Unveiling the Diversity of Immunoglobulin Heavy Constant Gamma (IGHG) Gene Segments in Brazilian Populations Reveals 28 Novel Alleles and Evidence of Gene Conversion and Natural Selection

Abstract

Even though immunoglobulins are critical for immune responses and human survival, the diversity of the immunoglobulin heavy chain gene ( IGH ) is poorly known and mostly characterized only by serological methods. Moreover, this genomic region is not well-covered in genomic databases and genome-wide association studies due to particularities that impose technical difficulties for its analysis. Therefore, the IGH gene has never been systematically sequenced across populations. Here, we deliver an unprecedented and comprehensive characterization of the diversity of the IGHG1, IGHG2 , and IGHG3 gene segments, which encode the constant region of the most abundant circulating immunoglobulins: IgG1, IgG2, and IgG3, respectively. We used Sanger sequencing to analyze 357 individuals from seven different Brazilian populations, including five Amerindian, one Japanese-descendant and one Euro-descendant population samples. We discovered 28 novel IGHG alleles and provided evidence that some of them may have been originated by gene conversion between common alleles of different gene segments. The rate of synonymous substitutions was significantly higher than the rate of the non-synonymous substitutions for IGHG1 and IGHG2 ( p = 0.01 and 0.03, respectively), consistent with purifying selection. Fay and Wu's test showed significant negative values for most populations ( p < 0.001), which indicates that positive selection in an adjacent position may be shaping IGHG variation by hitchhiking of variants in the vicinity, possibly the regions that encode the Ig variable regions. This study shows that the variation in the IGH gene is largely underestimated. Therefore, exploring its nucleotide diversity in populations may provide valuable information for comprehension of its evolution, its impact on diseases and vaccine research.

Coming together at the hinges: Therapeutic prospects of IgG3

“…With 29 reported allelic variants ( Table 1 ) defined to date, IgG3 is the most polymorphic of the human IgG subclasses ( Figure 2 ). 36 , 37 Unlike other subclasses that vary principally in terms of isolated amino acid substitutions, IgG3 also has structural allotypes that vary in the number of exon repeats (from 1 to 3) in the core hinge. 38–41 While there is little to suggest direct functional relevance of most allotypic variation among IgG subclasses, 38 associations between IgG allotypes and a wide variety of infections, malignancies, and autoimmune conditions have been observed.…”

A Novel Framework for Characterizing Genomic Haplotype Diversity in the Human Immunoglobulin Heavy Chain Locus

“…The immunoglobulin heavy chain (IGH) locus, specifically, consists of >50 variable (IGHV), >20 diversity (IGHD), 6 joining (IGHJ), and 9 constant (IGHC) functional/open reading frame (F/ORF) genes that encode the heavy chains of expressed Abs (4). Greater than 250 IGH gene segment alleles are curated in the ImMunoGeneTics Information System (IMGT) database (4), and this number continues to increase (2,(5)(6)(7)(8)(9)(10)(11). The locus is enriched for single nucleotide variants (SNVs) and large structural variants (SVs) involving functional genes (5,(12)(13)(14)(15)(16)(17)(18)(19), at which allele frequencies are known to vary among human populations (2,19,20).…”

A novel framework for characterizing genomic haplotype diversity in the human immunoglobulin heavy chain locus

“…Greater than 250 functional/ORF IGH gene segment alleles are curated in the IMmunoGeneTics Information System (IMGT) database 2 , and this number continues to increase [3][4][5][6][7][8][9][10] . The locus is enriched for single nucleotide variants (SNVs) and large structural variants (SVs) involving functional genes 3,[11][12][13][14][15][16][17][18] , at which allele frequencies are known to vary among human populations 4,18,19 .…”