{"id":"https://openalex.org/W7225320042","doi":"https://doi.org/10.21203/rs.3.rs-11620386/v1","title":"Which genes' splicing changes with age? A genome-wide analysis of 2.8 million junction tests in GTEx v8","display_name":"Which genes' splicing changes with age? A genome-wide analysis of 2.8 million junction tests in GTEx v8","publication_year":2026,"publication_date":"2026-11-05","ids":{"openalex":"https://openalex.org/W7225320042","doi":"https://doi.org/10.21203/rs.3.rs-11620386/v1"},"language":"en","primary_location":{"id":"doi:10.21203/rs.3.rs-11620386/v1","doi":"https://doi.org/10.21203/rs.3.rs-11620386/v1","is_oa":true,"landing_page_url":"https://doi.org/10.21203/rs.3.rs-11620386/v1","pdf_url":"https://www.researchsquare.com/article/rs-11620386/latest.pdf","source":{"id":"https://openalex.org/S4306525896","display_name":"Research Square","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":[],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"Research Square","raw_type":"posted-content"},"volume":null,"type":"preprint","is_traditional":true,"indexed_in":["crossref"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://www.researchsquare.com/article/rs-11620386/latest.pdf","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5052966556","display_name":"John Hemming","orcid":"https://orcid.org/0000-0002-9520-8730","observed_orcids":["https://orcid.org/0000-0002-9520-8730"]},"institutions":[],"countries":[],"is_corresponding":true,"raw_author_name":"John Hemming","raw_affiliation_strings":["Cirrostratus Exedra Ltd"],"raw_orcid":"https://orcid.org/0000-0002-9520-8730","affiliations":[{"raw_affiliation_string":"Cirrostratus Exedra Ltd","institution_ids":[]}]}],"institutions":[],"countries_distinct_count":0,"institutions_distinct_count":0,"corresponding_author_ids":["https://openalex.org/A5052966556"],"corresponding_institution_ids":[],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":true,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10604","display_name":"RNA Research and Splicing","score":0.9994999766349792,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T10604","display_name":"RNA Research and Splicing","score":0.9994999766349792,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T12610","display_name":"RNA regulation and disease","score":9.999999747378752e-05,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10676","display_name":"Genetics, Aging, and Longevity in Model Organisms","score":9.999999747378752e-05,"subfield":{"id":"https://openalex.org/subfields/1302","display_name":"Aging"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/pre-mrna-splicing","display_name":"pre-mRNA splicing","score":0.8730000257492065},{"id":"https://openalex.org/keywords/aging","display_name":"aging","score":0.8100000023841858},{"id":"https://openalex.org/keywords/tissue-specific-splicing","display_name":"tissue-specific splicing","score":0.6840000152587891},{"id":"https://openalex.org/keywords/splicing-regulators","display_name":"splicing regulators","score":0.6480000019073486},{"id":"https://openalex.org/keywords/alternative-splicing","display_name":"alternative splicing","score":0.6919999718666077},{"id":"https://openalex.org/keywords/kynurenine-pathway","display_name":"kynurenine pathway","score":0.7440000176429749},{"id":"https://openalex.org/keywords/gtex-v8","display_name":"GTEx v8","score":0.6990000009536743},{"id":"https://openalex.org/keywords/hnrnph1","display_name":"HNRNPH1","score":0.6869999766349792},{"id":"https://openalex.org/keywords/steroidogenic-factor-1","display_name":"steroidogenic factor 1","score":0.796999990940094},{"id":"https://openalex.org/keywords/rbm39","display_name":"RBM39","score":0.9950000047683716},{"id":"https://openalex.org/keywords/bclaf1","display_name":"BCLAF1","score":0.9559999704360962}],"concepts":[{"id":"https://openalex.org/C54458228","wikidata":"https://www.wikidata.org/wiki/Q237218","display_name":"RNA splicing","level":4,"score":0.902999997138977},{"id":"https://openalex.org/C94671646","wikidata":"https://www.wikidata.org/wiki/Q207551","display_name":"Intron","level":3,"score":0.7871000170707703},{"id":"https://openalex.org/C104317684","wikidata":"https://www.wikidata.org/wiki/Q7187","display_name":"Gene","level":2,"score":0.6326000094413757},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.5717999935150146},{"id":"https://openalex.org/C194583182","wikidata":"https://www.wikidata.org/wiki/Q21114084","display_name":"Alternative splicing","level":4,"score":0.5464000105857849},{"id":"https://openalex.org/C54355233","wikidata":"https://www.wikidata.org/wiki/Q7162","display_name":"Genetics","level":1,"score":0.5415999889373779},{"id":"https://openalex.org/C70721500","wikidata":"https://www.wikidata.org/wiki/Q177005","display_name":"Computational biology","level":1,"score":0.45989999175071716},{"id":"https://openalex.org/C73758832","wikidata":"https://www.wikidata.org/wiki/Q7578564","display_name":"Splicing factor","level":5,"score":0.4307999908924103},{"id":"https://openalex.org/C2780989783","wikidata":"https://www.wikidata.org/wiki/Q7578557","display_name":"splice","level":3,"score":0.42739999294281006},{"id":"https://openalex.org/C41282012","wikidata":"https://www.wikidata.org/wiki/Q3928341","display_name":"RNA-binding protein","level":4,"score":0.4004000127315521},{"id":"https://openalex.org/C40000846","wikidata":"https://www.wikidata.org/wiki/Q915868","display_name":"Spliceosome","level":5,"score":0.3817000091075897},{"id":"https://openalex.org/C67705224","wikidata":"https://www.wikidata.org/wiki/Q11053","display_name":"RNA","level":3,"score":0.37220001220703125},{"id":"https://openalex.org/C105580179","wikidata":"https://www.wikidata.org/wiki/Q188928","display_name":"Messenger RNA","level":3,"score":0.36550000309944153},{"id":"https://openalex.org/C2909513124","wikidata":"https://www.wikidata.org/wiki/Q210538","display_name":"DNA Damage Repair","level":4,"score":0.336899995803833},{"id":"https://openalex.org/C64962909","wikidata":"https://www.wikidata.org/wiki/Q5611160","display_name":"Group II intron","level":5,"score":0.3215999901294708},{"id":"https://openalex.org/C165864922","wikidata":"https://www.wikidata.org/wiki/Q411391","display_name":"Regulation of gene expression","level":3,"score":0.30559998750686646},{"id":"https://openalex.org/C2776401178","wikidata":"https://www.wikidata.org/wiki/Q12050496","display_name":"Feature (linguistics)","level":2,"score":0.30320000648498535},{"id":"https://openalex.org/C162317418","wikidata":"https://www.wikidata.org/wiki/Q252857","display_name":"Transcriptome","level":4,"score":0.3000999987125397},{"id":"https://openalex.org/C197077220","wikidata":"https://www.wikidata.org/wiki/Q720988","display_name":"Human genome","level":4,"score":0.29670000076293945},{"id":"https://openalex.org/C47124935","wikidata":"https://www.wikidata.org/wiki/Q468289","display_name":"Trans-splicing","level":5,"score":0.2937999963760376},{"id":"https://openalex.org/C193244246","wikidata":"https://www.wikidata.org/wiki/Q5432696","display_name":"False discovery rate","level":3,"score":0.28529998660087585},{"id":"https://openalex.org/C150194340","wikidata":"https://www.wikidata.org/wiki/Q26972","display_name":"Gene expression","level":3,"score":0.2694999873638153},{"id":"https://openalex.org/C60644358","wikidata":"https://www.wikidata.org/wiki/Q128570","display_name":"Bioinformatics","level":1,"score":0.26499998569488525}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.21203/rs.3.rs-11620386/v1","doi":"https://doi.org/10.21203/rs.3.rs-11620386/v1","is_oa":true,"landing_page_url":"https://doi.org/10.21203/rs.3.rs-11620386/v1","pdf_url":"https://www.researchsquare.com/article/rs-11620386/latest.pdf","source":{"id":"https://openalex.org/S4306525896","display_name":"Research Square","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":[],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"Research Square","raw_type":"posted-content"}],"best_oa_location":{"id":"doi:10.21203/rs.3.rs-11620386/v1","doi":"https://doi.org/10.21203/rs.3.rs-11620386/v1","is_oa":true,"landing_page_url":"https://doi.org/10.21203/rs.3.rs-11620386/v1","pdf_url":"https://www.researchsquare.com/article/rs-11620386/latest.pdf","source":{"id":"https://openalex.org/S4306525896","display_name":"Research Square","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":[],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"Research Square","raw_type":"posted-content"},"sustainable_development_goals":[{"id":"https://metadata.un.org/sdg/3","score":0.8048999905586243,"display_name":"Good health and well-being"}],"study_designs":[],"awards":[],"funders":[{"id":"https://openalex.org/F4320332161","display_name":"National Institutes of Health","ror":"https://ror.org/01cwqze88"},{"id":"https://openalex.org/F4320337338","display_name":"National Heart, Lung, and Blood Institute","ror":"https://ror.org/012pb6c26"},{"id":"https://openalex.org/F4320337346","display_name":"National Institute of Mental Health","ror":"https://ror.org/04xeg9z08"},{"id":"https://openalex.org/F4320337347","display_name":"National Institute on Drug Abuse","ror":"https://ror.org/00fq5cm18"},{"id":"https://openalex.org/F4320337348","display_name":"National Human Genome Research Institute","ror":"https://ror.org/00baak391"},{"id":"https://openalex.org/F4320337349","display_name":"NIH Office of the Director","ror":"https://ror.org/00fj8a872"},{"id":"https://openalex.org/F4320337351","display_name":"National Cancer Institute","ror":"https://ror.org/040gcmg81"},{"id":"https://openalex.org/F4320337359","display_name":"National Institute of Neurological Disorders and Stroke","ror":"https://ror.org/01s5ya894"},{"id":"https://openalex.org/F4320338403","display_name":"Common Fund","ror":"https://ror.org/001d55x84"}],"has_content":{"pdf":true,"grobid_xml":true},"content_urls":{"pdf":"https://content.openalex.org/works/W7225320042.pdf","grobid_xml":"https://content.openalex.org/works/W7225320042.grobid-xml"},"referenced_works_count":8,"referenced_works":["https://openalex.org/W1599031322","https://openalex.org/W1971846931","https://openalex.org/W2774883395","https://openalex.org/W2784173234","https://openalex.org/W2787729717","https://openalex.org/W2981658955","https://openalex.org/W3133859624","https://openalex.org/W4410962788"],"related_works":["https://openalex.org/W7225330673","https://openalex.org/W2883803503","https://openalex.org/W7225243464","https://openalex.org/W7118070242","https://openalex.org/W2204950746","https://openalex.org/W420015091","https://openalex.org/W7116891218","https://openalex.org/W7117702528","https://openalex.org/W2985398088","https://openalex.org/W6939838735"],"abstract_inverted_index":{"Abstract":[0],"Background.":[1],"Changes":[2],"in":[3,42,53,142,193,214,246,259,311,337],"pre-mRNA":[4],"splicing":[5,198,213,223,254,306,319],"are":[6,16],"a":[7,101,131,278,312],"recurrent":[8],"feature":[9],"of":[10,30,80,167,216,221,261,272,281,333],"human":[11],"aging,":[12],"but":[13,309],"which":[14],"genes":[15,157,191,286],"most":[17,40,186,202,226],"and":[18,70,125,155,177,182,209,219,240,294,322,350],"least":[19,161,195],"affected":[20],"across":[21,113],"tissues":[22],"is":[23,307,343],"not":[24],"well":[25],"established.":[26],"Our":[27],"earlier":[28],"analysis":[29],"four":[31],"kynurenine-pathway":[32],"enzymes":[33],"found":[34],"age-associated":[35,168,212],"shifts":[36],"towards":[37],"truncated":[38],"isoforms,":[39],"strongly":[41,341],"AFMID.":[43],"Here":[44],"we":[45],"extend":[46],"the":[47,54,201,225,232,264,300,318],"same":[48],"approach":[49],"to":[50,173,324,345],"every":[51],"gene":[52],"GTEx":[55,338],"v8":[56],"junction":[57,83,266],"matrix.":[58],"Methods.":[59],"Junction":[60],"read":[61,355],"counts":[62],"for":[63,96,119,291],"17,382":[64],"samples":[65],"were":[66,73,128,147,185,200],"restructured":[67],"by":[68,317],"tissue,":[69],"annotated":[71],"junctions":[72],"grouped":[74],"into":[75],"intron":[76],"clusters.":[77],"In":[78],"each":[79],"49":[81,217],"tissues,":[82,176,197,218],"usage":[84],"was":[85,111,178,224],"modelled":[86],"on":[87],"donor":[88],"age":[89,150,181,244,342],"alone":[90],"with":[91,149],"quasi-binomial":[92],"regression,":[93],"fitted":[94,129],"simultaneously":[95],"all":[97],"junctions;":[98],"estimates":[99,352],"matched":[100],"standard":[102],"implementation":[103],"(r":[104],"=":[105],"1.000).":[106],"False":[107],"discovery":[108],"rate":[109],"(FDR)":[110],"controlled":[112],"2.78":[114],"million":[115],"tests.":[116],"Models":[117],"adjusted":[118,351],"sex,":[120],"RNA":[121],"integrity,":[122],"ischaemic":[123],"time":[124],"death":[126,346],"circumstance":[127],"as":[130],"secondary":[132],"analysis.":[133],"Results.":[134],"Of":[135],"910,929":[136],"testable":[137,192],"tissue":[138,248],"\u00d7":[139],"cluster":[140],"events":[141,169],"15,503":[143],"genes,":[144,236,315],"107,594":[145],"(11.8%)":[146],"associated":[148],"at":[151,160,194,277,299],"FDR":[152],"<":[153],"0.05,":[154],"10,786":[156],"(70%)":[158],"had":[159,211],"one":[162],"such":[163],"event.":[164],"The":[165],"share":[166],"ranged":[170],"from":[171,256,328],"1%":[172],"33%":[174],"between":[175],"highest":[179],"where":[180],"ventilator-case":[183],"status":[184],"tightly":[187],"linked.":[188],"Among":[189],"9,320":[190],"20":[196],"regulators":[199],"consistently":[203],"age-linked:":[204],"HNRNPH1,":[205],"SF1,":[206],"RBM39,":[207],"BCLAF1":[208],"LUC7L3":[210],"34\u201339":[215],"regulation":[220],"mRNA":[222],"enriched":[227,290],"biological":[228],"process":[229],"(7.4-fold).":[230],"At":[231],"other":[233],"extreme,":[234],"584":[235],"including":[237],"COX4I1,":[238],"DDOST":[239],"RPL13,":[241],"showed":[242],"no":[243],"association":[245],"any":[247],"despite":[249],"precise":[250],"estimates.":[251],"Age":[252],"shifted":[253],"away":[255,327],"principal":[257,330],"isoforms:":[258],"62%":[260],"significant":[262],"events,":[263],"principal-isoform":[265],"lost":[267],"share.":[268],"After":[269],"adjustment,":[270],"97.7%":[271],"effects":[273],"kept":[274],"their":[275,282,329],"direction,":[276],"median":[279],"57%":[280],"crude":[283,349],"size;":[284],"3,662":[285],"retained":[287],"an":[288],"event,":[289],"actin-cytoskeleton,":[292],"muscle":[293],"extracellular-matrix":[295],"functions.":[296],"AFMID":[297],"ranked":[298],"95th":[301],"percentile":[302],"genome-wide.":[303],"Conclusions.":[304],"Age-associated":[305],"widespread":[308],"concentrated":[310],"few":[313],"hundred":[314],"led":[316],"machinery":[320],"itself,":[321],"tends":[323],"move":[325],"transcripts":[326],"isoforms.":[331],"Much":[332],"its":[334],"tissue-to-tissue":[335],"variation":[336],"reflects":[339],"how":[340],"linked":[344],"circumstance,":[347],"so":[348],"should":[353],"be":[354],"together.":[356]},"counts_by_year":[],"updated_date":"2026-11-09T13:22:03.289127","created_date":"2026-11-06T00:00:00"}