piRNAs derived from ancient viral processed pseudogenes as transgenerational sequence-specific immune memory in mammals.
Endogenous bornavirus-like nucleoprotein elements (EBLNs) are sequences within vertebrate genomes derived from reverse transcription and integration of ancient bornaviral nucleoprotein mRNA via the host retrotransposon machinery. While species with EBLNs appear relatively resistant to bornaviral disease, the nature of this association is unclear. We hypothesized that EBLNs could give rise to antiviral interfering RNA in the form of PIWI-interacting RNAs (piRNAs), a class of small RNA known to silence transposons but not exogenous viruses. We found that in both rodents and primates, which acquired their EBLNs independently some 25-40 million years ago, EBLNs are present within piRNA-generating regions of the genome far more often than expected by chance alone (ℙ = 8 × 10(-3)-6 × 10(-8)). Three of the seven human EBLNs fall within annotated piRNA clusters and two marmoset EBLNs give rise to bona fide piRNAs. In both rats and mice, at least two of the five EBLNs give rise to abundant piRNAs in the male gonad. While no EBLNs are syntenic between rodent and primate, some of the piRNA clusters containing EBLNs are; thus we deduce that EBLNs were integrated into existing piRNA clusters. All true piRNAs derived from EBLNs are antisense relative to the proposed ancient bornaviral nucleoprotein mRNA. These observations are consistent with a role for EBLN-derived piRNA-like RNAs in interfering with ancient bornaviral infection. They raise the hypothesis that retrotransposon-dependent virus-to-host gene flow could engender RNA-mediated, sequence-specific antiviral immune memory in metazoans analogous to the CRISPR/Cas system in prokaryotes.
Department of Viral Oncology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
Nicholas F
NF
Parrish
Department of Viral Oncology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
Kan
K
Fujino
Department of Pathology, Medical School and Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
Yusuke
Y
Shiromoto
Department of Molecular Biology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Yuka W
YW
Iwasaki
Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Hongseok
H
Ha
Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Jinchuan
J
Xing
Department of Viral Oncology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan Center for Emerging Virus Research, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
Akiko
A
Makino
Department of Pathology, Medical School and Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
Satomi
S
Kuramochi-Miyagawa
Department of Pathology, Medical School and Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
Toru
T
Nakano
Department of Molecular Biology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Haruhiko
H
Siomi
Department of Viral Oncology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan Department of Tumor Viruses, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Tomoyuki
T
Honda
Department of Viral Oncology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan Department of Tumor Viruses, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan.
Keizo
K
Tomonaga
D000818:Animals; D007156:Immunologic Memory / Q000502:physiology*; D008322:Mammals; D011323:Primates; D011544:Pseudogenes; D034741:RNA, Small Interfering / Q000502:physiology*; D051381:Rats
D034741:RNA, Small Interfering
CRISPR/Cas; endogenous viral elements; paleovirology; piRNA; retrotransposon