Poorly expressed alleles of several human immunoglobulin heavy chain variable (IGHV) genes are common in the human population

ABSTRACT Extensive diversity has been identified in the human heavy chain immunoglobulin locus, including allelic variation, gene duplication, and insertion/deletion events. Several genes have been suggested to be deleted in many haplotypes. Such findings have commonly been based on inference of germline repertoire from data sets covering antibody heavy chain encoding transcripts. The inference process operate under conditions that may limit identification of genes transcribed at low levels. The presence of rare transcripts that would indicate the presence of poorly expressed alleles in haplotypes that otherwise appear to have deleted these genes has now been assessed. Alleles IGHV1-2*05, IGHV1-3*02, IGHV4-4*01, and IGHV7-4-1*01 were all identified as being expressed at very low levels from multiple haplotypes, haplotypes that by inference often appeared not to express these genes at all. These alleles harbor unusual sequence variants that may compromise the functionality of the encoded products. Transcripts of two of these alleles to a large degree do not encode a functional product, suggesting that these alleles might be non-functional. It is proposed that the functionality status of immunoglobulin genes should also include assessment of their ability to encode functional protein products.