Fc gamma receptors: Their evolution, genomic architecture, genetic variation, and impact on human disease

Fc gamma receptors (FcγRs) are a family of receptors that bind IgG antibodies and interface at the junction of humoral and innate immunity. Precise regulation of receptor expression provides the necessary balance to achieve healthy immune homeostasis by establishing an appropriate immune threshold to limit autoimmunity but respond effectively to infection. The underlying genetics of the FCGR gene family are central to achieving this immune threshold by regulating affinity for IgG, signaling efficacy, and receptor expression. The FCGR gene locus was duplicated during evolution, retaining very high homology and resulting in a genomic region that is technically difficult to study. Here, we review the recent evolution of the gene family in mammals, its complexity and variation through copy number variation and single-nucleotide polymorphism, and impact of these on disease incidence, resolution, and therapeutic antibody efficacy. We also discuss the progress and limitations of current approaches to study the region and emphasize how new genomics technologies will likely resolve much of the current confusion in the field. This will lead to definitive conclusions on the impact of genetic variation within the FCGR gene locus on immune function and disease.