biostudies-literatureRecinos YNHGRI NIH HHSNINDS NIH HHSNIHNIGMS NIH HHSNational Science Foundation100563https://www.ebi.ac.uk/biostudies/studies/S-EPMC11228892biostudies-literatureUnknown4(6)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.Cell genomicsLineage-specific splicing regulation of MAPT gene in the primate brain.PMC11228892P50NS048843S10OD021764R01 HG012359S10OD012351R35GM145279R01HG012359R01 NS125018R35 GM145279R01NS125018Yeh YTPhillips BLRecinos YWang XBao SZhang CWeyn-Vanhentenryck SMSwanson MSfalseLineage-specific splicing regulation of MAPT gene in the primate brain.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.2024-01-01T00:00:00Z2024 Jun2026-06-01T07:37:34.422Z2025-04-04T11:25:14.209ZS-EPMC112288923877236810.1016/j.xgen.2024.100563