title: Conservation and Innovation of APOBEC3A Restriction Functions during Primate Evolution.
abstract: LINE-1 (long interspersed element-1) retroelements are the only active autonomous endogenous retroelements in human genomes. Their retrotransposition activity has created close to 50% of the current human genome. Due to the apparent costs of this proliferation, host genomes have evolved multiple mechanisms to curb LINE-1 retrotransposition. Here, we investigate the evolution and function of the LINE-1 restriction factor APOBEC3A, a member of the APOBEC3 cytidine deaminase gene family. We find that APOBEC3A genes have evolved rapidly under diversifying selection in primates, suggesting changes in APOBEC3A have been recurrently selected in a host-pathogen "arms race." Nonetheless, in contrast to previous reports, we find that the LINE-1 restriction activity of APOBEC3A proteins has been strictly conserved throughout simian primate evolution in spite of its pervasive diversifying selection. Based on these results, we conclude that LINE-1s have not driven the rapid evolution of APOBEC3A in primates. In contrast to this conserved LINE-1 restriction, we find that a subset of primate APOBEC3A genes have enhanced antiviral restriction. We trace this gain of antiviral restriction in APOBEC3A to the common ancestor of a subset of Old World monkeys. Thus, APOBEC3A has not only maintained its LINE-1 restriction ability, but also evolved a gain of antiviral specificity against other pathogens. Our findings suggest that while APOBEC3A has evolved to restrict additional pathogens, only those adaptive amino acid changes that leave LINE-1 restriction unperturbed have been tolerated.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA hsmalik@fhcrc.org.
authors.forename: Richard N
authors.initials: RN
authors.lastname: McLaughlin
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Jacob T
authors.initials: JT
authors.lastname: Gable
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA Department of Microbiology, University of Washington, Seattle.
authors.forename: Cristina J
authors.initials: CJ
authors.lastname: Wittkopp
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Michael
authors.initials: M
authors.lastname: Emerman
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, WA hsmalik@fhcrc.org.
authors.forename: Harmit S
authors.initials: HS
authors.lastname: Malik
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002520:Cercopithecidae; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D015894:Genome, Human; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D011323:Primates; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D018626:Retroelements
chemical_list: D011506:Proteins; D018626:Retroelements; C121399:APOBEC3A protein, human; D003564:Cytidine Deaminase
keywords: APOBEC3A; LINE-1; innate immunity; positive selection; primates.; restriction factor; retroelements