{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Recinos Y"],"funding":["NHGRI NIH HHS","NINDS NIH HHS","NIH","NIGMS NIH HHS","National Science Foundation"],"pagination":["100563"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11228892"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["4(6)"],"pubmed_abstract":["Divergence of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is widespread in mammals, including primates, but the underlying mechanisms and functional impact are poorly understood. Here, we modeled cassette exon inclusion in primate brains as a quantitative trait and identified 1,170 (∼3%) exons with lineage-specific splicing shifts under stabilizing selection. Among them, microtubule-associated protein tau (MAPT) exons 2 and 10 underwent anticorrelated, two-step evolutionary shifts in the catarrhine and hominoid lineages, leading to their present inclusion levels in humans. The developmental-stage-specific divergence of exon 10 splicing, whose dysregulation can cause frontotemporal lobar degeneration (FTLD), is mediated by divergent distal intronic MBNL-binding sites. Competitive binding of these sites by CRISPR-dCas13d/gRNAs effectively reduces exon 10 inclusion, potentially providing a therapeutically compatible approach to modulate tau isoform expression. Our data suggest adaptation of MAPT function and, more generally, a role for AS in the evolutionary expansion of the primate brain."],"journal":["Cell genomics"],"pubmed_title":["Lineage-specific splicing regulation of MAPT gene in the primate brain."],"pmcid":["PMC11228892"],"funding_grant_id":["P50NS048843","S10OD021764","R01 HG012359","S10OD012351","R35GM145279","R01HG012359","R01 NS125018","R35 GM145279","R01NS125018"],"pubmed_authors":["Yeh YT","Phillips BL","Recinos Y","Wang X","Bao S","Zhang C","Weyn-Vanhentenryck SM","Swanson MS"],"additional_accession":[]},"is_claimable":false,"name":"Lineage-specific splicing regulation of MAPT gene in the primate brain.","description":"Divergence of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is widespread in mammals, including primates, but the underlying mechanisms and functional impact are poorly understood. Here, we modeled cassette exon inclusion in primate brains as a quantitative trait and identified 1,170 (∼3%) exons with lineage-specific splicing shifts under stabilizing selection. Among them, microtubule-associated protein tau (MAPT) exons 2 and 10 underwent anticorrelated, two-step evolutionary shifts in the catarrhine and hominoid lineages, leading to their present inclusion levels in humans. The developmental-stage-specific divergence of exon 10 splicing, whose dysregulation can cause frontotemporal lobar degeneration (FTLD), is mediated by divergent distal intronic MBNL-binding sites. Competitive binding of these sites by CRISPR-dCas13d/gRNAs effectively reduces exon 10 inclusion, potentially providing a therapeutically compatible approach to modulate tau isoform expression. Our data suggest adaptation of MAPT function and, more generally, a role for AS in the evolutionary expansion of the primate brain.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jun","modification":"2026-06-01T07:37:34.422Z","creation":"2025-04-04T11:25:14.209Z"},"accession":"S-EPMC11228892","cross_references":{"pubmed":["38772368"],"doi":["10.1016/j.xgen.2024.100563"]}}