Nonrandom allele associations between unlinked protein loci: are the polymorphisms of the immunoglobulin constant regions adaptive?

Abstract

Consistent linkage disequilibrium was observed between independently segregating protein loci. In natural populations of the European rabbit Oryctolagus cuniculus, highly significant, nonrandom associations between alleles of the constant regions of the immunoglobulin light and heavy chains were found, both within localities and between localities. We suggest that the population genetic data presented here are relevant to the adaptive significance of the genetic polymorphisms of the antibody constant regions.An antibody molecule is composed of two types of polypeptide chains, the immunoglobulin (Ig) heavy (H) and light (L) chains, each type consisting of a variable (V) region and a constant (C) region. The V regions are involved in the recognition and targeting of the (foreign) antigen, while the Ig C regions mediate the antibody functions. In most species studied, including man, genetic polymorphisms have been observed at loci controlling the Ig C regions. Since their discovery (1), the structural and genetic bases of these so-called "Ig allotypes" have been extensively studied, often revealing an unusual degree of complexity (reviewed in ref.2).It is generally agreed that the special genomic mechanisms underlying the variability of the antibody V regions are the outcome of an adaptive process. The biological significance of the genetic diversity of the C regions is, however, not understood. Extensive genetic diversity could, in multiloci systems, be generated by purely random processes (3, 4), but the fact that microorganisms often manipulate the host's immune response by interacting with the C regions of the antibody has suggested that genetic diversity at this level might be part of an immune defense strategy and could affect survival (5).In the European rabbit (Oryctolagus cuniculus L.), serologically defined polymorphisms have been described for both the H chain and L chain (1, 2). As in other species, Hand L-chain polymorphisms segregate as unlinked codominant Mendelian alleles. The different b-locus allotypes (b4, b5, b6, and b9) are associated with multiple amino acid differences throughout the C region of the K L chain. Although alleles can differ by up to 33% in amino acid sequence (6, 7), studies at the genome level have confirmed them as true alleles at a single gene locus (8,9). A most interesting finding was that the nucleotide sequences of b-locus alleles differ almost exclusively by base-pair substitutions causing amino acid replacements (7-9).The two allelic forms e14 and elS of the e locus, which controls the C region of the IgG H chain differ by only one amino acid change (10). Whereas b-locus allotypes seem to evolve very rapidly, phylogenetic data indicate that the serological markers of the e-locus polymorphisms have been conserved in evolution (11-15).These observations might suggest that in rabbit, Ig allotypes are the outcome of adaptive evolution. However, the actual adaptive importance of genetic variation in populations can only be assessed by studying the extent to which t...

Inferring the Evolutionary History of the European Rabbit (Oryctolagus cuniculus) from Molecular Markers

“…The subsequent colonization of the rest of continental Europe happened during the Middle Ages, and the analysis of protein polymorphism , immunoglobulin allotypes (van der Loo et al 1987Loo et al , 2001 and mtDNA diversity in both extant and extinct populations (Hardy et al 1995) indicate that this process was a mixture of a geographical expansion promoted by human-induced habitat changes together with the emergence of domestic breeds and the release of animals of mixed origin for hunting purposes (Callou 2003). Disentangling between the two processes is extremely difficult because rabbit domestication likely took place in southern France at approximately the same time (Callou 2003), but the future use of markers that are informative between ancestral wild populations and present-day breeds will certainly help to address this question.…”

Genome Mapping and Genomics in Domestic Animals

“…The first relevant data came from the analysis of the so-called immunoglobulin allotypes (Mage et al 1973). The study of the IgKC1 and IgVH1 loci revealed a remarkable contrast between the high levels of diversity found in rabbits from the Iberian Peninsula and the homogeneity of other European populations, including very similar domestic breeds (Cazenave et al 1987;van der Loo 1987;van der Loo et al 1987van der Loo et al , 1991. However, a coherent picture of the evolutionary history of the rabbit started to emerge only a few years later, with the work of Biju- Duval et al (1991) based on the analysis of mtDNA.…”

Restriction fragment alleles of the rabbit IGHG genes with reference to the rabbit IGHGCH2 or e locus polymorphism

“…They are also the target of pathogens (Kim et al . 1999), and different lines of evidence suggest that genetic variation in this region is adaptive (van der Loo et al . 1987, 1996).…”