{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:20:35Z","timestamp":1791724835678,"version":"4.3.4"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:00:00Z","timestamp":1748908800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["ebm-journal.org"],"crossmark-restriction":true},"short-container-title":["Exp. Biol. Med."],"abstract":"<jats:p>An individual\u2019s genetics contributes to their risk of developing amyotrophic lateral sclerosis (ALS); however, there is still a large proportion of the heritability of ALS to be understood. Part of this missing heritability may lie in complex variants, such as the long interspersed element 1 (L1) retrotransposon, which have yet to be evaluated. The majority of L1 insertions in the human genome are no longer able to retrotranspose, but to date 279 retrotransposition-competent (RC) L1s have been reported. Many RC-L1s are polymorphic for their presence\/absence; therefore, each individual will have a different number and complement of RC-L1s. These elements have been hypothesized to be involved in disease processes by multiple mechanisms such as somatic mutation by retrotransposition, the triggering of neuroinflammation and DNA damage. We hypothesize that L1s may influence disease development either through their effects on endogenous genes or through the properties that enable them to retrotranspose. Whole genome sequencing data from the New York Genome Center ALS consortium were used to characterize L1 variation identifying 2,803 polymorphic L1 elements and association analysis was performed in European individuals (ALS\/ALS with other neurological disorder (ALSND) n = 2,653, controls n = 320). There were no individual L1 elements associated with disease, but we did identify a significant increase in the number of RC-L1s in ALS\/ALSND genomes (p = 0.01) and the presence of \u226546 RC-L1s showed the most significant association (OR = 1.09 (1.02\u20131.16), p = 0.01) with disease. Analysis of individual L1s and their association with age at onset and survival identified one L1 whose presence was significantly associated with a lower age at onset (52.7\u00a0years) compared to homozygous absent individuals (59.2\u00a0years) (padj = 0.009). Our study has identified novel genetic factors for both disease risk and age at onset in ALS providing further evidence for the role of L1 retrotransposons in neurodegenerative diseases.<\/jats:p>","DOI":"10.3389\/ebm.2025.10575","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T09:46:11Z","timestamp":1748943971000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Retrotransposition-competent L1s are increased in the genomes of individuals with amyotrophic lateral sclerosis"],"prefix":"10.3389","volume":"250","author":[{"given":"Abigail L.","family":"Pfaff","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulev","family":"K\u00f5ks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1056\/nejmra1510092","article-title":"Mobile DNA in health and disease","volume":"377","author":"Kazazian","year":"2017","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"5899","DOI":"10.1093\/emboj\/cdf592","article-title":"Human L1 element target-primed reverse transcription in vitro","volume":"21","author":"Cost","year":"2002","journal-title":"EMBO J"},{"key":"B3","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/0092-8674(93)90078-5","article-title":"Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition","volume":"72","author":"Luan","year":"1993","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s13100-016-0065-9","article-title":"Roles for retrotransposon insertions in human disease","volume":"7","author":"Hancks","year":"2016","journal-title":"Mobile DNA"},{"key":"B5","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1016\/s0092-8674(00)81997-2","article-title":"Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition","volume":"87","author":"Feng","year":"1996","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1073\/pnas.0809964106","article-title":"Non-LTR retrotransposons encode noncanonical RRM domains in their first open reading frame","volume":"106","author":"Khazina","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1808","DOI":"10.1126\/science.1722352","article-title":"Reverse transcriptase encoded by a human transposable element","volume":"254","author":"Mathias","year":"1991","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1016\/s0092-8674(00)81998-4","article-title":"High frequency retrotransposition in cultured mammalian cells","volume":"87","author":"Moran","year":"1996","journal-title":"Cell"},{"key":"B9","doi-asserted-by":"publisher","first-page":"D68","DOI":"10.1093\/nar\/gkw925","article-title":"L1Base 2: more retrotransposition-active LINE-1s, more mammalian genomes","volume":"45","author":"Penzkofer","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B10","doi-asserted-by":"publisher","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":"B11","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1086\/341718","article-title":"A comprehensive analysis of recently integrated human Ta L1 elements","volume":"71","author":"Myers","year":"2002","journal-title":"The Am J Hum Genet"},{"key":"B12","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1136\/jnnp-2018-319210","article-title":"Retrotransposons in the development and progression of amyotrophic lateral sclerosis","volume":"90","author":"Savage","year":"2019","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"B13","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s13100-019-0176-1","article-title":"Diseases of the nERVous system: retrotransposon activity in neurodegenerative disease","volume":"10","author":"Tam","year":"2019","journal-title":"Mobile DNA"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.1111\/ene.14393","article-title":"Amyotrophic lateral sclerosis: a clinical review","volume":"27","author":"Masrori","year":"2020","journal-title":"Eur J Neurol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"2084","DOI":"10.1016\/s0140-6736(17)31287-4","article-title":"Amyotrophic lateral sclerosis","volume":"390","author":"van Es","year":"2017","journal-title":"The Lancet"},{"key":"B16","doi-asserted-by":"publisher","first-page":"3421","DOI":"10.1093\/hmg\/ddx233","article-title":"Repetitive element transcripts are elevated in the brain of C9orf72 ALS\/FTLD patients","volume":"26","author":"Prudencio","year":"2017","journal-title":"Hum Mol Genet"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1016\/j.celrep.2019.09.066","article-title":"Postmortem cortex samples identify distinct molecular subtypes of ALS: retrotransposon activation, oxidative stress, and activated glia","volume":"29","author":"Tam","year":"2019","journal-title":"Cell Rep"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e44099","DOI":"10.1371\/journal.pone.0044099","article-title":"Transposable elements in TDP-43-mediated neurodegenerative disorders","volume":"7","author":"Li","year":"2012","journal-title":"PLoS One"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1016\/j.celrep.2019.04.003","article-title":"Loss of nuclear TDP-43 is associated with decondensation of LINE retrotransposons","volume":"27","author":"Liu","year":"2019","journal-title":"Cell Rep"},{"key":"B20","doi-asserted-by":"publisher","first-page":"894","DOI":"10.3389\/fneur.2019.00894","article-title":"Transposable elements, inflammation, and neurological disease","volume":"10","author":"Saleh","year":"2019","journal-title":"Front Neurol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"5280","DOI":"10.1073\/pnas.0831042100","article-title":"Hot L1s account for the bulk of retrotransposition in the human population","volume":"100","author":"Brouha","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1916","DOI":"10.1101\/gr.218032.116","article-title":"The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology","volume":"27","author":"Gardner","year":"2017","journal-title":"Genome Res"},{"key":"B23","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/s41588-019-0562-0","article-title":"Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition","volume":"52","author":"Rodriguez-Martin","year":"2020","journal-title":"Nat Genet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"i333","DOI":"10.1093\/bioinformatics\/bts378","article-title":"DELLY: structural variant discovery by integrated paired-end and split-read analysis","volume":"28","author":"Rausch","year":"2012","journal-title":"Bioinformatics"},{"key":"B25","doi-asserted-by":"publisher","first-page":"6562","DOI":"10.3390\/ijms21186562","article-title":"An increased burden of highly active retrotransposition competent L1s is associated with Parkinson's disease risk and progression in the PPMI cohort","volume":"21","author":"Pfaff","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B26","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1038\/s41586-023-06046-z","article-title":"Widespread somatic L1 retrotransposition in normal colorectal epithelium","volume":"617","author":"Nam","year":"2023","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1093\/bioinformatics\/bts163","article-title":"Matrix eQTL: ultra fast eQTL analysis via large matrix operations","volume":"28","author":"Shabalin","year":"2012","journal-title":"Bioinformatics"},{"key":"B28","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/bs.irn.2024.04.007","article-title":"Recent advances in the genetics of familial and sporadic ALS","volume":"176","author":"Al-Chalabi","year":"2024","journal-title":"Int Rev Neurobiol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/s41525-021-00267-9","article-title":"Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis","volume":"7","author":"Al Khleifat","year":"2022","journal-title":"NPJ Genom Med"},{"key":"B30","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13041-022-00914-x","article-title":"Locus specific reduction of L1 expression in the cortices of individuals with amyotrophic lateral sclerosis","volume":"15","author":"Pfaff","year":"2022","journal-title":"Mol Brain"},{"key":"B31","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1016\/j.molcel.2019.05.024","article-title":"LINE-1 evasion of epigenetic repression in humans","volume":"75","author":"Sanchez-Luque","year":"2019","journal-title":"Mol Cell"},{"key":"B32","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.neures.2023.05.001","article-title":"Identification of epigenetically active L1 promoters in the human brain and their relationship with psychiatric disorders","volume":"195","author":"Watanabe","year":"2023","journal-title":"Neurosci Res"},{"key":"B33","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1186\/s13041-020-00694-2","article-title":"Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis","volume":"13","author":"Savage","year":"2020","journal-title":"Mol Brain"},{"key":"B34","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1038\/s41587-024-02215-1","article-title":"Startups probe hidden viruses in the 'dark genome' to treat disease","volume":"42","author":"Eisenstein","year":"2024","journal-title":"Nat Biotechnol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1111\/dmcn.16199","article-title":"Reverse transcriptase inhibitors in Aicardi-Gouti\u00e8res syndrome: a crossover clinical trial","volume":"67","author":"Crow","year":"2025","journal-title":"Dev Med Child Neurol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"2275","DOI":"10.1056\/nejmc1810983","article-title":"Reverse-transcriptase inhibitors in the aicardi-goutieres syndrome","volume":"379","author":"Rice","year":"2018","journal-title":"N Engl J Med"},{"key":"B37","doi-asserted-by":"publisher","first-page":"e802","DOI":"10.1212\/wnl.0000000000008869","article-title":"ALS phenotype is influenced by age, sex, and genetics: a population-based study","volume":"94","author":"Chi\u00f2","year":"2020","journal-title":"Neurology"},{"key":"B38","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1002\/ana.26752","article-title":"Genetic modifiers of age at onset for amyotrophic lateral sclerosis: a genome-wide association study","volume":"94","author":"Li","year":"2023","journal-title":"Ann Neurol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s13024-023-00669-6","article-title":"Genome-wide analyses identify NEAT1 as genetic modifier of age at onset of amyotrophic lateral sclerosis","volume":"18","author":"Li","year":"2023","journal-title":"Mol Neurodegeneration"},{"key":"B40","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.ygeno.2017.09.001","article-title":"Molecular genetics of the transcription factor GLIS3 identifies its dual function in beta cells and neurons","volume":"110","author":"Calderari","year":"2018","journal-title":"Genomics"},{"key":"B41","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.neuron.2013.02.026","article-title":"GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease","volume":"78","author":"Cruchaga","year":"2013","journal-title":"Neuron"}],"container-title":["Experimental Biology and Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.ebm-journal.org\/articles\/10.3389\/ebm.2025.10575\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T09:46:12Z","timestamp":1748943972000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ebm-journal.org\/articles\/10.3389\/ebm.2025.10575\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,3]]},"references-count":41,"alternative-id":["10.3389\/ebm.2025.10575"],"URL":"https:\/\/doi.org\/10.3389\/ebm.2025.10575","relation":{},"ISSN":["1535-3699"],"issn-type":[{"value":"1535-3699","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,3]]},"article-number":"10575"}}