Evolutionary instability drives structural diversity and disease susceptibility at the 16p12.2 locus

Extensive duplication in the African great ape lineage has led to substantial instability of chromosome 16p. We examined the sequence structure and evolutionary history of the 16p12.2 locus in 570 diverse human haplotypes and seven non-human primates. Human haplotypes vary greatly in size and exhibit ancestry-biased structure. We identify 5-14 clusters of distinct architecture at three segmental duplication (SD) blocks, generating 21 unique haplotype configurations. Two duplicons within these SDs, D5 and D6, mediate the neurodevelopmental disorder-associated 16p12.1 deletion; however, exact breakpoint positions and local sequence architecture vary across families. The region has toggled between orientations over the past 25 million years, and we identify 32 inversions in humans mediated by distinct duplicons. Evolutionary analyses reveal incomplete lineage sorting, interlocus gene conversion, and lineage-specific expansions, including human-specific expansions of D5 and D6. These findings highlight the evolutionary instability at 16p12.2 driving structural diversity and deletion susceptibility in humans.