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Department of Cancer Biology, Genome Plasticity Laboratory, The Scripps Research Institute, 5353 Parkside Drive RE107, Jupiter, Florida 33458, and INSERM U674, Functional Genomics of Solid Tumors, 27 rue Juliette Dodu, 75010 Paris, France
Received 17 May 2007/ Returned for modification 19 June 2007/ Accepted 7 August 2007
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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To circumvent this hurdle, a facile method was developed using recombinant inbred (RI) mouse strains as a crossover (CO) library to quickly and precisely locate potential recombination hot spots, and this method was applied to hot spots on mouse chromosome 19. Three CO sites in the BXD RI strains were confirmed to be bona fide recombination hot spots, validating this strategy. Finally, analyses of a highly polymorphic hot spot revealed that 4% of CO molecules display discontinuous conversion tracts, as well as persistent heteroduplex DNA in mature spermatozoa.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Localization of recombination hot spots. BXD recombinant inbred DNAs were purchased from the Jackson Laboratory (Bar Harbor, ME). Localization of hot spots in chromosome 19 among the first 26 BXD strains was performed by sequentially narrowing in on the interval known to contain the crossover in a given strain. The BXD RI strain distribution patterns were used as a starting point (http://www.informatics.jax.org/searches/riset_form.shtml). The Entrez mouse single nucleotide polymorphism (SNP) database was used as a first choice. However, in most cases, the identification of novel SNPs was required. Novel SNPs were identified by designing oligonucleotides across 1-kb intervals, amplifying the region in the B6, DBA, and BXD RI strains of interest, and sequencing. DNA sequence was obtained from ENSEMBL (http://www.ensembl.org/Mus_musculus/index.html, Ensembl release 34); repeats were identified using RepeatMasker (http://www.repeatmasker.org/cgi-bin/WEBRepeatMasker), and oligonucleotides were designed using Primer3 (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi; a 21-nucleotide primer, a melting temperature of 55°C, and 50% GC content were found to be optimal; all other values were left unchanged) in regions free of repeats. We designed 253 oligonucleotide pairs. Eight percent failed to amplify, and 33% did not yield any SNP between the B6 and DBA strains. The HS9, HS22, and HS37 recombination hot-spot B6 and DBA sequences, as well as the description of all the oligomers, are available upon request.
Sperm DNA extraction, quantification, and crossover analyses. DNA was prepared as previously described (43). DNA was dissolved in 5 mM Tris-HCl (pH 7.5) and digested with the SacII restriction enzyme to cleave outside the tested intervals. All PCRs were performed with a reaction buffer previously described (17) with 0.1 U of recombinant Taq polymerase (Invitrogen), 0.01 U of turbo Pfu polymerase (Stratagene), and 0.4 µM of each oligonucleotide in a volume of 10 µl. For Poisson amplification or the second round of CO detection, Cresol Red (Sigma) and sucrose (Sigma) were added to the PCR mix to allow direct gel loading of the samples.
The number of amplifiable molecules was determined using Poisson analysis. Typically, a serial dilution ranging from 10–2 to 10–5 was performed to estimate the overall number of amplifiable molecules. Once determined, 96 Poisson reactions were performed at the optimal dilution to obtain 30%- to 50%-positive reactions. The number of amplifiable molecules was then calculated as described previously (44). Primers used for Poisson amplifications were 19-7000640F (5'-GAC ACC CTC CAG GAC AGA ATC –3') and 19-7001899R (5'-GGG CTC TGA TGA AGT GGG AAG –3'). PCRs were performed at 96°C for 1 min, followed by 32 cycles at 96°C for 30 s, 60°C for 40 s, and 70°C for 1 min. Poisson reactions were run on a 1.5% agarose gel in 0.5x Tris-borate-EDTA containing ethidium bromide and visualized under UV light.
Optimal annealing temperature for each primer set was determined using a gradient PCR block by amplifying either a 1:1-ratio mix of B6 and DBA DNA as a negative control or the BXD RI strain DNA (BXD1 for HS9, BXD16 for HS22, and BXD21 for HS37), where the CO was located as a positive control. Sperm and brain DNA from a DBA-B6 heterozygous mouse confirmed the correct conditions. Despite multiple attempts, we were unable to detect any amplification in the DBA-to-B6 CO orientation at the HS37 hot spot, most likely due to a genomic duplication. To detect CO, allele-specific primers were designed to amplify across the HS9, HS22, and HS37 hot spots. Nucleotide differences between B6 and DBA are labeled in bold (see below). Nucleotides indicated in lowercase letters were added to raise the overall GC content of the oligomer (HS9-2F and HS22-6R).
HS9 5' allele-specific primers were HS9-B-1F (5'-AGC CCC CTT TAA AAG ACT TTT-3') and HS9-B-2F (5'-ggg gTT CAA GCT ACC CTC-3') for B6, HS9-D-1F (5'-GCC CCC TTT AAA AGA CTT TAA-3') and HS9-D-2F (5'-ggg gTT CAA GCT ACC CTT-3') for DBA. The 3' primers were HS9-B-4R (5'-TTG CCT GGG CAG GAG TAG-3') and HS9-B-3R (5'-TCT CCC TGC TGT GGA GTA-3') for B6 and HS9-D-4R (5'-TTG CCT GGG CAG GAG TAT-3') and HS9-D-3R (5'-TCT CCC TGC TGT GGA GTG-3'). The first round was performed using the HS9-1F and HS9-4R primer pair (3.5 kb) and the second round with the HS22-2F and HS22-3R primer pair (2.3 kb). First-round PCRs were performed at 96°C for 1 min, followed by 24 cycles at 95°C for 30 s, 60°C for 40 s, and 63°C for 3 min. Second-round PCRs were performed at 96°C for 1 min, followed by 28 cycles at 95°C for 30 s and 63°C for 2 min.
HS22 5' allele-specific primers were HS22-B-2F (5'-CCT CAA GGT CCT ACG-3') and HS22-B-3F (5'-GCC AGA CAC TGT AGC-3') for B6, HS22-D-2F (5'-CCT CAA GGT CCT ACC-3') and HS22-D-3F (5'-GCC AGA CAC TGT AGT-3') for DBA. The 3' primers were HS22-B-7R (5'-TCG CCG ACT GAT GAT-3') and HS22-B-6R (5'-ggc cgG CAT TTT AAT CTT CAT AG-3') for B6 and HS22-D-7R (5'-TCG CCG ACT GAT GAC-3') and HS22-D-6R (5'-ggc cgG CAT TTT AAT CTT CAT AC-3'). The first round was performed using the HS22-2F and HS22-7R primer pair (5.0 kb) and the second round with the HS22-3F and HS22-6R primer pair (4.6 kb). The first round of PCRs was performed at 96°C for 1 min, followed by 24 cycles at 96°C for 30 s, 60°C for 40 s, and 63°C for 4 min 30 s. The second round of PCRs was performed at 96°C for 1 min, followed by 28 cycles at 96°C for 30 s, 62°C for 40 s, and 63°C for 3 min 30 s.
HS37 5' allele-specific primers were HS37-B-2F (5'-CCA ATC TGT TTA AGG CCC-3') and HS37-B-3F (5'-TGA TGT TCC ATC CCA GCC-3') for B6 and HS37-D-2F (5'-CCA ATC TGT TTA AGG CCT-3') and HS37-D-3F (5'-TGA TGT TCC AAT CCA GCA-3') for DBA. The 3' primers were HS37-B-3R (5'-TAC TAA ACA CGG GGT CCC-3') and HS37-B-2R (5'-TTA AAT ACA TCC AAC ACC TGC-3') for B6 and HS37-D-3R (5'-TAC TAA ACA CGG GGT CCT-3') and HS37-D-2R (5'-TTA AAT ACA TCC AAC ACC TGT-3'). The first round was performed using the HS37-2F and HS37-3R primer pair (8.6 kb) and the second round with the HS37-3F and HS37-2R primer pair (3.0 kb). The first round of PCRs was performed at 96°C for 1 min, followed by 24 cycles at 96°C for 30 s, 59°C for 40 s, and 63°C for 7 min. The second round of PCRs was performed at 96°C for 1 min, followed by 28 cycles at 96°C for 30 s, 62°C for 40 s, and 63°C for 2 min 30 s.
All primary PCR products for HS9, HS22, and HS37 were digested with S1 nuclease to remove single-stranded DNA as previously described (43). One-hundred-fold-diluted S1-treated DNA was then used to seed the secondary PCRs.
Secondary PCR products (70% of total reaction volume) were run on 0.8% agarose gel in 0.5x Tris-borate-EDTA and visualized with ethidium bromide and UV light. Positive reactions were diluted 50-fold and reamplified using internal primers. For the HS22 hot spot, the primers used were HS22-reamp/F) 5'-TGA GAG ACA GAG GCA GGT AGG-3') and HS22-reamp/R (5'-CCG TCT GCC ACT GGT CTA TCT-3'). Reamplification PCRs were performed at 96°C for 1 min, followed by 24 cycles at 95°C for 30 s, 60°C for 40 s, and 63°C for 4 min, for both hot spots in a 7-µl reaction volume as described above. PCR products were purified using QIAGEN's (Valencia, CA) QIAquick 96-well PCR purification system, following the supplier's instructions. Each product was sequenced. HS22 sequencing primers were HS22-D (5'-GGA GAG TTG GCC CAG CAG TTA-3'), HS22-E (5'-CCA TCT AGA CCA CCC TGC AA-3'), HS22-F (5'-AGA CGG TCT CGT CTG TGA CCT-3'), HS22-G (5'-CAG GAG CCA GAC CAA TCC TGT-3'), HS22-H (5'-CAC CAT CGG CAG TGT TAC CT-3'), and HS22-K (5'-GGT GGG GAA TCC ATC TTT CTT G-3'). All subsequent sequence analyses were performed using Sequencher software (version 4.7; GeneCodes, Ann Arbor, MI).
The sequences of each recombinant molecule were aligned with the two reference sequences of B6 and DBA, on which known polymorphism locations were marked. Due to the overall limited sequence background, calling SNP identity was straightforward. In the case of complex mixed strands (BD #7, DB #2, and DB #4 [with BD indicating B6-DBA recombination and DB indicating the reverse]), we used an arbitrary peak ratio (low/high) of at least 0.6 to positively call a base as present in both SNPs. However, as shown in Fig. 4, electropherograms for each base peak were of identical height. Moreover, after well over 1,000 recombinant molecules were sequenced (this study; also unpublished data), no early PCR misincorporation was detected anywhere in the surveyed HS22 sequence, suggesting that this type of PCR artifact is extremely rare. It is therefore highly unlikely to be involved in the generation of the complex recombinant molecules observed.
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RESULTS AND DISCUSSION |
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A PCR strategy allowed the detection of recombinant molecules in both orientations, from B6 to DBA and from DBA to B6, at the HS22 hot spot. A total of 1,508,000 amplifiable molecules were scanned, which detected a total of 327 recombinant molecules in both orientations for four different heterozygote males of 2 and 12 months of age. All four mice showed similar recombination rates at HS22, averaging 2.17 x 10–4 (Table 1), irrespective of age (2 months, mice no. 1 and 2, or 12 months, mice no. 3 and 4) (Table 1) or the chromosome of origin (female DBA crossed to a male B6, D/B cross, mice no. 1 and 3, or the reverse B/D cross, mice no. 2 and 4) (Table 1). The B6-to-DBA orientation recombination frequency was consistently higher than that for DBA to B6, 2.26 x 10–4 versus 2.08 x 10–4, respectively, but this most likely reflects a slight reduction in PCR efficiency, as previously observed (43).
Complete sequencing of all 171 B6-DBA and 156 DBA-B6 recombinant molecules allowed the generation of recombination profiles across the HS22 hot spot in both orientations (Fig. 3A and C and 4). While CO appear to be reciprocal in their rate, their distribution displays a strong asymmetry and transmission distortion, with the B6-DBA orientation shifted 5' relative to the DBA-B6 orientation. This shift averaged 530 bp, with the B6-DBA center located at 2,569 bp whereas the DBA-B6 counterpart is located at 3,102 bp (Fig. 3A and C and 5A). This results in a gross overtransmission of the DBA allele within the hot spot (Fig. 5B), indicating that the B6 haplotype is the most active in DNA double-strand break (DSB) initiation.
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Identification of imperfect CO molecules at the HS22 hot spot. Unlike the case with previously described hot spots in the human and mouse genomes (8, 11, 15, 16, 18, 43), not all of the CO at HS22 were simple in this wild-type cross. Indeed, in both orientations an average of 4% of recombinants displayed evidence of partially repaired DNA and discontinuous conversion tracts (BD recombinant molecules 1 to 9 and DB recombinant molecules 1 to 4) (Fig. 3B and D and 4A and B). Mixed pools containing two (12.3%) or three (1.2%) simple recombinant molecules were easily identified by sequencing, since they show a central heteroduplex DNA region surrounded by clean edges. With an average 30% of positive pools, it is expected that 12.3% of them (among the positive pools) contain at least 2 CO. Indeed, 13.7% were observed. More importantly, increasing (by 2.5-fold) the number of amplifiable molecules to 2,000 using somatic (brain) DNA did not result in the generation of artifactual jump-PCR products (Fig. 1D). This experiment provided two important controls. First, it confirmed that the allele-specific amplification was very efficient. More importantly, it also demonstrated that potential jump-PCR artifacts were not generated at a detectable level. Finally, the average centers of these complex recombinant molecules were at locations almost identical to those of classic CO products, at 2,369 bp and 3,017 bp for the B6-DBA and DBA-B6 orientations, respectively; therefore, artifactual generation of these molecules is very unlikely. Indeed, in the case of jump-PCR products, one would expect a random distribution of CO across the 5 kb scanned, rather than the asymmetric and similarly centered products found for each orientation. These controls confirmed the bona fide nature of these complex recombinant molecules.
These partially repaired molecules were detected in both orientations (nine for B6-DBA and four for DBA-B6; Fig. 3B and D), and they could be separated into two classes. The first class of CO molecules still contained unrepaired heteroduplex regions (BD #7 and DB #1 and 3; Fig. 3B and D), as well as discontinuous conversion tracts. One molecule displayed a repaired region surrounded by heteroduplex DNA (DB #3; Fig. 3D), suggesting that repair could be initiated from the center of duplex DNA containing mismatches with an aborted repair tract. Such molecules have been observed in wild-type strains of yeast at recombination hot spots where artificial mismatches were introduced (9, 25); however, typically there was only one single heterology. The second class of complex CO molecules that were documented contained only discontinuous conversion tracts without any heteroduplex DNA present (BD #1 to #6 and DB #2 and #4; Fig. 3B and D). Two such complex recombinant molecules, BD #2 and BD #3, were independently identified twice. These discontinuous conversion tracts usually involved one or two closely spaced single polymorphisms (BD #1, #3, #4, #5, and #6 and DB #2 and #4; Fig. 3B and D). Only BD recombinant molecule #2 showed a longer discontinuous conversion tract, which spread over 130 bp. Finally, none of these imperfectly repaired CO molecules appeared to display any base scramble or microrearrangement in the CO intervals, suggesting that this process occurred normally during meiotic progression.
These findings imply that heteroduplex DNA is still present in spermatozoa well after the completion of meiosis. Thus, in addition to demonstrating the persistence of heteroduplexes in spermatid DNA at the HS22 locus, these molecules also provide insights into the repair mechanisms that are operational following resolution of dHJs in highly heterozygote recombinogenic regions. Specifically, the programmed induction of DSBs by Spo11 dimers in the very first stage of meiotic prophase provokes meiotic CO (22). Spo11 generates DSBs where the protein is covalently attached to the 5' strand termini, before being released by endonucleolytic cleavage and subsequent strand invasion (30). In the case of CO pathway repair, resolution of DSBs proceeds through strand synthesis, formation of dHJs, and cleavage, leading to a CO (22, 29). In all cases, this leaves heteroduplex DNA regions, which are then thought to be repaired via the mismatch repair machinery. Indeed, the detection and characterization of these mixed molecules suggest that once the dHJs have been resolved, a patchy repair process occurs where some but not all of the heteroduplex molecules can be repaired in time to copy either a B6 template or a DBA template. This observation was true in both orientations where small patches within or flanking a heteroduplex region could be observed.
Sometimes the heteroduplex region in HS22 had been repaired yet generated recombinant molecules with discontinuous conversion tracts. Such molecules have been observed at the mouse Psmb9 hot spot but only in the context of the Mlh1 deficiency (10). It is likely that such incomplete repair is directly linked to the level and probably type (simple mismatch versus large insertion/deletion) of polymorphism observed at recombination hot spots, as has been observed for yeast (12, 20). These molecules can also be explained by mismatch repair during strand invasion, as previously observed for yeast (1, 35). In this case, the discontinuous tracts would be a consequence of two possibilities for mismatch repair with the two repair tracts in an opposite orientation. Along these lines, it may be important that the 50-bp insertion/deletion is unique to the core of the HS22 hot spot.
Conclusions. Heretofore such a high level of polymorphism between strands in the vicinity of recombination hot spots has been found only at human hypermutable minisatellites, where sequence divergences between various repeats at a given locus range from 5% to 20% (Table 2). In this case, extremely complex repeat shuffling was observed to occur by an as yet undefined mechanism (4, 14). The discontinuous conversion tracts observed at the HS22 hot spot in 4% of CO products may explain this apparent complexity detected at hypermutable minisatellites, where the repair machinery's struggle to rapidly restore complex heteroduplex molecules either during strand invasion or following dHJ resolution leads to either conversion or CO events (7, 15). This would, in turn, provide a driving mechanism for the extreme tandem repeat shuffling observed at these loci (6, 19, 36). Interestingly, another example of discontinuous conversion tracts is recombination events at 17p11.2, which lead to either duplications or deletions associated with autosomal dominant Charcot-Marie-Tooth type 1A disease and hereditary neuropathy with liability to pressure palsies, respectively (26).
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ACKNOWLEDGMENTS |
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This is publication 19024 from The Scripps Research Institute.
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FOOTNOTES |
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Published ahead of print on 20 August 2007.
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