{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:17:08Z","timestamp":1785428228507,"version":"3.56.0"},"reference-count":94,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Sciences","doi-asserted-by":"publisher","award":["25K09594"],"award-info":[{"award-number":["25K09594"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"award":["25K09594"],"award-info":[{"award-number":["25K09594"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Eutherian mammals possess 11 metavirus-derived genes, collectively known as the sushi-ichi retrotransposon homologue (SIRH)\/Retrotransposon Gag-like (RTL) genes. Several members of this group function in microglia, where SIRH3\/RTL6, SIRH8\/RTL5, and SIRH10\/RTL9 mediate innate immune responses against bacterial-, viral-, and fungal-derived pathogen-associated molecular patterns, respectively, whereas SIRH11\/RTL4 responds to noradrenaline and is thought to contribute to stress-responsive brain functions. In addition, the retroviral Env-derived gene ERVPb1 has been implicated in yolk sac-derived resident macrophage lineages, suggesting that both Gag- and Env-derived domesticated genes contributed to the evolution of mammalian neuroimmune systems. Microglia are now recognized as central regulators of neural circuit formation, brain homeostasis, and neuroimmune function, and their dysfunction has been implicated in a wide range of neurological and psychiatric disorders. Here, we review current knowledge of virus-derived genes that have shaped the functional evolution of microglia. We also revisit the concept of \u201cPlacenta-driven evolution,\u201d which proposes that the relatively hypomethylated developmental environment of extraembryonic tissues, including the placenta and yolk sac, facilitates the retention and functional co-option of virus-derived sequences, thereby accelerating eutherian evolution. Finally, by integrating recent advances in virus-derived genes and retroelement biology, we discuss how this evolutionary framework may extend beyond extraembryonic tissues to other hypomethylated developmental environments, including the germline and preimplantation embryos.<\/jats:p>","DOI":"10.3390\/ijms27146322","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:12:38Z","timestamp":1784257958000},"page":"6322","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Virus-Derived Domesticated Genes in Microglia and Resident Macrophages: Insights into Placenta-Driven Evolution in Mammals"],"prefix":"10.3390","volume":"27","author":[{"given":"Masahito","family":"Irie","sequence":"first","affiliation":[{"name":"Department of Epigenetics, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan"},{"name":"Faculty of Nursing, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8458-6069","authenticated-orcid":false,"given":"Fumitoshi","family":"Ishino","sequence":"additional","affiliation":[{"name":"Department of Epigenetics, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2566-9961","authenticated-orcid":false,"given":"Tomoko","family":"Kaneko-Ishino","sequence":"additional","affiliation":[{"name":"Faculty of Nursing, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/35057062","article-title":"Initial sequencing and analysis of the human genome","volume":"409","author":"Lander","year":"2001","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1126\/science.abj6987","article-title":"The complete sequence of a human genome","volume":"376","author":"Nurk","year":"2022","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3321","DOI":"10.1128\/JVI.74.7.3321-3329.2000","article-title":"An en-velope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells express-ing the type D mammalian retrovirus receptor","volume":"74","author":"Blond","year":"2000","journal-title":"J. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/35001608","article-title":"Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis","volume":"403","author":"Mi","year":"2000","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1006\/geno.2001.6494","article-title":"A retrotransposon-derived gene, PEG10, is a novel imprinted gene located on human chromosome 7q21","volume":"73","author":"Ono","year":"2001","journal-title":"Genomics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1101\/gr.172701","article-title":"Human-ovine comparative sequencing of a 250-kb imprinted domain encompassing the callipyge (clpg) locus and identifica-tion of six imprinted transcripts: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8","volume":"11","author":"Charlier","year":"2001","journal-title":"Genome Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/ng1699","article-title":"Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality","volume":"38","author":"Ono","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/ng.2007.51","article-title":"Role of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placenta","volume":"40","author":"Sekita","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12127","DOI":"10.1073\/pnas.0902925106","article-title":"Syncytin-A knockout mice demon-strate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene","volume":"106","author":"Dupressoir","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1073\/pnas.1112304108","article-title":"A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast","volume":"108","author":"Dupressoir","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kaneko-Ishino, T., and Ishino, F. (2012). The role of genes domesticated from LTR retrotransposons and retroviruses in mammals. Front. Microbiol., 3.","DOI":"10.3389\/fmicb.2012.00262"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20120507","DOI":"10.1098\/rstb.2012.0507","article-title":"Paleovirology of \u2018syncytins\u2019, retroviral env genes exapted for a role in placentation","volume":"368","author":"Lavialle","year":"2013","journal-title":"Phil. Trans. R. Soc. B"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"511","DOI":"10.2183\/pjab.91.511","article-title":"Mammalian-specific genomic functions: Newly acquired traits generated by genomic imprinting and LTR retrotransposon-derived genes in mammals","volume":"91","author":"Ishino","year":"2015","journal-title":"Proc. Jpn. Acad. Ser. B Phys. Biol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0378-1119(98)00296-0","article-title":"A retrotransposon family from the pufferfish (fugu) Fugu rubripes","volume":"215","author":"Poulter","year":"1998","journal-title":"Gene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"msae061","DOI":"10.1093\/molbev\/msae061","article-title":"The Diverse Evolutionary Histories of Domesticated Metaviral Capsid Genes in Mammals","volume":"41","author":"Henriques","year":"2024","journal-title":"Mol. Biol. Evol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Suzuki, S., Ono, R., Narita, T., Pask, A.J., Shaw, G., Wang, C., Kohda, T., Alsop, A.E., Graves, J.A.M., and Kohara, Y. (2007). Re-trotransposon Silencing by DNA Methylation Can Drive Mammalian Genomic Imprinting. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.0030055"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Edwards, C.A., Mungall, A.J., Matthews, L., Ryder, E., Gray, D.J., Pask, A.J., Shaw, G., Graves, J.A., Rogers, J., and Dunham, I. (2008). The evolution of the DLK1-DIO3 imprinted domain in mammals. PLoS Biol., 6.","DOI":"10.1371\/journal.pbio.0060135"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1093\/molbev\/mst014","article-title":"Genesis and regulatory wiring of retroelement-derived domesticated genes: A phylogenomic perspective","volume":"30","year":"2013","journal-title":"Mol. Biol. Evol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100360","DOI":"10.1016\/j.xcrm.2021.100360","article-title":"Se-creted retrovirus-like GAG-domain-containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology","volume":"2","author":"Pandya","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100153","DOI":"10.1074\/jbc.RA120.015960","article-title":"Global proteomics of Ubqln2-based murine models of ALS","volume":"296","author":"Whiteley","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/ng.2007.56","article-title":"Deletions and epimutations affecting the human chromosome 14q32.2 imprinted region in individuals with paternal and ma-ternal upd(14)-like phenotypes","volume":"40","author":"Kagami","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/gtc.12830","article-title":"The role of eutherian-specific RTL1 in the nervous system and its implications for the Kagami-Ogata and Temple syndromes","volume":"26","author":"Kitazawa","year":"2021","journal-title":"Genes Cells"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1093\/hmg\/ddac110","article-title":"RTL1\/PEG11 imprinted in human and mouse brain mediates anxiety-like and social behaviors and regulates neuronal excitability in the locus coeruleus","volume":"31","author":"Chou","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"dev200976","DOI":"10.1242\/dev.200976","article-title":"Retro-virus-derived acquired genes, RTL5 and RTL6, are novel constituents of the innate immune system in the eutherian brain","volume":"149","author":"Irie","year":"2022","journal-title":"Development"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ishino, F., Itoh, J., Irie, M., Matsuzawa, A., Naruse, M., Suzuki, T., Hiraoka, Y., and Kaneko-Ishino, T. (2023). Retrovirus-Derived RTL9 Plays an Important Role in Innate Antifungal Immunity in the Eutherian Brain. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241914884"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.cell.2010.01.022","article-title":"Pattern recognition receptors and inflammation","volume":"140","author":"Takeuchi","year":"2010","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Fiebich, B.L., Batista, C.R.A., Saliba, S.W., Yousif, N.M., and de Oliveira, A.C.P. (2018). Role of microglia TRLs in neurodegeneration. Front. Cell. Neurosci., 12.","DOI":"10.3389\/fncel.2018.00329"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Irie, M., Yoshikawa, M., Ono, R., Iwafune, H., Furuse, T., Yamada, I., Wakana, S., Yamashita, Y., Abe, T., and Ishino, F. (2015). Cognitive function related to the Sirh11\/Zcchc16 gene acquired from an LTR retrotransposon in eutherians. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005521"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ishino, F., Itoh, J., Matsuzawa, A., Irie, M., Suzuki, T., Hiraoka, Y., Yoshikawa, M., and Kaneko-Ishino, T. (2024). RTL4, a Retrovirus-Derived Gene Implicated in Autism Spectrum Disorder, Is a Microglial Gene That Responds to Noradrenaline in the Postnatal Brain. Int. J. Mol. Sci., 25.","DOI":"10.1101\/2024.10.23.619930"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/nrn3722","article-title":"Microglia and brain macrophages in the molecular age: From origin to neuropsychiatric disease","volume":"15","author":"Prinz","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1126\/science.1202529","article-title":"Synaptic pruning by microglia is necessary for normal brain development","volume":"333","author":"Paolicelli","year":"2011","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.neuron.2012.03.026","article-title":"Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner","volume":"74","author":"Schafer","year":"2012","journal-title":"Neuron"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/glia.22389","article-title":"The \u201cquad-partite\u201d synapse: Microglia-synapse interactions in the developing and ma-ture CNS","volume":"61","author":"Schafer","year":"2013","journal-title":"Glia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1038\/nm.4397","article-title":"Microglia emerge as central players in brain disease","volume":"23","author":"Salter","year":"2017","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/s12974-023-02901-y","article-title":"Noteworthy perspectives on microglia in neuropsychiatric disorders","volume":"20","author":"Zhu","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Shiura, H., Kitazawa, M., Kaneko-Ishino, T., and Ishino, F. (2026). Placenta-Driven Evolution: Viral Gene Acquisition and PEG10\u2019s Essential Roles in Eutherian Placenta. Biomolecules, 16.","DOI":"10.3390\/biom16010161"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1093\/molbev\/msh010","article-title":"Mammalian housekeeping genes evolve more slowly than tissue-specific genes","volume":"21","author":"Zhang","year":"2004","journal-title":"Mol. Biol. Evol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.semcdb.2018.04.008","article-title":"It takes a village: Phagocytes play a central role in fungal immunity","volume":"89","author":"Feldman","year":"2019","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-immunol-030409-101229","article-title":"Innate Antifungal Immunity: The Key Role of Phagocytes","volume":"29","author":"Brown","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/44605","article-title":"The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens","volume":"401","author":"Underhill","year":"1999","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nrm2217","article-title":"Lysosomes: Fusion and function","volume":"8","author":"Luzio","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1146\/annurev-physiol-021014-071649","article-title":"Lysosomal Physiology","volume":"77","author":"Xu","year":"2015","journal-title":"Annu. Rev. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.neuron.2012.12.029","article-title":"Rare complete knockouts in humans: Population distribution and significant role in autism spectrum disorders","volume":"77","author":"Lim","year":"2013","journal-title":"Neuron"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"104943","DOI":"10.1016\/j.neuint.2020.104943","article-title":"Noradrenaline as a key neurotransmitter in modulating microglial activation in stress response","volume":"143","author":"Sugama","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Hellwig, S., Heinrich, A., and Biber, K. (2013). The brain\u2019s best friend: Microglial neurotoxicity revisited. Front. Cell. Neurosci., 7.","DOI":"10.3389\/fncel.2013.00071"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Matsuzawa, A., Lee, J., Nakagawa, S., Itoh, J., Takahashi Ueda, M., Mitsuhashi, S., Kochi, Y., Kaneko-Ishino, T., and Ishino, F. (2021). HERV-Derived Ervpb1 Is Conserved in Simiiformes, Exhibiting Expression in Hematopoietic Cell Lineages Including Macro-phages. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094504"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.ygeno.2005.08.011","article-title":"The approximately 30-million-year-old ERVPb1 envelope gene is evo-lutionarily conserved among hominoids and Old World monkeys","volume":"86","author":"Aagaard","year":"2005","journal-title":"Genomics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1742-4690-2-19","article-title":"Functional characterization of two newly identified Human Endogenous Retrovirus coding envelope genes","volume":"2","author":"Blaise","year":"2005","journal-title":"Retrovirology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1016\/j.stemcr.2017.04.023","article-title":"Di-rected Differentiation of Human Pluripotent Stem Cells to Microglia","volume":"8","author":"Douvaras","year":"2017","journal-title":"Stem. Cell Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.cell.2016.09.024","article-title":"Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations","volume":"167","author":"Quach","year":"2016","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1038\/srep01462","article-title":"A novel human endogenous retroviral protein inhibits cell-cell fusion","volume":"3","author":"Sugimoto","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1126\/science.1194637","article-title":"Fate mapping analysis reveals that adult microglia derive from primitive macrophages","volume":"330","author":"Ginhoux","year":"2010","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"a020537","DOI":"10.1101\/cshperspect.a020537","article-title":"Origin of microglia: Current concepts and past controversies","volume":"7","author":"Ginhoux","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1038\/s41423-025-01368-6","article-title":"Microglia across evolution: From conserved origins to functional divergence","volume":"22","author":"Shimizu","year":"2025","journal-title":"Cell. Mol. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.cell.2019.08.053","article-title":"Microglia Biology: One Century of Evolving Concepts","volume":"179","author":"Prinz","year":"2019","journal-title":"Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1126\/science.1230835","article-title":"Com-parative analysis of bat genomes provides insight into the evolution of flight and immunity","volume":"339","author":"Zhang","year":"2013","journal-title":"Science"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/s41586-020-2486-3","article-title":"Six reference-quality genomes reveal evolution of bat adaptations","volume":"583","author":"Jebb","year":"2020","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1099\/vir.0.044412-0","article-title":"DNA viruses and the cellular DNA-damage response","volume":"93","author":"Turnell","year":"2012","journal-title":"J. Gen. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1590\/S0100-879X2000000200001","article-title":"An update on the physiology of two- and three-toed sloths","volume":"33","author":"Gilmore","year":"2000","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1086\/303383","article-title":"The Zoogeography of Mammalian Basal Metabolic Rate","volume":"156","author":"Lovegrove","year":"2000","journal-title":"Am. Nat."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.immuni.2017.04.013","article-title":"Biochemical Underpinnings of Immune Cell Metabolic Phenotypes","volume":"46","author":"Olenchock","year":"2017","journal-title":"Immunity"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1146\/annurev-immunol-042718-041739","article-title":"Disease Tolerance as an Inherent Component of Immunity","volume":"37","author":"Martins","year":"2019","journal-title":"Annu Rev. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Irie, M., Koga, A., Kaneko-Ishino, T., and Ishino, F. (2016). An LTR Retrotransposon-Derived Gene Displays Lineage-Specific Structural and Putative Species-Specific Functional Variations in Eutherians. Front Chem., 4.","DOI":"10.3389\/fchem.2016.00026"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Ishino, F., Irie, M., Shiura, H., Kohda, T., and Kaneko-Ishino, T. (2026). A eutherian-specific metaviral gene, RTL6, coordinates microglial inflammatory responsiveness and state regulation. BioRxiv.","DOI":"10.64898\/2026.07.15.738833"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/ni.1863","article-title":"The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors","volume":"11","author":"Kawai","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"E131\u2013136","DOI":"10.1038\/ncb0502-e131","article-title":"AP-1 as a regulator of cell life and death","volume":"4","author":"Shaulian","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/ncb822","article-title":"Molecular interpretation of ERK signal duration by imme-diate early gene products","volume":"4","author":"Murphy","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ceb.2007.02.001","article-title":"The JNK signal transduction pathway","volume":"19","author":"Weston","year":"2007","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S0168-9525(97)01181-5","article-title":"Cytosine methylation and the ecology of intragenomic parasites","volume":"13","author":"Yoder","year":"1997","journal-title":"Trends Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/2413","article-title":"Transcription of IAP endogenous retroviruses is constrained by cytosine methylation","volume":"20","author":"Walsh","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4743","DOI":"10.1093\/nar\/gkm455","article-title":"Widely variable endogenous retroviral methylation levels in human placenta","volume":"35","author":"Reiss","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1101\/gr.233585.117","article-title":"LTRs activated by Epstein-Barr virus-induced transfor-mation of B cells alter the transcriptome","volume":"28","author":"Leung","year":"2018","journal-title":"Genome Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1126\/science.1063443","article-title":"Epigenetic reprogramming in mammalian development","volume":"293","author":"Reik","year":"2001","journal-title":"Science"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41580-019-0159-6","article-title":"The diverse roles of DNA methylation in mammalian development and disease","volume":"20","author":"Greenberg","year":"2019","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.molcel.2012.11.001","article-title":"The dynam-ics of genome-wide DNA methylation reprogramming in mouse primordial germ cells","volume":"48","author":"Seisenberger","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1126\/science.1229277","article-title":"Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine","volume":"339","author":"Hackett","year":"2013","journal-title":"Science"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/B978-0-12-416027-9.00005-X","article-title":"Primordial germ-cell development and epigenetic reprogramming in mammals","volume":"104","author":"Leitch","year":"2013","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/nature22812","article-title":"Principles of early human development and germ cell program from conserved model systems","volume":"546","author":"Kobayashi","year":"2017","journal-title":"Nature"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1098\/rstb.2011.0042","article-title":"Epigenetic reprogramming in the germline: Towards the ground state of the epigenome","volume":"366","author":"Hajkova","year":"2011","journal-title":"Philos. Trans. R Soc. Lond. B Biol. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1242\/dev.129.8.1807","article-title":"Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells","volume":"129","author":"Lee","year":"2002","journal-title":"Development"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0925-4773(02)00181-8","article-title":"Epigenetic reprogramming in mouse primordial germ cells","volume":"117","author":"Hajkova","year":"2002","journal-title":"Mech. Dev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/brain\/122.1.27","article-title":"Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological dis-orders","volume":"122","author":"Dalmau","year":"1999","journal-title":"Brain"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1002\/ana.1288","article-title":"Molecular and clinical diversity in paraneoplastic immunity to Ma proteins","volume":"50","author":"Rosenfeld","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.jneuroim.2005.08.019","article-title":"The human PNMA family: Novel neuronal proteins implicated in paraneoplastic neurological disease","volume":"169","author":"Jenne","year":"2005","journal-title":"J. Neuroimmunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/s43587-025-00852-y","article-title":"The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity","volume":"5","author":"Wood","year":"2025","journal-title":"Nat. Aging"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.1002\/ajmg.a.32472","article-title":"Evidence that SIZN1 is a candidate X-linked mental retardation gene","volume":"146A","author":"Cho","year":"2008","journal-title":"Am. J. Med. Genet."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ajhg.2011.05.028","article-title":"Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth","volume":"89","author":"Hanson","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1159\/000334392","article-title":"The genetics of 3-m syndrome: Unravelling a potential new regulatory growth pathway","volume":"76","author":"Hanson","year":"2011","journal-title":"Horm. Res. Paediatr."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/s41588-023-01324-y","article-title":"Transcription of MERVL retrotransposons is required for preimplantation embryo development","volume":"55","author":"Sakashita","year":"2023","journal-title":"Nat. Genet."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/s41586-025-09571-1","article-title":"A human-specific regulatory mechanism revealed in a pre-implantation model","volume":"647","author":"Fueyo","year":"2025","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"eadv5257","DOI":"10.1126\/science.adv5257","article-title":"Endogenous retroviruses synthesize heterologous chimeric RNAs to reinforce human early embryo development","volume":"391","author":"Xiang","year":"2026","journal-title":"Science"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1742-4690-1-32","article-title":"Identification of endogenous retroviral reading frames in the human genome","volume":"1","author":"Villesen","year":"2004","journal-title":"Retrovirology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/1742-4690-8-90","article-title":"Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses","volume":"8","author":"Subramanian","year":"2011","journal-title":"Retrovirology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"baw087","DOI":"10.1093\/database\/baw087","article-title":"gEVE: A genome-based endogenous viral element database provides comprehensive viral pro-tein-coding sequences in mammalian genomes","volume":"2016","author":"Nakagawa","year":"2016","journal-title":"Database"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6322\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T07:55:32Z","timestamp":1784534132000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6322"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":94,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146322"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146322","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]}}}