Evolutionary history of the low-affinity Fc gamma receptor copy number variable locus: diversity, disease and helminth infection

Low-affinity Fc receptors for immunoglobulin G (IgG) are expressed on a variety of leucocytes and play an important role in immune responses to pathogens. Copy number and functional single nucleotide variation in the low affinity FCGR region is associated with lupus, malaria, and possibly rheumatoid arthritis. We analysed variation at this locus in a global survey of 946 individuals from 51 populations. We found no large differences in copy number distribution together with little association with flanking SNP haplotypes suggesting a high recurrent mutation rate of this CNV. Coalescent analysis of population data suggests a mutation rate of about 0.1% per generation. A model of recurrent duplication and deletion mediated by non-allelic homologous recombination is supported by breakpoint mapping of homozygous deletions. Given the functional relevance of the sequence variation typed, infectious disease burden may be involved in shaping variation. Indeed, helminth pathogen richness is significantly correlated with the frequency of the NA1 variant of FCGR3B (P=0.0018) and an active form of the FCGR2C receptor (P=0.0005). Maximum-likelihood analysis of sequence evolution in mammals supports a model where positive selection acted on lineages with high levels of helminth infection (P= 0.006). Positive selection has acted on a subset of amino acids in FCGR3 which were mapped to the crystal structure and formed three patches on the receptor likely to influence the interaction with IgG.