Birth, decay, and reconstruction of an ancient TRIMCyp PNAS PLUS gene fusion in primate genomes

Ray Malfavon-Borjaa,b, Lily I. Wuc, Michael Emermanb,c, and Harmit Singh Malikb,d,1 aDepartment of Genome Sciences, University of Washington, Seattle, WA 98195; and Divisions of bBasic Sciences and cHuman Biology, and dHoward Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 AUTHOR SUMMARY

Fossil viral imprints in animal genomes have [e.g., HIV-1, HIV-2, simian immunodefi- considerably revised previous estimates 6mya ciency virus from the African green monkey CypA1 Owl Monkey fi about the age and evolution of viral lineages 43mya (SIVagm), feline immunode ciency virus Saddle-back Tamarin (1). They have revealed, for instance, that Pygmy Marmoset (FIV)] and extinct (e.g., reconstructed

Loss of Monkeys

lentiviruses, a genus of retroviruses that CypA3 Spider Monkey New World RELIK and pSIV) lentiviruses. However, includes the virus that causes AIDS, HIV, 18mya the 32 million-y-old version of TRIMCypA3 Colobus were likely ancient primate pathogens (2), Silvery Leaf Langur restricted none of the tested viruses, a result Francois' Leaf Langur even though HIV has arisen in humans only CypA3 of just eight amino acids acquired after birth. 6mya Southern Pig-tailed Macaque CypA4 in the past 100 y. Complementing this Lion-tailed Macaque Thus, like the two previous versions of “fossil” record is evidence of host antiviral CypA2 Celebes Crested Macaque TRIMCyp (in owl monkeys and macaques), gene evolution in response to lentiviruses. Stump-tailed Macaque evolution of TRIMCypA3 involved a forfei- Monkeys Crab-eating Macaque Old World Here,wedescribeagenefusionevent Rhesus Macaque ture of broad restrictive activity. Based that gave birth to a primate antiviral gene, Vervet Monkey on the precedent of TRIMCypA1 and TRIMCypA3,43Mya.Tracingthebirthand Patas Monkey TRIMCypA2, we propose that this forfeiture Talapoin TRIMCypA3’ fi subsequent decay of the ancient antiviral De Brazza's Monkey was due to sgainofspeci city

activity of this fossilized antiviral gene 20mya against a lentiviral capsid (which we have not reveals echoes of an ancient lentiviral in- White-cheeked Gibbon sampled). Alternatively, these changes could Agile Gibbon fection that raged deep in primate history. Island Siamang Gibbon have occurred to alleviate the otherwise ex- TRIM5 encodes a potent defense against Orangutan pensive costs associated with TRIMCypA’s 32mya Gorilla a wide range of retroviruses in mammalian Hominoids promiscuous binding to other host proteins. Human α Loss of fi genomes (reviewed in ref. 3). TRIM5 CypA3 Bonobo Despite nding only decayed remnants encounters incoming virions within an Chimp of TRIMCypA3 inasubsetofextantpri- infected cell by specifically recognizing the mate genomes, our evolutionary recon- viral capsid and manifesting an early, Fig. P1. Phylogenetic relationship among simian struction of its ancient antiviral activity MICROBIOLOGY primates, represented by New World monkeys, postentry block to viral infection. The viral reveals that TRIMCypA3 likely evolved in α Old World monkeys, and hominoids. Arrows with capsid-binding (B30.2) domain of TRIM5 titles (“CypA1,”“CypA2,”“CypA3,”“Loss of response to an ancient pathogen, likely a proteins has undergone recurrent, dra- CypA3,” and “CypA4”) indicate the point at lentivirus, 43 Mya, after which it was pre- matic alterations over the course of pri- which the retrogene was acquired or lost in served in some primates for at least 10 mil- mate evolution, likely in response to primate evolution. We infer that CypA3 was lost lion y. Our study highlights the remarkable retroviral evolution and diversity. The at least twice in primate evolution, in New World convergent evolution of TRIMCyp evolu- dramatic innovations selected on host- Monkeys and in the great apes. tion as antiviral defenses in primate evolu- encoded TRIM5 are exemplified by two tion. It also provides unprecedented insight gene fusions between TRIM5 and Cyclophilin A (CypA)retrogenes, into an ancient retroviral infection in early primate evolution that where the CypA protein has functionally replaced the B30.2 do- would otherwise be obscured from scientific discovery. main that occurred independently in owl monkey and macaque genomes (4). The resulting protein fusion is a potent antiviral 1. Patel MR, Emerman M, Malik HS (2011) Paleovirology—Ghosts and gifts of viruses past. against those lentiviruses whose capsid protein naturally binds Curr Opin Virol 1(4):304–309. CypA. Thus, TRIMCyp gene fusions present a unique beacon 2. Gifford RJ (2012) Viral evolution in deep time: Lentiviruses and mammals. Trends Genet 28(2):89–100. with which to identify ancient events that created antiviral genes 3. Johnson WE, Sawyer SL (2009) Molecular evolution of the antiretroviral TRIM5 gene. with a specificity toward lentiviruses. Immunogenetics 61(3):163–176. Starting with an analysis of the rhesus macaque genome and 4. Stoye JP, Yap MY (2008) Chance favors a prepared genome. Proc Natl Acad Sci USA 105 – extending it to all simian primates, we found a third CypA retrogene (9):3177 3178. (CypA3)proximaltoTRIM5 in all Old World monkey and gibbon genomes. Although CypA3 is a pseudogene, we found that it was still transcribed as TRIMCypA3 in some primate genomes. Phylo- Author contributions: R.M.-B., M.E., and H.S.M. designed research; R.M.-B., L.I.W., and M.E. genetic and evolutionary analyses revealed that CypA3 was born in performed research; R.M.-B., L.I.W., M.E., and H.S.M. analyzed data; and R.M.-B., M.E., and the common ancestor of simian primates 43 Mya and that it was H.S.M. wrote the paper. fl preserved for 10 million y as an active gene in the lineage leading to The authors declare no con ict of interest. Old World monkeys and hominoids before being lost or pseudo- This article is a PNAS Direct Submission. genized in all extant primates (Fig. P1). Freely available online through the PNAS open access option. Using this evolutionary information, we were able to reconstruct Data deposition: The sequences reported in this paper have been deposited in the Gen- the sequence of TRIMCypA3 both immediately following its birth Bank database (accession nos. KC146412–KC146414 and JX896147–JX896164). (43 Mya) and just before its pseudogenization (32 Mya). We found 1To whom correspondence should be addressed. E-mail: [email protected]. that at birth, TRIMCypA3 encoded an antiviral protein capable of See full research article on page E583 of www.pnas.org. blocking the early steps of replication of a panel of modern Cite this Author Summary as: PNAS 10.1073/pnas.1216542110.

www.pnas.org/cgi/doi/10.1073/pnas.1216542110 PNAS | February 12, 2013 | vol. 110 | no. 7 | 2447 Downloaded by guest on September 28, 2021