17q21.31 region with MAPT gene is hotspot for chromosomal rearrangements. Common 900 kb inversion polymorphism defines H2 haplotype prevalent in Europeans but nearly absent in Asians and Africans. H2 haplotype ancestral in hominoids and underwent positive selection in Europeans. H2 links to 17q21.31 microdeletion syndrome, top cause of idiopathic mental retardation in Europeans. Inversion heterozygosity occurs specifically on H2 chromosomes, not H1. Mother homozygous for H2 transmitted deleted chromosome to child with microdeletion syndrome. Allele-specific sensitivity to rearrangements in H2 causes predisposition when heterozygous for inversion status.