Although the factors that determine individual yeast and mouse DSB hot spots may differ, the overall patterns and intensities of DSB are remarkably similar in the two organisms, in particular when regions corresponding to similar fractions of the genome are compared (see window sizes and tag densities in ). Thus, despite an ~200-fold difference in genome size, yeast and mouse form meiotic DSBs at similar levels (~160/cell in yeast, 200–300/cell in mice) (Pan et al., 2011
; Kauppi et al., 2011
). In both organisms, irregularly alternating domains of greater and lower DSB activity are evident at multiple levels of resolution, with varying hot spot density and individual DSB activity both contributing to domain patterns. Interestingly, these higher-order patterns appear to be conserved among related but diverged strains and species in both yeast and mouse (Mancera et al., 2008
; Paigen et al., 2008
), as if DSB domains reflect higher-order chromosome features that diverge less rapidly than underlying sequences.
Factors responsible for DSB domains remain unknown, but studies point toward a role for chromosome structure and organization. At the time of DSB formation, chromosomes are organized into chromatin loops anchored to an axis, a linear protein structure enriched for cohesins and for meiosis-specific proteins with HORMA domains (Hunter, 2007
). A remarkable study by Panizza et al. (2011)
recently showed that a subset of the Spo11 accessory proteins required for DSB formation are also axis associated. However, most DSBs form in loop sequences (Blat et al., 2002
), raising the possibility that DSB formation involves recruitment of Spo11-bound sequences to chromosome axes through interactions with Spo11 accessory proteins ().
DSB levels could be potentially affected by regional differences in loop size, in the ratio of loop-associated to axis-associated segments, or in axis protein composition. Consistent with this, mutating condensins in Caenorhabditis elegans
increases axis length and also leads to increased DSB formation (Mets and Meyer, 2009
). Moreover, in many organisms, including mice and humans, meiotic chromosome axes are longer and recombination frequencies greater in females than in males. Most strikingly, the short region of homology between the X and Y sex chromosomes, also called the pseudoautosomal region, has the greatest DSB activity density in the mouse genome (Smagulova et al., 2011
) and also has a longer than normal axis and shorter chromatin loops (Kauppi et al., 2011
In addition to the alternating domains seen in most of the genome, specific chromosome elements show reduced levels of recombination and DSBs. Centromeres and pericentric regions display reduced meiotic recombination in many organisms (Lichten, 2008
), and Pan et al. show reduced DSB formation in an ~5 kb region around yeast centromeres and in an ~20 kb region adjacent to telomeres. Mouse centric and telomeric regions contain highly repetitive sequences, and Smagulova et al. did not analyze these regions. It will be of interest to establish whether DSBs still form at reduced levels in these regions in mammals, as they do in yeast, or whether DSB formation is truly silenced in these regions.
Both yeast and mouse genomes contain dispersed repeated elements that are at risk for deleterious genome rearrangement through nonallelic recombination (Sasaki et al., 2010
). Pan et al. found DSBs to be substantially reduced (~5- to 10-fold) in Ty elements, the major repeat family in yeast, as would be expected from their closed chromatin conformation (Lichten, 2008
). By contrast, some human repeats, such as retrotransposon THE-1A LTRs, are highly recombinogenic in correlation with the presence of predicted PRDM9 binding sequences, and Smagulova et al. report that the related MTC and MTD LTRs of mouse are also enriched for PRDM9-binding sites and DSB hot spots. Given the dynamic nature of mammalian hot spots and the diversity of PRDM9, it will be interesting to evaluate the generality of these findings. In any case, selective pressure for sequence-directed DSB formation must be strong enough in mammals to overcome disadvantages of DSB formation in sequences at risk for nonallelic recombination.