Structural diversity and African origin of the 17q21.31 inversion polymorphism

Area of Science:

• Human population genetics
• Genomics
• Evolutionary biology

Background:

• The 17q21.31 inversion polymorphism, comprising direct (H1) and inverted (H2) haplotypes, is associated with varying disease susceptibilities and evolutionary selection pressures.
• Understanding the genetic diversity and structural variations within this polymorphic region is crucial for interpreting its role in human adaptation and disease.

Purpose of the Study:

• To investigate the genetic diversity and structural landscape of the 17q21.31 inversion polymorphism across diverse human populations, with a focus on African ancestries.
• To characterize the evolutionary history of structural haplotypes, including recurrent gene duplications, and their frequencies in different global populations.

Main Methods:

• Genomic analysis of 2,700 individuals to identify and characterize structural haplotypes within the 17q21.31 region.
• Detailed mapping of complex rearrangements, including double recombination events and partial duplications of the KANSL1 gene.
• Comparative analysis of haplotype frequencies across African, European, and other global populations to infer evolutionary trajectories.

Main Results:

• Characterization of eight distinct structural haplotypes, ranging from 1.08-1.49 Mb, with evidence of a 30-kb H1-H2 double recombination event.
• Recurrent partial duplications of the KANSL1 gene were identified on both H1 and H2 haplotypes, achieving high frequencies in European populations.
• An ancestral H2 haplotype (H2'), lacking KANSL1 duplications, was found enriched in African hunter-gatherer groups but scarce in West African populations.

Conclusions:

• The H1 and H2 segmental duplications arose independently prior to human migration out of Africa.
• The recent high frequencies of these duplications in Europeans suggest strong recent selection or genetic drift.
• The distinct distribution of ancestral and duplicated haplotypes highlights complex evolutionary histories shaped by migration, selection, and genetic drift.