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How many IGH, IGK, IGL genes in the human genome? Where are they localized?

• IGH
  The total number of the human IGH genes per haploid genome is 206-212:

  • 170-176 genes are localized in the human IGH locus on chromosome 14 at 14q32.33
  • 35 orphons are on chromosomes 15 and 16
  • 1 processed gene is on chromosome 9
• IGK
  The total number of the human IGK genes per haploid genome is 107:

  • 82 genes are localized in the human IGK locus on chromosome 2 at 2p11.2
  • 25 orphons are on chromosomes 1, 2, 15 and 22 or unlocalized
• IGL
  The total number of the human IGL genes per haploid genome is 93-102

  • 87-96 genes are localized in the human IGL locus on chromosome 22 at 22q11.2
  • 6 orphons are on chromosomes 8 and 22, outside of the major IGL locus.

What is the organization of the human IGH, IGK and IGL loci?

• IGH
  The human IGH locus on chromosome 14 at 14q32.33 spans 1250 kb. It consists of 170-176 genes: 123-129 IGHV, 27 IGHD, 9 IGHJ and 11 IGHC genes. Allelic IGHC multigene deletions (designated as I to VI), duplications (III, IV, V) or triplications (III) have been described in healthy individuals. The number of IGHC genes may vary from 5 in multigene deletions to probably up to 19 in triplications.
• IGK
  The human IGK locus on chromosome 2 at 2p11.2 spans 1820 kb. It consists of 82 genes: 76 IGKV, 5 IGKJ and a unique IGKC gene. IGKV genes are organized in two clusters separated by 800 kb. In a rare haplotype which does not contain the IGKV distal cluster, the IGK locus consists of 46 genes: 40 IGKV, 5 IGKJ and 1 IGKC genes.
• IGL
  The human IGL locus on chromosome 22 at 22q11.2 spans 1050 kb. It consists of 87-96 genes: 73-74 IGLV, 7-11 IGLJ and 7-11 IGLC genes depending on the haplotypes, each IGLC gene being preceded by one IGLJ gene in the 7-IGLC haplotypes. The 8-, 9-, 10- and 11-IGLC haplotypes are characterized by 1, 2, 3 or 4 additional IGLC genes each one probably preceded by one IGLJ.
  The recent sequencing of the chromosome 22 long arm confirmed the organization of the IGL locus and localized that locus at 6 megabases from the centromere.

How many functional IG genes? What is the expressed IG repertoire?

• IGH
  The number of functional genes in the human IGH locus is 76-84 per haploid genome. This potential germline (non rearranged) repertoire comprises 38-46 IGHV, 23 IGHD, 6 IGHJ and 9 IGHC genes.
  The expressed Ig heavy chain repertoire comprises 10⁷ V-D-J-REGIONs associated to one or the other of the 9 C-REGIONs. The C-REGION determines the Ig heavy chain type (mu, delta, gamma, alpha or epsilon) and the Ig class (IgM, IgD, IgG, IgA or IgE).
  Potential germline repertoire:

  • IGHV: 38-46 FUNCTIONAL genes, belonging to 6 or 7 subgroups
  • IGHD: 23 FUNCTIONAL genes
  • IGHJ: 6 FUNCTIONAL genes
  • IGHC: 9 FUNCTIONAL genes
• IGK
  The number of functional genes in the human IGK locus is 37-42 per haploid genome (23-26 in the rare haplotype without the IGKV distal cluster). This potential germline (non rearranged) repertoire comprises 31-36 IGKV, 5 IGKJ and 1 IGKC genes.
  The expressed Ig kappa chain repertoire comprises 6.10⁴ V-J-REGIONs associated to the IGKC C-REGION.
  Potential germline repertoire:

  • IGKV: 31-36 FUNCTIONAL genes, belonging to 5 subgroups
  • IGKJ: 5 FUNCTIONAL genes
  • IGKC: 1 FUNCTIONAL gene
• IGL
  The number of functional genes in the human IGL locus is 37-43 per haploid genome. This potential germline (non rearranged) repertoire comprises 29-33 IGLV, 4-5 IGLJ and 4-5 IGLC genes.
  The expressed Ig lambda chain repertoire comprises 4.10⁴ V-J-REGIONs associated to one or the other of the 4-5 C-REGIONs.
  Potential germline repertoire:

  • IGLV: 29-33 FUNCTIONAL genes, belonging to 10 subgroups
  • IGLJ: 4-5 FUNCTIONAL genes
  • IGLC: 4-5 FUNCTIONAL genes in the 7-IGLC gene haplotype

How to make 10⁷ Ig-Heavy, 4.10⁴ Ig-Lambda and 6.10⁴ Ig-Kappa chains? (10¹² different antibodies)

• IGH
  From the IGH genes to the immunoglobulin heavy chains
  The V-D-J rearrangements (D-J then V to D-J rearrangements) in the B cells create a combinatorial diversity of 5200-6300 recombinations. Two additional mechanisms contribute to the Ig heavy chain diversity: the N diversity (N, for Nucleotides) which results from the deletion and/or addition of nucleotides at random by the terminal deoxynucleotidyltransferase and creates, at the V-D-J junction, a region not encoded in the germline DNA and somatic mutations which affect specifically the V-D-J rearranged genes.
  The first expressed Ig heavy chain is mu (C-REGION encoded by IGHM). During B cell maturation, a second recombination mechanism, designated as switch, leads to the replacement of the IGHM gene by another IGHC gene and to the expression of Ig heavy gamma, alpha or epsilon chains and of other Ig classes (IgG, IgA or IgE, respectively).
• IGK
  From the IGK genes to the immunoglobulin kappa chains
  The IGK V-J rearrangements in the B cells create a combinatorial diversity of 150-170 recombinations. The main additional mechanism which contributes to the Ig kappa chain diversity is the mechanism of somatic mutations which affect specifically the V-J rearranged genes. In contrast to the Ig heavy chains, the Ig kappa chains have a very limited junctional diversity and there is usually no N-diversity. The lack of N diversity at the IGKV-J junction is explained by the chronological order of the Ig locus rearrangements: during B cell differentiation, the IGK V-J rearrangements occur after the IGH V-D-J rearrangements, when the deoxynucleotidyltranferase is no more expressed.
• IGL
  From the IGL genes to the immunoglobulin lambda chains
  The IGL V-J rearrangements in the B cells create a combinatorial diversity of 116-165 recombinations. The main additional mechanism which contributes to the Ig lambda chain diversity is the mechanism of somatic mutations which affect specifically the V-J rearranged genes. In contrast to the Ig heavy chains, the Ig lambda chains have a very limited junctional diversity and there is usually no N diversity. The lack of N diversity at the IGLV-J junction is explained by the chronological order of the Ig locus rearrangements: during B cell differentiation, the IGL V-J rearrangements occur after the IGH V-D-J rearrangements, when the deoxynucleotidyltransferase is no more expressed. Usually the IGL V-J rearrangements occur after the IGK V-J rearrangements in B cells in which IGK V-J rearrangements were unproductive.

What is the structure of an immunoglobulin and its different chains?

• Ig-Heavy
  An immunoglobulin consists of two identical heavy chains of 50-70 kDa and two identical light (kappa or lambda) chains of 25 kDa. Each heavy chain comprises a variable domain and 3 or 4 constant domains depending from chain type. The variable domain (V-D-J-REGION) of the heavy chain is encoded by the rearrangement of 3 genes: 1 IGHV, 1 IGHD and 1 IGHJ. The 3 or 4 constant domains and the hinge if present (C-REGION) are encoded by 1 IGHC gene.
• Ig-Kappa
  An immunoglobulin consists of two identical heavy chains of 50-70 kDa and two identical light (kappa or lambda) chains of 25 kDa. Each kappa chain comprises two domains: a variable domain and a constant domain. The variable domain (V-J-REGION) of the kappa chain is encoded by the rearrangement of 2 genes: 1 IGKV and 1 IGKJ. The constant domain is encoded by the IGKC gene.
• Ig-Lambda
  An immunoglobulin consists of two identical heavy chains of 50-70 kDa and two identical light (kappa or lambda) chains of 25 kDa. Each lambda chain comprises two domains: a variable domain and a constant domains. The variable domain (V-J-REGION) of the lambda chain is encoded by the rearrangement of 2 genes: 1 IGLV and IGLJ. The constant domain is encoded by one of the IGLC genes.

Are all the human IG genes known ? How to analyse the expressed variable IG genes?

• IGH
  All the human IGH genes are known and well characterized. The human IGH genes were approved by the HUGO Nomenclature committee in 1999 and entered in the Genome Database GDB, Canada and into Entrez Gene at NCBI, USA.
  A complete list is available in the IMGT Repertoire.
  IMGT/GENE-DB an IMGT database for the human IG and TR genes
  IMGT/V-QUEST, an IMGT tool for the analysis of the Variable genes, provides:

  1. the identification of the IGHV, IGHD and IGHJ genes involved in the rearrangements,
  2. the characterization of the V-D-J-JUNCTION,
  3. the identification of the somatic mutations,
  4. the 2D representation or Collier de Perles.
• IGK
  All the human IGK genes are known and well characterized. The human IGK genes were approved by the HUGO Nomenclature committee in 1999 and entered in the Genome Database GDB, Canada and into Entrez Gene at NCBI, USA.
  A complete list is available in the IMGT Repertoire.
  IMGT/GENE-DB an IMGT database for the human IG and TR genes
  IMGT/V-QUEST, an IMGT tool for the analysis of the Variable genes, provides:

  1. the identification of the IGKV and IGKJ genes involved in the rearrangements,
  2. the characterization of the V-J-JUNCTION,
  3. the identification of the somatic mutations,
  4. the 2D representation or Collier de Perles.
• IGL
  All the human IGL genes are known and well characterized. The human IGL genes were approved by the HUGO Nomenclature committee in 1999 and entered in the Genome Database GDB, Canada and into Entrez Gene at NCBI, USA.
  A complete list is available in the IMGT Repertoire.
  IMGT/GENE-DB an IMGT database for the human IG and TR genes
  IMGT/V-QUEST, an IMGT tool for the analysis of the Variable genes, provides:

  1. the identification of the IGLV and IGLJ genes involved in the rearrangements,
  2. the characterization of the V-J-JUNCTION,
  3. the identification of the somatic mutations,
  4. the 2D representation or Collier de Perles.

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Created:

11/06/2001

Last updated:

22/09/2023

Authors:

Elodie Foulquier and Marie-Paule Lefranc

Editor:

Chantal Ginestoux

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