Polymorphisms of a human variable heavy chain gene show linkage with constant heavy chain genes.

Abstract

In this study, restriction fragment length polymorphisms (RFLPs) were identified with an immunoglobulin variable heavy chain region (Ig VH) probe and the inheritance of the polymorphisms was analyzed in families. Linkage within the VHII gene cluster and between the VHII and Ig CH genes was investigated by lod (logarithm of odds) score analysis. In addition, the position of the VHII genes was determined in relation to another polymorphic locus-D14S1, which is tightly linked and centromeric to the CH genes. Genetic associations between genes in the CH and VH clusters were analyzed.These RFLPs represent genetically characterized VH region polymorphisms and it is hoped that they will facilitate the study of disease correlations as well as further the understanding of the genetics of the immunoglobulin heavy chain genes in humans.The immunoglobulins consist of four polypeptide chains, two heavy (H) and two light (L), each of which contains a variable (V) region-encoded amino terminus covalently attached to a constant (C) region-encoded carboxyl terminus. The V region polypeptides can be divided into functional segments categorized as framework regions (FR1-4) and hypervariable or complementarity-determining regions (CDR1-3). Each VH polypeptide is composed of sequences encoded by three different genetic elements. These are (i) V region sequences coding for amino acids 1-98, which form FR1-3 and CDR1 and CDR2; (it) diversity (D) region sequences coding for amino acids 99-103, which form CDR3; and (iil) joining (J) region sequences coding for amino acids 103-110, forming FR4 (1-3). A rearranged VH sequence can be recombined subsequently to the 5' end of any CH subclass region sequence by a process known as class switching (4), which illustrates that a single VH gene can be combined with any of the CH genes (5, 6).Antibody specificity is determined by genetic differences in the V region genes (idiotypes) (6)(7)(8)(9). This idiotypic variation has been studied extensively in mice and rabbits. As early as 1963, antigenic determinants located on V regions of rabbit IgH chains were found (10). Pedigree analysis of rabbits homozygous for two different VH region allotypes demonstrated that VH and CH region allotypes were linked, although recombinants were observed (11).Mendelian studies involving idiotypic determinants of mice have determined that the Ig CH and Ig VH loci are also linked (9, 12-15), although separated by a substantial distance (2). Mouse strains of the same allotype have identical VH gene families; however, in comparisons between inbred strains, each VH gene family is comparable in number but not in the composition of the individual VH genes (16).Utilizing molecular data, it was shown that polytnorphisms in VH coding sequences are directly responsible for two major anti-arsonate idiotypes in A/J mice (17) as well as for different responses to proteins bearing the hapten (4-hydroxy-3-nitrophenyl)acetyl (18). Furthermore, a molecular genetic study of germline variation in six inbred mouse strains demons...

Ethnic differences of polymorphism of an immunoglobulin VH3 gene.

“…The Black with a 6.8-kb+ band was 87.5% Black and 12.5% Native American. 4 of the Asians with 6.8-kb+ bands also had the usual M8 bands at 7.0 and 5.0 kb (Table II and, (Fig. 3, lane 7).…”

“…Samples were also obtained from family members of five of these volunteers, and from a sixth family (No. 0172), none of whose members were included in the main study population. Ethnicity of all subjects was determined by direct questioning by one Of the 52 Asian subjects, 50 were 100% Asian; these included 20 Chinese, 10 Koreans, 7 Japanese, 4 Cambodians, 1 Vietnamese, and 1 Filippino. 7 Asians were of mixed Asian ethnicity, including 5 subjects who were at least half Cambodian (2 were 25% Chinese, 1 was 50% Chinese, 1 was 50% Vietnamese, and 1 was 12.5% Chinese and 12.5% Vietnamese) and 2 others who were at least half Chinese (1 was 25% Vietnamese and 1 was 50% Japanese).…”

“…An increasing body of data shows that many VH genes are polymorphic (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The repeated cloning of the exact sequences of several VH genes from unrelated people indicates, however, that many VH elements are highly conserved in the population.…”

A fetally expressed immunoglobulin VH1 gene belongs to a complex set of alleles.

“…Recent studies indicate that many human VH genes are polymorphic, presumably the result of extensive duplication, deletion, gene conversion, and point mutation in the VH cluster( [10][11][12][13][14][15][16][17][18][19][20][21]. The repeated cloning ofsome VH sequences from unrelated individuals (4)(5)(6)(7)(8)(22)(23)(24)(25)(26)(27) and the results of sequence-specific hybridization studies ( 19-21 ) suggest that polymorphic VH loci are commonly dominated by only a few conserved alleles (i.e., two to four) (20).…”

Variable‐Constant Segment Genotype of Immunoglobulin Kappa is Associated with Increased Risk for Rheumatoid Arthritis

“…Because a small frequency of genetic recombination (less than 0.5%) interferes with linkage disequilibrium (36), and thus by inference, disease-association studies, the significant association with C, and apparent lack of association with the B3 or CDSA markers may be due to recombination between C,, B3, and CDSA. For the human immunoglobulin heavy-chain region located on human chromosome 14, the recombination frequency between variable-region markers and allotypic markers of the IgG heavy chain has been estimated at 4% (36). Physical mapping shows a hot spot between the most V,-proximal constant segment C, and all of the C, segments (37).…”