus Gene Order, CNV and Haplotypes

The relative positions (locus gene order) of the IGHV, IGHD, IGHJ and IGHC genes are shown in the Homo sapiens IGH locus from its 5′ end to its 3′ end (Table 3). Gene order is according to the IMGT Locus gene order (IMGT® http://www.imgt.org (accessed on 20 February2022 ), IMGT Repertoire (IG and TR) > 1. Locus and Genes > 3. Locus descriptions > Locus gene order > IGH. The number ‘0’ indicates that the relative position is unknown. The three most recently identified genes (IGHV1-68D, IGHV(III-67-4D, IGHV(III-67-3D) are numbered as insertions with a dot (gene order 17.1, 17.2 and 17.3) in the gene order to preserve comparisons with the reference ruler adopted in the description of the Homo sapiens IGH polymorphisms [5]. Genes of the related proteins of interest (RPI) used as markers in the locus are indicated with their orientation.
Table 3

Homo sapiens IGH locus: IMGT gene order and copy number variations (CNV).

IMGT Gene NameFunctionalityIMGT Gene Order in LocusIMGT GeneCopy Number Variations (CNV) Nomenclature,RPI Aliases (If Recent Changes)
Orientation in Locus
IGHV1-NL1P0N.d
IGHV3-NL1F0N.d
IGHV7-NL1P0N.d
IGHV(III)-82P1direct
IGHV7-81ORF2direct
IGHV4-80P3direct
IGHV3-79P4direct
IGHV(II)-78-1P5direct
IGHV5-78P6direct
IGHV7-77N.d.7direct
IGHV(III)-76-1P8direct
IGHV3-76P9direct
IGHV3-75P10direct
IGHV(II)-74-1P11direct
IGHV3-74F12direct
IGHV3-73F13direct
IGHV3-72F14direct
IGHV3-71P15direct
IGHV2-70F, ORF16directCNV1-5prime
IGHV1-69DF17direct
IGHV1-68DP17.1direct
IGHV(III)-67-4DP17.2directHomo sapiens IGH CNV1
IGHV(III)-67-3DP17.3directIGHV(17-20)7(3F,4P)
IGHV1-69-2F18direct
IGHV3-69-1P19direct
IGHV2-70DF20direct
IGHV1-69F21directCNV1-3prime
IGHV1-68P22direct
IGHV(III)-67-4P23direct
IGHV(III)-67-3P24direct
IGHV(III)-67-2P25direct
IGHV(II)-67-1P26direct
SLC20A1P1nr27directRPI (GLVR1)
IGHV1-67P28direct
IGHV3-66F29direct
IGHV(II)-65-1P30direct
IGHV3-65P31direct
IGHV3-64F32direct
GOLGA4P3nr33directRPI (Golgin)
IGHV3-63P34direct
IGHV(II)-62-1P35direct
IGHV3-62F, P36direct
IGHV4-61F, ORF37direct
IGHV(II)-60-1P38direct
IGHV3-60P39direct
IGHV4-59F40direct
IGHV1-58F41direct
IGHV3-57P42direct
IGHV7-56P43direct
IGHV4-55P44direct
IGHV3-54P45direct
IGHV(II)-53-1P46direct
IGHV3-53F47direct
IGHV3-52P48direct
IGHV(II)-51-2P49direct
IGHV8-51-1ORF, P50direct
IGHV5-51F51direct
IGHV3-50P52direct
IGHV(II)-49-1P53direct
IGHV3-49F54direct
IGHV3-48F55direct
IGHV(III)-47-1P56direct
IGHV3-47P57direct
IGHV(II)-46-1P58direct
IGHV1-46F59direct
IGHV1-45F60direct
IGHV(II)-44-2P61direct
IGHV(IV)-44-1P62direct
IGHV(III)-44P63direct
IGHV(II)-43-1P64direct
IGHV3-43F65direct
IGHV3-42P66direct
IGHV3-41P67direct
IGHV(II)-40-1P68direct
IGHV7-40P69direct
IGHV4-39F70directCNV2-5prime
IGHV1-38-4ORF71direct
IGHV(III)-38-1DP72direct
IGHV3-38-3ORF73direct
IGHV(III)-44DP74direct
IGHV(II)-43-1DP75directHomo sapiens IGH CNV2
IGHV3-43DF76directIGHV(71-80)10(2F,2O,6P)
IGHV3-42DP77direct
IGHV7-40DP78direct
IGHV4-38-2F79direct
IGHV(III)-38-1P80direct
IGHV3-38ORF81directCNV2-3prime
IGHV3-37P82direct
IGHV3-36P83direct
IGHV3-35F, ORF84direct
IGHV7-34-1P85direct
IGHV4-34F86directCNV3-5prime a
IGHV3-33-2P87direct
IGHV(II)-33-1P88direct
IGHV3-33F89direct
GOLGA4P1nr90direct
IGHV3-32P91direct
IGHV(II)-31-1P92direct
IGHV4-31F93direct
IGHV3-30-52P94direct
IGHV(II)-30-51P95direct
IGHV3-30-5F96direct
IGHV3-30-42P97direct
IGHV(II)-30-41P98direct
IGHV4-30-4F99directHomo sapiens IGH CNV3
IGHV3-30-33P100directIGHV(87-112)26(8F,16P,2RPI)
IGHV(II)-30-32P101direct
IGHV3-30-3F102direct
IGHV3-30-22P103direct
IGHV(II)-30-21P104direct
IGHV4-30-2F105direct
IGHV4-30-1F106direct
IGHV3-30-2P107direct
IGHV(II)-30-1P108direct
IGHV3-30F109direct
GOLGA4P2nr110direct
IGHV3-29P111direct
IGHV(II)-28-1P112direct
IGHV4-28F113directCNV3-3prime
IGHV7-27P114direct
IGHV(II)-26-2P115direct
IGHV(III)-26-1P116direct
IGHV2-26F117direct
IGHV(III)-25-1P118direct
IGHV3-25ORF, P119direct
IGHV1-24F120directCNV4-5prime
IGHV3-23DF121directHomo sapiens IGH CNV4
IGHV(III)-22-2DP122directIGHV(121-123)3(1F,2P)
IGHV(II)-22-1DP123direct
IGHV3-23F124directCNV4-3prime
IGHV(III)-22-2P125direct
IGHV(II)-22-1P126direct
IGHV3-22P127direct
IGHV3-21F128direct
IGHV(II)-20-1P129direct
IGHV3-20F, ORF130direct
IGHV3-19P131direct
IGHV1-18F132direct
SLC20A1P2nr133direct
IGHV1-17P134direct
IGHV(III)-16-1P135direct
IGHV3-16ORF136direct
IGHV(II)-15-1P137direct
IGHV3-15F138direct
IGHV1-14P139direct
IGHV(III)-13-1P140direct
IGHV3-13F141direct
IGHV1-12P142direct
IGHV(III)-11-1P143direct
IGHV3-11F, P144directCNV5-5prime
IGHV2-10P145directHomo sapiens IGH CNV5
IGHV3-9F146directIGHV(145-149)5(4F,1P), split into:
IGHV1-8F147directIGHV-e1 (145-147)3(2F,1P)
IGHV5-10-1F148direct
IGHV3-64DF149directIGHV-e2 (148-149)2(2F)
IGHV3-7F150directCNV5-3prime
IGHV3-6P151direct
IGHV(III)-5-2P152direct
IGHV(III)-5-1P153direct
IGHV2-5F154directCNV6-5prime
IGHV7-4-1F155directHomo sapiens IGH CNV6 IGHV(155)1(1F)
IGHV4-4F156directCNV6-3prime
IGHV1-3F157direct
IGHV(III)-2-1P581direct
IGHV1-2F159direct
RPS8P1nr160direct
ADAM6nr161direct
IGHV(II)-1-1P162direct
IGHV6-1F, P163direct
FAM30Anr164oppositeRPI (KIAA0125)
IGHD1-1F165direct
IGHD2-2F166direct
IGHD3-3F167direct
IGHD4-4F168direct
IGHD5-5F169direct
IGHD6-6F170direct
IGHD1-7F171direct
IGHD2-8F172direct
IGHD3-9F173direct
IGHD3-10F174direct
IGHD4-11ORF175direct
IGHD5-12F176direct
IGHD6-13F177direct
IGHD1-14ORF178direct
IGHD2-15F179direct
IGHD3-16F180direct
IGHD4-17F181direct
IGHD5-18F182direct
IGHD6-19F183direct
IGHD1-20F184direct
IGHD2-21F185direct
IGHD3-22F186direct
IGHD4-23ORF187direct
IGHD5-24ORF188direct
IGHD6-25F189direct
IGHD1-26F190direct
IGHJ1PP191direct
IGHD7-27F192direct
IGHJ1F193direct
IGHJ2F194direct
IGHJ2PP195direct
IGHJ3F196direct
IGHJ4F197direct
IGHJ5F198direct
IGHJ3PP199direct
IGHJ6F200direct
IGHMF201direct
IGHDF202directCNV7-5prime
IGHG3F203direct
IGHG1F204directHomo sapiens IGH CNV7 b
IGHEP1P205directIGHC(203-211)9(7F,1OP,1P)
IGHA1F206direct
IGHGPORF, P207direct
IGHG2F208direct
IGHG4F209direct
IGHEF210direct
IGHA2F211direct

N.d: Not defined (for IG and TR). nr: nonrelevant (for RPI). a The CNV3-5prime has been moved to IGHV4-34 (F) upstream in the locus (instead of IGHV3-32 (P) in [5]) to select a functional gene as 5prime and include one additional amplification unit, lacking in haplotype F. b No CNV7-3prime has been defined for the Homo sapiens IGH CNV7, owing to the non-identification of a 3′ borne for the IGH locus. CNV7 involving V genes are in pale green (CNV1 to CNV6), CNV7 involving C genes is in pale blue (CNV7).

The gene IGHV(II)-20-1 (gene order 129) is an exception as being only represented by a V-RS. Its V-REGION is replaced by the Alu Homo-sapiens_IGH_Alu-20-1 preceded by an undetermined region and the Alu Homo-sapiens_IGH_Alu-20-3 (AC245166 accession number in IMGT/LIGM-DB). IMGT copy number variation (CNV) nomenclature and definition illustrated with the Homo sapiens IGH locus Copy number variations (CNV) [2,5,141] are numbered from 5′ to 3′ in the locus. (IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Web resources > IMGT Repertoire (IG and TR) > Locus gene order > Human (Homo sapiens) IGH). Seven CNV are displayed in Table 3, six for the IGHV genes (CNV1 to CNV6) and one (CNV7) for the IGHC genes. The IMGT CNV nomenclature comprises the genus and species (Latin names in italics) (i.e., Homo sapiens), the locus (i.e., IGH) and the CNV number (i.e., CNV1). A CNV is delimited by a 5prime gene and a 3prime gene. The IMGT standardized definition of a CNV comprises, the group, then between parentheses the order of the start gene (the gene which follows the CNV-5prime), a dash and the order of the end gene (the gene which precedes the CNV-3prime), then the total number of genes involved in the CNV (between the 5prime and 3prime, including RPI gene(s) if present) followed, between parentheses, by the number of IG or TR per functionality (and the number of RPI if present). For instance, the definition of ‘Homo sapiens IGH CNV1′ is ‘IGHV(17-20)7(3F,4P)’ (Table 3). The letters ‘i’ for insertion, ‘d’ for deletion, ‘e’ for exchange added to the CNV number indicates the status of a given gene, in a given haplotype for a given CNV, for instance, CNV1i [5] (p 39–40). IMGT CNV haplotypes illustrated with the Homo sapiens IGH locus IMGT CNV haplotypes are described based on the variability of the number of genes present for a given CNV. The description of the CNV is achieved by comparison with the IGH locus [2,5] (IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Web resources > IMGT Repertoire (IG and TR) > 1. Locus and genes > 2. Locus representation > IGH: Human). The horizontal main line is conventionally referred to as ‘haplotype A’. A well-characterized CNV example is the Homo sapiens IGH CNV3 IGHV(87-112)26(8F,16P,2RPI), for which six haplotypes A to F [5,141] correspond to polymorphic amplifications of genes, found in individuals of different populations. These polymorphisms are described as insertion/deletion between IGHV4-34 (86, CNV3-5prime) and IGHV4-28 (113, CNV3-3prime) (Table 4). Haplotype A is from GRCh37 and corresponds to the main line of IMGT Locus Representation [2] (Figure 5). Haplotype B is from GRCh38 and corresponds to BAC clone sequences [141] from the CHORI-17 BAC library. The CNV corresponds to the amplification of a motif of three or four genes: the first one is a pseudogene belonging to the IGHV(II) clan, the second one is a functional gene belonging to the IGHV3 subgroup (in blue) or to the IGHV4 subgroup (in green) and the third one (or the fourth if presence of GOLGA4P1 or GOLGA4P2 (yellow) or IGHV4-30-1) is a pseudogene of the IGHV3 subgroup (Table 4).
Table 4

Homo sapiens IGH locus CNV haplotypes.

CNV.IGHV GenesFctGene OrderHaplotypes
ABCDEFG
CNV1-5primeIGHV2-70F,ORF16
Homo sapiens IGH CNV1IGHV(17-20)7(3F,4 P)IGHV1-69DF17
IGHV1-68DP 17.1
IGHV(III)-67-4DP17.2
IGHV(III)-67-3DP17.3
IGHV1-69-2F18
IGHV3-69-1P19
IGHV2-70DF20
CNV1-3primeIGHV1-69F21
CNV2-5primeIGHV4-39F70
Homo sapiens IGH CNV2IGHV(71-80)10(2F,2O,6P)IGHV1-38-4ORF71
IGHV(III)-38-1DP72
IGHV3-38-3ORF73
IGHV(III)-44DP74
IGHV(III)-43-1DP75
IGHV3-43DF76
IGHV3-42DP77
IGHV7-40DP78
IGHV4-38-2F79
IGHV(III)-38-1P80
CNV2-3primeIGHV3-38ORF81
CNV3-5primeIGHV4-34F86
Homo sapiens IGH CNV3IGHV(87-112) 26(8F,16P,2RPI)IGHV3-33-2P87
IGHV(II)-33-1P88
IGHV3-33F89
GOLGA4P1nr90
IGHV3-32P91
IGHV(II)-31-1P92
IGHV4-31F93
IGHV3-30-52P94
IGHV(II)-30-51P95
IGHV3-30-5F96
IGHV3-30-42P97
IGHV(II)-30-41P98
IGHV4-30-4F99
IGHV3-30-33P100
IGHV(II)-30-32P101
IGHV3-30-3F102
IGHV3-30-22P103
IGHV(II)-30-21P104
IGHV4-30-2F105
IGHV4-30-1F106
IGHV3-30-2P107
IGHV(II)-30-1P108
IGHV3-30F109
GOLGA4P2nr110
IGHV3-29P111
IGHV(II)-28-1P112
CNV3-3primeIGHV4-28F113
CNV4-5primeIGHV1-24F120
Homo sapiens IGH CNV4IGHV(121-123)3(1F,2P)IGHV3-23DF121
IGHV(III)-22-2DP122
IGHV(II)-22-1DP123
CNV4-3primeIGHV3-23F124
CNV5-5primeIGHV3-11F,P144
Homo sapiens IGH CNV5IGHV(145-149)5(4F,1P)IGHV2-10P145
IGHV3-9F146
IGHV1-8F147
IGHV5-10-1F148
IGHV3-64DF149
CNV5-3primeIGHV3-7F150
CNV6-5primeIGHV2-5F154
IGHV(155)1(1F) aIGHV7-4-1F155
CNV6-3primeIGHV4-4F156
aHomo sapiens IGH CNV6
Homo sapiens IGH CNV7IGHC(203-211)9(7F,1OP,1 P)IGHG3F203
IGHG1F204
IGHEP1P205
IGHA1F206
IGHGPORF, P207
IGHG2F208
IGHG4F209
IGHEF210
IGHA2F211

Genes present in haplotype A (including CNV-5prime and CNV-3prime) are shown in orange. A pale green color in haplotype A indicates that, in other haplotypes, there is an insertion at these positions. Genes present, as insertion in these other haplotypes by comparison to haplotype A, are shown in green. Genes absent by comparison to haplotype A are shown in red. For CNV3, the column on the right of the haplotypes highlights the duplicated motifs with colors based on the subgroup or clan: blue (IGHV3), green (IGHV4), dark red (IGHV(II). The two golgin genes are in yellow.

The graphical representation of the CNV3 is available at Human (Homo sapiens) Polymorphism by insertion/deletion between IGHV4-34 and IGHV4-28 (haplotypes A to F) on chromosome 14 (14q32.33) (http://www.imgt.org/IMGTrepertoire/index.php?section=LocusGenes&repertoire=locus&species=human&group=IGH/haplotypes#locus) (accessed on 20 February 2022). The Homo sapiens IGH locus on chromosome 14 (14q32.33) is characterized by a remarkable IGH CNV, the CNV7 IGHC(203-211)9(7F,1OP,1P) with seven haplotypes A to G (Table 4), with six of them (haplotypes B to G) corresponding to multigene deletions I to VI (Figure 6), identified on both chromosomes 14 in healthy individuals lacking several subclasses [2,5]. Multigene deletions of haplotypes B to G (either identical or different, on both chromosomes in a given individual) are designated I to VI according to the chronological order in which they were found (reviewed in [5]). Deletion I, first identified by the absence of the Gm1 allotypes in a 70-year-old healthy Tunisian woman (TAK3), homozygous for that deletion [142,143] allowed the ordering of the Homo sapiens IGHC genes in the IGH locus [144,145]. Deletions I and II [142,143,146] (haplotypes B and C), found in healthy individuals from consanguineous families, involve highly homologous spots of recombination [147], as also described in a healthy individual (T17) homozygous for deletion III (haplotype D) and lacking IgA1, IgG2, IgG4 and IgE [148].
Figure 6

Haplotypes A to G of the Homo sapiens IGH CNV7 IGHC(203-211)9(7F,1OP,1P) of the IGH locus on chromosome 14 (14q32.33) [2,5]. The top line corresponds to haplotype A. The multigene deletions I to VI [142,143,144,145,146,147,148] correspond to the CNV7 haplotypes B to G (Table 4). (IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Web resources > IMGT Repertoire (IG and TR) > 1. Locus and genes > 2. Locus representation > IGH: > Human IGHC multigene deletions in healthy individuals http://www.imgt.org/IMGTrepertoire/LocusGenes/locus/human/IGH/multigeneIGHC.html (accessed on 20 February 2022). (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org) (accessed on 20 February 2022).

5.2. Homo sapiens IGK Locus

5.2.1. IGK Locus Representation

The Homo sapiens IGK locus is located on chromosome 2, on the short arm, at band 2p11.2 [2]. The orientation of the locus reverse (REV) on the chromosome has been determined by the analysis of translocations, involving the IGK locus, in leukemia and lymphoma. The Homo sapiens IGK locus spans 1820 kb [2,5] (Figure 7). The human IGK locus consists of 76 IGKV genes belonging to seven subgroups, five IGKJ genes and a unique IGKC gene [2,5] (Figure 7). The 76 IGKV genes are organized in two clusters separated by 800 kb [2,5]. The IGKV distal cluster in 5′ of the locus and in the most centromeric position) spans 400 kb and comprises 36 genes. The IGKV proximal cluster (in 3′ of the locus, closer to IGKC, and in the most telomeric position) spans 600 kb and comprises 40 genes [2,5] (Figure 7).
Figure 7

Representation of the human IGK locus at 2p12 (REV orientation on the chromosome) [2,5]. The boxes representing the genes are not to scale. Exons are not shown. The IGKV genes of the proximal V-CLUSTER are designated by a number for the subgroup, followed by a hyphen and a number for the localization from 3′ to 5′ in the locus. The IGKV genes of the distal duplicated V-CLUSTER are designated by the same numbers as the corresponding genes in the proximal V-CLUSTER, with the letter D added. Arrows show the IGKV genes polarity which is opposite to that of the J-C-CLUSTER [2]. IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Repertoire (IG and TR) 1. Locus and genes > 2. Locus representations > IGK: Human (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org) (accessed on 20 February 2022).

5.2.2. IGK Locus Gene Order, CNV and Haplotypes

IGK Gene order (Table 5) is according to the IMGT Locus gene order (IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Repertoire (IG and TR) > 1. Locus and Genes > 3. Locus descriptions > Locus gene order > IGK) [2,5].
Table 5

Homo sapiens IGK locus: IMGT gene order, copy number variations (CNV) and haplotypes.

IMGT Gene Name FunctionalityIMGT Gene Orderin LocusIMGT Gene Orientation in LocusCopy Number Variations (CNV)Haplotypes
AB
IGKV1-NL1 F0N.d
IGKV3D-7 F1oppositeHomo sapiens IGK CNV1 IGKV(1-36)36(16F,4O,14P,1FO,1FP)
IGKV1D-8 F2opposite
IGKV1D-43 F3opposite
IGKV1D-42 ORF4opposite
IGKV2D-10 P5opposite
IGKV3D-11 F6opposite
IGKV1D-12 F7opposite
IGKV1D-13 F8opposite
IGKV2D-14 P9opposite
IGKV3D-15 F, P10opposite
IGKV1D-16 F11opposite
IGKV1D-17 F12opposite
IGKV6D-41 ORF13opposite
IGKV2D-18 P14opposite
IGKV2D-19 P15opposite
IGKV3D-20 F, ORF16opposite
IGKV6D-21 F17opposite
IGKV1D-22 P18opposite
IGKV2D-23 P19opposite
IGKV2D-24 ORF20opposite
IGKV3D-25 P21opposite
IGKV2D-26 F22opposite
IGKV1D-27 P23opposite
IGKV2D-28 F24opposite
IGKV2D-29 F25opposite
IGKV2D-30 F26opposite
IGKV3D-31 P27opposite
IGKV1D-32 P28opposite
IGKV1D-33 F29opposite
IGKV3D-34 P30opposite
IGKV1D-35 P31opposite
IGKV2D-36 P32opposite
IGKV1D-37 ORF33opposite
IGKV2D-38 P34opposite
IGKV1D-39 F35opposite
IGKV2D-40 F36opposite
IGKV2-40 F37direct
IGKV1-39 F, P38direct
IGKV2-38 P39direct
IGKV1-37 ORF40direct
IGKV2-36 P41direct
IGKV1-35 P42direct
IGKV3-34 P43direct
IGKV1-33 F44direct
IGKV1-32 P45direct
IGKV3-31 P46direct
IGKV2-30 F47direct
IGKV2-29 F, P48direct
IGKV2-28 F49direct
IGKV1-27 F50direct
IGKV2-26 P51direct
IGKV3-25 P52direct
IGKV2-24 F53direct
IGKV2-23 P54direct
IGKV1-22 P55direct
IGKV6-21 F56direct
IGKV3-20 F57direct
IGKV2-19 P58direct
IGKV2-18 P59direct
IGKV1-17 F60direct
IGKV1-16 F61direct
IGKV3-15 F62direct
IGKV2-14 P63direct
IGKV1-13 F, P64direct
IGKV1-12 F65direct
IGKV3-11 F66direct
IGKV2-10 P67direct
IGKV1-9 F68direct
IGKV1-8 F69direct
IGKV3-7 ORF70direct
IGKV1-6 F71direct
IGKV1-5 F72direct
IGKV2-4 P73direct
IGKV7-3 P74direct
IGKV5-2 F75opposite
IGKV4-1 F76opposite
IGKJ1 F77direct
IGKJ2 F78direct
IGKJ3 F79direct
IGKJ4 F80direct
IGKJ5 F81direct
IGKC F82direct

CNV1 involving V genes is in pale green. Genes present in both haplotypes A and B are in orange. The deletion in haplotype B is in red.

The Homo sapiens IGK CNV1 IGKV(1-36)36(16F,4O,14P,1FO,1FP) corresponds to two haplotypes (Table 5). The first one (haplotype A), by far the most common in the populations, is characterized by the presence of the distal cluster in 5′ of the IGK locus and in the most centromeric position (Figure 7). This distal cluster results from the duplication of 36 genes of the proximal cluster and spans 400 kb. The haplotype B lacking the distal cluster has only been found once [2].

5.3. Homo sapiens IGL Locus

5.3.1. IGL Locus Representation

The Homo sapiens IGL locus is located on chromosome 22, on the long arm, at band 22q11.2 [2], The orientation of the locus forward (FWD) on the chromosome has been determined by the analysis of translocations, involving the IGL locus, in leukemia and lymphoma. The Homo sapiens IGL locus spans 1050 kb [2,5] (Figure 8). The human IGL locus consists of 73–74 IGLV genes belonging to 11 subgroups, 7 to 11 IGLJ and 7 to 11 IGLC genes depending on the haplotypes, each IGLC gene being preceded by one IGLJ gene [2,5] (Figure 8). The IGLV genes localized on 900 kb define three distinct V-CLUSTER (A, B, C) based on the IGLV gene subgroup content [149] (Figure 8).
Figure 8

Representation of the human IGL locus at 22q11.2 (FWD orientation on the chromosome) [2,5]. The boxes representing the genes are not to scale. Exons are not shown. (A–C) refer to three distinct V-CLUSTER based on the IGLV gene subgroup content [149]. Pseudogenes that could not be assigned to subgroups with functional genes are designated by a Roman numeral between parentheses, corresponding to the clans, followed by a hyphen, and a number for the localization from 3′ to 5′ in the locus. IMGT® http://www.imgt.org (Accessed on 20 February 2022), IMGT Repertoire (IG and TR) 1. Locus and genes > 2. Locus representations > IGL: Human (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org) (accessed on 20 February 2022).

5.3.2. IGL Lous Gene Order, CNV and Haplotypes

IGL gene order is according to the IMGT Locus gene order (IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Repertoire (IG and TR) > 1. Locus and Genes > 3. Locus descriptions > Locus gene order > IGL. One, two, three or four additional IGLC genes, each one most probably preceded by one IGLJ, have been shown to characterize IGLC haplotypes with 8, 9, 10 or 11 genes [150,151] (Table 6). Although these genes have not yet been systematically sequenced, the evidence of the polymorphisms is strongly supported by restriction fragment length polymorphisms (RFLP) and Southern blot analysis [150,151].
Table 6

Homo sapiens IGL locus: IMGT gene order, copy number variations (CNV) and haplotypes.

IMGT Gene NameFunctionalityIMGT Gene Orderin LocusIMGT Gene Orientation in LocusCopy Number Variations (CNV), RPI Aliases (if Recent Changes)Haplotypes
ABCDE
IGLV(I)-70P1direct
FRAMENPnr2opposite
IGLV4-69F3direct
IGLV(I)-68P4direct
IGLV10-67P5direct
IGLV(IV)-66-1P6direct
IGLV(V)-66P7direct
IGLV(IV)-65P8direct
IGLV(IV)-64P9direct
IGLV(I)-63P10direct
IGLV1-62P11direct
IGLV8-61F12direct
IGLV4-60F, P13direct
IGLV(IV)-59P14direct
IGLV(V)-58P15direct
BMP6P1 nr16direct
IGLV6-57F17direct
IGLV(I)-56P18direct
IGLV(IV)-55-1P18.1direct
IGLV11-55ORF19direct
IGLV10-54F, P20direct
IGLV(IV)-53P21direct
VPREB1 F22directRPI (CD179A)
IGLV5-52F23direct
IGLV1-51F24direct
IGLV1-50ORF25direct
IGLV9-49F26direct
IGLV5-48ORF, P27direct
IGLV1-47F28direct
IGLV7-46F, P29direct
IGLV5-45F30direct
IGLV1-44F31direct
IGLV7-43F32direct
IGLV(I)-42P33direct
IGLV(VII)-41-1P34direct
IGLV1-41ORF, P35direct
IGLV1-40F36direct
IGLV5-39F37direct
IGLV(I)-38P38direct
IGLV5-37F39direct
IGLV1-36F40direct
IGLV7-35P41direct
ZNF280B nr42oppositeRPI (5′OY11.1)
ZNF280A nr43oppositeRPI (3′OY11.1)
PRAME nr44oppositeRPI (CT130)
IGLV2-34P45direct
IGLV2-33ORF46direct
IGLV3-32ORF47direct
IGLV3-31P48direct
IGLV3-30P49direct
BCRP4 nr50directRPI (BCRL4)
POM121L1P nr51oppositeRPI (POM121L1)
GGTLC2 nr52directRPI (GGTL4)
LOC129026 nr53directRPI (GGTLC1P)
IGLV3-29P54direct
IGLV2-28P55direct
IGLV3-27F56direct
IGLV3-26P57direct
IGLV(VI)-25-1P58direct
IGLV3-25F59direct
IGLV3-24P60direct
IGLV2-23F61direct
IGLV(VI)-22-1P62direct
IGLV3-22F, P63direct
IGLV3-21F64direct
IGLV(I)-20P65direct
IGLV3-19F66direct
IGLV2-18F67direct
IGLV3-17P68direct
IGLV3-16F69direct
IGLV3-15P70direct
IGLV2-14F71direct
IGLV3-13P72direct
IGLV3-12F, P73direct
IGLV(I)-11-1P73.1direct
IGLV2-11F74direct
IGLV3-10F75direct
IGLV3-9F, P76direct
IGLV2-8F77direct
IGLV3-7P78direct
IGLV3-6P79direct
IGLV2-5P80direct
IGLV3-4P81direct
IGLV4-3F82direct
IGLV3-2P83direct
IGLV3-1F84direct
IGLJ1F85direct
IGLC1F, ORF86direct
IGLJ2F87direct
IGLC2F88directCNV1-5′prime
IGLJ2AN.d88.1directHomo sapiens IGL CNV1 IGLJ-IGLC(88-89)8(N.d)
IGLC2AN.d88.2direct
IGLJ2BN.d88.3direct
IGLC2BN.d88.4direct
IGLJ2CN.d88.5direct
IGLC2CN.d88.6direct
IGLJ2DN.d88.7direct
IGLC2DN.d88.8direct
IGLJ3F89directCNV1-3′prime
IGLC3F90direct
IGLJ4ORF91direct
IGLC4P92direct
IGLJCBN5ORF93direct
IGLC5P94direct
IGLJ6F95direct
IGLC6F, P96direct
IGLJ7F97direct
IGLC7F98direct

CNV1 involving J and C genes is in pale blue. In the haplotype representation, CNV-5prime and CNV-3prime as well as the duplicated genes present in the haplotypes B, C, D, E are in orange. A pale orange color indicates that these positions correspond to insertion in other haploypes.

6. T Cell Receptor IMGT Copy Number Variations (CNV) and Haplotypes

6.1. Homo sapiens TRB Locus

6.1.1. TRB Locus Representation

The Homo sapiens TRB locus is located on chromosome 7, on the long arm, at band 7q34 [3]. The orientation of the locus forward (FWD) on the chromosome has been determined by the analysis of translocations, involving the TRB locus, in leukemia and lymphoma. The Homo sapiens TRB locus spans 620 kb [3] (Figure 9). The human TRB locus consists of 64–67 TRBV genes belonging to 32 subgroups. Except for TRBV30, localized downstream of the TRBC2 gene, in the inverted orientation of transcription, all the other TRBV genes are located upstream of a duplicated D-J-C-cluster, which comprises, for the first part TRBD1, six TRBJ and the TRBC1 gene, and for the second part, TRBD2, eight TRBJ and the TRBC2 gene [3] (Figure 9).
Figure 9

Representation of the human TRB locus at 7q34 (FWD orientation on the chromosome). The boxes representing the genes are not to scale. Exons are not shown. The TRBV genes are designated by a number for the subgroup followed, whenever there are several genes belonging to the same subgroup, by a hyphen and a number for their relative localization in the locus. Numbers increase from 5′ to 3′ in the locus. T3 to T8 indicate trypsinogen or trypsinogen-like genes. T3 (PRSS3P3, TRY3) is at 7.4 kb upstream of TRBV1. Single arrows show genes whose polarity is opposite to that of the D-J-C-CLUSTER. Double arrows indicate insertion/deletion polymorphisms. IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Repertoire (IG and TR) 1. Locus and genes > 2. Locus representations > TRB: Human (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org) (accessed on 20 February 2022).

MOXDP2 (monooxygenase DBH-like 2) (5′ borne, opposite orientation relative to the locus) is located upstream of PRSS58 (serine protease 58, trypsinogen-like TRYX3, TRY1) opposite orientation relative to the locus, identified 41 kb upstream of TRBV1 (P). EPHB6 (EPH receptor B6) (3′ borne, direct orientation relative to the locus) has been identified 41 kb downstream of TRBV30 (F), the most 3′ gene in the locus.

6.1.2. TRB Gene Order, CNV and Haplotypes

TRB gene order is according to the IMGT Locus gene order (IMGT® http://www.imgt.org (accessed on 20 February 2020), IMGT Repertoire (IG and TR) > 1. Locus and Genes > 3. Locus descriptions > Locus gene order > TRB. A polymorphism by insertion/deletion of 3 genes between the TRBV4-2 and TRBV7-2 genes, encompassing 21 kb, has been described in the human TRB locus [152,153]. It corresponds to haplotype A (L36092) and haplotype B (L36190) and involves three TRBV genes: the pseudogene TRBV3-2, and the functional TRBV4-3 and TRBV6-3 genes [154]. The CNV has been defined as Homo sapiens TRB CNV1 TRBV(11-14)4(3F, 1P) (Table 7). A second CNV, Homo sapiens TRB CNV2 T4-T8(70-74)5(nr) involves trypsinogene-like genes localized between TRBV29-1 and TRBD1 (Table 6). Two haplotypes have been described, with haplotype B having a deletion of two genes T7 and T8. Detailed sequence analysis of this CNV and characterization of new haplotypes may represent markers of the evolution of the TRB locus between populations and between species.
Table 7

Homo sapiens TRB locus: IMGT gene order, copy number variations (CNV) and haplotypes.

IMGT Gene NameFunctionalityIMGT Gene OrderIMGT Gene Orientation in LocusCopy Number Variation (CNV)Haplotypes
AB
TRBV1P3direct
TRBV2F4direct
TRBV3-1F5direct
TRBV4-1F6direct
TRBV5-1F7direct
TRBV6-1F8direct
TRBV7-1ORF9direct
TRBV4-2F10directCNV1-5prime
TRBV6-2F11directHomo sapiens TRB CNV1 TRBV(11-14)4(3F,1P)
TRBV3-2P12direct
TRBV4-3F13direct
TRBV6-3F14direct
TRBV7-2F15directCNV1-3prime
TRBV8-1P16direct
TRBV5-2P17direct
TRBV6-4F18direct
TRBV7-3F, ORF19direct
TRBV8-2P20direct
TRBV5-3ORF21direct
TRBV9F22direct
TRBV10-1F, P23direct
TRBV11-1F24direct
TRBV12-1P25direct
TRBV10-2F26direct
TRBV11-2F27direct
TRBV12-2P28direct
TRBV6-5F29direct
TRBV7-4F, P30direct
TRBV5-4F31direct
TRBV6-6F32direct
TRBV7-5P33direct
TRBV5-5F34direct
TRBV6-7ORF35direct
TRBV7-6F36direct
TRBV5-6F37direct
TRBV6-8F38direct
TRBV7-7F39direct
TRBV5-7ORF40direct
TRBV6-9F41direct
TRBV7-8F42direct
TRBV5-8F43direct
TRBV7-9F44direct
TRBV13F45direct
TRBV10-3F46direct
TRBV11-3F47direct
TRBV12-3F48direct
TRBV12-4F49direct
TRBV12-5F50direct
TRBV14F51direct
TRBV15F52direct
TRBV16F, P53direct
TRBV17ORF54direct
TRBV18F55direct
TRBV19F56direct
TRBV20-1F57direct
TRBV21-1P58direct
TRBV22-1P59direct
TRBV23-1ORF60direct
TRBV24-1F61direct
TRBV25-1F62direct
TRBVAP63direct
TRBV26P64direct
TRBVBP65direct
TRBV27F66direct
TRBVCP67opposite
TRBV28F68direct
TRBV29-1F69directCNV2-5prime
T4nr70directHomo sapiens TRB CNV2T4-T8(70-74)5(nr)
T5nr71direct
T6nr72direct
T7nr73direct
T8nr74direct
TRBD1F75directCNV2-3prime
TRBJ1-1F76direct
TRBJ1-2F77direct
TRBJ1-3F78direct
TRBJ1-4F79direct
TRBJ1-5F80direct
TRBJ1-6F81direct
TRBC1F82direct
TRBD2F83direct
TRBJ2-1F84direct
TRBJ2-2F85direct
TRBJ2-2PORF86direct
TRBJ2-3F87direct
TRBJ2-4F88direct
TRBJ2-5F89direct
TRBJ2-6F90direct
TRBJ2-7F91direct
TRBC2F92direct
TRBV30F, P93opposite

CNV1 which involve V genes is in pale green. CNV2 which involve trypsinogen-like genes is in violet. Genes present in both haplotypes A and B are in orange. The deletions in haplotypes B are in red.

6.2. Homo sapiens TRA/TRD Locus

6.2.1. TRA/TRD Locus Representation

The Homo sapiens TRA locus is located on chromosome 14, on the long arm, at band 14q11.2 [3]. The orientation of the locus forward (FWD) on the chromosome has been determined by the analysis of translocations, involving the TRA and TRD loci, in leukemia and lymphoma. The Homo sapiens TRA spans 1000 kb [3] (Figure 10). The human TRA locus consists of 54 TRAV genes belonging to 41 subgroups, 61 TRAJ genes localized on 71 kb, and a unique TRAC gene [3] (Figure 10). The organization of the TRAJ genes on a large area is quite unusual and has not been observed in the other IG or TR loci. Moreover, the TRD locus is nestled in the TRA locus between the TRAV and TRAJ genes [3] (Figure 10). V-J rearrangements in the TRA locus, therefore, result in the deletion of the TRD D-J-C cluster genes localized on the same chromosome. This occurs in two steps: first, the deletion of the TRD D-J-C cluster, which results from a rearrangement between deltaRec (sequence located upstream of the cluster) and pseudoJalpha (sequence located downstream of the cluster (this rearrangement generates a T cell receptor excision circle (TREC), a biomarker for normal T cell development), then a TRAV to TRAJ rearrangement.
Figure 10

Representation of the human TRA locus at 14q11.2 (FWD orientation on the chromosome) [3]. The boxes representing the genes are not to scale. Exons are not shown. The TRAV genes are designated by a number for the subgroup, followed, whenever there are several genes belonging to the same subgroup, by a hyphen and a number for their relative localization in the locus. Numbers increase from 5′ to 3′ in the locus. The TRD genes are nestled in the TRA locus [3]. IMGT® http://www.imgt.org (accessed on 20 February 2020), IMGT Repertoire (IG and TR) 1. Locus and genes > 2. Locus representations > TRA: Human (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org) (accessed on 20 February 2020).

No 5′ borne conserved between species has been identified upstream of TRAV1-1 (F), the most 5′ gene in the locus. DAD1 (defender against cell death) (3’ borne) has been identified 13 kb downstream of TRAC (F), the most 3’ gene in the locus (Figure 10).

6.2.2. TRA/TRD Gene Order, CNV and Haplotypes

TRA/TRD gene order is according to the IMGT Locus gene order (IMGT® http://www.imgt.org (accessed on 20 February 2020), IMGT Repertoire (IG and TR) > 1. Locus and Genes > 3. Locus descriptions > Locus gene order > TRA/TRD. Although no CNV or haplotype has been described for the Homo sapiens TRA/TRD locus, the corresponding columns are available to provide a frame for future descriptions (Table 8).
Table 8

Homo sapiens TRA/TRD locus: IMGT gene order, copy number variations (CNV) and haplotypes.

IMGT Gene NameFunctionalityIMGT Locus Gene Order in LocusIMGT Gene Orientation in LocusCopy Number Variations (CNV)Haplotypes
TRAV1-1F1direct
TRAV1-2F2direct
TRAV2F3direct
TRAV3F, P4direct
TRAV4F5direct
TRAV5F6direct
TRAV6F7direct
TRAV7F8direct
TRAVAP9direct
TRAV8-1F10direct
TRAV9-1F11direct
TRAV10F12direct
TRAV11P13direct
TRAV12-1F14direct
TRAV8-2F15direct
TRAV8-3F16direct
TRAVBP17direct
TRAV13-1F18direct
TRAV14-1P19direct
TRAV11-1P20direct
TRAV12-2F21direct
TRAV8-4F22direct
TRAV8-5P23direct
TRAV13-2F24direct
TRAV14/DV4F25direct
TRAV9-2F26direct
TRAV15P27direct
TRAV12-3F28direct
TRAV8-6F29direct
TRAV16F30direct
TRAV17F31direct
TRAV18F32direct
TRAV19F33direct
TRAVCP34direct
TRAV20F35direct
TRAV21F36direct
TRAV8-6-1P37direct
TRAV22F38direct
TRAV23/DV6F39direct
TRDV1F40direct
TRAV24F41direct
TRAV25F42direct
TRAV26-1F43direct
TRAV8-7P44direct
TRAV27F45direct
TRAV28P46direct
TRAV29/DV5F, P47direct
TRAV30F48direct
TRAV31P49direct
TRAV32P50direct
TRAV33P51direct
TRAV26-2F52direct
TRAV34F53direct
TRAV35F, P54direct
TRAV36/DV7F55direct
TRAV37P56direct
TRAV38-1F57direct
TRAV38-2/DV8F58direct
TRAV39F59direct
TRAV40F60direct
TRAV41F61direct
TRAV46P62direct
TRDV2F63direct
TRDD1F64direct
TRDD2F65direct
TRDD3F66direct
TRDJ1F67direct
TRDJ4F68direct
TRDJ2F69direct
TRDJ3F70direct
TRDCF71direct
TRDV3F72opposite
TRAJ61ORF73direct
TRAJ60P74direct
TRAJ59ORF75direct
TRAJ58ORF76direct
TRAJ57F77direct
TRAJ56F78direct
TRAJ55P79direct
TRAJ54F80direct
TRAJ53F81direct
TRAJ52F82direct
TRAJ51P83direct
TRAJ50F84direct
TRAJ49F85direct
TRAJ48F86direct
TRAJ47F87direct
TRAJ46F88direct
TRAJ45F89direct
TRAJ44F90direct
TRAJ43F91direct
TRAJ42F92direct
TRAJ41F93direct
TRAJ40F94direct
TRAJ39F95direct
TRAJ38F96direct
TRAJ37F97direct
TRAJ36F98direct
TRAJ35F99direct
TRAJ34F100direct
TRAJ33F101direct
TRAJ32F102direct
TRAJ31F103direct
TRAJ30F104direct
TRAJ29F105direct
TRAJ28F106direct
TRAJ27F107direct
TRAJ26F108direct
TRAJ25ORF109direct
TRAJ24F110direct
TRAJ23F111direct
TRAJ22F112direct
TRAJ21F113direct
TRAJ20F114direct
TRAJ19ORF115direct
TRAJ18F116direct
TRAJ17F117direct
TRAJ16F118direct
TRAJ15F119direct
TRAJ14F120direct
TRAJ13F121direct
TRAJ12F122direct
TRAJ11F123direct
TRAJ10F124direct
TRAJ9F125direct
TRAJ8F, P126direct
TRAJ7F127direct
TRAJ6F128direct
TRAJ5F129direct
TRAJ4F130direct
TRAJ3F131direct
TRAJ2ORF132direct
TRAJ1ORF133direct
TRACF134direct

6.3. Homo sapiens TRG Locus

TRG gene order is according to the IMGT Locus gene order (IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Repertoire (IG and TR) > 1. Locus and Genes > 3. Locus descriptions > Locus gene order > TRG.

6.3.1. TRG Locus Representation

The Homo sapiens TRG locus is located on chromosome 7, on the short arm, at band 7p14 [3]. The orientation of the locus reverse (REV) on the chromosome has been determined by the analysis of chromosome 7 inversions inv(7)(p14-q34), involving the TRG and TRB loci in ataxia-telangiectasia patients, and in leukemia. The Homo sapiens TRG locus spans 160 kb [3,115] (Figure 11). The human TRG locus consists of 12-15 TRGV genes belonging to 6 subgroups, upstream of a duplicated J-C cluster, which comprises, for the first part, three TRGJ and the TRGC1 gene, and for the second part, two TRGJ and the TRGC2 gene [3,115] (Figure 11). TRGV9, expressed in 80–95% of the human peripheral γδ T cells, is the unique member of subgroup 2. TRGV10 and TRGV11, single members of subgroups 3 and 4, respectively, have been found rearranged and transcribed, but they are ORF that cannot be expressed in a gamma chain, due to a splicing defect of the premessenger [3].
Figure 11

Representation of the human TRG locus at 7p14 (REV orientation on the chromosome) [3]. The boxes representing the genes are not to scale. Exons are not shown. A double arrow indicates an insertion/deletion polymorphism. The TRGV3P gene, a polymorphic gene by insertion has been identified by Southern hybridization in a rare haplotype but has not been sequenced. IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Repertoire (IG and TR) 1. Locus and genes > 2. Locus representations > TRG: Human (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org) (accessed on 20 February 2022).

AMPH (amphiphysin) (5′ borne) has been identified 16 kb upstream of TRGV1 (ORF), the most 5′ gene in the locus. STARD3NL (STARD3 N-terminal like) (3′ borne) has been identified 9,4 kb downstream of TRGC2 (F), the most 3′ gene in the locus.

6.3.2. TRG Gene Order, CNV and Haplotypes

TRG gene order is according to the IMGT Locus gene order (IMGT® http://www.imgt.org (accessed on 20 February 2022), IMGT Repertoire (IG and TR) > 1. Locus and Genes > 3. Locus descriptions > Locus gene order > TRG. The total number of TRG genes per haploid genome is 19 or 22 of which 11 to 13 are functional (Table 9) [3].
Table 9

Homo sapiens TRG locus: IMGT gene order, copy number variations (CNV) and haplotypes.

IMGT Gene NameFunctionalityIMGT Gene Orderin LocusIMGT Gene Orientation in LocusCopy Number Variations (CNV)Haplotypes
ABC
TRGV1ORF1direct
TRGV2F2direct
TRGV3F3directCNV1-5prime
TRGV3PP4directHomo sapiens TRG CNV1TRGV(4-6)3(2F,1P)
TRGV4F5direct
TRGV5F6direct
TRGV5PP7directCNV1-3prime
TRGV6P8direct
TRGV7P9direct
TRGV8F10direct
TRGVAP11direct
TRGV9F12direct
TRGV10ORF13direct
TRGVBP14direct
TRGV11ORF15direct
TRGJP1F16direct
TRGJPF17direct
TRGJ1F18direct
TRGC1F19direct
TRGJP2F20direct
TRGJ2F21direct
TRGC2F22direct

CNV1 which involves V genes is in pale green. Haplotype B has a deletion of 2 genes (red) compared to haplotype A. Haplotype C has an insertion of 1 gene (green) compared to haplotype A. The pale green color indicates the insertion in other haplotypes.

Polymorphisms in the number of TRGV genes and in the exon number of the TRGC2 gene have been described in different populations [155,156,157,158,159,160,161]. A variation of the number of the TRGV subgroup genes (from seven to ten) has been observed [156,157,161]. These allelic polymorphisms, which result from the deletion of V4 and V5, or from the insertion of an additional V gene V3P, between V3 and V4, can be detected by restriction fragment polymorphism (RFLP) [115,156,157,161]. The two TRGC genes, which are 16 kb apart, result, with their associated TRGJ genes, from a recent duplication in the locus. However, there are several structural differences [115]. TRGJP1, TRGJ1, and TRGC1 cross-hybridize to TRGJP2, TRGJ2, and TRGC2, respectively [158,159,160,161], whereas the TRGJP has no equivalent in the duplicated TRGJP2-J2-C2 cluster [160]. The TRGC1 gene has three exons [158], whereas the TRGC2 gene has four or five exons, owing to the duplication of a region that includes exon 2 [155]. The allelic polymorphism of the TRGC2 gene with duplication (C2(2x)) or triplication (C2(3x)) of exon 2 can be identified by RFLP [155]. The exon 2 of the TRGC1 gene has a cysteine [159] involved in the interchain disulfide bridge, whereas this cysteine is not conserved in the exon 2 of the human TRGC2 gene. Enhancer and silencer sequences have been characterized by 6.5 kb downstream of the TRGC2 gene [162].

7. IUIS NOM IMGT-NC Validation of IMGT® Creations and Updates

IMGT® Creations and updates (http://www.imgt.org/IMGTinformation/creations/) (accessed on 20 February 2022) are published on the IMGT site after completion of the biocuration of new IG and TR loci, genes and/or alleles. The lists of the data available for validation by IUIS NOM IMGT-NC comprise: IMGT/LIGM-DB: the creation of the IMGT Locus reference (i.e., IMGT000062), if relevant, and updates of annotation of previous references sequences. IMGT/GENE-DB: number of genes and alleles per group (IGHV, IGHD, IGHJ and IGHC, or IGKV, IGKJ and IGKC, or IGLV, IGLJ, IGLC), entered in the database, following the annotation of the IMGT Locus reference (with a link to IMGT/GENE-DB update), and FASTA file of the sequences per group. Web resources: creation or update of up to 18 web pages in IMGT Repertoire (IG and TR) (Table 10). These web pages include Locus representation, Locus bornes, Locus description, Locus gene order, Locus in genome assembly, Gene table per group (V, D, J, C), Potential germline repertoire per group (V, D, J), Alignment of alleles per gene (V, D, J, C), Protein displays: per group (V, J, C), and IMGT Colliers de Perles: per gene and domain (V, C), and [CDR1-IMGT.CDR2-IMGT.CDR3-IMGT] lengths: per V subgroup.
Table 10

IMGT® Creations and updates: List of the web pages validated by IUIS NOM IMGT-NC.

Genus SpeciesIGHIGKIGLTRBTRATRDTRG
Locus representationIGHIGKIGLTRB TRA/TRDTRG
Locus bornesIGHIGKIGLTRB TRA/TRD TRG
Locus descriptionIGHIGKIGLTRB TRA/TRD TRG
Locus gene orderIGHIGKIGL TRB TRA/TRDTRG
Locus in genome assemblyIGHIGKIGL TRB TRA/TRD TRG
Gene table: VIGHVIGKVIGLVTRBVTRAVTRDVTRGV
Gene table: DIGHDnrnrTRBDnrTRDDnr
Gene table: JIGHJIGHJIGHJTRBJTRAJ TRDJTRGJ
Gene table: CIGHCIGHCIGHCTRBCTRACTRDCTRGC
Potential germline repertoireIGHV IGHD IGHJIGKVIGLV TRBV TRBD TRBJTRAVTRDV TRDD TRDJTRGV
V, D, J or V, Jnrnrnrnr
IGKJIGLJTRAJTRGJ
Alignment of alleles: per VXXXXXXX
Alignment of alleles: per DXnrnrXnrXnr
Alignment of alleles: per JXXXXXXX
Alignment of alleles: per CXXXXXXX
Protein displays: VIGHVIGKVIGLVTRBVTRAVTRDVTRGV
Protein displays: JIGHJIGKJIGLJTRBJTRAJTRDJTRGJ
Protein displays: CIGHCIGKCIGLCTRBCTRACTRDCTRGC
Colliers de Perles: per V domainXXXXXXX
Colliers de Perles: per C domainXXXXXXX
[CDR1-IMGT.CDR2-IMGT.CDR3-IMGT] lengths: per V subgroupXXXXXXX
The IUIS NOM validation consists in the control of the conformity of the data to the IUIS NOM IMGT-NC requirements for nomenclature assignment and to the IMGT Scientific chart rules based on CLASSIFICATION (genes and alleles names) NUMEROTATION (IMGT unique numbering), DESCRIPTION (labels) and that of their presentation in the IMGT Repertoire (IG and TR) [1,2,3,114]. The seven IG and TR loci of the dog (Canis lupus familiaris) and Rhesus monkey (Macaca mulatta) have been fully annotated. Species for which most of the IG and TR loci are annotated include cat (Felis catus), bovine (Bos taurus), sheep (Ovis aries) and goat (Capra hircus). Standardized IMGT biocuration led to the comparative study of the T cell receptor beta locus of veterinary species [163] based on the Homo sapiens TRB locus and to a comparative analysis of Bos taurus and Ovis aries TRA/TRD loci [164]. A recent comparative study on the evolution of the TRG locus in mammals [165] has highlighted the benefice of using the same IMGT standards, for the same locus, across species. If an ‘IMGT® Creations and updates’ correspond to genes previously approved in an ‘IUIS NOM IMGT-NC Report’, a link to the report on the IUIS site is provided [114]. This includes the reports of inferred alleles (new potential alleles deduced by inference from high-throughput sequencing of expressed repertoires) submitted by the “Inferred Allele Review Committee” (IARC) working group of the “Adaptive Immune Receptor Repertoire” (AIRR) community [166].

8. Conclusions

IMGT®, http://www.imgt.org (accessed on 20 February 2022), the global reference in immunogenetics and immunoinformatics created by Marie-Paule Lefranc (LIGM, Université de Montpellier and CNRS), provides a unique scientific and computing frame for bridging loci, genes, alleles, sequences and structures of the IG or antibodies, TR and MH of the adaptive immune responses in humans and in other jawed vertebrates [167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182]. The IMGT standards are used for the description of the polymorphisms (genes, allotypes, alleles) [183,184,185,186,187,188,189,190], molecular mechanisms, genome evolution [191,192], susceptibility to diseases, autoimmunity, structure-functions, repertoire in infectious diseases [193,194,195,196,197,198], clonality and sequence analysis in leukemia and lymphoma [199,200,201,202,203,204,205,206], analysis of the content of the Fab and scFv combinatorial phage display libraries screened for identification of novel therapeutic antibody specificities [207,208,209,210,211,212,213], antibody engineering [5,23,26,42,45,47,50,196]. The IMGT locus, gene order, CNV, haplotypes new concepts have been formalized for the comparison of genomic polymorphisms between different assemblies (chromosomes of individuals) in a given species for entries in databases. These concepts are also used for establishing the IMGT nomenclature of the IG and TR genes of new loci of genome assemblies of new species, differences in gene content in haplotypes, from fish to humans, as recently demonstrated, between strains, for the Salmonid IGH and TRA/TRD loci [139,140].
  166 in total

1.  Human Gm, Km, and Am allotypes and their molecular characterization: a remarkable demonstration of polymorphism.

Authors:  Marie-Paule Lefranc; Gérard Lefranc
Journal:  Methods Mol Biol       Date:  2012

2.  The complete 685-kilobase DNA sequence of the human beta T cell receptor locus.

Authors:  L Rowen; B F Koop; L Hood
Journal:  Science       Date:  1996-06-21       Impact factor: 47.728

Review 3.  IMGT, a system and an ontology that bridge biological and computational spheres in bioinformatics.

Authors:  Marie-Paule Lefranc; Véronique Giudicelli; Laetitia Regnier; Patrice Duroux
Journal:  Brief Bioinform       Date:  2008-04-19       Impact factor: 11.622

4.  Antibody V and C domain sequence, structure, and interaction analysis with special reference to IMGT®.

Authors:  Eltaf Alamyar; Véronique Giudicelli; Patrice Duroux; Marie-Paule Lefranc
Journal:  Methods Mol Biol       Date:  2014

5.  Selection of a macaque Fab with framework regions like those in humans, high affinity, and ability to neutralize the protective antigen (PA) of Bacillus anthracis by binding to the segment of PA between residues 686 and 694.

Authors:  Emmanuelle Laffly; Ludivine Danjou; Florence Condemine; Dominique Vidal; Emmanuel Drouet; Marie-Paule Lefranc; Chantal Bottex; Philippe Thullier
Journal:  Antimicrob Agents Chemother       Date:  2005-08       Impact factor: 5.191

6.  High-Throughput Immunogenetics for Clinical and Research Applications in Immunohematology: Potential and Challenges.

Authors:  Anton W Langerak; Monika Brüggemann; Frédéric Davi; Nikos Darzentas; Jacques J M van Dongen; David Gonzalez; Gianni Cazzaniga; Véronique Giudicelli; Marie-Paule Lefranc; Mathieu Giraud; Elizabeth A Macintyre; Michael Hummel; Christiane Pott; Patricia J T A Groenen; Kostas Stamatopoulos
Journal:  J Immunol       Date:  2017-04-17       Impact factor: 5.422

7.  High-affinity, human antibody-like antibody fragment (single-chain variable fragment) neutralizing the lethal factor (LF) of Bacillus anthracis by inhibiting protective antigen-LF complex formation.

Authors:  Thibaut Pelat; Michael Hust; Emmanuelle Laffly; Florence Condemine; Chantal Bottex; Dominique Vidal; Marie-Paule Lefranc; Stefan Dübel; Philippe Thullier
Journal:  Antimicrob Agents Chemother       Date:  2007-05-21       Impact factor: 5.191

8.  Simultaneous absence of the human IgG1, IgG2, IgG4 and IgA1 subclasses: immunological and immunogenetical considerations.

Authors:  G Lefranc; H Chaabani; E Van Loghem; M P Lefranc; G De Lange; A N Helal
Journal:  Eur J Immunol       Date:  1983-03       Impact factor: 5.532

9.  IMGT, the international ImMunoGeneTics information system: a standardized approach for immunogenetics and immunoinformatics.

Authors:  Marie-Paule Lefranc
Journal:  Immunome Res       Date:  2005-09-20
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  1 in total

1.  Tetraploid Ancestry Provided Atlantic Salmon With Two Paralogue Functional T Cell Receptor Beta Regions Whereof One Is Completely Novel.

Authors:  Unni Grimholt; Arvind Y M Sundaram; Cathrine Arnason Bøe; Maria K Dahle; Morten Lukacs
Journal:  Front Immunol       Date:  2022-06-17       Impact factor: 8.786
  1 in total

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