Ethnic differences of polymorphism of an immunoglobulin VH3 gene.

Abstract

The VH26 germline gene occupies two different loci, due to gene duplication, and is one of the most frequently expressed human immunoglobulin VH genes. This report identifies the alleles of each VH26 locus and describes distinct patterns of VH26 polymorphism in three ethnic groups. Oligonucleotide probes targeting VH26 were used in sequence-specific RFLP analysis of DNA from 72 Caucasians, 52 Asians, 35 American Blacks, and members of six families. The A locus, on a 7.0-kb TaqI band, was detected in 89% of Caucasians, 75% of Asians, and 26% of Blacks (x2 = 46, P < 0.0005). The B locus, detected on a 5.0-kb band in nearly all subjects, was found to have additional alleles occurring at 6.8 kb in 10% of Asians and 3% of Blacks (X2 = 7.8, P < 0.02) and at 3.7 kb in 1.4% of Caucasians, 21% of Asians, and 9% of Blacks (x2 = 13.8, P < 0.001). In Asians only, the 3.7-kb hybridization band represented a multiple-duplication unit containing three or four gene copies. Duplications of other VH26 alleles, and null alleles of the B locus, were also seen. An exact VH26 sequence was cloned from the 5.0-kb allele and likely exists in the 7.0-and 6.8-kb alleles. A novel sequence cloned from the 3.7-kb allele differed from VH26 by nine nucleotides and appears to have evolved by gene conversion in CDR2. The total diploid gene dose of the A and B loci ranged from one to as many as six copies of VH26-containing genes, and from zero to as many as six to eight copies of the 3.7-kb allele. We conclude that ethnic differences in polymorphism exist at both VH26 loci. These differences could influence VH26 expression because they involve variations in gene copy number and coding region sequence. (J. Clin. Invest. 1995. 96:1591-1600

Evolution by the birth-and-death process in multigene families of the vertebrate immune system

“…It has been shown that the rate of nonsynonymous nucleotide substitution is significantly higher than that of synonymous substitution at the complementarity-determining regions of V H and V L genes (47). This observation once suggested the possibility that V H and V L genes might also be subject to overdominant selection, but recent studies have shown that the extent of V H or V L gene polymorphism within loci is much lower than that of MHC genes (48)(49)(50). Therefore, it seems that a higher rate of nonsynonymous substitution than that of synonymous substitution in V H and V L genes is caused by directional selection rather than overdominant or balancing selection.…”

A comprehensive profile of DNA copy number variations in a Korean population: identification of copy number invariant regions among Koreans

“…Previous reports suggested that polymorphic gene duplication may frequently occur in Ig loci including 14q32.33 (Ig heavy variable cluster) and 22q11.2 (Ig heavy chain constant region and Ig lamda) (Sasso et al, 1995;van der Burg et al, 2002;Buckland et al, 2003). It is likely that the copy number variation of the Ig loci may not be from the germ line but a de novo CNV enriched during LCL generation.…”

True

“…[38][39][40] The V H and V L gene sequences consistently revealed significant deviations from the germline V H and V L genes. Although some of the detected nucleotide changes may be due to genetic polymorphisms, [41][42][43] most of them likely represented somatic mutations. Analyses of the mutation patterns indicated not only stimulation, but also selection by antigen, based on the accumulation of R mutations on CDR in most of the cases (see Table 2).…”