{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T19:56:02Z","timestamp":1776023762404,"version":"3.50.1"},"posted":{"date-parts":[[2023,8,7]]},"group-title":"Genomics","reference-count":102,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,12,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Due to alternative splicing, human protein-coding genes average over eight RNA isoforms, resulting in nearly four distinct protein coding sequences per gene. Long-read RNAseq (IsoSeq) enables more accurate quantification of isoforms, shedding light on their specific roles. To assess the medical relevance of measuring RNA isoform expression, we sequenced 12 aged human frontal cortices (6 Alzheimer\u2019s disease cases and 6 controls; 50% female) using one Oxford Nanopore PromethION flow cell per sample. Our study uncovered 53 new high-confidence RNA isoforms in medically relevant genes, including several where the new isoform was one of the most highly expressed for that gene. Specific examples include\n                  <jats:italic>WDR4<\/jats:italic>\n                  (61%; microcephaly),\n                  <jats:italic>MYL3<\/jats:italic>\n                  (44%; hypertrophic cardiomyopathy), and\n                  <jats:italic>MTHFS<\/jats:italic>\n                  (25%; major depression, schizophrenia, bipolar disorder). Other notable genes with new high-confidence isoforms include\n                  <jats:italic>CPLX2<\/jats:italic>\n                  (10%; schizophrenia, epilepsy) and\n                  <jats:italic>MAOB<\/jats:italic>\n                  (9%; targeted for Parkinson\u2019s disease treatment). We identified 1,917 medically relevant genes expressing multiple isoforms in human frontal cortex, where 1,018 had multiple isoforms with different protein coding sequences, demonstrating the need to better understand how individual isoforms from a single gene body are involved in human health and disease, if at all. Exactly 98 of the 1,917 genes are implicated in brain-related diseases, including Alzheimer\u2019s disease genes such as\n                  <jats:italic>APP<\/jats:italic>\n                  (A\u03b2 precursor protein; five),\n                  <jats:italic>MAPT<\/jats:italic>\n                  (tau protein; four), and\n                  <jats:italic>BIN1<\/jats:italic>\n                  (eight). As proof of concept, we also found 99 differentially expressed RNA isoforms between Alzheimer\u2019s cases and controls, despite the genes themselves not exhibiting differential expression. Our findings highlight the significant knowledge gaps in RNA isoform diversity and their medical relevance. Deep long-read RNA sequencing will be necessary going forward to fully comprehend the medical relevance of individual isoforms for a \u201csingle\u201d gene.\n                <\/jats:p>","DOI":"10.1101\/2023.08.06.552162","type":"posted-content","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T14:00:17Z","timestamp":1691416817000},"source":"Crossref","is-referenced-by-count":12,"title":["Using deep long-read RNAseq in Alzheimer\u2019s disease brain to assess medical relevance of RNA isoform diversity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6177-9316","authenticated-orcid":false,"given":"Bernardo Aguzzoli","family":"Heberle","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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