Evolutionary Dynamics of the Interferon-Induced Transmembrane Gene Family in Vertebrates

Zhang C (2012) Evolutionary Dynamics of the Interferon-Induced Transmembrane Gene Family in Vertebrates. PLoS ONE 7(11): e49265. doi:10.1371/journal.pone.0049265 Evolutionary Dynamics of the Interferon-Induced Transmembrane Gene Family in Vertebrates Zhao Zhang 0 Jun Liu 0 Meng Li 0 Hui Yang 0 Chiyu Zhang 0 Marc Robinson-Rechavi, University of Lausanne, Switzerland 0 1 Institute of Life Sciences, Jiangsu University , Jiangsu , China , 2 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming , China , 3 Diagnostic center for pathogens, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China Vertebrate interferon-induced transmembrane (IFITM) genes have been demonstrated to have extensive and diverse functions, playing important roles in the evolution of vertebrates. Despite observance of their functionality, the evolutionary dynamics of this gene family are complex and currently unknown. Here, we performed detailed evolutionary analyses to unravel the evolutionary history of the vertebrate IFITM family. A total of 174 IFITM orthologous genes and 112 pseudogenes were identified from 27 vertebrate genome sequences. The vertebrate IFITM family can be divided into immunity-related IFITM (IR-IFITM), IFITM5 and IFITM10 sub-families in phylogeny, implying origins from three different progenitors. In general, vertebrate IFITM genes are located in two loci, one containing the IFITM10 gene, and the other locus containing IFITM5 and various numbers of IR-IFITM genes. Conservation of evolutionary synteny was observed in these IFITM genes. Significant functional divergence was detected among the three IFITM sub-families. No gene duplication or positive selection was found in IFITM5 sub-family, implying the functional conservation of IFITM5 in vertebrate evolution, which is involved in bone formation. No IFITM5 locus was identified in the marmoset genome, suggesting a potential association with the tiny size of this monkey. The IFITM10 sub-family was divided into two groups: aquatic and terrestrial types. Functional divergence was detected between the two groups, and five IFITM10-like genes from frog were dispersed into the two groups. Both gene duplication and positive selection were observed in aquatic vertebrate IFITM10-like genes, indicating that IFITM10 might be associated with the adaptation to aquatic environments. A large number of lineage- and species-specific gene duplications were observed in IR-IFITM sub-family and positive selection was detected in IR-IFITM of primates and rodents. Because primates have experienced a long history of viral infection, such rapid expansion and positive selection suggests that the evolution of primate IR-IFITM genes is associated with broad-spectrum antiviral activity. - Funding: This work was supported by the Open Project of State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, CAS (GREKF10-08), the Top-notch personnel Project of Jiangsu University to CZ, and a grant from National Natural Science Foundation of China (No. 30900793) to HY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. First discovered by cDNA library screening in 1984 [1], the interferon-induced transmembrane (IFITM) gene family plays critical roles in a variety of cellular processes and contains IFITM1, IFITM2, IFITM3, IFITM5, IFITM6, IFITM7, IFITM10 and some IFITM-like genes [2]. Except for IFITM5 that is specifically expressed in bone cells in an interferon (IFN)independent way [3,4], all IFITM genes can be stimulated by IFN [5,6], and are widely expressed in tissues and organs [2]. IFITM family members contain a conservative CD225 domain and two terminal hypervariable regions [2]. The CD225 domain accounts for more than half of the protein in length, containing one intact transmembrane domain (TMD), two S-palmitoylation sites regions and partial TMD in the C-terminus of the protein. The S-palmitoylation sites have been demonstrated to play important roles in post-translational processing and stability of IFITM proteins [7]. The N-terminal hypervariable region generally contains 21 amino acid residues and the C-terminal one includes a TMD (Fig. 1) [8]. In different vertebrates, the functions of different IFITM members diverge. IFITM1, IFITM2 and IFITM3 are involved in cell adhesion [9], antiproliferation [9], tumor suppression [10,11], and germ cell and embryonic development [12]. More recently, these genes were identified as novel types of antiviral restriction factors with a wide spectrum of antiviral activity against influenza A viruses (e.g. H1N1 viruses), West Nile virus, dengue virus, filoviruses, HIV-1, HCV, venezuelan equine encephalitis virus (VEEV), chikungunya virus (CHIKV), vesicular stomatitis virus (VSV) and even SARS-coronavirus [8,1318]. The main function of IFITM5 is associated with bone development in vertebrates [4,19,20]. IFITM6 seems to be involved in macrophage functions in tumor suppression [20]. To date, however, there is no information about the functions of IFITM7 and IFITM10. Several antiviral restriction factors (e.g. APOBEC3G, Tetherin, and SAMHD1) have been demonstrated to evolve under positive selective pressure from viruses [2129]. As important virus inhibitors, IFITM1, IFITM2 and IFITM3 may have also undergone a similar co-evolutionary process, such as other antiviral Figure 1. Domain analysis and sequence characteristics of IFITM gene family. Sequence logos were generated based on the alignment of all IFITM and IFITM-like genes identified (160 sequences) in this study. (A) Gene structure of all IFITM and IFITM-like genes. (B) Logos of the C-terminal region, CD225 domain and N-terminal region. doi:10.1371/journal.pone.0049265.g001 restriction factors do. Despite this connection, relationships between antiviral functions and adaptive evolution in IFITM family have seldom been reported and although previous reports had illustrated the phylogenetic history of IFITM family in some eukaryotic species [2,30,31], there has been no detailed information about IFITM genes in vertebrates. In this study, we performed detailed evolutionary analyses not only to test whether the primate IFITM genes evolved under positive selection throughout primate evolution, but also to unravel the evolutionary history of vertebrate IFITM family. IFITM Gene Repertoires in Vertebrates To characterize the IFITM gene repertoires in vertebrates, we searched 27 vertebrate genome sequences with high genome coverage ($66) or representing the major evolutionary lineages in vertebrate phylogeny (such as opossum, lizard, platypus, etc.), using previously described IFITM sequences as queries. The taxa included ten non-mammalian vertebrates (fi (...truncated)