PRDM9 directs genetic recombination away from functional genomic elements

Thursday, October 11, 2012 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center, Building 45	NIDDK	GEN/GENOM-2

* FARE Award Winner

Authors

• K Brick
• F Smagulova
• P Khil
• G Petukhova
• RD Camerini-Otero

Abstract

Meiotic recombination begins with the formation of DNA double strand breaks (DSBs) which occur at a subset of genomic loci called hotspots. The control of recombination has recently been linked to the activity of a meiosis-specific histone H3 methyl-transferase (PRDM9), which is thought to define DSB hotspot sites via DNA binding of its zinc-finger domain. Still, Prdm9 knockout mice remain proficient at initiating recombination, therefore, the role of PRDM9 in determining the sites of DSB hotspots remains unclear. We used a novel ChIP-Seq variant to pull down single stranded DNA bound by the meiotic recombinase, DMC1. Using this method, we precisely mapped DSB hotspots genome-wide in Prdm9 knockout mice and in several congenic mouse strains. Our data show that PRDM9 determines the location of virtually all DSB hotspots in the mouse genome, with the notable exception of the pseudo-autosomal region – the site of an obligate crossover in every meiosis. While DSBs still accumulate in hotspots in Prdm9-knockout mice, >75% of DSBs occur at promoters, enhancers and other functional elements. Such sites are infrequently targeted in wild-type mice (4%) illustrating an important, unexpected role of the PRDM9 protein in sequestering the recombination machinery away from functional genomic elements.

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