Inversion of 17q21.31 MAPT region is polymorphic in great apes. Inversions occurred independently in chimpanzees and humans. Human inversion breakpoints match LRRC37 gene family duplications. H2 configuration is ancestral state for great apes and humans. H2 evolved greater sequence homology promoting microdeletions. Microdeletions of H2 associate with mental retardation in European populations. H2 haplotype is enriched in Europeans. Chimpanzee and orangutan share H2-like architecture. Inversion toggling recurs during primate evolution. H1 haplotype arose via inversion from H2 in humans. Segmental duplications mediate recurrent inversions. H2 instability explains disease susceptibility in Europeans. Phylogenetic analysis roots H2 as primate ancestral. SNP haplotypes confirm independent human-chimp inversions. BAC sequencing details H2 versus H1 structure. FISH assays distinguish H1/H2 in primates.