Structural Diversity and African Origin of the 17q21.31 Inversion Polymorphism

The 17q21.31 inversion polymorphism is one of the most dynamic and complex regions of the human genome. Direct (H1) and inverted (H2) haplotypes show evidence of differential predispositions to disease and potential positive selection. We investigated the origin, population stratification, and extent of structural variation in 2700 diverse individuals with a specific focus on African genetic diversity. We identify eight structural haplotypes that vary dramatically in size as a result of changes in orientation, gene organization, and duplication architecture. More complex duplication architectures involving KANSL1 have increased dramatically in frequency in Europeans and are virtually absent in other continental groups. A specific H2 haplotype (H2’) with a simpler duplication architecture is enriched among African hunter-gatherer groups yet essentially absent from West Africans populations. While H1 and H2 duplications arose independently and prior to the human migration out of Africa, they have reached high frequencies especially among Europeans either due to genetic drift or selective sweeps.