PRDM9-mediated meiotic hotspot specification is constrained in humans despite extensive sequence diversity
- 1The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, MD, USA
Abstract
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 chromatin profiling. Despite extensive sequence diversity within the ZNF array, most alleles function indistinguishably from common A and C hotspot-specifying alleles, revealing that human PRDM9 function is more constrained than its sequence diversity predicts. In contrast, rare and infertility-associated variants occupy two functional extremes: either abundant and novel DNA binding specificity or minimal DNA binding, suggesting that both gain- and loss-of-function alleles may disrupt symmetric hotspot specification during meiosis, thus representing a plausible contributor to human infertility. Together, our findings define the functional landscape of human PRDM9 variation and provide a framework for interpreting the impact of newly discovered PRDM9 alleles.
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BibTeX
@misc{cosby2026prdm9mediated,
title = {{PRDM9-mediated meiotic hotspot specification is constrained in humans despite extensive sequence diversity}},
author = {R. L. Cosby and M. Brolinson King and A. M. Poch and M. B. Evans and D. E. Watkins-Chow and B. Young and S. Ralls and V. Gomez-Lobo and K. I. Aston and D. F. Conrad and T. S. Macfarlan},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.10.750150},
url = {https://www.biorxiv.org/content/10.64898/2026.09.10.750150v1},
note = {CC0},
}
RIS
TY - UNPB
TI - PRDM9-mediated meiotic hotspot specification is constrained in humans despite extensive sequence diversity
AU - R. L. Cosby
AU - M. Brolinson King
AU - A. M. Poch
AU - M. B. Evans
AU - D. E. Watkins-Chow
AU - B. Young
AU - S. Ralls
AU - V. Gomez-Lobo
AU - K. I. Aston
AU - D. F. Conrad
AU - T. S. Macfarlan
PY - 2026
DA - 2026/09/10
PB - bioRxiv
DO - 10.64898/2026.09.10.750150
UR - https://www.biorxiv.org/content/10.64898/2026.09.10.750150v1
AB - 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 chromatin profiling. Despite extensive sequence diversity within the ZNF array, most alleles function indistinguishably from common A and C hotspot-specifying alleles, revealing that human PRDM9 function is more constrained than its sequence diversity predicts. In contrast, rare and infertility-associated variants occupy two functional extremes: either abundant and novel DNA binding specificity or minimal DNA binding, suggesting that both gain- and loss-of-function alleles may disrupt symmetric hotspot specification during meiosis, thus representing a plausible contributor to human infertility. Together, our findings define the functional landscape of human PRDM9 variation and provide a framework for interpreting the impact of newly discovered PRDM9 alleles.
ER -