PRDM9 Is a Major Determinant of Meiotic Recombination Hotspots in Humans and Mice

TLDR

Meiotic recombination occurs in narrow genomic hotspots. The study demonstrates that the Prdm9 gene is a key determinant of hotspot specification. PRDM9 zinc‑finger polymorphisms in mice and humans dictate hotspot usage, with the human consensus allele binding a 13‑mer motif enriched at hotspots and PRDM9 variants strongly associated with genome‑wide hotspot variability, establishing PRDM9 as the molecular driver of meiotic recombination distribution.

Abstract

Meiotic recombination events cluster into narrow segments of the genome, defined as hotspots. Here, we demonstrate that a major player for hotspot specification is the Prdm9 gene. First, two mouse strains that differ in hotspot usage are polymorphic for the zinc finger DNA binding array of PRDM9. Second, the human consensus PRDM9 allele is predicted to recognize the 13-mer motif enriched at human hotspots; this DNA binding specificity is verified by in vitro studies. Third, allelic variants of PRDM9 zinc fingers are significantly associated with variability in genome-wide hotspot usage among humans. Our results provide a molecular basis for the distribution of meiotic recombination in mammals, in which the binding of PRDM9 to specific DNA sequences targets the initiation of recombination at specific locations in the genome.