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

The fact that we found evidence of a large tract of sequence exchange between the proximal and distal IGKV units lends support to this notion. However, fully understanding the relationship between segmental duplication and SNP density in the human IG regions will undoubtedly require further sequencing and comparisons of additional haplotypes. We must also acknowledge the potential for confounding effects related to the use of mosaic reference sequences for this comparison 13,17,31 , which were generated from multiple large insert libraries constructed from diploid tissues, in some cases of unknown ethnicity. Considering this, it is possible that a comparison of CH17 IG regions to references generated from individuals with different ethnic backgrounds could result in artifactual differences between loci. However, because our findings are supported by existing V gene allelic variation data at the population level, it seems unlikely that the difference in variability between loci is due to ethnic origin of the tissue. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/006866 doi: bioRxiv preprint If the difference in SNP density observed here between the IG V gene clusters is in fact genuine, it raises the question of whether increased genetic diversity in IGH has any functional consequences. Given that SNP density within V gene coding regions in the CH17 haplotype was also higher in IGH compared to IGL and IGK, it could be speculated that mechanisms associated with an increased number of polymorphisms locus-wide in IGHV, could by default, result in greater IGHV gene diversity and a more variable expressed antibody repertoire. Intriguingly, in natural antibodies, the IG heavy chains are considered to play a more prominent role in epitope binding than IG light chains, although this is primarily attributed to residues of the third complementary determining region (CDRH3) not encoded by IGHV gene segments 46