Ancestry-Specific Structural Variation at 17q21.31 Reveals a Novel H1 Sub-Haplotype and Functional Effects on Tau Biology

The locus contains the H1 and H2 haplotypes, which differ by a large inversion and are associated with distinct risks for neurodegenerative disease. To characterize ancestry- and haplotype-specific tau isoform expression, targeted long-read Iso-Seq was performed on human postmortem brain tissue samples from caudate and Middle Frontal Gyrus, as well as induced pluripotent stem cell–derived neurons and astrocytes.

Samples represented multiple haplotype groups and ancestries, including a newly identified African-enriched H1 sub-haplotype (H1_A). Full-length transcript sequencing was used to identify known and novel MAPT isoforms, quantify relative isoform usage, and compare splicing patterns across tissues and cell types. These data provide a resource for understanding how population-specific genomic structure at 17q21.31 may shape tau biology and neurodegenerative disease susceptibility.