Sequencing of the human IG light chain loci from a hydatidiform mole BAC library reveals locus-specific signatures of genetic diversity

Corey T Watson; Karyn Meltz Steinberg; Tina A Graves-Lindsay; Rene L Warren; Maika Malig; Jacqueline E Schein; Richard K Wilson; Rob Holt; Evan Eichler; Felix Breden

Antibodies are essential components of the immune system that play key roles in processes associated with innate and adaptive immunity 1 . They are expressed by B-cells as either cell surface receptors or secreted proteins, and are formed by two pairs of identical "heavy" and "light" immunoglobulin (IG) protein chains, encoded by genes located at three primary loci in the human genome: the IG heavy chain (IGH) at 14q32.33, and the two IG light chain regions, lambda (IGL) and kappa (IGK), located at 22q11.2 and 2p11.2 2 . Specifically, through a unique mechanism referred to as V-(D)-J recombination 3 , individual Variable (V), Diversity (D), and Joining (J) genes at the IGH locus, and V and J genes at either the IGK or IGL loci recombine somatically at the DNA level to generate templates for the subsequent transcription and translation of antibody heavy and light chains, respectively. V-(D)-J recombination is accompanied by the random addition and deletion of nucleotides at the junctions of the combined V, D, and J genes by terminal deoxynucleotide transferase (TdT). The extreme variability observed in expressed antigen-naïve B-cell antibody repertoires is due to this combinatorial and junctional diversity, and partly ensures that the immune system is able to recognize and mount effective immune responses against a diverse range of potential pathogens. At the population and species level, IG haplotype and allelic variation also make important contributions to the diversity of expressed antibody repertoires [4] [5] [6] [7] ; however, broader roles of IG genetic polymorphism in antibody function are generally less well understood 8 .