Abstract
The human Ig heavy chain constant locus (IGHC) is composed of nine functional and two pseudo genes. Extensive polymorphism consisting of deletions, duplications and point mutations have been observed in this locus. The mechanism underlying these deletions and duplications have been postulated to be either non-equal homologous recombination during the meiosis or looping out excision. As a part of this study, 15 patients with selective IgG1 deficiency were screened for IGHC deletions. The frequency of deletions among immunodeficient patients was 19%. In another study the influence of gene duplications on serum level of antibody in 63 healthy Caucasian individuals with heterozygous duplications (encompassing G2 and G4) was determined. No consistent positive influence of duplications on serum levels of either IgG2 or IgG4 was observed.
Study of the influence of gene deletions on serum level of antibody in individuals with heterozygous gene deletions encompassing Cyl gene showed significant decrease on serum levels of IgG1 but a significant increase of IgG3 levels. Individuals with heterozygous deletions of the Cy2 and Cy4 also showed significant decreases in serum levels of the affected subclass. In a study on 500 healthy individuals from three major human races (Negroid, Mongoloid and Caucasoid), the highest haplotype frequency of duplications was found in the Mongoloid population (22%), followed by the Caucasian (10%) and Negroid population (5%). The corresponding frequencies of deletions were 2, 1.5, and 3.5%, respectively. New types of multiple and single duplications (IGHGl-IGHG4, IGHEPI-IGHG2, IGHGP) were found in this study. The most common duplication, found in all populations studied, encompasses the IGHAI-IGHE genes. The only deletion common to all racial groups was an isolated deletion of the IGHG4 gene.
To date, fifteen distinct IGHC deletion haplotypes and nine IGHC duplications have been described. In two other studies, the bovine genes for Ca and Cy3 were cloned and sequenced. The results revealed that there are three gamma genes, one Ca, one Cu and one Ce gene in the bovine immunoglobulin heavy chain constant region gene locus. A small duplication of 84 bp in the bovine IGHG3 gene, possibly resulting from an unequal crossing-over was found, confirming the same mechanism as in human.
Altogether, these studies show that the Ig heavy chain constant locus is continuously being affected by new deletions and duplications, leading to immunoglobulin diversity. The evolutionary process of the IGHC locus appears to be progressive.
