{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T02:04:01Z","timestamp":1792461841316,"version":"4.5.0"},"posted":{"date-parts":[[2025,6,28]]},"group-title":"Genomics","reference-count":128,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,28]],"date-time":"2025-06-28T00:00:00Z","timestamp":1751068800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["OF-LCG; MOH-000504"],"award-info":[{"award-number":["OF-LCG; MOH-000504"]}],"id":[{"id":"https:\/\/ror.org\/03cpyc314","id-type":"ROR","asserted-by":"publisher"}]},{"award":["MOH-000550-00"],"award-info":[{"award-number":["MOH-000550-00"]}],"id":[{"id":"https:\/\/ror.org\/04x3cxs03","id-type":"ROR","asserted-by":"publisher"}]},{"award":["H24P2M0002"],"award-info":[{"award-number":["H24P2M0002"]}],"id":[{"id":"https:\/\/ror.org\/04x3cxs03","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U24MD015970"],"award-info":[{"award-number":["U24MD015970"]}],"id":[{"id":"https:\/\/ror.org\/0493hgw16","id-type":"ROR","asserted-by":"publisher"}]},{"award":["20697"],"award-info":[{"award-number":["20697"]}],"id":[{"id":"https:\/\/ror.org\/00w3qhf76","id-type":"ROR","asserted-by":"publisher"}]},{"award":["MOP 115071"],"award-info":[{"award-number":["MOP 115071"]}],"id":[{"id":"https:\/\/ror.org\/01gavpb45","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The placenta is critical for fetal development and mediates the effects of pregnancy complications on offspring metabolic health, yet it is often poorly characterized in genomic studies. Existing transcriptomic analyses rely on adult tissue-based references, which overlook developmentally important isoform diversity. We used largest-in-class long-read RNA-seq (N=72) to create a comprehensive placental transcriptome reference, identifying 37,661 high-confidence isoforms (14,985 novel) across 12,302 genes (2,759 novel). Contrary to characterizations of the placenta as a \u201ctranscriptomic void,\u201d we found transcriptional breadth and complexity comparable to adult tissues, with extraordinary splicing diversity in genes controlling obesity, lactogen production and growth, including 108 distinct\n                  <jats:italic>CSH1<\/jats:italic>\n                  (placental lactogen) isoforms. This improved reference offers two advantages: First, it reduced inferential uncertainty in isoform quantification by 30% and increased the yield of high-confidence transcripts. Applying this reference to short-read RNA-seq datasets (N=344) of gestational diabetes mellitus (GDM), we found that placental transcription mediated 36% of GDM effects on birth weight, with novel\n                  <jats:italic>CSH1<\/jats:italic>\n                  isoforms identified as key mediators. We further uncovered ancestry-specific effects, with distinct\n                  <jats:italic>CSH1<\/jats:italic>\n                  isoforms mediating larger effects in European (24.4%) than Asian (13.4%) populations. Our results establish that utilizing long-read-based, tissue-specific transcriptomic annotations is critical, enabling isoform-resolved analyses that provide greater sensitivity than conventional gene-level approaches for understanding placental function and context-specific variation across diverse biobanks.\n                <\/jats:p>","DOI":"10.1101\/2025.06.26.661362","type":"posted-content","created":{"date-parts":[[2025,6,28]],"date-time":"2025-06-28T04:30:10Z","timestamp":1751085010000},"source":"Crossref","is-referenced-by-count":4,"title":["Long-read transcriptome assembly reveals vast transcriptional complexity in the placenta associated with metabolic and endocrine function"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6685-1930","authenticated-orcid":false,"given":"Sean T.","family":"Bresnahan","sequence":"first","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center, Department of Epidemiology, Houston, 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Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3442-0033","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9rique","family":"White","sequence":"additional","affiliation":[{"name":"Department of Biology, Sherbrooke University, Sherbrooke, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-\u00c9tienne","family":"Jacques","sequence":"additional","affiliation":[{"name":"Department of Biology, Sherbrooke University, Sherbrooke, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7752-2585","authenticated-orcid":false,"given":"Marie-France","family":"Hivert","sequence":"additional","affiliation":[{"name":"Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA"},{"name":"Department of Medicine, Sherbrooke University, Sherbrooke, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3530-3023","authenticated-orcid":false,"given":"Shiao-Yng","family":"Chan","sequence":"additional","affiliation":[{"name":"A*STAR Institute for Human Development and Potential, Singapore, Singapore"},{"name":"National University of Singapore, Yong Loo Lin School of Medicine, Department of Obstetrics & Gynecology, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8401-0545","authenticated-orcid":false,"given":"Michael I.","family":"Love","sequence":"additional","affiliation":[{"name":"University of North Carolina\u2013Chapel Hill, Departments of Genetics & Biostatistics, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5901-8403","authenticated-orcid":false,"given":"Jonathan Y.","family":"Huang","sequence":"additional","affiliation":[{"name":"A*STAR 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