Molecular Evolution of the CCR Cluster in Domestic Cats and other Mammal Species

Abstract

The chemokine receptors that form the OCR cluster: CCR1, CCR2, CCR3 and CCR5, have important roles in humoral and cellular immune responses. CCR2, CCR3 and CCR5 have also been described in humans as coreceptors for the human immunodeficiency virus (HIV). Furthermore, mutations in CCR2 (CCR2-64I) and CCR5 (CCR5432) have been shown to affect HIV transmission and the kinetics of AIDS progression. The OCR gene cluster was isolated from domestic cats in order to further analyze those four receptors within the Felidae family. Because felines are naturally infected with feline immunodeficiency virus (Fly), but only domestic cats seem to develop an AIDS-like disease, characterizing feline OCR genes could help in the study of lentivirus-host coevolution. Results revealed evidence for historic gene conversion between the adjacent CCR2 and CCR5 genes in different mammalian orders (Primates, Cetartiodactyla, Carnivora and Rodentia), resulting in higher than anticipated levels of homology observed between the two genes within these orders. Further analyses showed that gene conversion is particularly high within the Felidae, with an uncommon concentration of rare alleles in CCR2 and CCR5 from domestic cat, pumas and lions. The chemokine network is highly complex and is constantly evolving to optimize immune response. One of the described adaptations between CCR2 and CCR5 receptors is the ability to heterodimerize. For this to happen, the receptors need to share a high level of similarity, which could lead to selection for the homogenizing role of gene conversion between CCR2 and CCR5.