PRDM9-mediated meiotic hotspot specification is constrained in humans despite extensive sequence diversity
PRDM9 specifies meiotic recombination hotspots through a rapidly evolving C2H2 zinc-finger (ZNF) coding minisatellite that determines DNA-binding specificity. Although this minisatellite harbors extraordinary allelic diversity in humans, the functional consequences of most naturally occurring variants remain unknown. Here we functionally characterize 80 human PRDM9 alleles using genome-wide…
A study has revealed that human PRDM9-mediated meiotic hotspot specification is limited, despite the genetic diversity of the PRDM9 gene. PRDM9 creates hotspots for meiotic recombination via a rapidly evolving C2H2 zinc-finger (ZNF) coded minisatellite. Despite the extensive sequence diversity found within this ZNF array, the vast majority of human PRDM9 alleles exhibit nearly identical function to common alleles A and C. This indicates that human PRDM9 function is more constrained than its genetic diversity suggests.
However, rare and infertility-associated variants in the PRDM9 gene do not follow this pattern. These rare variants exhibit either abundant and novel DNA binding specificity or minimal DNA binding altogether. The presence of these two functional extremes suggests that both gain- and loss-of-function alleles may disrupt symmetric hotspot specification during meiosis. This disruption is proposed to be a potential contributor to human infertility.
In summary, the research defines the functional landscape of human PRDM9 variation, providing a framework for understanding the impact of newly discovered PRDM9 alleles on meiosis and infertility.
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