Olfactomedin domain-containing proteins: evolution, functional divergence, expression patterns and damaging SNPs

Olfactomedin domain-containing proteins appear to facilitate neurodevelopment, cell adhesion, intercellular interactions, and protein-protein interactions, and the disruption of their expression will lead to dramatic developmental perturbations and lethality. The aim of the present work was to study how these genes evolved in metazoans and diverged after their duplication as well as to characterize their expression profiles and detrimental mutations. We conducted an exhaustive survey of olfactomedin domain-containing genes in genomic databases, identifying 235 olfactomedin-like (OLF) proteins in 29 representative species covering all the main metazoan lineages. Phylogenetic analyses allowed us to define nine different subfamilies of OLF genes, and subfamily IX, which specifically includes two immunoglobulin domains, was identified for the first time in arthropods. Functional divergence analysis suggested that the function of this arthropod-specific OLF subfamily might have diverged from that of other subfamilies. Expression pattern analysis of OLF genes in humans and rats showed that human OLF genes tended to be highly expressed in the brain, while rat OLF genes were inclined to be expressed in the ovary and brain. We used the SIFT and PolyPhen servers in dbNSFP to distinguish deleterious mutations from neutral mutations for each member of the OLF gene family. The results showed that OLFML2B contains the most destructive SNPs (up to 61), while none of the mutations in OLFM2, OLFM4 and LPHN2 were predicted to be harmful. Taken together, these findings may not only enhance understanding of the phylogenetic relationships of the OLF family but also aid future studies on OLF protein regulation of nervous system development and immune function.