IMGT Repertoire (IG and TR) 1. Locus and genes

DNA

Overview

The human IGH locus is located on the chromosome 14 [1], at band 14q32.33, at the telomeric extremity of the long arm [2,3]. One processed gene has been localized on chromosome 9, and IGH orphons have been identified on chromosomes 15 and 16. The total number of IGH genes per haploid genome is 170 to 176 depending from the haplotypes (206 to 212, if the orphons and the processed gene are included) of which 77 to 84 genes are functional [4-6].

The list of human IGH genes is available at IMGT/GENE-DB.

Human IGH locus at 14q32.33

The human IGH locus at 14q32.33 spans 1250 kilobases (kb). The orientation of the locus has been determined by the analysis of translocations, involving the IGH locus, in leukemia and lymphoma. The most 5' IGHV genes occupy a position very close to the chromosome 14q telomere whereas the IGHC genes are in a more centromeric position.
The human IGH locus consists of 123 to 129 IGHV genes [7-14], depending from the haplotypes, 27 IGHD segments [15-19] belonging to 7 subgroups, 9 IGHJ segments [19,20], and, in the most frequent haplotype, 11 IGHC genes [21-35]. Eighty-two to 88 IGHV genes belong to 7 subgroups, whereas 41 pseudogenes, which are too divergent to be assigned to subgroups, have been assigned to the 4 clans. Seven non-mapped IGHV genes have been described as insertion/deletion polymorphism but have not yet been precisely located.
The potential genomic IGH repertoire is more limited since it comprises 38-46 functional IGHV genes belonging to 6 or 7 subgroups depending from the haplotypes [14], 23 IGHD, 6 IGHJ, and, in the most frequent haplotype, 9 IGHC genes.
Allelic IGHC multigene deletions [22,23,36-41], duplications or triplications [42-45] have been described in healthy individuals. I to VI refer to the type of deletion (for review, see [41]), duplication, or triplication, defined by the deleted, duplicated or triplicated genes (For example, deletion I [22,23,36] is designated as del G1-EP1-A1-GP-G2-G4). The number of IGHC genes may vary from 5 in deletion I to probably up to 19 in triplication III. Duplicated and triplicated genes have, in all cases but one, not been sequenced.

Orphons and processed gene

Thirty-five IGH genes have been found outside the main locus in other chromosomal localizations corresponding to 4 chromosomal orphon sets. These genes designated as orphons cannot contribute to the synthesis of the immunoglobulin chains, even if they have an Open Reading Frame (ORF). Nine IGHV orphons and 10 IGHD orphons have been described on chromosome 15 (15q11.2), and 16 IGHV orphons on chromosome 16 (16p11.2) [12,13]. In addition, one IGHC processed gene, IGHEP2 is localized on chromosome 9 (9p24.2-p24.1) [46]. This is so far the only processed Ig gene described.

Total number of human IGH genes

The total number of human IGH genes per haploid genome is 170 to 176 depending from the haplotypes (206 to 212, if the orphons and the processed gene are included) of which 76 to 84 genes are functional [47].

IG and TR number of genes: Human
Nomenclature and overview of the human immunoglobulin genes (IMGT Education)

Nomenclature

IGHV gene nomenclature

Human IGHV genes are designated by a number for the subgroup, followed by an hyphen and a number for the localization from 3' to 5' in the locus [5,7].
Seven genes which have been described as insertion polymorphism but which have not been precisely located are designated by a number for the subgroup, followed by an hyphen and a small letter: IGHV1-c, IGHV1-f, IGHV3-d, IGHV3-g, IGHV3-h, IGHV4-b, IGHV5-a. A putative gene IGHV7-77 was not found by Matsuda et al. [11]. These genes are not counted in the potential repertoire [13,47] and have a provisional designation.
Pseudogenes which could not be assigned to subgroups with functional genes are designated by a roman number between parentheses, corresponding to the clans, followed by an hyphen and a number for the localization from 3' to 5' in the locus. All these pseudogenes have truncations.
Clans comprise, respectively:
- clan I: IGHV1, IGHV5 and IGHV7 subgroup genes
- clan II: IGHV2, IGHV4 and IGHV6 subgroup genes, and pseudogenes IGHV(II)
- clan III: IGHV3 subgroup genes, and pseudogenes IGHV(III)
- clan IV: one pseudogene IGHV(IV)-44.
Allelic polymorphisms by insertion/deletion concern:
- the IGHV7-4-1 gene
- a 50 kb insertion of 5 genes (3-30-5, 4-30-4, 3-30-3, 4-30-2, 4-30-1) observed in 45% Caucasoids.
Sequences of the polymorphic IGHV3-30-5 gene cannot be differentiated from those of the IGHV3-30 gene. All sequences are described therefore as "IGHV3-30 alleles" by comparison to the alleles*01 of IGHV3-30 (M83134). However, it is not excluded that some of theses "alleles" belong exclusively to IGHV3-30-5.
Sequences of the polymorphic IGHV4-30-1 gene cannot be differentiated from those of the IGHV4-31 gene. All sequences are described therefore as "IGHV4-31" alleles by comparison to the allele*01 of IGHV4-31 (L10098). However, it is not excluded that some of these "alleles" belong exclusively to IGHV4-30-1.

IMGT and HUGO gene nomenclatures

IMGT gene names have been approved by the Human Genome Organization (HUGO) Nomenclature Committee (HGNC) in 1999. Note that, in the HGNC symbols, parentheses of the truncated pseudogene names are omitted, and capital letters replace the lower-case letters found in the seven provisional IMGT gene names. Otherwise all the gene names (symbols) are identical in IMGT and HGNC nomenclatures.
Gene definitions (full names) are identical (including parentheses) in IMGT and HGNC nomenclatures.

Links between IMGT, HGNC and NCBI Gene

The Complete list of the human immunoglobulin and T cell receptor IMGT gene names (symbols) provides the IMGT definition (full name), the gene functionality, the IMGT accession number of the reference sequence, the number of alleles per gene, and the and NCBI Gene accession ID. The table below reports entries which concern the IGH locus or groups and are found in the OMIM and NCBI Gene genome databases, and in HGNC:

IMGT name	IMGT definition (a)	OMIM	NCBI Gene	HGNC
IGH locus	Immunoglobulin heavy locus	-	3492	IGH
IGHC group	Immunoglobulin heavy constant group	(b)	(b)	(b)
IGHD group	Immunoglobulin heavy diversity group	146910	50648	IGHD
IGHJ group	Immunoglobulin heavy joining group	147010	3506	IGHJ
IGHV group	Immunoglobulin heavy variable group	147070	3509	IGHV

(a) The locus definition is identical in IMGT, HGNC and NCBI Gene. The IMGT 'group' concept comprises genes of the major locus and of the chromosomal orphon sets, whereas the HGNC IG group symbols only refer to genes of the major locus.

(b) There is no entry for the IGHC group in the OMIM, NCBI Gene database and HGNC. The individual OMIM entries for the IGHC genes are the following: IGHA1: 146900, IGHA2: 147000, IGHD: 147170, IGHE: 147180, IGHG1: 147100, IGHG2: 147110, IGHG3: 147120, IGHG4: 147130, IGHM: 147020. Individual NCBI Gene entries are reported in the complete gene name list. HGNC symbols for the IGHC genes are identical to IMGT gene names.

Protein

Proteins encoded by the IGH locus are the immunoglobulin heavy chains. They result from the recombination (or rearrangement), at the DNA level, of three genes: IGHV, IGHD and IGHJ, with deletion of the intermediary DNA to create a rearranged IGHV-D-J gene. The rearranged IGHV-D-J gene is transcribed with the IGHM gene and translated into an immunoglobulin mu chain. The gamma, alpha or epsilon heavy chains, result from a new recombination (or switch), again at the DNA level, between sequences designated as "Switch" and localized upstream of the IGHM and of each of the functional IGHG, IGHA and IGHE constant genes. This recombination, accompanied by the deletion of the intermediary DNA, allows the IGHV-D-J initially transcribed with the IGHM, to be now transcribed with a IGHG, IGHA or IGHE gene, and translated into a gamma, alpha or epsilon chain. Translation of the variable germline genes involved in the IGHV-D-J rearrangements are available at Protein displays. Compared to the germline genes, the rearranged variable genes will acquire somatic mutations during the B cell differentiation in the lymph nodes, which will considerably increase their diversity. These somatic mutations can be analysed using the IMGT/V-QUEST tool. The junctions can be analysed with IMGT/JunctionAnalysis.

Alleles and mutation

Mutations which correspond to allelic polymorphisms of the functional germline IGHV, IGHD, IGHJ and IGHC genes are described in Alignments of alleles [47] and Tables of alleles.

Translocations

Translocations in which the human IGH locus is implicated frequently result from errors of the recombinase enzyme complexe (RAG1, RAG2, ...), responsable of the Immunoglobulin and T cell receptor V-J and V-D-J rearrangements, or from errors of the switch enzyme. IGHV, IGHD or IGHJ recombination signals or isolated heptamer (first case) or switch sequences (second case) are observed at the breakpoints.

t(3;14)(q27;q32)
t(4;14)(p16;q32)
t(5;14)(q31;q32)
t(8;14)(q11;q32)
t(8;14)(q24;q32)
t(10;14)(q24;q32)
t(11;14)(q13;q32)
t(14;18)(q32;q21)
t(14;19)(q32;q13.1)

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