| Human Molecular Genetics | Pages |
©1999 Oxford University Press |
Homologous DNA exchanges in humans can be explained by the yeast double-strand break repair model: a study of 17p11.2 rearrangements associated with CMT1A and HNPP
Introduction
Results And Discussion
Materials And Methods
Patients
Sequence of the 1.7 kb hotspot NsiI-EcoRI region
Acknowledgements
References
Homologous DNA exchanges in humans can be explained by the yeast double-strand break repair model: a study of 17p11.2 rearrangements associated with CMT1A and HNPP
Received July 13, 1999; Revised and Accepted September 1, 1999
Rearrangements in 17p11.2, responsible for the 1.5 Mb duplications and deletions associated, respectively, with autosomal dominant Charcot-Marie-Tooth type 1A disease (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are a suitable model for studying human recombination. Rearrangements in 17p11.2 are caused by unequal crossing-over between two homologous 24 kb sequences, the CMT1A-REPs, that flank the disease locus and occur in most cases within a 1.7 kb hotspot. We sequenced this hotspot in 28 de novo patients (25 CMT1A and three HNPP), in order to localize precisely, at the DNA sequence level, the crossing-overs. We show that some chimeric CMT1A-REPs in de novo patients (10/28) present conversion of DNA segments associated with the crossing-over. These rearrangements can be explained by the double-strand break (DSB) repair model described in yeast. Fine mapping of the de novo rearrangements provided evidence that the successive steps of this model, heteroduplex DNA formation, mismatch correction and gene conversion, occurred in patients. Furthermore, the model explains 17p11.2 recombinations between chromosome homologues as well as between sister chromatids. In addition, defective mismatch repair of the heteroduplex DNA, observed in two patients, resulted in two heterozygous chimeric CMT1A-REPs which can be explained, as in yeast, by post-meiotic segregation. This work supports the hypothesis that the DSB repair model of DNA exchange may apply universally from yeasts to humans.
INTRODUCTION
The exchange of segments of chromosome arms, or recombination, is the central mechanism by which genetic diversity is introduced. This mechanism has been studied mainly in fungi. Our knowledge of how this occurs in higher eukaryotes, especially in mammals, remains very limited. In mammals, recombination has been studied by analysis of `hotspots' where the frequency of meiotic exchange per unit of physical distance is very high (1-3): for example, the major histocompatibility complex (MHC) in mice (4), the immunoglobulin heavy chain genes (5), the [beta]-globin gene cluster (6) and the Duchenne muscular dystrophy gene (7). The most suitable model for this analysis, however, is the 17p11.2 rearrangements associated with Charcot-Marie-Tooth type 1A disease (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), two autosomal dominant disorders of the peripheral nervous system (2,8-10).
CMT1A is caused most often by the duplication of a 1.5 Mb region within 17p11.2 (11,12), whereas HNPP is associated, in 80-90% of patients, with a deletion of the same region (13,14). The duplications and deletions of the 17p11.2 region are the reciprocal products of unequal inter- or intrachromosomal crossovers due to the misalignment of two homologous 24 kb flanking sequences, the proximal and distal CMT1A-REPs (Fig. 1) (2,14-18). The high degree of homology of these repeat sequences (98.7%) could explain the high frequency of recombinations between the proximal and distal CMT1A-REPs (19). A rearrangement hotspot has been identified in a 1.7 kb NsiI-EcoRI region of the CMT1A-REPs where ~75% of all crossovers occur (2,10,20). Because of the presence of divergent bases in the proximal and distal CMT1A-REPs, the recombination hotspot has now been mapped in an interval of <1 kb (2,3).
Figure 1. Representation of a de novo rearrangement between a distal and a proximal CMT1A-REP on distinct homologous chromosomes 17, during maternal and paternal meioses. The gamete bearing the deleted chromosome would give rise to a de novo HNPP patient, whereas the gamete with the duplicated chromosome would cause de novo CMT1A. The two rearranged chromosomes 17 bear chimeric CMT1A-REP with a crossover breakpoint as indicated.
In a previous analysis of 40 de novo cases, we showed that 17p11.2 rearrangements occur by two distinct sex-dependent chromosomal events. Rearrangements of paternal origin, essentially duplications, are generated mostly by unequal crossing-over between two chromosome 17 homologues, whereas duplications and deletions of maternal origin result from an intrachromosomal process (2,18,21). Inter- and intrachromosomal events are also responsible for 22q11.2 and 7q11.23 deletions associated with Williams-Beuren (WBS) and CATCH 22 syndromes, respectively (22).
In the present study of these chromosomal events in a series of 28 de novo rearrangements, the sequences of the parental proximal and distal CMT1A-REPs were compared with the chimeric copy in the de novo patient, in order to localize the crossovers in the 1 kb hotspot region at the level of the DNA sequence. The use of five previously unknown divergent bases (3) in the 1 kb hotspot permitted refinement of the localization of the sites of DNA exchange between the CMT1A-REPs. We show that some chimeric CMT1A-REPs in de novo patients present conversion of DNA segments associated with the crossover. Furthermore, in two de novo patients, their chimeric CMT1A-REPs were heterozygous for one and four successive divergent bases, respectively. This observation appears to result from defective mismatch repair and post-meiotic segregation (PMS), as in yeast. These data are compatible with the double-strand break (DSB) repair model described in Saccharomyces cerevisiae (23,24) which can generate both meiotic crossovers and gene conversion. The similarities between human recombination and the yeast DSB repair model are discussed.
RESULTS AND DISCUSSION
In order to determine the type of chromosomal event resulting in de novo 17p11.2 rearrangements and the parental origin, allelic segregation of 17p11.2 microsatellite and restriction fragment length polymorphism (RFLP) markers was studied in 23 as yet unanalysed de novo duplications. The results, combined with the 40 de novo cases previously reported (2), confirm that there are two distinct sex-dependent mechanisms of chromosomal recombination. As shown in Table 1, interchromosomal recombination between the two chromosome 17 homologues occurred primarily during paternal meioses (49/54), whereas intrachromosomal crossovers were generated preferentially during maternal gametogenesis (6/7). The relationship between the mechanism and the sex of the transmitting parent is statistically significant (P < 10-5).
Table 1. Parental origin and chromosomal mechanism of 63 de novo 17p11.2 rearrangements
| Mechanism | Paternal origin | Maternal origin | Total |
| Interchromosomal | 49 (CMT1A) | 5 (CMT1A) | 54 |
| Intrachromosomal | 1 (CMT1A) | 6 (4 CMT1A; 2 HNPP) | 7 |
| ND | 1 (HNPP) | 1 (HNPP) | 2 |
Twenty-eight de novo rearrangements (25 CMT1A and 3 HNPP) in the 1.7 kb NsiI-EcoRI hotspot region were sequenced for fine mapping of the breakpoints. Twenty-three of the 28 were reported previously (2) and five were newly sequenced (patients 21.3P, 397M, 1262M, 406P, 460M). The previous study performed with the 23 sequenced de novo cases showed that most rearrangements were located within a 741 bp interval, but the recent identification, in controls, of five new divergent bases within this interval (3) permits more precise localization of the sites of exchange between the CMT1A-REPs. These five new divergent bases, in addition to the 15 already known (10), were analysed in the chimeric CMT1A-REP of the 28 de novo rearrangements and in the proximal and distal CMT1A-REPs of the transmitting parent, in order to identify the proximal or distal origin of the DNA segments comprising the chimeric CMT1A-REP (Fig. 2).
Figure 2. The 1.7 kb hotspot region in the chimeric CMT1A-REP of 28 de novo 17p11.2 rearrangements. Twenty bases (represented by vertical lines) diverge between the proximal and distal CMT1A-REPs. Five are polymorphic (indicated by lower case letters): three are found only in the proximal CMT1A-REP (r = A or G; y = C or T; y = C or T); two are found in both proximal and distal CMT1A-REPs (k = G or T; r = A or G). The five recently identified divergent bases are in bold. Each horizontal line represents the chimeric CMT1A-REP of a de novo patient. White lozenges indicate that the divergent base belongs to the proximal CMT1A-REP, and black lozenges that they belong to the distal CMT1A-REP. Non-informative polymorphic bases are represented as hatched lozenges. Grey lozenges indicate bases for which patients are heterozygous. The family identification number is indicated on the left. The parental origin of the rearrangement is indicated as P (paternal) or M (maternal). The family number is preceded by an asterisk when the recombination occurred between sister chromatids, and is boxed for the three de novo HNPP patients. The `simple' or `complex' appearance of the chimeric CMT1A-REP is indicated, respectively, by an `s' and a `c' to the right of the figure. Most of the rearrangements occurred within a 1200 bp region, represented by the dashed line at the top of the figure.
This analysis evidenced several different types of DNA exchange between the proximal and distal CMT1A-REPs during gametogenesis. Approximately 70% (18/28) of the exchanges produced `simple' chimeric CMT1A-REPs in which a DNA segment from the proximal CMT1A-REP is joined to a segment of the distal homologue (see patient 150P or 283P). Several types of `complex' chimeric CMT1A-REP (10/28) were also observed, in which segments from the proximal and distal CMT1A-REPs alternate in the chimeric product. The chimeric CMT1A-REP from patient 395P consisted of four segments, derived, in order, from the proximal/distal/proximal/distal CMT1A-REPs of his father. This alternation of sequences can only be explained by gene conversion associated with the crossover between the proximal and distal CMT1A-REPs during meiosis. The conversion of DNA segments associated with crossovers was observed: (i) in de novo CMT1A (patients 271P, 309M, 21.3P, 397M, 1-3P, 395P, 631P, 75P and 160P) and in de novo HNPP cases (patient 902M); (ii) during interchromosomal rearrangements (patients 271P, 397M, 1-3P, 395P, 631P, 75P and 160P) and during sister chromatid exchanges (patients 309M, 21.3P and 902M); and (iii) in paternal (n = 7) and in maternal (n = 3) gametes. Four conversions were suspected previously in a study of 23 HNPP patients (3). They were familial cases, however, and it was not possible to distinguish between conversions and sequence polymorphisms.
The observed association of crossover and conversion can be explained by the DSB repair model described in yeast (23-26). This model was proposed initially by Resnick (25), but was developed by Szostak et al. (23), in particular as a model for meiosis (23). This model, which accounts for meiotic recombination, comprises several steps. (i) The recombination event is initiated early in the prophase of meiosis I by DSBs (27,28). (ii) A heteroduplex DNA structure that can migrate is generated and converted to double Holliday junctions which are the first chemically stable connections between homologues at the DNA level (29). (iii) During the last stage of homologous recombination, the double Holliday junctions are cleaved, yielding recombinant molecules with or without exchanged flanking sequences. These different steps are illustrated in detail in Figure 3.
Figure 3. The double-strand break (DSB) repair model can account for the rearrangements observed in de novo 17p11.2 rearrangements. (1) The double-stranded DNA from proximal (black) and distal (grey) CMT1A-REPs are represented with eight successive divergent bases of the 1.7 kb NsiI-EcoRI region. (2) Cleavage of one double-strand and resection of the two 5[prime] strand termini by an exonuclease creates single-stranded 3[prime] OH-ended tails. (3) One of these single-stranded tails can invade a homologous duplex. (4) The 3[prime] OH ends act as a primer to initiate DNA repair synthesis using the intact donor strand as template. This step results in the formation of heteroduplex mismatched regions, represented by black dots. This heteroduplex structure can extend and migrate. (5) The branched structures are converted to double Holliday junctions which are stable recombination intermediates. (6) The correction of mismatches in the heteroduplex DNA is performed by the mismatch repair machinery using the 3[prime]->5[prime] or 5[prime]->3[prime] DNA strands as templates. Arbitrarily, only the regions repaired using the 3[prime]->5[prime] DNA strand templates are represented in the figure. (7) The resolution of the double Holliday junctions can occur in two ways, depending on the type of cleavage (at a and b, or at a and c), yielding crossover products with or without conversion (I and II, respectively) or non-crossover products with the parental flanking sequences, with or without conversion (III and IV, respectively). The type I product corresponds to part of the chimeric CMT1A-REP in patient 395P (Fig. 2).
The recombination events present in patients with de novo 17p11.2 rearrangements present similarities with the DSB repair model. The recombinations were found essentially within a 1200 bp region. Most of the conversions were located, however, in a 300 bp interval which contains the five polymorphic bases (Fig. 2). We hypothesize that these polymorphisms might have been generated by a DSB that introduced conversion segments without crossover into a CMT1A-REP (i.e. Fig. 3, step 7, product III). In yeast, conversion segments arise from gap repair, through DNA synthesis on the displaced strand (Fig. 3, step 4). If the resulting heteroduplex DNA has mismatched bases, they will be corrected by excision of one of the mismatched strands, followed by DNA synthesis using the other strand as template. For example, in Figure 3 (steps 5 and 6), we have represented the mismatch repair machinery using the 3[prime]->5[prime] DNA strand as template. The two resulting crossover products are for one associated with a conversion (type I), and for the other without conversion (type II). Introduction of heterozygous restriction sites in the S.cerevisiae genome has shown that approximately half of the exchanges were associated with gene conversion events (30,31). Only one-third of our series of 28 de novo rearrangements presented conversion events associated with the crossovers, although the proportion is certainly underestimated because they can only be detected if there are differences in the sequences of the proximal and distal CMT1A-REPs and, even then, the polymorphic bases in the transmitting parents (k, r, y, y, r) were not always informative.
In S.cerevisiae, the size of the 3[prime]-terminal single-stranded tail is ~600 bp (32,33). The heteroduplex DNA, formed by invasion of a homologous duplex by the free 3[prime] single-stranded tail (Fig. 3, step 4), extends beyond the single-stranded tail through branch migration. In our series of de novo rearrangements, heteroduplexes extended from ~200 to >800 bp in length. For example, the heteroduplex in patient 271P was >650 bp in length and extended from the divergent T/C bases situated at 110 bp of the NsiI site to the more centromeric r/r polymorphic bases located at 670 bp (Fig. 2). In patient 75P, in whom the proximal CMT1A-REP segment was telomeric to the NsiI-EcoRI region, the heteroduplex was >800 bp in length.
The chimeric CMT1A-REPs of patients 160P and 21.3P were heterozygous for one and four successive divergent bases, respectively (Fig. 4). At each site, one base from the proximal CMT1A-REP and one base from the distal REP were detected. This observation can be explained by the presence in the patients of two distinct populations of chimeric CMT1A-REPs. The peaks of the electropherograms corresponding to the bases were similar, suggesting that the two populations are equally represented (Fig. 4). This heterozygosity of the chimeric CMT1A-REP is highly suggestive that, after the formation of the heteroduplex DNA (Fig. 3, steps 4 and 5), some mismatched base pairs were not corrected by the mismatch repair system. In patient 160P, one base remained uncorrected; in patient 21.3P, four mismatched bases remained. The mismatches were then conserved throughout all the subsequent steps of meiosis, until the S phase preceding the first mitosis in the zygote that generates two distinct populations of chimeric CMT1A-REP with no mismatches (Fig. 5). In yeast, this phenomenon is referred to as PMS (34). We noted that the de novo rearrangement in patient 21.3P resulted from an intrachromosomal recombination. This suggests that at least some sister chromatid exchanges are meiotic.
Figure 4. Heterozygosity at one or more polymorphic sites in the chimeric CMT1A-REP of two patients. The proximal and distal CMT1A-REP sequences from the transmitting parents and the chimeric CMT1A-REP sequences from two corresponding de novo CMT1A patients are shown. (a) De novo patient 160P is heterozygous at one divergent site (T/C) in his chimeric CMT1A-REP. The nucleotide position from the NsiI restriction site on Figure 2 is indicated at the top of the electropherograms. (b) Sequence analysis of the chimeric CMT1A-REP from patient 21.3P showed that he is heterozygous at four successive divergent bases (G/A, C/T, C/T and A/G). The order of the four divergent bases is inverted with regard to Figure 2.
Figure 5. Defective mismatch repair results in two populations of chimeric CMT1A-REP. (a) (1) The heteroduplex, formed by the double Holliday junctions in the DSB repair model, is represented by black dots (see step 5 in Fig. 3). The resolution of these double Holliday junctions, by cleavage at a and b, is performed without correction of the mismatched base pairs. (2) The two resulting products, or chimeric CMT1A-REPs, with mismatch conservation are boxed (types I and II). (3) If the gamete which contains a chromosome 17 with a type I chimeric CMT1A-REP participates in fertilization, replication during the S phase, just before the first mitosis, will generate two populations of chimeric CMT1A-REP (types I-A and I-B). Thus, the resulting embryo will be heterozygous for the divergent bases which were not corrected in the heteroduplex. (b) Representation at the chromosomal level of type I segregation after fertilization. Paternal (17 P) and maternal (17 M) chromosome 17 homologues are represented with one chromatid each in the zygote. The paternal chromosome carries the type I chimeric CMT1A-REP with mismatches represented by a black dot. After replication, each chromosome 17 has sister chromatids, with type I-A and type I-B chimeric CMT1A-REPs. Mitosis generates two cells, each with a different type of chimeric CMT1A-REP.
In yeast, DSBs occur in meiotic cells, in particular in regions of chromatin where DNA is accessible, i.e. sites that are hypersensitive to DNase I and micrococcal nuclease (MNase) (35-39), with a preference for promotor regions of genes as illustrated by the recombination hotspot at the ARG4 and HIS4 loci in S.cerevisiae (38,40). The hotspot of recombination in the CMT1A-REPs is located, however, in the 3[prime] end of the human heme A:farnesyltransferase gene (COX10), in the sequence of intron V (19). It would be interesting to test the accessibility of chromatin in the 1200 bp region of the CMT1A-REPs where most of the crossovers were observed in patients.
Klein et al. (41) have shown that human DNA inserts in yeast artificial chromosomes (YACs) can undergo DSBs when amplified in yeasts, and that the degree of double-strand breakage during meiosis reflects the degree of meiotic recombination in these sequences in humans. This suggests that human DNA is capable of DSB repair-mediated recombination during yeast meioses. It also suggests that human DNA contains sequences, probably exposed in open chromatin, that are recognized by the yeast DSB repair machinery. These sequences, when expressed in yeast, appear to dictate the positions and frequencies of DSBs. A heptameric DNA sequence (ATGACGT) surrounding the M26 mutation in the ade6 gene in Schizosaccharomyces pombe is postulated to act as such a signal (42). This sequence was not found in the 1.2 kb hotspot region of the human CMT1A-REPs, although other sequences that potentially could promote recombination have been detected (2). A study performed in six patients with Hunter syndrome showed that the inversion between the IDS gene and its IDS-2 pseudogene frequently is associated with conversions of DNA segments and may also be explained by the DSB repair model (43).
In conclusion, we have confirmed the existence of interhomologue and intrachromosomal events of rearrangement at 17p11.2 which are sex-dependent. Interchromosomal rearrangements occur mostly during spermatogenesis, whereas intrachromosomal rearrangements are generated preferentially during oogenesis. In addition, we showed that the gene conversions associated with crossovers are found in both interchromosomal and intrachromosomal DNA exchanges and occur during paternal as well as maternal meioses. These rearrangements are compatible with the yeast DSB repair model. This model is therefore able to account for duplications, deletions and conversions. Furthermore, heterozygous sites were detected in chimeric CMT1A-REP which appear to result from defective mismatch repair and PMS, as in yeast. The similarity between recombination phenomena in yeasts and humans indicates that the DSB repair model may be a universal mechanism for homologous DNA exchange.
MATERIALS AND METHODS
Patients
17p11.2 duplications and deletions were detected by gene dosage on Southern blots in 59 unrelated CMT1 patients and four HNPP patients, respectively. The parents of these patients presented no clinical or electrophysiological abnormalities and no rearrangements in the 17p11.2 region. The parental origin of 17p11.2 rearrangements and the chromosomal mechanisms were determined by allele segregation of the following 17p11.2 microsatellite markers D17S953, D17S122 (RM11GT), D17S839, D17S955, D17S921, D17S922, D17S1357 and D17S1358 (44,45), and RFLP probes VAW409R3a, EW401 and VAW412. The parental origin of 10 de novo CMT1A patients was reported previously (46,47).
Sequence of the 1.7 kb hotspot NsiI-EcoRI region
The 1.7 kb NsiI-EcoRI region was amplified with primers that were specific to either the proximal or the distal CMT1A-REP. The primer sequences and the PCR conditions were described previously (2). This region was amplified independently from the proximal and distal CMT1A-REPs of the transmitting parents and from the chimeric CMT1A-REP of their affected child. The 2.2 kb amplification products were digested with appropriate restriction enzymes in order to confirm the specificity of the PCR reaction: NsiI, EcoRI and EcoRI-NsiI for PCR fragments from parental proximal and distal CMT1A-REPs and from chimeric CMT1A-REP, respectively. After isolation on agarose gel and purification (Qiaquick gel purification kit; Qiagen, Valencia, CA), fragments were sequenced with an automated fluorescent DNA ABI PRISM 377 sequencer (Perkin Elmer, Foster City, CA) using the Dye Primer Sequencing kit (Perkin Elmer). Sequences were analysed with the Sequence Navigator Program, version 1.0 (Perkin Elmer).
ACKNOWLEDGEMENTS
The authors thank Drs P. Bouche, P. Bridge, V. Ionasescu, M. Mayer, V. Layet, N. Lévy, N. Tachi and N. Wood for referring some of the families, and Christiane Penet, Yolaine Pothin, Jacqueline Bou, Agnès Camuzat and Isabelle Lagroua for technical assistance, and Drs R. Gouider and N. Birouk for medical assistance. We thank Drs A. Nicolas and C. Mézard for critical reading of the manuscript. J.L. was supported by a fellowship from the Fondation pour la Recherche Médicale (FRM). This study was supported by the Association Française contre les Myopathies (AFM), the Assistance Publique des Hôpitaux de Paris (AP-HP), the Association pour le Développement de la Recherche sur les Maladies Génétiques Neurologiques et Psychiatriques (ADRMGNP) and Biomed 2 concerted action CT961614.
REFERENCES
+To whom correspondence should be addressed. Tel: +33 1 42 16 21 82; Fax: +33 1 44 24 36 58; Email: leguern{at}ccr.jussieu.fr
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