Gene flux shapes diversity and evolution of the ancient 17q21.31 inversion polymorphism

Abstract

A hallmark of chromosomal inversions is that they suppress recombination between haplotypes, allowing inversion haplotypes to persist as single co-inherited units. To determine the extent to which inversions nevertheless permit genetic exchange, we investigated a common 979-kb inversion polymorphism at the human 17q21.31 locus. This locus exhibits deep divergence between the reference (H1) and inverted (H2) haplotypes, extensive segmental duplications (SDs) flanking the inversion, and association with neurodegenerative diseases, developmental disorders, and fertility-related phenotypes. Using single-cell sperm genome sequencing data, we directly measured recombination rates between H1 and H2 haplotypes and found near-complete suppression of single-crossover events between the haplotypes. The rare single crossovers that did occur were mediated by non-allelic homologous recombination between shared H1 and H2 SDs, generating novel duplication architectures. In contrast, two-switch events consistent with gene conversion or double crossovers, spanning 17-150 kb, occurred throughout the inversion at rates exceeding genome-wide estimates for events of comparable size. Consistent with recurring genetic exchange, we identified 99 distinct H1-H2 recombinant haplotypes segregating in All of Us genomes, including 26 with combinations of H1 and H2 SDs. These recombinant haplotypes facilitated dissection of the inversion's effects on fertility-related phenotypes; using a large parent-embryo dataset, we found that H2 additively increases female crossover rates across chromosomes and that KANSL1 duplications do not explain this effect. Finally, ancestral recombination graphs dated H1-H2 gene flux (the exchange of genetic material between alternative arrangements) to approximately 100-500 thousand years ago, revealing that H1 and H2 haplotypes have co-segregated for at least half a million years. Together, these results demonstrate that inversions can be permeable barriers to recombination, with ongoing gene flux influencing the diversity and evolution of inversion polymorphisms.