Lineage-specific splicing regulation of MAPT gene in the primate brain

• Published in: Cell genomics 2024-06, Vol.4 (6), p.100563, Article 100563
• Main Authors: Recinos, Yocelyn, Bao, Suying, Wang, Xiaojian, Phillips, Brittany L., Yeh, Yow-Tyng, Weyn-Vanhentenryck, Sebastien M., Swanson, Maurice S., Zhang, Chaolin
• Format: Article
• Language: English
• Subjects: alternative splicing; MAPT/tau; MBNL; primate brain evolution; tauopathies
• ISSN: 2666-979X; 2666-979X
• DOI: 10.1016/j.xgen.2024.100563

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. [Display omitted] •OU models identified 1,170 cassette exons with lineage-specific splicing•These splicing shifts are under stabilizing selection in primate brain evolution•MAPT exon 2 and exon 10 underwent anticorrelated, two-step splicing shifts•MAPT exon 10 splicing divergence is mediated by divergent MBNL-binding sites Recinos et al. identified over 1,000 alternative exons showing evolutionarily divergent splicing under stabilizing selection in primate brains. Among them, they found microtubule-associated protein tau (MAPT) exon 2 and exon 10 underwent anticorrelated, two-step splicing shifts, which may suggest adaptation of tau function.