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

Perhaps the most important contribution of the full IGK and IGL sequences of the CH17 haplotype data presented here is that, for the first time, locus-wide genetic diversity between IGH, IGL, and IGK could be compared in the same haploid genome in relation to corresponding reference haplotypes. Our first observation from this comparison was that the number of V gene allelic differences among the CH17 haplotypes was highest in IGHV. This finding is perhaps not surprising given that allelic richness is also known to be highest in IGHV based on available genetic data in the IMGT database. In addition, studies of substitution patterns in heavy and light chain V genes have also revealed evidence for increased diversity in IGHV compared to IGLV and IGKV 23, 39 . Strikingly, however, when we extended our comparison to include all SNPs within the three loci, we found that locus-wide genetic diversity was also much higher in IGHV, indicating that increased diversity in this locus is not limited to within V gene coding regions. IGHV SNP density is also higher than that observed for killer cell immunoglobulin-like The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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 IGKV gene duplications/deletions (e.g., IGKV1-5 and IGKV3-20) has also more recently been noted from expressed antibody repertoire data, although these await confirmation as germline polymorphisms 34 . Thus, in total, liberal estimates from the literature indicate that only 4-6 light chain functional/ORF V genes are known to occur in SVs, in stark contrast to ~29 in IGHV 7, 8 . In line with this difference, four V gene-containing SVs were identified in the CH17 IGHV haplotype compared to zero defined in IGLV and IGKV.