{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:48:18Z","timestamp":1785419298719,"version":"3.56.0"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T00:00:00Z","timestamp":1663545600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T00:00:00Z","timestamp":1663545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Genet Genomics"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Timelines of population-level effects of viruses on humans varied from the evolutionary scale of million years to contemporary spread of viral infections. Correspondingly, these events are exemplified by: (i) emergence of human endogenous retroviruses (HERVs) from ancient germline infections leading to stable integration of viral genomes into human chromosomes; and (ii) wide-spread viral infections reaching a global pandemic state such as the COVID-19 pandemic. Despite significant efforts, understanding of HERV\u2019s roles in governance of genomic regulatory networks, their impacts on primate evolution and development of human-specific physiological and pathological phenotypic traits remains limited. Remarkably, present analyses revealed that expression of a dominant majority of genes (1696 of 1944 genes; 87%) constituting high-confidence down-steam regulatory targets of defined HERV loci was significantly altered in cells infected with the SARS-CoV-2 coronavirus, a pathogen causing the global COVID-19 pandemic. This study focused on defined sub-sets of DNA sequences derived from HERVs that are expressed at specific stages of human preimplantation embryogenesis and exert regulatory actions essential for self-renewal and pluripotency. Evolutionary histories of LTR7\/HERVH and LTR5_Hs\/HERVK were charted based on evidence of the earliest presence and expansion of highly conserved (HC) LTR sequences. Sequence conservation analyses of most recent releases 17 primate species\u2019 genomes revealed that LTR7\/HERVH have entered germlines of primates in Africa after the separation of the New World Monkey lineage, while LTR5_Hs\/HERVK successfully colonized primates\u2019 germlines after the segregation of Gibbons\u2019 species. Subsequently, both LTR7 and LTR5_Hs undergo a marked\u2009~\u2009fourfold\u2013fivefold expansion in genomes of Great Apes. Timelines of quantitative expansion of both LTR7 and LTR5_Hs loci during evolution of Great Apes appear to replicate the consensus evolutionary sequence of increasing cognitive and behavioral complexities of non-human primates, which seems particularly striking for LTR7 loci and 11 distinct LTR7 subfamilies. Consistent with previous reports, identified in this study, 351 human-specific (HS) insertions of LTR7 (175 loci) and LTR5_Hs (176 loci) regulatory sequences have been linked to genes implicated in establishment and maintenance of na\u00efve and primed pluripotent states and preimplantation embryogenesis phenotypes. Unexpectedly, HS-LTRs manifest regulatory connectivity to genes encoding markers of 12 distinct cells\u2019 populations of fetal gonads, as well as genes implicated in physiology and pathology of human spermatogenesis, including Y-linked spermatogenic failure, oligo- and azoospermia. Granular interrogations of genes linked with 11 distinct LTR7 subfamilies revealed that mammalian offspring survival (MOS) genes seem to remain one of consistent regulatory targets throughout\u2009~\u200930 MYA of the divergent evolution of LTR7 loci. Differential GSEA of MOS versus non-MOS genes identified clearly discernable dominant enrichment patterns of phenotypic traits affected by MOS genes linked with LTR7 (562 MOS genes) and LTR5_Hs (126 MOS genes) regulatory loci across the large panel of genomics and proteomics databases reflecting a broad spectrum of human physiological and pathological traits. GSEA of LTR7-linked MOS genes identified more than 2200 significantly enriched records of human common and rare diseases and gene signatures of 466 significantly enriched records of Human Phenotype Ontology traits, including Autosomal Dominant (92 genes) and Autosomal Recessive (93 genes) Inheritance. LTR7 regulatory elements appear linked with genes implicated in functional and morphological features of central nervous system, including synaptic transmission and protein\u2013protein interactions at synapses, as well as gene signatures differentially regulated in cells of distinct neurodevelopmental stages and morphologically diverse cell types residing and functioning in human brain. These include Neural Stem\/Precursor cells, Radial Glia cells, Bergman Glia cells, Pyramidal cells, Tanycytes, Immature neurons, Interneurons, Trigeminal neurons, GABAergic neurons, and Glutamatergic neurons. GSEA of LTR7-linked genes identified significantly enriched gene sets encoding markers of more than 80 specialized types of neurons and markers of 521 human brain regions, most prominently, subiculum and dentate gyrus. Identification and characterization of 1944 genes comprising high-confidence down-steam regulatory targets of LTR7 and\/or LTR5_Hs loci validated and extended these observations by documenting marked enrichments for genes implicated in neoplasm metastasis, intellectual disability, autism, multiple cancer types, Alzheimer\u2019s, schizophrenia, and other brain disorders. Overall, genes representing down-stream regulatory targets of ancient retroviral LTRs exert the apparently cooperative and exceedingly broad phenotypic impacts on human physiology and pathology. This is exemplified by altered expression of 93% high-confidence LTR targets in cells infected by contemporary viruses, revealing a convergence of virus-inflicted aberrations on genomic regulatory circuitry governed by ancient retroviral LTR elements and interference with human cells\u2019 differentiation programs.<\/jats:p>","DOI":"10.1007\/s00438-022-01954-7","type":"journal-article","created":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T11:02:58Z","timestamp":1663585378000},"page":"1711-1740","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Molecular diversity and phenotypic pleiotropy of ancient genomic regulatory loci derived from human endogenous retrovirus type H (HERVH) promoter LTR7 and HERVK promoter LTR5_Hs and their contemporary impacts on pathophysiology of Modern Humans"],"prefix":"10.1007","volume":"297","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2523-8264","authenticated-orcid":false,"given":"Gennadi V.","family":"Glinsky","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,19]]},"reference":[{"issue":"6","key":"1954_CR1","doi-asserted-by":"publisher","first-page":"1588","DOI":"10.1073\/pnas.1515798113","volume":"113","author":"G Amster","year":"2016","unstructured":"Amster G, Sella G (2016) Life history effects on the molecular clock of autosomes and sex chromosomes. Proc Natl Acad Sci U S A 113(6):1588\u20131593","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"1954_CR2","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1186\/s12864-021-08085-0","volume":"22","author":"MI Autio","year":"2021","unstructured":"Autio MI, Bin Amin T, Perrin A, Wong JY, Foo RS, Prabhakar S (2021) Transposable elements that have recently been mobile in the human genome. BMC Genomics 22(1):789. https:\/\/doi.org\/10.1186\/s12864-021-08085-0 (PMID: 34732136)","journal-title":"BMC Genomics"},{"key":"1954_CR3","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s13100-015-0041-9","volume":"6","author":"W Bao","year":"2015","unstructured":"Bao W, Kojima KK, Kohany O (2015) Repbase update, a database of repetitive elements in eukaryotic genomes. Mob DNA 6:11. https:\/\/doi.org\/10.1186\/s13100-015-0041-9","journal-title":"Mob DNA"},{"key":"1954_CR4","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/j.stem.2018.06.014","volume":"23","author":"TS Barakat","year":"2018","unstructured":"Barakat TS, Halbritter F, Zhang M, Rendeiro AF, Perenthaler E, Bock C, Chambers I (2018) Functional dissection of the enhancer repertoire in human embryonic stem cells. Cell Stem Cell 23:276\u2013288","journal-title":"Cell Stem Cell"},{"key":"1954_CR5","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/S0960-9822(99)80390-X","volume":"9","author":"M Barbulescu","year":"1999","unstructured":"Barbulescu M, Turner G, Seaman MI, Deinard AS, Kidd KK, Lenz J (1999) Many human endogenous retrovirus K (HERV-K) proviruses are unique to humans. Curr Biol 9:861\u2013868","journal-title":"Curr Biol"},{"key":"1954_CR6","doi-asserted-by":"publisher","first-page":"12507","DOI":"10.1128\/JVI.79.19.12507-12514.2005","volume":"79","author":"R Belshaw","year":"2005","unstructured":"Belshaw R, Dawson AL, Woolven-Allen J, Redding J, Burt A, Tristem M (2005) Genomewide screening reveals high levels of insertional polymorphism in the human endogenous retrovirus family HERV-K(HML2): implications for present-day activity. J Virol 79:12507\u201312514","journal-title":"J Virol"},{"key":"1954_CR7","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1086\/406830","volume":"46","author":"RJ Britten","year":"1971","unstructured":"Britten RJ, Davidson EH (1971) Repetitive and non-repetitive DNA sequences and a speculation on the origins of evolutionary novelty. Q Rev Biol 46:111\u2013138","journal-title":"Q Rev Biol"},{"key":"1954_CR8","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1038\/nrmicro1263","volume":"3","author":"F Bushman","year":"2005","unstructured":"Bushman F et al (2005) Genome-wide analysis of retroviral DNA integration. Nat Rev Microbiol 3:848\u2013858","journal-title":"Nat Rev Microbiol"},{"key":"1954_CR9","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/nature13679","volume":"513","author":"L Carbone","year":"2014","unstructured":"Carbone L et al (2014) Gibbon genome and the fast karyotype evolution of small apes. Nature 513:195\u2013201","journal-title":"Nature"},{"issue":"11","key":"1954_CR10","doi-asserted-by":"publisher","first-page":"e76257","DOI":"10.7554\/eLife.76257","volume":"18","author":"T Carter","year":"2022","unstructured":"Carter T, Singh M, Dumbovic G, Chobirko JD, Rinn JL, Feschotte C (2022) Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo. Elife 18(11):e76257. https:\/\/doi.org\/10.7554\/eLife.76257 (Epub ahead of print. PMID: 35179489)","journal-title":"Elife"},{"issue":"1","key":"1954_CR11","first-page":"13","volume":"6","author":"A Cereseto","year":"2004","unstructured":"Cereseto A, Giacca M (2004) Integration site selection by retroviruses. AIDS Rev 6(1):13\u201321","journal-title":"AIDS Rev"},{"key":"1954_CR12","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/1471-2105-14-128","volume":"14","author":"EY Chen","year":"2013","unstructured":"Chen EY et al (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform 14:128","journal-title":"BMC Bioinform"},{"issue":"558\u2013566","key":"1954_CR13","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1038\/ng.2965","volume":"46","author":"A Fort","year":"2014","unstructured":"Fort A, Hashimoto K, Yamada D, Salimullah M, Keya CA, Saxena A, Bonetti A, Voineagu I, Bertin N, Kratz A, Noro Y, Wong C-H, de Hoon M, Andersson R, Sandelin A, Suzuki H, Wei C-L, Koseki H, Hasegawa Y, Forrest ARR, Carninci P (2014) Deep transcriptome profiling of mammalian stem cells supports a regulatory role for retrotransposons in pluripotency maintenance. Nat Genet 46(558\u2013566):1015. https:\/\/doi.org\/10.1038\/ng.2965","journal-title":"Nat Genet"},{"issue":"7","key":"1954_CR14","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.35989","volume":"2","author":"DR Fuentes","year":"2018","unstructured":"Fuentes DR, Swigut T, Wysocka J (2018) Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation. Elife 2(7):e35989. https:\/\/doi.org\/10.7554\/eLife.35989 (PMID:30070637;PMCID:PMC6158008)","journal-title":"Elife"},{"key":"1954_CR15","doi-asserted-by":"publisher","DOI":"10.1186\/s12977-015-0172-6","author":"P Gemmell","year":"2015","unstructured":"Gemmell P, Hein J, Katzourakis A (2015) Orthologous endogenous retroviruses exhibit directional selection since the chimp-human split. Retrovirology. https:\/\/doi.org\/10.1186\/s12977-015-0172-6","journal-title":"Retrovirology"},{"key":"1954_CR16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01339","author":"P Gemmell","year":"2019","unstructured":"Gemmell P, Hein J, Katzourakis A (2019) The exaptation of HERV-H: evolutionary analyses reveal the genomic features of highly transcribed elements. Front Immunol. https:\/\/doi.org\/10.3389\/fimmu.2019.01339","journal-title":"Front Immunol"},{"key":"1954_CR17","doi-asserted-by":"publisher","first-page":"E611","DOI":"10.1073\/pnas.1217134110","volume":"110","author":"GC Gibb","year":"2013","unstructured":"Gibb GC, Hills SFK (2013) Intergenerational mutation rate does not equal long-term evolutionary substitution rate. Proc Natl Acad Sci USA 110:E611\u2013E611","journal-title":"Proc Natl Acad Sci USA"},{"issue":"6","key":"1954_CR18","doi-asserted-by":"publisher","first-page":"925","DOI":"10.4161\/cc.8.6.7937","volume":"8","author":"GV Glinsky","year":"2009","unstructured":"Glinsky GV (2009) Human genome connectivity code links disease-associated SNPs, microRNAs and pyknons. Cell Cycle 8(6):925\u2013930","journal-title":"Cell Cycle"},{"key":"1954_CR19","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1093\/gbe\/evv081","volume":"7","author":"GV Glinsky","year":"2015","unstructured":"Glinsky GV (2015) Transposable elements and DNA methylation create in embryonic stem cells human- specific regulatory sequences associated with distal enhancers and noncoding RNAs. Genome Biol Evol 7:1432\u20131454. https:\/\/doi.org\/10.1093\/gbe\/evv081","journal-title":"Genome Biol Evol"},{"key":"1954_CR20","doi-asserted-by":"publisher","first-page":"2774","DOI":"10.1093\/gbe\/evw185","volume":"8","author":"GV Glinsky","year":"2016","unstructured":"Glinsky GV (2016a) Mechanistically distinct pathways of divergent regulatory DNA creation contribute to evolution of human-specific genomic regulatory networks driving phenotypic divergence of homo sapiens. Genome Biol Evol 8:2774\u20132788","journal-title":"Genome Biol Evol"},{"key":"1954_CR21","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.canlet.2016.08.001","volume":"381","author":"GV Glinsky","year":"2016","unstructured":"Glinsky GV (2016b) Single cell genomics reveals activation signatures of endogenous SCARS networks in aneuploid human embryos and clinically intractable malignant tumors. Cancer Lett 381:176\u2013193","journal-title":"Cancer Lett"},{"key":"1954_CR22","doi-asserted-by":"publisher","DOI":"10.1101\/022913v3","author":"GV Glinsky","year":"2017","unstructured":"Glinsky GV (2017) Human-specific features of pluripotency regulatory networks link NANOG with fetal and adult brain development. BioRxiv. https:\/\/doi.org\/10.1101\/022913v3","journal-title":"BioRxiv"},{"key":"1954_CR23","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1089\/dna.2019.4988","volume":"39","author":"GV Glinsky","year":"2020","unstructured":"Glinsky GV (2020a) A catalogue of 59,732 human-specific regulatory sequences reveals unique to human regulatory patterns associated with virus-interacting proteins, pluripotency and brain development. DNA Cell Biol 39:126\u2013143. https:\/\/doi.org\/10.1089\/dna.2019.4988","journal-title":"DNA Cell Biol"},{"key":"1954_CR24","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1007\/s10577-020-09639-w","volume":"28","author":"GV Glinsky","year":"2020","unstructured":"Glinsky GV (2020b) Impacts of genomic networks governed by human-specific regulatory sequences and genetic loci harboring fixed human-specific neuro-regulatory single nucleotide mutations on phenotypic traits of Modern Humans. Chromosom Res 28:331\u2013354. https:\/\/doi.org\/10.1007\/s10577-020-09639-w","journal-title":"Chromosom Res"},{"key":"1954_CR25","doi-asserted-by":"publisher","first-page":"129","DOI":"10.3390\/biomedicines8050129","volume":"8","author":"GV Glinsky","year":"2020","unstructured":"Glinsky GV (2020c) Tripartite combination of candidate pandemic mitigation agents: vitamin D, quercetin, and estradiol manifest properties of medicinal agents for targeted mitigation of the COVID-19 pandemic defined by genomics-guided tracing of SARS-CoV-2 targets in human cells. Biomedicines 8:129. https:\/\/doi.org\/10.3390\/biomedicines8050129","journal-title":"Biomedicines"},{"key":"1954_CR26","doi-asserted-by":"publisher","first-page":"974","DOI":"10.3389\/fonc.2021.638363","volume":"11","author":"GV Glinsky","year":"2021","unstructured":"Glinsky GV (2021) Genomics-guided drawing of molecular and pathophysiological components of malignant regulatory signatures reveals a pivotal role in human diseases of stem cell-associated retroviral sequences and functionally-active hESC enhancers. Front Oncol 11:974. https:\/\/doi.org\/10.3389\/fonc.2021.638363","journal-title":"Front Oncol"},{"key":"1954_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2019.101456","volume":"37","author":"GV Glinsky","year":"2019","unstructured":"Glinsky GV, Barakat TS (2019) The evolution of great apes has shaped the functional enhancers\u2019 landscape in human embryonic stem cells. Stem Cell Res 37:101456","journal-title":"Stem Cell Res"},{"issue":"6","key":"1954_CR28","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2018.e00667","volume":"4","author":"G Glinsky","year":"2018","unstructured":"Glinsky G, Durruthy-Durruthy J, Wossidlo M, Grow EJ, Weirather JL, Au KF, Wysocka J, Sebastiano V (2018) Single cell expression analysis of primate-specific retroviruses-derived HPAT lincRNAs in viable human blastocysts identifies embryonic cells co-expressing genetic markers of multiple lineages. Heliyon 4(6):e00667. https:\/\/doi.org\/10.1016\/j.heliyon.2018.e00667 (PMID:30003161;PMCID:PMC6039856)","journal-title":"Heliyon"},{"key":"1954_CR29","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.stem.2015.01.005","volume":"16","author":"J G\u00f6ke","year":"2015","unstructured":"G\u00f6ke J, Lu X, Chan Y-S, Ng H-H, Ly L-H, Sachs F, Szczerbinska I (2015) Dynamic transcription of distinct classes of endogenous retroviral elements marks specific populations of early human embryonic cells. 1052 Cell Stem Cell 16:135\u2013141. https:\/\/doi.org\/10.1016\/j.stem.2015.01.005","journal-title":"1052 Cell Stem Cell"},{"key":"1954_CR30","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1006\/viro.1993.1535","volume":"196","author":"NL Goodchild","year":"1993","unstructured":"Goodchild NL, Wilkinson DA, Mager DL (1993) Recent evolutionary expansion of a subfamily of RTVL-H human endogenous retrovirus-like elements. Virology 196:778\u2013788. https:\/\/doi.org\/10.1006\/viro.1993.1535","journal-title":"Virology"},{"key":"1954_CR31","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1038\/nature14308","volume":"522","author":"EJ Grow","year":"2015","unstructured":"Grow EJ, Flynn RA, Chavez SL, Bayless NL, Wossidlo M, Wesche DJ, Martin L, Ware CB, Blish CA, Chang HY, Pera RA, Wysocka J (2015) Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature 522:221\u2013225. https:\/\/doi.org\/10.1038\/nature14308 (PMID: 25896322)","journal-title":"Nature"},{"key":"1954_CR32","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.1093\/molbev\/msy143","volume":"35","author":"G Guffanti","year":"2018","unstructured":"Guffanti G, Bartlett A, Klengel T, Klengel C, Hunter R, Glinsky G, Macciardi F (2018) Novel bioinformatics approach identifies transcriptional profiles of lineage-specific transposable elements at distinct loci in the human dorsolateral prefrontal cortex. Mol Biol Evol 35:2435\u20132453","journal-title":"Mol Biol Evol"},{"key":"1954_CR33","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1111\/apm.12475","volume":"124","author":"K Hanke","year":"2016","unstructured":"Hanke K, Hohn O, Bannert N (2016) HERV-K (HML-2), a seemingly silent subtenant - but still waters run deep. APMIS 124:67\u201387. https:\/\/doi.org\/10.1111\/apm.12475","journal-title":"APMIS"},{"key":"1954_CR34","doi-asserted-by":"publisher","first-page":"3439","DOI":"10.1073\/pnas.1418652112","volume":"112","author":"K Harris","year":"2015","unstructured":"Harris K (2015) Evidence for recent, population-specific evolution of the human mutation rate. Proc Natl Acad Sci USA 112:3439\u20133444","journal-title":"Proc Natl Acad Sci USA"},{"key":"1954_CR35","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1073\/pnas.0307885100","volume":"101","author":"JF Hughes","year":"2004","unstructured":"Hughes JF, Coffin JM (2004) Human endogenous retrovirus K solo-LTR formation and insertional polymorphisms: implications for human and viral evolution. Proc Natl Acad Sci 101:1668\u20131672","journal-title":"Proc Natl Acad Sci"},{"issue":"7","key":"1954_CR36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006883","volume":"13","author":"J Ito","year":"2017","unstructured":"Ito J, Sugimoto R, Nakaoka H, Yamada S, Kimura T, Hayano T, Inoue I (2017) Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses. PLoS Genet 13(7):e1006883. https:\/\/doi.org\/10.1371\/journal.pgen.1006883","journal-title":"PLoS Genet"},{"issue":"5","key":"1954_CR37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009846","volume":"18","author":"J Ito","year":"2022","unstructured":"Ito J, Seita Y, Kojima S, Parrish NF, Sasaki K, Sato K (2022) A hominoid-specific endogenous retrovirus may have rewired the gene regulatory network shared between primordial germ cells and na\u00efve pluripotent cells. PLoS Genet 18(5):e1009846. https:\/\/doi.org\/10.1371\/journal.pgen.1009846","journal-title":"PLoS Genet"},{"key":"1954_CR38","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1002\/bies.201500096","volume":"38","author":"Z Izsv\u00e1k","year":"2016","unstructured":"Izsv\u00e1k Z, Wang J, Singh M, Mager DL, Hurst LD (2016) Pluripotency and the endogenous retrovirus HERVH: conflict or serendipity? BioEssays 38:109\u2013117. https:\/\/doi.org\/10.1002\/bies.201500096","journal-title":"BioEssays"},{"key":"1954_CR39","doi-asserted-by":"publisher","first-page":"R107","DOI":"10.1186\/gb-2012-13-11-r107","volume":"13","author":"D Kelley","year":"2012","unstructured":"Kelley D, Rinn J (2012) Transposable elements reveal a stem cell-specific class of long noncoding RNAs. Genome Biol 13:R107. https:\/\/doi.org\/10.1186\/gb-2012-13-11-r107","journal-title":"Genome Biol"},{"key":"1954_CR40","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s13100-017-0107-y","volume":"9","author":"KK Kojima","year":"2018","unstructured":"Kojima KK (2018) Human transposable elements in repbase: genomic footprints from fish to humans. Mob DNA 9:2. https:\/\/doi.org\/10.1186\/s13100-017-0107-y","journal-title":"Mob DNA"},{"key":"1954_CR41","doi-asserted-by":"publisher","first-page":"eaar6343","DOI":"10.1126\/science.aar6343","volume":"360","author":"ZN Kronenberg","year":"2018","unstructured":"Kronenberg ZN et al (2018) High-resolution comparative analysis of great ape genomes. Science 360:eaar6343","journal-title":"Science"},{"issue":"W1","key":"1954_CR42","doi-asserted-by":"publisher","first-page":"W90","DOI":"10.1093\/nar\/gkw377","volume":"44","author":"MV Kuleshov","year":"2016","unstructured":"Kuleshov MV et al (2016) Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 44(W1):W90\u2013W97","journal-title":"Nucleic Acids Res"},{"key":"1954_CR43","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1038\/ng.600","volume":"42","author":"G Kunarso","year":"2010","unstructured":"Kunarso G, Chia N-Y, Jeyakani J, Hwang C, Lu X, Chan Y-S, Ng H-H, Bourque G (2010) Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat Genet 42:631\u2013634. https:\/\/doi.org\/10.1038\/ng.600","journal-title":"Nat Genet"},{"issue":"39","key":"1954_CR44","doi-asserted-by":"publisher","first-page":"15716","DOI":"10.1073\/pnas.1211740109","volume":"109","author":"KE Langergraber","year":"2012","unstructured":"Langergraber KE et al (2012) Generation times in wild chimpanzees and gorillas suggest earlier divergence times in great ape and human evolution. Proc Natl Acad Sci U S A 109(39):15716\u201315721","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1113\u20131117","key":"1954_CR45","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1038\/ng.710","volume":"42","author":"S Loewer","year":"2010","unstructured":"Loewer S, Cabili MN, Guttman M, Loh Y-H, Thomas K, Park IH, Garber M, Curran M, Onder T, Agarwal S, Manos PD, Datta S, Lander ES, Schlaeger TM, Daley GQ, Rinn JL (2010) Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet 42(1113\u20131117):1131. https:\/\/doi.org\/10.1038\/ng.710","journal-title":"Nat Genet"},{"key":"1954_CR46","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/nsmb.2799","volume":"21","author":"X Lu","year":"2014","unstructured":"Lu X, Sachs F, Ramsay L, Jacques P-\u00c9, G\u00f6ke J, Bourque G, Ng H-H (2014) The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity. Nat Struct Mol Biol 21:423\u2013425. https:\/\/doi.org\/10.1038\/nsmb.2799","journal-title":"Nat Struct Mol Biol"},{"key":"1954_CR47","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1006\/viro.1995.0012","volume":"213","author":"DL Mager","year":"1995","unstructured":"Mager DL, Freeman JD (1995) HERV-H endogenous retroviruses: presence in the new world branch but amplification in the old world primate lineage. Virology 213:395\u2013404. https:\/\/doi.org\/10.1006\/viro.1995.0012","journal-title":"Virology"},{"key":"1954_CR48","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nbt.1630","volume":"28","author":"CY McLean","year":"2010","unstructured":"McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, Wenger AM, Bejerano G (2010) GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol 28:495\u2013501","journal-title":"Nat Biotechnol"},{"key":"1954_CR49","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/nature09774","volume":"471","author":"CY McLean","year":"2011","unstructured":"McLean CY, Reno PL, Pollen AA, Bassan AI, Capellini TD, Guenther C, Indjeian VB, Lim X, Menke DB, Schaar BT, Wenger AM, Bejerano G, Kingsley DM (2011) Human-specific loss of regulatory DNA and the evolution of human-specific traits. Nature 471:216\u2013219","journal-title":"Nature"},{"issue":"38","key":"1954_CR50","doi-asserted-by":"publisher","first-page":"10607","DOI":"10.1073\/pnas.1600374113","volume":"113","author":"P Moorjani","year":"2016","unstructured":"Moorjani P, Amorim CE, Arndt PF, Przeworski M (2016) Variation in the molecular clock of primates. Proc Natl Acad Sci U S A 113(38):10607\u201310612","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1954_CR51","doi-asserted-by":"publisher","first-page":"12426","DOI":"10.1073\/pnas.1413299111","volume":"111","author":"M Ohnuki","year":"2014","unstructured":"Ohnuki M, Tanabe K, Sutou K, Teramoto I, Sawamura Y, Narita M, Michiko N, Tokunaga Y, Masahiro N, Watanabe A, Yamanaka S, Takahashi K (2014) Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential. Proc Natl Acad Sci USA 111:12426\u201312431. https:\/\/doi.org\/10.1073\/pnas.1413299111","journal-title":"Proc Natl Acad Sci USA"},{"key":"1954_CR52","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1016\/j.stem.2019.03.012","volume":"24","author":"J Pontis","year":"2019","unstructured":"Pontis J, Planet E, Offner S, Turelli P, Duc J, Coudray A, Theunissen TW, Jaenisch R, Trono D (2019) Hominoid-specific transposable elements and KZFPs facilitate human embryonic genome activation and control transcription in naive human ESCs. Cell Stem Cell 24:724-735.e5. https:\/\/doi.org\/10.1016\/j.stem.2019.03.012","journal-title":"Cell Stem Cell"},{"key":"1954_CR53","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/nature12886","volume":"505","author":"K Pr\u00fcfer","year":"2014","unstructured":"Pr\u00fcfer K et al (2014) The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505:43\u201349","journal-title":"Nature"},{"key":"1954_CR54","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1126\/science.aao1887","volume":"358","author":"K Pr\u00fcfer","year":"2017","unstructured":"Pr\u00fcfer K et al (2017) A high-coverage Neandertal genome from Vindija Cave in Croatia. Science 358:655\u2013658","journal-title":"Science"},{"key":"1954_CR55","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.coviro.2017.07.001","volume":"25","author":"C R\u00f6mer","year":"2017","unstructured":"R\u00f6mer C, Singh M, Hurst LD, Izsv\u00e1k Z (2017) How to tame an endogenous retrovirus: HERVH and the evolution of human pluripotency. Curr Opin Virol Anim Models Viral Dis Paleovirol 25:49\u201358. https:\/\/doi.org\/10.1016\/j.coviro.2017.07.001","journal-title":"Curr Opin Virol Anim Models Viral Dis Paleovirol"},{"key":"1954_CR56","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/1742-4690-9-111","volume":"9","author":"FA Santoni","year":"2012","unstructured":"Santoni FA, Guerra J, Luban J (2012) HERV-H RNA is abundant in human embryonic stem cells and a precise marker for pluripotency. Retrovirology 9:111. https:\/\/doi.org\/10.1186\/1742-4690-9-111","journal-title":"Retrovirology"},{"issue":"29","key":"1954_CR57","doi-asserted-by":"publisher","first-page":"0776","DOI":"10.1126\/sciadv.abc0776","volume":"7","author":"NK Schaefer","year":"2021","unstructured":"Schaefer NK, Shapiro B, Green RE (2021) An ancestral recombination graph of human, Neanderthal, and Denisovan genomes. Sci Adv 7(29):0776. https:\/\/doi.org\/10.1126\/sciadv.abc0776","journal-title":"Sci Adv"},{"key":"1954_CR58","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/S0092-8674(02)00864-4","volume":"110","author":"AR Schr\u00f6der","year":"2002","unstructured":"Schr\u00f6der AR et al (2002) HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110:521\u2013529","journal-title":"Cell"},{"key":"1954_CR59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0060605","volume":"8","author":"W Shin","year":"2013","unstructured":"Shin W, Lee J, Son SY, Ahn K, Kim HS, Han K (2013) Human-specific HERV-K insertion causes genomic variations in the human genome. PLoS ONE 8:e60605. https:\/\/doi.org\/10.1371\/journal.pone.0060605 (PMID: 23593260)","journal-title":"PLoS ONE"},{"key":"1954_CR60","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s13100-1214020-00230-y","volume":"12","author":"J Storer","year":"2021","unstructured":"Storer J, Hubley R, Rosen J, Wheeler TJ, Smit AF (2021) The Dfam community resource of transposable element families, sequence models, and genome annotations. Mob DNA 12:2. https:\/\/doi.org\/10.1186\/s13100-1214020-00230-y","journal-title":"Mob DNA"},{"key":"1954_CR61","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1186\/1742-4690-8-90","volume":"8","author":"RP Subramanian","year":"2011","unstructured":"Subramanian RP, Wildschutte JH, Russo C, Coffin JM (2011) Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 8:90. https:\/\/doi.org\/10.1186\/1742-4690-8-90","journal-title":"Retrovirology"},{"key":"1954_CR62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009587","volume":"17","author":"K Takahashi","year":"2021","unstructured":"Takahashi K, Nakamura M, Okubo C, Kliesmete Z, Ohnuki M, Narita M, Watanabe A, Ueda M, Takashima Y, Hellmann I, Yamanaka S (2021) The pluripotent stem cell-specific transcript ESRG is dispensable for human pluripotency. PLoS Genet 17:e1009587. https:\/\/doi.org\/10.1371\/journal.pgen.1009587","journal-title":"PLoS Genet"},{"key":"1954_CR63","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1038\/10343","volume":"22","author":"S Tavazoie","year":"1999","unstructured":"Tavazoie S, Hughes JD, Campbell MJ, Cho RJ, Church GM (1999) Systematic determination of genetic network architecture. Nat Genet 22:281\u2013285","journal-title":"Nat Genet"},{"key":"1954_CR64","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1016\/j.stem.2016.06.011","volume":"19","author":"TW Theunissen","year":"2016","unstructured":"Theunissen TW, Friedli M, He Y, Planet E, O\u2019Neil RC, Markoulaki S, Pontis J, Wang H, Iouranova A, Imbeault M, Duc J, Cohen MA, Wert KJ, Castanon R, Zhang Z, Huang Y, Nery JR, Drotar J, Lungjangwa T, Trono D, Ecker JR, Jaenisch R (2016) Molecular criteria for defining the naive human pluripotent state. Cell Stem Cell 19:502\u2013515. https:\/\/doi.org\/10.1016\/j.stem.2016.06.011","journal-title":"Cell Stem Cell"},{"key":"1954_CR65","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s13100-018-0142-3","volume":"9","author":"J Thomas","year":"2018","unstructured":"Thomas J, Perron H, Feschotte C (2018) Variation in proviral content among human genomes mediated by LTR recombination. Mob DNA 9:36. https:\/\/doi.org\/10.1186\/s13100-018-0142-3","journal-title":"Mob DNA"},{"key":"1954_CR66","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1016\/S0960-9822(01)00455-9","volume":"11","author":"G Turner","year":"2001","unstructured":"Turner G, Barbulescu M, Su M, Jensen-Seaman MI, Kidd KK, Lenz J (2001) Insertional polymorphisms of full-length endogenous retroviruses in humans. Curr Biol 11:1531\u20131535","journal-title":"Curr Biol"},{"key":"1954_CR67","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s12977-015-0232-y","volume":"13","author":"L Vargiu","year":"2016","unstructured":"Vargiu L, Rodriguez-Tom\u00e9 P, Sperber GO, Cadeddu M, Grandi N, Blikstad V, Tramontano E, Blomberg J (2016) Classification and characterization of human endogenous retroviruses; mosaic forms are common. Retrovirology 13:7. https:\/\/doi.org\/10.1186\/s12977-015-0232-y","journal-title":"Retrovirology"},{"issue":"405\u2013409","key":"1954_CR68","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1038\/nature13804","volume":"516","author":"J Wang","year":"2014","unstructured":"Wang J, Xie G, Singh M, Ghanbarian AT, Rask\u00f3 T, Szvetnik A, Cai H, Besser D, Prigione A, Fuchs NV, Schumann GG, Chen W, Lorincz MC, Ivics Z, Hurst LD, Izsv\u00e1k Z (2014) Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells. Nature 516(405\u2013409):1248. https:\/\/doi.org\/10.1038\/nature13804","journal-title":"Nature"},{"key":"1954_CR69","doi-asserted-by":"publisher","first-page":"E2326","DOI":"10.1073\/pnas.1602336113","volume":"113","author":"JH Wildschutte","year":"2016","unstructured":"Wildschutte JH, Williams ZH, Montesion M, Subramanian RP, Kidd JM, Coffin JM (2016) Discovery of unfixed endogenous retrovirus insertions in diverse human populations. Proc Natl Acad Sci USA 113:E2326\u2013E2334. https:\/\/doi.org\/10.1073\/pnas.1602336113 (PMID: 27001843)","journal-title":"Proc Natl Acad Sci USA"},{"key":"1954_CR70","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1002\/cpz1.90","volume":"1","author":"Z Xie","year":"2021","unstructured":"Xie Z, Bailey A, Kuleshov MV, Clarke DJB, Evangelista JE, Jenkins SL, Lachmann A, Wojciechowicz ML, Kropiwnicki E, Jagodnik KM, Jeon M, Maayan A (2021) Gene set knowledge discovery with enrichr. Curr Protoc 1:90. https:\/\/doi.org\/10.1002\/cpz1.90","journal-title":"Curr Protoc"},{"key":"1954_CR71","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1038\/s41588-019-0479-7","volume":"51","author":"Y Zhang","year":"2019","unstructured":"Zhang Y, Li T, Preissl S, Amaral ML, Grinstein JD, Farah EN, Destici E, Qiu Y, Hu R, Lee AY, Chee S, Ma K, Ye Z, Zhu Q, Huang H, Fang R, Yu L, Izpisua Belmonte JC, Wu J, Evans SM, Chi NC, Ren B (2019) Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells. Nat Genet 51:1380\u20131388. https:\/\/doi.org\/10.1038\/s41588-019-0479-7","journal-title":"Nat Genet"}],"container-title":["Molecular Genetics and Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00438-022-01954-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00438-022-01954-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00438-022-01954-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T06:20:43Z","timestamp":1666678843000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00438-022-01954-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,19]]},"references-count":71,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["1954"],"URL":"https:\/\/doi.org\/10.1007\/s00438-022-01954-7","relation":{},"ISSN":["1617-4615","1617-4623"],"issn-type":[{"value":"1617-4615","type":"print"},{"value":"1617-4623","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,19]]},"assertion":[{"value":"7 May 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 September 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Dr. Glinsky is co-founder of the OncoScar, LLC, an early-stage biotechnology company dedicated to exploration of the potential translational utility of stem cell-associated retroviral sequences.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}