Evolutionary dynamics of the interferon-induced transmembrane gene family in vertebrates

Abstract

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.

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.

Figure 2. Bayesian tree of the vertebrate IFITM gene family.

Bayesian tree was constructed by MrBayes v3.1.2 with 8 million generations. Branch confidence values are shown at the nodes. Scale bar corresponds to 0.2 substitutions per site. (A) Phylogenetic tree of all IFITM genes. (B) Sub-tree of IFITM5 genes. (C) Sub-tree of IFITM10 genes. Three stars represent 3 earlier progenitors of the IFITM family. Circle, square and triangle represent immunity-related IFITM, IFITM10 and IFITM5 genes, respectively. Different colors indicate different taxa.

Figure 3. Bayesian tree of IR-IFITM genes in 14 eutheria species.

Scale bar corresponds to 0.05 substitutions per site. Blue, purple and red represent hominids (human, chimpanzee, gorilla and orangutan), Old World monkey (macaque) and New World monkey (marmoset), respectively. Other species are shown in black.

Figure 4. Syntenic context and chromosome location of the vertebrate IFITM genes.

(A) Syntenic context and chromosome location of IFITM family. (B) Order and orientation of IFITM genes in the gene-cluster. Two-connected boxes represent two exons of each IFITM gene and the arrow indicates the orientation of transcription. Only chromosomes containing genes from IFITM gene-cluster and/or IFITM10 are shown in panel B.

Figure 5. Functional divergence of the vertebrate IFITM families.

Estimate of functional divergence was performed in the conservative region (CD225 domain). The X-axis stands for IFITM amino acids position and the Y-axis represents the values of θ, which indicates the level of functional divergence. (A) IFITM5 vs. IFITM10; (B) IFITM10 vs. IR-IFITM; (C) IFITM5 vs. IR-IFITM; (D) terrestrial IFITM10 vs. aquatic IFITM10.

Figure 6. Pairwise comparisons of dN and dS for IFITM gene family.

(A) clades II and III; (B) clade I; (C) the primate IR-IFITM genes; (D) the rodent IR-IFITM genes.