Association of poly-purine/poly-pyrimidine sequences with meiotic recombination hot spots

Abstract

Background: Meiotic recombination events have been found to concentrate in 1-2.5 kilo base regions, but these recombination hot spots do not share a consensus sequence and why they occur at specific sites is not fully understood. Some previous evidence suggests that poly-purine/poly-pyrimidine (poly-pu/py) tracts (PPTs), a class of sequence with distinctive biochemical properties, could be involved in recombination, but no general association of PPTs with meiotic recombination hot spots has previously been reported.

Results: We used computational methods to investigate in detail the relationship between PPTs and hot spots. We show statistical associations of PPT frequency with hot spots of meiotic recombination initiating lesions, double-strand breaks, in the genome of the yeast S. cerevisiae and with experimentally well characterized human meiotic recombination hot spots. Supporting a possible role of poly-pu/py-rich sequences in hot spot recombination, we also found that all three single nucleotide polymorphisms previously shown to be associated with human hot spot activity changes occur within sequence contexts of 14 bp or longer that are 85% or more poly-pu/py and at least 70% G/C. These polymorphisms are all close to the hot spot mid points. Comparing the sequences of experimentally characterized human hot spots with the orthologous regions of the chimpanzee genome previously shown not to contain hot spots, we found that in all five cases in which comparisons for the hot spot central regions are possible with publicly available sequence data, there are differences near the human hot spot mid points within sequences 14 bp or longer consisting of more than 80% poly-pu/py and at least 50% G/C.

Conclusion: Our results, along with previous evidence for the unique biochemical properties and recombination-stimulating potential of poly-pu/py-rich sequences, suggest that the possible functional involvement of this type of sequence in meiotic recombination hot spots deserves further experimental exploration.

Figure 1

Association of high PPT frequencies with yeast hot spots. Mean frequencies of PPTs with length minima between 12 and 20 bp in 177 hot spots of meiotic double-strand breaks (DSBs) in the genome of the yeast S. cerevisiae compared with the mean frequencies in 40 DSB cold spots and 233 other regions comprising the remainder of the genome sequence. Error bars are plus and minus one standard error of the mean.

Figure 2

Densities of high GC-content PPTs relative to human hot spot locations. Sliding window plots of the densities of PPTs of at least 12 bp, with GC-contents above the mean for PPTs over the regions we investigated, relative to hot spot locations in A): a 292 kb region of the human MHC Class II region in which 7 hot spots are known and B): a 206 kb region of human chromosome 1 in which 8 hot spots are known. Vertical dotted lines represent hot spot mid point locations. Sliding windows were 10 kb wide and moved in steps of 100 bp. Locations of genes in the regions are shown below the plots with arrows indicating direction of transcription.