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

Divergence of 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 anti-correlated, 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 suggests adaptation of MAPT function and, more generally, a role for AS in the evolutionary expansion of the primate brain.