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

Two factors suggest that the higher rate of SVs in IGH may be attributable to the increased fraction of the locus covered by segmentally duplicated sequences. First, segmental duplications are known to be associated with SVs genome-wide 42 , and second, duplications have been shown specifically to facilitate structural variation in IGH 7 . Segmental duplications and tandem repeats also mediate sequence exchange either through gene conversion or recombination, that can either result in the homogenization of paralogous sequences 29, 30, 43 , or in an increase in genetic diversity 44, 45 . Illustrating the latter of these two scenarios, we found that for IGHV, SNP density was highest in regions including segmental duplications, particularly those with >95% sequence identity with their paralogs; similar trends were not noted for SNP density estimates calculated within non-SD repeat regions (Table 2) . Importantly, SDs with >95% identity comprised nearly twice the fraction of IGHV sequence than IGLV sequence, which may in part explain the differences observed in SNP density between IGH and IGL. It is also worth noting that the difference in the fraction of SDs between IGH and the light chain regions would be greater if the 222 Kbp of novel sequence (comprised primarily of SDs) identified in IGH by our previous study 7 were also included. In addition to this, assessments of CHM1 SNP density across autosomal telomeres and centromeres revealed that the telomeric region on chr14 containing IGHV had both elevated levels of SNP diversity, and increased SD . CC-BY-NC 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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 overlap, compared to analogous regions on other autosomes. This suggests that the genomic location of IGHV has also likely contributed to the increased genetic variation we observe in this locus compared to IGKV and IGLV.