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TheFv1 virus resistance gene is a coopted endogenous retrovirus (ERV) sequence related to thegag gene of the MuERV-L ERV family. Three majorFv1 resistance alleles have been identified in laboratory mice, and they target virus capsid genes to produce characteristic patterns of resistance to mouse leukemia viruses (MLVs). We identifiedFv1 in 3 of the 4Mus subgenera; its absence fromCoelomys and 1 of 3 species ofPyromys indicateFv1 was acquired shortly after the origin of theMus genus. We sequencedFv1 genes from 21 mice representative of the major taxonomic groups ofMus . Two lines of evidence indicate thatFv1 has had antiviral function for 7 million years of evolution. First, 2 species of African pygmy mice (subgenusNannomys ) show anFv1 -like MLV resistance, and transduced cells expressing theNannomys Fv1 gene reproduce this resistance pattern. Second, sequence comparisons suggest thatFv1 has been involved in genetic conflicts throughoutMus evolution. We found evidence for strong positive selection ofFv1 and identified 6 codons that show evidence of positive selection: 3 codons in the C-terminal region including 2 previously shown to contribute toFv1 restriction in laboratory mice, and 3 codons in a 10-codon segment overlapping the major homology region ofFv1 ; this segment is known to be involved in capsid multimerization. This analysis suggests thatFv1 has had an antiviral role throughoutMus evolution predating exposure of mice to the MLVs restricted by laboratory mouseFv1 , and suggests a mechanism forFv1 restriction.

Origin, antiviral function and evidence for positive selection of the gammaretrovirus restriction gene Fv1 in the genus Mus