Alternative titles; symbols
HGNC Approved Gene Symbol: IGH
Cytogenetic location: 14q32.33 Genomic coordinates (GRCh38): 14:105,586,437-106,879,844 (from NCBI)
Immunoglobulins (Ig) are the antigen recognition molecules of B cells. An Ig molecule is made up of 2 identical heavy chains and 2 identical light chains (see 147200) joined by disulfide bonds so that each heavy chain is linked to a light chain and the 2 heavy chains are linked together. Each Ig heavy chain has an N-terminal variable (V) region containing the antigen-binding site and a C-terminal constant (C) region, encoded by a C region gene (e.g., IGHG1, 147100), that provides effector or signaling functions. The heavy chain V region is encoded by 3 types of genes: V genes, joining (J) genes (see 147010), and diversity (D) genes (see 146910). Random selection of just 1 gene of each type to assemble a V region accounts for the great diversity of V regions among Ig molecules. The heavy chain locus on chromosome 14 contains approximately 40 functional V genes, followed by approximately 25 functional D genes and approximately 6 functional J genes. Due to polymorphism, the numbers of functional V, J, and D genes differ among individuals (Janeway et al., 2005).
Allotypic variations in the V region of immunoglobulin chains have been extensively studied in the rabbit. The first allotypic determinant to be identified in the V region of human immunoglobulins was designated Hv1 (Wang et al., 1978). Hv1 is located in the V region of human immunoglobulin heavy (H) chains of G, M, and A classes. It is inherited as an autosomal dominant with a gene frequency in whites of 0.189 and in blacks of 0.278. Pandey et al. (1980) demonstrated lack of linkage between Hv1 and the 2 C-region markers: Gm (IgG H chains) and Km (kappa-type light chains).
Gene conversion provides an explanation for the maintenance of a large number of variable region genes for immunoglobulins that do not deviate drastically. It is 1 of the 2 classes of mechanisms known that can act on families of genes to maintain their sequence homology; the other is unequal crossing over (Baltimore, 1981). Walter and Cox (1988) studied the heavy chain variable region V(H) genes to determine the extent of genetic variation and the distribution of selected polymorphic loci. Through the use of restriction endonuclease site polymorphisms, they found linkage disequilibrium between the V(H2) and V(H3) subclass loci and extensive variation. Their preliminary estimate of the number of V(H) genes was 50. The authors hypothesized that the genetic variation observed at these loci may be associated with genetic differences in immune response and with varying susceptibility to autoimmune disorders.
Schroeder et al. (1988) found that the unique V(H) gene segment that contributes to the fetal heavy chain repertoire is the V(H) gene segment most proximal to the gene that encodes the constant region of the mu chain and is positioned 77 kb on the 5-prime side of the J(H) region.
Buluwela and Rabbitts (1988) demonstrated a V(H) gene about 95 kb from the C-mu gene and suggested that this is probably the first functional V(H) segment of the heavy chain complex.
Capra and Tucker (1989) reviewed current knowledge on the human immunoglobulin heavy chain genes.
Walter et al. (1990) described the physical organization of the human immunoglobulin heavy chain gene complex. Two-dimensional DNA electrophoresis was used to map the V(H) region. They demonstrated a common insertion/deletion polymorphism of 80 kb, involving 3 V(H) gene segments. They estimated that there are about 76 V(H) gene segments: about 25 V(H)1, 5 V(H)2, 28 V(H)3, 14 V(H)4, 3 V(H)5, and 1 V(H)6.
Walter and Cox (1991) characterized 10 V(H) polymorphic loci of the V(H)2, V(H)3, V(H)4, and V(H)5 families. They identified 2 regions, one in the V(H) region and one in the C(H) region, with low linkage disequilibrium; in these areas, linkage disequilibrium values were approximately 1/3,000 of that observed in other portions of the IGH region. Thus, the high amount of recombination observed in the subtelomeric portion of chromosome 14 appears to be the result of specific hot spots for recombination, rather than a general increase.
The V(H) segments map to 3 loci: chromosome 14, chromosome 15 (Cherif and Berger, 1990), and chromosome 16 (Matsuda et al., 1990). However, only the chromosome 14 locus contains the J segments that are essential for somatic generation of the V gene. Expression of V(H) segments on chromosomes 15 and 16 requires interchromosomal recombination, which has not been demonstrated in B lymphocytes. The IGH region on chromosome 14 spans a total of about 2.5-3 Mb as demonstrated by pulsed field gel electrophoresis. Matsuda et al. (1993) constructed a physical map of the 0.8-Mb DNA fragment that contains the 3-prime 64 variable region gene segments. They estimated that the total number of human V(H) segments is about 120, including at least 7 orphons. (Orphons are dispersed single pseudogenes derived from tandemly repeated families or gene clusters. Orphons may serve as a reservoir of sequences that can evolve new functions, and have probably been important factors in the evolution of higher organisms.)
Wintle and Cox (1994) mapped 4 V(H) gene segments to human chromosome 16 and 2 to chromosome 15. Using cosmid and yeast artificial chromosome clones, Tomlinson et al. (1994) amplified and sequenced 24 V(H) segments from somatic cell hybrids and assigned them to 15q11.2 and 16p11.2. In addition, they located a cluster of D segments on 15q11.2, previously thought to be located on 14q32.3. They proposed that the segments on chromosome 16 arose by an interchromosomal duplication and identified the corresponding region on chromosome 14. Taken together with the completion of a map of the human V(H) locus on 14q32.3, the total number of V(H) segments identified to that time was 117, which accounted for most, if not all, human germline V(H) segments. Tomlinson et al. (1994) noted that although 10 of the V(H) segments on chromosomes 15 and 16 have open reading frames (ORFs), and at least 1 has apparently functional recombination signals, none of them produces functional antibody in vivo.
Sasso et al. (1995) noted that, on the basis of sequence homology, V(H) genes fall into 7 classes, numbered 1 to 7. About half of the V(H) germline genes belong to the largest family, V(H)3. The haploid genome contains more than 100 V(H) genes. The functional repertoire is dominated by considerably fewer genes than this total because many are pseudogenes and because, for unclear reasons, a number of the V(H) genes are expressed more often than expected from random use.
Matsuda et al. (1998) reported the determination of the complete map and nucleotide sequence of the 957-kb DNA encompassing the V(H) locus, which is adjacent to the 14q telomere. The locus consists of 123 V(H) segments. Matsuda et al. (1998) classified these segments according to structure and utilization into 39 functional, 1 transcribed, 4 ORFs, and 79 pseudogenes.
Using pyrosequencing to study the IGHV1, IGHV3, and IGHV4 gene subgroups in Papua New Guineans, Wang et al. (2011) identified a novel IGHV3 gene, IGHV3-NL1*01, which differs from the nearest previously reported gene by 15 nucleotides. They also identified 16 novel IGHV alleles. Wang et al. (2011) concluded that genetic variation of Ig genes can be explored efficiently in different human populations using high-throughput pyrosequencing.
Yuan et al. (2020) analyzed 294 anti-SARS-CoV-2 antibodies and found that immunoglobulin G heavy-chain variable region 3-53 (IGHV3-53) is the most frequently used IGHV gene for targeting the receptor-binding domain of the spike protein. Cocrystal structures of 2 IGHV3-53-neutralizing antibodies with receptor-binding domain, with or without Fab CR3022, at 2.33- to 3.20-angstrom resolution revealed that the germline-encoded residues dominate recognition of the angiotensin I converting enzyme-2 (ACE2; 300335)-binding site. This binding mode limits the IGHV3-53 antibodies to short complementarity-determining region H3 loops but accommodates light-chain diversity. These IGHV3-53 antibodies show minimal affinity maturation and high potency.
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