Human Molecular Genetics, 2000, Vol. 9, No. 10 1525-1532
© 2000 Oxford University Press
The most frequent constitutional translocation in humans, the t(11;22)(q23;q11) is due to a highly specific Alu-mediated recombination
Imperial Cancer Research Fund, Department of Medical Oncology, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Charterhouse Square, London ECIM 6BQ, UK
Received 22 February 2000; Revised and Accepted 4 April 2000.
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ABSTRACT |
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The t(11;22) is the most common recurrent non-Robertsonian constitutional translocation in humans, having been reported in more than 160 unrelated families. Balanced carriers are at risk of having offspring with the derivative 22 syndrome owing to 3:1 meiotic non-disjunction event. Clinical features of the der(22) syndrome include mental retardation, craniofacial abnormalities and congenital heart defects. The breakpoints for the t(11;22) translocation have been mapped to specific Alu repeats on chromosomes 11 and 22, indicating that this event is due to an Alu–Alu recombination. Remarkably, in five samples derived from individuals with no apparent common ancestry the der(11) and der(22) breakpoints appear to be almost identical at the genomic sequence level. The small number of base differences between the samples indicates some variation in the position of the breakpoints, although this appears to be quite limited. Indeed, the der(11) breakpoints are all located within a region of just 32 bp and the der(22) breakpoints within 21 bp. If, as suggested by current data, the widespread occurrence of this translocation is due to multiple independent events, our results suggest that this particular Alu–Alu recombination is subject to an unprecedented degree of selection.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The t(11;22) is the most common constitutional translocation in humans. In contrast to most constitutional translocations, which appear as single sporadic events, the t(11;22) translocation has been reported in more than 160 unrelated families (1–3). Individuals who carry the balanced form of the translocation have a risk that their offspring may have the derivative 22 [der(22)] syndrome owing to a 3:1 meiotic non-disjunction event. Affected offspring usually carry a supernumerary derivative 22 chromosome and are thus effectively trisomic for part of chromosome 22 and part of chromosome 11. The clinical features of patients with the der(22) syndrome include mental retardation, cranio-facial abnormalities and congenital heart defects (4). Segregation analysis has shown that the risk of unbalanced offspring born to female heterozygotes may be as high as 10%, with a significant risk to offspring of male heterozygotes (3). The frequency of abortions among offspring of balanced carriers is also raised. Although balanced carriers for this translocation are normal it has been suggested that they may have a 10-fold increased risk of breast cancer (5).
A variety of evidence suggests the occurrence of multiple original t(11;22) translocation events. A family has been described in which a child carried the translocation, which was lacking in either parent. Non-paternity was excluded through the analysis of 10 microsatellite markers distributed on 10 different chromosomes and three VNTRs on three different chromosomes (6). The translocation appears to occur in families with no common ancestry and a variety of racial and ethnic backgrounds and, additionally, familial heteromorphic variants of the derivative 22 have been described.
The trisomic region on chromosome 22 overlaps the region hemizygously deleted in another congenital anomaly disorder, velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS). The breakpoint on chromosome 22 for the t(11;22) translocation has been mapped to the same interval as a 1.5 Mb distal deletion breakpoint for VCFS (7). The identification of the breakpoints on chromosomes 11 and 22 is therefore an important aid to our understanding of the nature of these inherited defects.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The breakpoint for the t(11;22) translocation, previously mapped between the markers D11S29 and D11S144 (8,9) was further localized using flow-sorted aliquots of der(11) and der(22) chromosomes. PCR analysis (Fig. 1a) showed that D11S4516 (one end of YAC 785E12) was distal and that D11S1340 and D11S1169 were proximal to the breakpoint (10). These data placed the breakpoint within the region of overlap between YACs 785E12 and 911F02 (10), consistent with recent mapping data (11,12).
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The apolipoprotein gene cluster (APOA1, APOC3, APOA4) was also found to lie in this region of overlap (data not shown). A series of PACs and a BAC was isolated using primer combinations for the APO gene cluster and D11S1169 (Table 1). Markers within this region were PCR mapped against these clones (Fig. 1b). Fluorescence in situ hybridization (FISH) experiments against the cell line GM06229 determined that the clone 1062M21 (Fig. 1c) was split by the translocation. These data implied that the APO gene cluster was distal to the breakpoint and effectively narrowed the breakpoint interval described recently (11).
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Pulsed field gel analysis (data not shown) suggested that the breakpoint lay within 50 kb of the APO gene cluster. Conventional Southern analysis was performed on genomic DNAs from the cell lines GM06229 and GM06275 derived from balanced carriers and placenta (Fig. 2a and b). The probe APOP3-P4 (Fig. 3) hybridized to a germline 21 kb EcoRI fragment in all samples, a 50 and 26 kb novel fragment in GM06229 and GM06275 DNA, respectively (Fig. 2a). The 21 kb EcoRI fragment was identified within a BAC clone 227C10 and subcloned. The probe 1122A1-B1 (Fig. 3) from the other end of the 21 kb EcoRI fragment hybridized to the same 21 kb germline fragment (Fig. 2b) and a novel 13.5 kb fragment in the cell lines GM06229 and GM06275. These data suggested that the breakpoint in both cell lines lay within this 21 kb EcoRI fragment. In order to compare the breakpoints from a greater range of sources, DNA was extracted from lymphoblastoid and fibroblast cell lines derived from balanced (GM06229, GM06275 and GM04403) and unbalanced (GM06228, GM03371 and GM00084A) carriers and a blood sample from a patient A with a balanced translocation. The probe APOP3-P4 detected a DraIII germline band of 17.5 kb in all samples and a rearranged fragment of 8.5 kb in all the samples except the placental control. These data, together with the breakpoint analysis (below), indicate that the size difference seen for the rearranged fragments (Fig. 2A) is due to an EcoRI polymorphism. The 8.5 kb DraIII fragment was expected to contain the der(22) chromosome junction, consistent with its presence in both balanced and unbalanced individuals. The probe ET82-83 (Fig. 3) detects a 21 kb EcoRI germline fragment and a 13.5 kb rearranged fragment in all the samples from balanced carriers and, unexpectedly, in the apparently unbalanced cell line GM03371. The 13.5 kb EcoRI fragment was expected to contain the der(11) chromosome junction and therefore should be present only in balanced carriers. This discrepancy was resolved by reanalysing the karyotype of GM03371. It was found to have the karotype: 47,XX,inv(9)(p13q21)pat, t(11;22)(q23;q11)mat,+der(22)t(11;22)(q23;q11)mat and therefore contained a der(11) and two der(22) chromosomes. Such a karyotype has been observed previously and is thought to arise from alternate segregation at meiosis I followed by either meiosis II or post-zygotic non-disjunction of the der(22) (11,13–15). The Southern data indicated that all the breakpoints clustered in a 15 kb region of chromosome 11 between APOP3-P4 and ET82-83, the size similarity of the rearrangements suggesting a highly specific form of recombination.
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In order to isolate the breakpoint, long-range inverse PCR (LR-IPCR) (16) was performed on DNA from GM06229 digested with EcoRI. A 1.8 kb product was amplified, subcloned and sequenced (data not shown) (GenBank accession no. AF226670). Comparison with chromosome 11 germline sequence from the BAC clone 442e11 (GenBank accession no. AC007707) indicated that novel sequence was present following an Alu repeat. Database searches revealed that this novel sequence was present in a previously sequenced BAC b563b9 (GenBank accession no. AC007708) attributed to chromosome 22. Significantly, this chromosome 22 germline sequence also contained a truncated (100 bp) Alu element at the fusion point. It was noted that non-identical sequences related to the chromosome 22-specific sequence were present in other BACs consistent with the mapping of the chromosome 22 breakpoint to a low copy repeat (LCR22) sequence (7,17). Another BAC clone, 3090 O16, was identified in the genome survey sequence (GSS) database and was used in FISH experiments against metaphase cells from the cell line GM06229 (Fig. 1d) demonstrating signals on the normal chromosome 22, the der(11) and the der(22). These data indicated that the GM06229 der(11) breakpoint was contained within the 1.8 kb IPCR product and was located within an Alu repeat. Primers placed on chromosome 11 and 22 sequence in the 1.8 kb product, external to the Alu repeat, amplified a junctional 540 bp product from GM06229, GM06275, GM03371, GM04403 and patient A DNA but not from normal placental DNA (Fig. 4a). The sequences of all these products (Fig. 4b) show a high level of similarity i.e. >98%. The sequence of the der(22) breakpoint (the inverse of the 1.8 kb LR-IPCR and 540 bp PCR product) could be predicted using sequences from the two genomic clones 442e11 and b563b9. The predicted breakpoint sequence was confirmed by PCR using DNA from the cell lines GM06229, GM06275, GM03371, GM04403 and patient A (Fig. 4a). With the exception of the placental control a reciprocal junctional 570 bp product was amplified and sequenced (Fig. 4c). These products also show a high level of similarity (>98%).
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Given the high degree of similarity between the breakpoints observed by PCR and Southern blotting, it is important to exclude the possibility of contamination during either cell culture or DNA extraction. It is unlikely that these junctional products amplified by PCR arise from contamination due to a number of consistent base differences and the lack of products from normal genomic DNA. Another possible reason for the similarity between the breakpoints is that GM06229, GM06275, GM03371, GM04403 and patient A are not truly independent. However, the individuals from whom the cell lines were derived and who provided the blood sample are not directly related. Contamination of the cell lines during culture also seems unlikely as two are lymphoid and the other two are derived from fibroblasts and the sample from patient A was not cultured. Furthermore, there are distinct karyotypic differences between the cell lines (Table 2). GM03371 is of particular interest as this cell line is derived from a black individual and has a highly distinctive karyotype. The cell type, age, ethnic origin and karyotpye for all the samples used are summarized in Table 2.
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Since the t(11;22) is due to an Alu–Alu recombination it is not possible to identify the precise fusion points. However, alignment (Fig. 4d and e) of the junctional sequences with the germline sequences of the clones 442e11 and b563b9 limits the der(11) breakpoints of GM06229, GM06275, patient A and GM04403 to a 15 bp region (Fig. 4d) that is identical within the Alu repeats on chromosomes 11 and 22. The GM03371 der(11) breakpoint appears to be located in an adjacent 16 bp. The der(22) breakpoints (Fig. 4e) of patient A, GM03371 and GM04403 are located in an 11 bp region, whereas the breakpoints in GM06229 and GM06275 are located in an adjacent 9 bp region.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The location of the breakpoint on chromosome 11 had previously been predicted from haplotype analysis to be in an AT-rich repeat (12). However, our analysis has placed the breakpoint within a particular Alu repeat 350 bp proximal to the AT-rich sequence. Although the breakpoint region on chromosome 11 is rich in Alu repeats (18 Alus in the 21 kb EcoRI fragment) the recombination occurs consistently in a particular Alu of the Sb subtype (18), 9 kb proximal to the APOA4 gene and 20 kb distal to a putative APOA4-like gene (Fig. 3). Similarly, the breakpoint on chromosome 22 is located in a truncated Alu element (Alu–Sq subtype) located in one of the LCR22 repeat regions between COMT (distal) and ZNF74 (proximal) (7) and within a gap in the recently defined chromosome 22 sequences (19). A probe from the chromosome 22 sequence close to the breakpoint hybridized to approximately seven differently sized bands in EcoRI-digested genomic DNA (data not shown). This not only supported the idea that the breakpoint lies within an LCR22 but, when compared with the highly consistent rearranged fragment sizes (Fig. 2), strongly suggested that the breakpoint is consistently within this LCR22 and does not involve other LCR22 members on chromosome 22. The PCR analysis of the breakpoint sequences (Fig. 4) is consistent with this interpretation. It has been proposed that the LCR22s could mediate duplications and deletions of the 22q11 region by homologous recombination mechanisms (17). The distal breakpoint for a 1.5 Mb deletion associated with DGS and with VCFS has also been mapped to the same interval (7) and could involve breakage of the same region. The study of other constitutional translocations supports the concept that the LCR22s may be preferentially involved. The breakpoints for a t(17;22) translocation associated with neurofibromatosis type I have been shown to map to the inverted sub-repeats within the proximal and distal LCR22s (20,21). Also, a constitutional t(1;22) translocation associated with an ependymoma has been shown to involve breakage in the same LCR22 as that for the 1.5 Mb VFCS/DGS deletion breakpoint (22).
An examination of the sequences on chromosomes 11 and 22 surrounding the t(11;22) breakpoints does not reveal any particular homologies other than the presence of Alu repeats. Alu-mediated recombination is known to be responsible for a variety of genetic disorders. These events include alterations to the LDL receptors (23), 
-globin (24) and ß-globin genes (25), the c-sis oncogene (26) and apolipoprotein B (27). Both Alu segments involved in the t(11;22) translocation contain a ‘core’ Alu sequence (5'-CCTGTAATCCCAGCACTTTGG-GAGGC-3') (Fig. 4d and e) which has been associated with other Alu-mediated recombinations (28). This ‘core’ sequence contains a pentanuceotide motif CCAGC, which is also part of chi, an 8 bp sequence known to stimulate recBC-mediated recombination in Escherichia coli (29). It is not entirely clear whether this ‘core’ sequence is recombinogenic or if the association with Alu repeats involved in recombination is circumstantial due to it being highly conserved between different classes of Alu
One possible explanation for the remarkable similarity between the breakpoints in unrelated individuals is that the t(11;22) translocation is a single ancestral event and the differences we have observed represent subsequent mutations. However, the available evidence suggests that the relatively high frequency of the t(11;22) in the human population may be due to multiple independent events (3), with a case of a de novo paternal translocation having been described (6). If the t(11;22) breakpoints we have characterized are due to independent events it would appear to involve a form of Alu-mediated recombination with a remarkable degree of specificity not observed with other recurrent translocations such as those associated with cancer. Although cancer-associated translocations are not usually thought to be directly mediated by Alu recombination, there is some evidence that the t(9;22) translocation associated with chronic myeloid leukemia and the t(11;22) translocation associated with Ewing sarcoma may be associated with repeated elements including Alu repeats (30,31). In these examples, however, there is variation in the genomic breakpoint positions although it is clear that there is a selection for fusions that result in the expression of in-frame chimeric mRNAs. It therefore may be speculated that the constitutional t(11;22) translocation event is selected for by a similar mechanism. It is conceivable that the high degree of specificity observed here is due to the requirement to express a particular fused mRNA transcript. The effect of the translocation on the expression of the genes surrounding the breakpoint is currently unknown and, in particular, the possibility that a fused transcript may be expressed remains to be determined.
Although individuals with a balanced t(11;22) translocation do not appear to be affected adversely, a 10-fold increased risk of breast cancer was reported (5) in a small study of eight families. The molecular characterization of the t(11;22) will facilitate the analysis of a cohort of breast cancer patients to investigate whether there is an association between this translocation and sporadic breast cancer. In this context it is interesting to note that this region of chromosome 11 has been shown to undergo loss of heterozygosity in this region in a wide variety of cancers (32–35).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Chromosome flow sorting
Metaphase chromosome suspensions were prepared from the lymphoblastoid cell line GM06229 as described previously (36) and stained with chromomycin A3 and Hoechst 33258. Flow analysis identified the peaks due to the der(11) and der(22) and these were sorted into 500 chromosome aliquots in preparation for PCR analysis.
Cell lines and DNA isolation
The cell lines GM06229, GM06228, GM0275, GM03371, GM00084A and GM04403 were obtained from the Coriell Cell Repository (Camden, NJ). These cell lines were cultured in RPMI 1640 with Glutamax (Gibco BRL, Paisley, UK), 20% fetal calf serum, penicillin and streptomycin. Genomic DNA was isolated from blood and cell lines using the Pure-gene DNA isolation kit (Gentra Systems, Ashby de la Zouch, UK).
Isolation of genomic clones and DNA purification
The YACs 911 F02 and 785 E12 were obtained from the CEPH mega YAC libray held at the MRC UK Human Genome Mapping Project Resource Centre (Hinxton, Cambridge, UK). The screening of the BAC and PAC libraries was carried out by Research Genetics (Huntsville, AL) using the probes ZPR1-4 and APOP3-P4. The clone 3090 O16 was also obtained from Research Genetics.
YAC DNA was isolated using the Pure-gene DNA isolation kit (Gentra Systems) from 2 day cultures in AHC medium at 30°C. Plasmid DNA was isolated using the Wizard DNA Purification System (Promega, Southampton, UK) from overnight cultures in Luria–Bertani broth with the appropriate antibiotic at 37°C.
Polymerase chain reaction (PCR)
PCR was performed using Taq polymerase supplied by the ICRF (London, UK). A 50 µl reaction comprised 1x buffer (Promega, containing MgCl), 200 µM dNTPs, 50 µmol oligonucleotide primers and 1 U Taq polymerase. For PCR from genomic DNA ~500 ng of DNA was added and for cloned DNA ~1 ng was added to each reaction. Samples were subjected to 94°C for 1 min followed by 30 cycles of 94°C for 20 s, 56°C for 20 s, 1 min at 72°C, followed by a final incubation at 72°C for 10 min. This was repeated for nested reactions. LR-IPCR was performed as described by Willis et al. (16) using the XL-PCR kit (PE Applied Biosystems, Warrington, UK) on genomic DNA from GM06229 digested with EcoRI with the primers C30XL1REXT, C1XL1, C30XL1R and C1XL2 (Table 1) in nested LR-IPCRs. The primers used for mapping with the flow-sorted chromosomes, YAC, PAC, BAC clones and generating probes for Southern analysis were 785E12L1 and 785E12L2 (D11S4615), APOP3 and APOP4 (APOP3-P4), ET82 and ET83 (ET82-83), ZPR1 and ZPR4 (ZPR1-4, D11S1169), D11S1340A and D11S1340B (D11S1340) and 1122A1 and 1122B1 (1122A1-B1) (Table 1). The der(11) breakpoints were amplified using the primers CHR22XL11, C1XL15, CHR22XL10 and C1XL14 in nested PCRs. The der(22) primers were amplified using the primers CHR22XL12, C1XL10, CHR22XL5 and C1XL9 (Table 1) in nested PCRs. PCR products were then either cloned using the TOPO or TOPO-XL TA cloning kits (Invitrogen, Groningen, The Netherlands) or used directly.
FISH analysis
FISH was performed as described by Pinkel et al. (37) using fluorescently labelled PAC and BAC clones (1062 M21, 676 L8, 227 C10 and 3090 O16) hybridized to metaphase chromosome spreads from GM06229 counter-stained with DAPI.
DNA sequence analysis
Sequencing reactions were performed using the BigDye Terminator Cycle Sequencing Ready Reaction DNA sequencing kit (PE Applied Biosystems) according to the manufacturer’s instructions using specific and M13 forward and reverse primers. Samples were either plasmid preparations purified using the Wizard DNA purification system (Promega) or PCR products purified using centricon 100 concentrators (Amicon, Beverley, MA). The reaction products were resolved on a 4.8% polyacrylamide gel run using the ABI PRISM 377 DNA sequencer (PE Applied Biosystems).
Gel electrophoresis and Southern blot analysis
Genomic DNA was digested with the enzymes EcoRI and DraIII (Promega) according to the manufacturer’s instructions. Standard 20 x 25 cm agarose gels (0.4–0.7%) were run in 1x TBE for between 24 and 48 h depending on the size of fragments to be resolved. Gels were blotted on to Hybond N+ (Amersham, Little Chalfont, UK). The probes were labelled with [32P]dCTP using the multi-prime labelling kit (Amersham) and hybridized overnight at 65°C in a solution comprising 6x SSC, 0.5% SDS and 5x Denhardt’s. The filters were then washed twice in 2x SSC at 65°C for 15 min followed by 2x SSC, 0.1% SDS at 65°C for 30 min and finally 0.1x SSC at 65°C for 10 min. The pattern of hybridization was visualized using phosphor screens (Kodak, Hemel Hempstead, UK) exposed to the washed filters and scanned with a Storm 840 (Molecular Dynamics, Sunnyvale, CA) PhosphoImager.
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ACKNOWLEDGEMENTS |
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We thank John Sgouros, ICRF for valuable discussions in the course of this work, Professor Joy Delhanty for provision of blood from t(11;22) patients and Dr Louise Jones for invaluable technical assistance.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +44 20 7882 6002; Fax: +44 20 7882 6004; Email: b.young@icrf.icnet.uk
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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