Inter-species differences in male meiotic recombination initiation

Authors

• F Pratto
• K Brick
• J Cloutier
• B Davies
• P Donnelly
• RD Camerini-Otero

Abstract

Recombination during meiosis is initiated by the introduction of double-strand breaks (DSBs). In most organisms, these breaks occur at discrete locations in the genome called recombination hotspots. We have developed methods to generate genome-wide DSB maps in mouse and human and have shown that PRDM9, a meiosis specific protein that binds DNA in a sequence specific manner, determines where DSB hotspots are located. In human males, DSB formation is enhanced at subtelomeric regions, and this bias is consistent across individuals with different PRDM9 alleles. To investigate how much of this can be attributed to DNA sequence or to other nuclear factors we determined the pattern of DSB formation in a mouse that carries a human allele of PRDM9 and a human chromosome 21. We obtained mice with one copy of the human allele and one copy of the mouse allele. In this system, DSB hotspots determined by human PRDM9 on the human chromosome are no longer enriched at the subtelomeric region implying that DNA sequence is not sufficient to drive the subtelomeric bias in DSB formation seen in human males. Strikingly, we found that in mouse chromosomes, the human PRDM9 allele defines ~80% of DSBs whereas in the human chromosome 21, the pattern reverts and the mouse PRDM9 is dominant over the human counterpart. This data supports a model where the dominance of one PRDM9 allele over other is explained by changes in the DNA sequence as the result of erosion of the binding motifs.

Scientific Focus Area: Genetics and Genomics

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