Reduced FCGR3B copy number is associated with increased risk of systemic lupus erythematosus (SLE). The five FCGR2/3 genes are arranged across two highly paralogous genomic segments on chromosome 1q23. Previous studies have suggested mechanisms for structural rearrangements at the FCGR2/3 locus and have proposed mechanisms whereby altered FCGR3B copy number predisposes to autoimmunity, but the high degree of sequence similarity between paralogous genes and segments has prevented precise definition of the molecular events and their functional consequences. To pursue the genomic pathology associated with FCGR3B copy number variation (CNV), we integrated sequencing data from fosmid and BAC clones and sequence-captured DNA from FCGR3B-deleted genomes to establish a detailed map of allelic and paralogous sequence variation across the FCGR2/3 locus. This analysis identified two highly paralogous 24.5kb blocks within the FCGR2C/FCGR3B/FCGR2B locus that are devoid of non-polymorphic paralogous sequence variations (PSVs) and that define the limits of the genomic regions in which non-allelic homologous recombination leads to FCGR2C/3B CNV. Further, the data showed evidence of swapping of haplotype blocks between these highly paralogous blocks that most likely has arisen from sequential ancestral recombination events across the region. Functionally, we found by flow cytometry, western blotting and cDNA sequencing that individuals with FCGR3B-deleted alleles show ectopic expression of Fc-gamma RIIb on natural killer cells. We conclude that FCGR3B deletion juxtaposes the 5ยด-regulatory sequences of FCGR2C with the coding sequence of FCGR2B, creating a chimeric gene from which Fc-gamma RIIb is expressed ectopically on NK cells and provides a new explanation for SLE risk associated with reduced FCGR3B gene copy number.
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