U.S. Department of Health and Human Services

Guiding Genetic Rearrangement to Protect the Genome

Scientists discovered that genetic rearrangement—the process by which cells intentionally break, shuffle, and repair their DNA to create new combinations of genes—is directed away from functional genomic regions. Genetic rearrangement occurs naturally in cells destined to become sperm and eggs to generate genetic diversity, ensuring that each new organism will be unique. This process can be beneficial in that new, advantageous traits can arise from these genetic rearrangements; but, if it goes awry, this process can also generate abnormalities that result in miscarriages, congenital birth defects, and mental retardation. Researchers in the NIDDK’s Intramural Research Program and colleagues previously demonstrated that locations in the genome where genetic rearrangements occur more frequently—“hotspots”—were associated with the activity of a protein called PRDM9, but they did not know if the hotspot location was determined by PRDM9. 
To evaluate PRDM9’s role, the researchers mapped hotspots in two mouse strains that were nearly genetically identical, but encoded different versions of PRDM9. They found a similar number of hotspots in the two different strains, but almost no overlap in the locations of the hotspots. Hotspots in the two lines centered on distinct DNA sequences that aligned with the predicted DNA-binding sites for the different PRDM9 proteins. This indicated that the location of rearrangement hotspots was dependent on PRDM9. When the scientists looked at mice genetically engineered to lack PRDM9, they found that rearrangements still occurred in hotspots, but that these hotspots were not in the same locations as those in normal mice. Rather, the hotspots in mice without PRDM9 were re-routed to sites in the genome associated with gene activity. The researchers propose that PRDM9 directs the rearrangement machinery to preferred sites in the genome and away from functional genomic regions. This re-routing away from important genomic elements may protect against potential harmful effects of genetic rearrangement. 
Brick K, Smagulova F, Khil P, Camerini-Otero RD, and Petukhova GV. Genetic recombination is directed away from functional genomic elements in mice. Nature 485: 642-645, 2012.