Antimicrobial RNases: genetic diversity and novel structure

Ribonuclease (RNase) 7 is a conserved member of the RNase A superfamily that is expressed in epithelial cells in response to proinflammatory stimuli. RNase 8 is its highly divergent paralog, detected thus far only in primate genomes. We examined the diversity of RNases 7 and 8 among human populations, a subject of particular interest given the existence of functional pseudogenes among the non‐human primate RNase 8s. Only two SNPs and four unique alleles were identified for human RNase 8 with unremarkable nucleotide sequence diversity (π = 0.00122 ± 0.00009) similar to that of human RNase 7 (π = 0.00073 ± 0.00022). Upon further review of the human genomic DNA (gDNA) RNase 8 sequence, we identified an additional start codon that could extend the open reading frame by 31 residues at the amino terminus. This extended amino terminus was also identified in gDNA of non‐human primates, and is expressed in human spleen and placental tissue, with the full length sequence, including the novel start codon and amino terminal extension, present on the major ~1 kB transcript. This amino terminal extension transforms RNase 8 from a canonical secretory protein into a configuration typical of a type II integral membrane protein with an extracellular ribonuclease‐like domain. These findings suggest that RNase 8 has diverged under unusual constraints and as such may have emerged with unique function as well as original structure.