Evolutionary Story of the Low/Medium-Affinity IgG Fc Receptor Gene Cluster

Abstract

Low/intermediate affinity Fc-gamma receptors (FcγR) are crucial for the recognition of immune complexes and IgG-sensitized microorganisms by phagocytic and cytotoxic effector cells. In all mammalian species studied so far, their genes are clustered in a single locus. However, this locus differs between humans and mice, both in the number of genes and the structure/function of the encoded receptors. We show that murine fcgr3 evolved through several steps into FCGR2A, its ortholog, which is specific to primates. One of these steps was the insertion of a retroviral element bringing a new intracellular exon comprising a non-canonical ITAM motif. We also show that the fcgr3-hspa6-fcgr4-fcgr2b module in mammals that has evolved in a FCGR2A-HSPA6-FCGR4-FCGR2B module in primates, was subsequently duplicated in apes through a Non-Allelic Homologous Recombination (NAHR), giving birth to FCGR2C, a hybrid gene between FCGR2B and FCGR2A. The FCGR4 duplication, which occurred simultaneously, eventually resulted in the emergence of FCGR3B, while FCGR3A remained the true FCGR4 ortholog. FCGR2C and FCGR3B, markers of this NAHR, are present in gorillas and chimpanzees, whereas they are absent in orangutans and more distant primates, such as gibbons and macaques. These data need to be taken into account when testing IgG-based therapies in animal species.

Keywords: FcgR; evolution; genetics; mammals; recombination; retroelement.

Figure 1

FCGR2A genesis. (A) Intron/exon organization of mouse Fcgr3 and human FCGR2B and FCGR2A genes. Homologous regions (defined by default BLAST E-value) were indicated by areas of identical colors. Major insertion events are indicated by dotted lines. Exons are abbreviated as follows: signal peptide 1 (S1) and 2 (S2), extracellular 1 (EC1) and 2 (EC2), transmembrane (TM) and intracytoplasmic 1 (C1), 2 (C2), and 3 (C3) domains. HSPA6 stands for Heat Shock Protein Family A (Hsp70) Member 6. HERV stands for Human Endogeneous RetroVirus. Exon and intron size are indicated above and below each gene. For clarity purposes, there is no correspondence between nucleotidic size of the represented genetic elements in kb and scale in the figure. Empty vertical bars represent non-coding exons. Flanking LTRs around HERV are shown as orange arrows. (B) Comparison of FCGR2A ITAM-like motif coding by retroelement with canonical ITAM motif. Dots indicate identity and dashes indicate gaps.

Figure 2

(A) Genomic organization of the FCGR2/3 cluster in mammals. Bioinformatic analysis of orthologous genes of human FCGR2A, FCGR2B, and FCGR3A (blue, yellow, and purple backgrounds, respectively). For gorilla and chimpanzee, the FCGR2/3 cluster is characterized by additional human orthologous FCGR2C and FCGR3B genes. Similarly, orthologous genes of human HSPA6 (red background) were found in all studied species whereas only gorilla and chimpanzee possess human orthologous HSPA7. (B) Non allelic homologous recombination between FCGR2A and FCGR2B leading to duplication of FCGR4 (giving birth to FCGR3B and FCGR3A) and emergence of FCGR2C.

Figure 3

PCR screening for orthologous genes of FCGR2A, FCGR2B, and FCGR2C.