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1.
Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia
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Velagaleti GV Bien-Willner GA Northup JK Lockhart LH Hawkins JC Jalal SM Withers M Lupski JR Stankiewicz P 《American journal of human genetics》2005,76(4):652-662
Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y-related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps approximately 900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter-->4p15.1::17q25.1-->17qter;7qter-->7p15.3::4p15.1-->4pter;8pter-->8q12.1::7p15.3-->7pter;17pter-->17q25.1::8q12.1-->8qter). Surprisingly, the 17q breakpoint maps approximately 1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3' of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed. 相似文献
2.
Molecular cytogenetic characterization of 17 rob(13q14q) Robertsonian translocations by FISH, narrowing the region containing the breakpoints. 总被引:3,自引:3,他引:0
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We have characterized 17 rob(13q14q) Robertsonian translocations, using six molecular probes that hybridize to the repetitive sequences of the centromeric and shortarm regions of the five acrocentric chromosomes by FISH. The rearrangements include six de novo rearrangements and the chromosomally normal parents, five maternally and three paternally inherited translocations, and three translocations of unknown origin. The D21Z1/D13Z1 and D14Z1/D22Z1 centromeric alpha-satellite DNA probes showed all rob(13q14q) chromosomes to be dicentric. The rDNA probes did not show hybridization on any of the 17 cases studied. The pTRS-47 satellite III DNA probe specific for chromosomes 14 and 22 was retained around the breakpoints in all cases. However, the pTRS-63 satellite III DNA probe specific for chromosome 14 did not show any signals on the translocation chromosomes examined. In 16 of 17 translocations studied, strong hybridization signals on the translocations were detected with the pTRI-6 satellite I DNA probe specific for chromosome 13. All parents of the six de novo rob(13q14q), including one whose pTRI-6 sequence was lost, showed strong positive hybridization signals on each pair of chromosomes 14 and 13, with pTRS-47, pTRS-63, and pTRI-6. Therefore, the translocation breakpoints in the majority of rob(13q14q) are between the pTRS-47 and pTRS-63 sequences in the p11 region of chromosome 14 and between the pTRI-6 and rDNA sequences within the p11 region of chromosome 13. 相似文献
3.
Nothwang HG Schröer A van der Maarel S Kübart S Schneider S Riesselmann L Menzel C Hinzmann B Vogt D Rosenthal A Fryns J Tommerup N Haaf T Ropers HH Wirth J 《Cytogenetics and cell genetics》2000,90(1-2):126-133
Mental retardation is a very common and extremely heterogeneous disorder that affects about 3% of the human population. Its molecular basis is largely unknown, but many loci have been mapped to the X chromosome. We report on two mentally retarded females with X;autosome translocations and breakpoints in Xp11, viz., t(X;17)(p11;p13) and t(X;20)(p11;q13). (Fiber-) FISH analysis assigned the breakpoints to different subbands, Xp11.4 and Xp11.23, separated by approximately 8 Mb. High-resolution mapping of the X- chromosome breakpoints using Southern blot hybridization resulted in the isolation of breakpoint-spanning genomic subclones of 3 kb and 0. 5 kb. The Xp11.4 breakpoint is contained within a single copy sequence, whereas the Xp11.23 breakpoint sequence resembles an L1 repetitive element. Several expressed sequences map close to the breakpoints, but none was found to be inactivated. Therefore, mechanisms other than disruption of X-chromosome genes likely cause the phenotypes. 相似文献
4.
Arun Kumar Laurie A. Becker Theresa W. Depinet J. Marie Haren C. Lisa Kurtz Nathaniel H. Robin Suzanne B. Cassidy Daynna J. Wolff S. Schwartz 《Human genetics》1998,103(2):173-178
To test the hypothesis that the phenotypic abnormalities seen in cases with apparently balanced chromosomal rearrangements
are the result of the presence of cryptic deletions or duplications of chromosomal material near the breakpoints, we analyzed
three cases with apparently balanced chromosomal rearrangements and phenotypic abnormalities. We characterized the breakpoints
in these cases by using microsatellite analysis by polymerase chain reaction and fluorescence in situ hybridization analysis
of yeast artificial chromosome clones selected from the breakpoint regions. Molecular characterization of the translocation
breakpoint in patient 1 [46,XY,t(2;6)(p22.2;q23.1)] showed the presence of a 4- to 6-Mb cryptic deletion between markers D6S412
and D6S1705 near the 6q23.1 breakpoint. Molecular characterization of the proximal inversion 7q22.1 breakpoint in patient
2 [46,XY,inv(7)(q22.1q32.1)] revealed the presence of a 4-Mb cryptic deletion between D7S651 and D7S515 markers. No deletion
or duplication of chromosomal material was found near the breakpoints in patient 3 [46,XX,t(2;6)(q33.1;p12.2)]. Our study
suggests that a systematic molecular study of breakpoints should be carried out in cases with apparently balanced chromosomal
rearrangements and phenotypic abnormalities, because cryptic deletions near the breakpoints may explain the phenotypic abnormalities
in these cases.
Received: 9 March 1998 / Accepted: 24 April 1998 相似文献
5.
N. Simon Thomas Viv Maloney Victoria Bryant Shuwen Huang Carole Brewer Katherine Lachlan Patricia A. Jacobs 《Human genetics》2009,125(2):181-188
The majority of constitutional reciprocal translocations appear to be unique rearrangements arising from independent events.
However, a small number of translocations are recurrent, most significantly the t(11;22)(q23;q11). Among large series of translocations
there may be multiple independently ascertained cases with the same cytogenetic breakpoints. Some of these could represent
additional recurrent rearrangements, alternatively they could be identical by descent (IBD) or have subtly different breakpoints
when examined under higher resolution. We have used molecular breakpoint mapping and haplotyping to determine the origin of
three pairs of reciprocal constitutional translocations, each with the same cytogenetic breakpoints. FISH mapping showed one
pair to have different breakpoints and thus to be distinct rearrangements. Another pair of translocations were IBD with identical
breakpoint intervals and highly conserved haplotypes on the derived chromosomes. The third pair, t(4;11)(p16.2;p15.4), had
the same breakpoint intervals by aCGH and fosmid mapping but had very different haplotypes, therefore they represent a novel
recurrent translocation. Unlike the t(11;22)(q23;q11), the formation of the t(4;11)(p16.2;p15.4) may have involved segmental
duplications and sequence homology at the breakpoints. Additional examples of recurrent translocations could be identified
if the resources were available to study more translocations using the approaches described here. However, like the t(4;11)(p16.2;p15.4),
such translocations are likely to be rare with the t(11;22) remaining the only common recurrent constitutional reciprocal
translocation. 相似文献
6.
Transforming growth factors type beta 1 and beta 2 are equipotent growth inhibitors of human breast cancer cell lines 总被引:4,自引:0,他引:4
G Zugmaier B W Ennis B Deschauer D Katz C Knabbe G Wilding P Daly M E Lippman R B Dickson 《Journal of cellular physiology》1989,141(2):353-361
At least one member of the TGF-beta family, TGF-beta 1, has been previously shown to inhibit the anchorage-independent growth of some human breast cancer cell lines (Knabbe et al., 1987; Arteaga et al., 1988). Members of the TGF-beta family might, therefore, provide new strategies for breast cancer therapy. We have studied the inhibitory effects of TGF-beta 1 and TGF-beta 2 on the anchorage-independent growth of the oestrogen receptor-negative cell lines MDA-MB-231, SK-BR-3, Hs578T, MDA-MB-468, and MDA-MB-468-S4 (an MDA-MB-468 clone not growth inhibited by EGF) and the estrogen receptor-positive cell lines MCF7, ZR-75-1, T-47D. TGF-beta 1 and TGF-beta 2 caused a 75-90% growth inhibition of MDA-MB-231, SK-BR-3, Hs578T, and MDA-MB-468 cells and a 50% growth inhibition of ZR-75-1 and early passage (less than 100) MCF7 cells. T-47D cells responded to TGF-beta only in serum-free conditions in the presence of IGF-1 or EGF. The growth of MDA-MB-468-S4 cells and late passage (greater than 500) MCF7 cells was not inhibited by TGF-beta 1 or TGF-beta 2. TGF-beta-sensitive MCF7 and MDA-MB-231 cells did not respond to Muellerian inhibiting substance (MIS), a TGF-beta-related polypeptide. TGF-beta 1 or TGF-beta 2 were mutually competitive for receptor binding with a similar affinity (Kd 25-130 pM, 1,000-13,000 sites per cell). To determine the time course of the TGF-beta effect, an anchorage-dependent growth assay was carried out using MDA-MB-231 cells. Growth inhibition occurred at 6 days, and cell-cycle changes were seen 12 hr after the addition of TGF-beta. Cells accumulated in the G1 phase and were thus inhibited from entering the S-phase. These data indicate that TGF-beta is a potent growth inhibitor in most breast cancer cell lines and provide a basis for studying TGF-beta effects in vivo. 相似文献
7.
Physical mapping of probes within 14q32, a subtelomeric region showing a high recombination frequency 总被引:6,自引:0,他引:6
The genetic linkage map of chromosome 14q32 contains 11 loci which span a distance of more than 60 cM. We have assigned 10 of these loci and the AKT1 proto-oncogene to segments of 14q32, using breakpoints derived from four independent chromosomal deletions or rearrangements. The most telomeric breakpoint was found in a proband (HSC 6) carrying a ring-14 chromosome. HSC 6 is monosomic for the distal part of 14q32, which contains the immunoglobulin heavy-chain locus (IGH), and random markers D14S20, D14S19, and D14S23. Two other chromosomal breakpoints, found in probands HSC 121 and HSC 981, could not be distinguished from each other using DNA probes, although the cytogenetic breakpoints appeared to be different at 14q32.32 and 14q32.31, respectively. The region between the breakpoints of HSC 6 and HSC 121 contains AKT1, D14S1, D14S17, and D14S16. The entire telomeric band 14q32 is assumed to contain about 10% of chromosome 14, or approximately 10 Mb. The 8 most telomeric loci, including D14S1, map to 14q32.32-qter, which measures only several megabases. However, these loci span a genetic distance of 23 cM. The high recombination frequency contrasts with the observation that two of the gamma genes in the IGH constant region show a high degree of linkage disequilibrium, though 180 kb apart. This finding suggests that a telomeric localization per se does not lead to a higher recombination frequency and favors the hypothesis that the higher recombination frequency at the telomeres may be due to specific "hot spots" for recombination. 相似文献
8.
Ou Z Jarmuz M Sparagana SP Michaud J Décarie JC Yatsenko SA Nowakowska B Furman P Shaw CA Shaffer LG Lupski JR Chinault AC Cheung SW Stankiewicz P 《Human genetics》2006,120(2):227-237
We report clinical findings and molecular cytogenetic analyses for two patients with translocations [t(14;17)(p12;p12) and t(15;17)(p12;p13.2)], in which the chromosome 17 breakpoints map at a large low-copy repeat (LCR) and a breakage-prone TRE-2 (USP6) oncogene, respectively. In family 1, a 6-year-old girl and her 5-year-old brother were diagnosed with mental retardation, short stature, dysmorphic features, and Charcot-Marie-Tooth disease type 1A (CMT1A). G-banding chromosome analysis showed a der(14)t(14;17)(p12;p12) in both siblings, inherited from their father, a carrier of the balanced translocation. Chromosome microarray and FISH analyses revealed that the PMP22 gene was duplicated. The chromosome 17 breakpoint was mapped within an ∼383 kb LCR17pA that is known to also be the site of several breakpoints of different chromosome aberrations including the evolutionary translocation t(4;19) in Gorilla gorilla. In family two, a patient with developmental delay, subtle dysmorphic features, ventricular enlargement with decreased periventricular white matter, mild findings of bilateral perisylvian polymicrogyria and a very small anterior commissure, a cryptic duplication including the Miller–Dieker syndrome region was identified by chromosome microarray analysis. The chromosome 17 breakpoint was mapped by FISH at the TRE-2 oncogene. Both partner chromosome breakpoints were mapped on the short arm acrocentric heterochromatin within or distal to the rRNA cluster, distal to the region commonly rearranged in Robertsonian translocations. We propose that TRE-2 together with LCR17pA, located ∼10 Mb apart, also generated the evolutionary gorilla translocation t(4;19). Our results support previous observations that the USP6 oncogene, LCRs, and repetitive DNA sequences play a significant role in the origin of constitutional chromosome aberrations and primate genome evolution. 相似文献
9.
I. A. Boussy 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》1988,76(4):627-639
Summary Translocations with euchromatic breakpoints were generated in lethal-free autosomes of Drosophila melanogaster. Pairs of initially homozygous-lethal translocations, matched for one breakpoint, were allowed to recombine for ten generations. At the end of the experiment, 10/47=21% of crosses (representing 8/26=31% of the intial translocations) had at least one line with at least one homokaryotypic third-instar larva, detected among a small sample of salivary gland preparations from each cross. Among these ten crosses, chromosome extractions were performed; 5/10 of the crosses (probably representing 4/8 of the translocations) had at least one chromosome set with relative viability greater than 15%–25%. To a first (and conservative) approximation, 5/47=11% of crosses showed improvement of viability of 1 of the translocations in the cross during the controlled recombination regime; overall, 4 of the 26 translocations (15%) showed improvement of viability. Partly because of the conservative criterion of viability used, this figure is less than the 20% of translocations that theoretically should be improvable. Pseudohomokaryotypes (pairs of translocations with both breakpoints nearly matching) did not behave as very fit homokaryotypes. However, some of them generated viable hyperploid assortment products that might be of practical interest to mask deleterious effects at breakpoints of translocations. The improvement of fitness of at least a proportion of low fitness translocation stocks by the use of a controlled recombination procedure should be feasible for many pest species. 相似文献
10.
Kathy J. Snow Sarah M. Wright Yong Woo Laura C. Titus Kevin D. Mills Lindsay S. Shopland 《Chromosoma》2011,120(1):61-71
Nuclear localization influences the expression of certain genes. Chromosomal rearrangements can reposition genes in the nucleus
and thus could impact the expression of genes far from chromosomal breakpoints. However, the extent to which chromosomal rearrangements
influence nuclear organization and gene expression is poorly understood. We examined mouse progenitor B cell lymphomas with
a common translocation, der(12)t(12;15), which fuses a gene-rich region of mouse chromosome12 (Mmu12) with a gene-poor region
of mouse chromosome15 (Mmu15). We found that sequences 2.3 Mb proximal and 2.7 Mb distal to the der(12)t(12;15) breakpoint
had different nuclear positions measured relative to the nuclear radius. However, their positions were similar on unrearranged
chromosomes in the same tumor cells and normal progenitor B cells. In addition, higher-order chromatin folding marked by three-dimensional
gene clustering was not significantly altered for the 7 Mb of Mmu15 sequence distal to this translocation breakpoint. Translocation
also did not correspond to significant changes in gene expression in this region. Thus, any changes to Mmu15 structure and
function imposed by the der(12)t(12;15) translocation are constrained to sequences near (<2.5 Mb) the translocation junction.
These data contrast with those of certain other chromosomal rearrangements and suggest that significant changes to Mmu15 sequence
are structurally and functionally tolerated in the tumor cells examined. 相似文献
11.
Genome architecture catalyzes nonrecurrent chromosomal rearrangements 总被引:18,自引:0,他引:18
Stankiewicz P Shaw CJ Dapper JD Wakui K Shaffer LG Withers M Elizondo L Park SS Lupski JR 《American journal of human genetics》2003,72(5):1101-1116
To investigate the potential involvement of genome architecture in nonrecurrent chromosome rearrangements, we analyzed the breakpoints of eight translocations and 18 unusual-sized deletions involving human proximal 17p. Surprisingly, we found that many deletion breakpoints occurred in low-copy repeats (LCRs); 13 were associated with novel large LCR17p structures, and 2 mapped within an LCR sequence (middle SMS-REP) within the Smith-Magenis syndrome (SMS) common deletion. Three translocation breakpoints involving 17p11 were found to be located within the centromeric alpha-satellite sequence D17Z1, three within a pericentromeric segment, and one at the distal SMS-REP. Remarkably, our analysis reveals that LCRs constitute >23% of the analyzed genome sequence in proximal 17p--an experimental observation two- to fourfold higher than predictions based on virtual analysis of the genome. Our data demonstrate that higher-order genomic architecture involving LCRs plays a significant role not only in recurrent chromosome rearrangements but also in translocations and unusual-sized deletions involving 17p. 相似文献
12.
The evolutionary history of human chromosome 7 总被引:6,自引:0,他引:6
We report on a comparative molecular cytogenetic and in silico study on evolutionary changes in human chromosome 7 homologs in all major primate lineages. The ancestral mammalian homologs comprise two chromosomes (7a and 7b/16p) and are conserved in carnivores. The subchromosomal organization of the ancestral primate segment 7a shared by a lemur and higher Old World monkeys is the result of a paracentric inversion. The ancestral higher primate chromosome form was then derived by a fission of 7b/16p, followed by a centric fusion of 7a/7b as observed in the orangutan. In hominoids two further inversions with four distinct breakpoints were described in detail: the pericentric inversion in the human/African ape ancestor and the paracentric inversion in the common ancestor of human and chimpanzee. FISH analysis employing BAC probes confined the 7p22.1 breakpoint of the pericentric inversion to 6.8 Mb on the human reference sequence map and the 7q22.1 breakpoint to 97.1 Mb. For the paracentric inversion the breakpoints were found in 7q11.23 between 76.1 and 76.3 Mb and in 7q22.1 at 101.9 Mb. All four breakpoints were flanked by large segmental duplications. Hybridization patterns of breakpoint-flanking BACs and the distribution of duplicons suggest their presence before the origin of both inversions. We propose a scenario by which segmental duplications may have been the cause rather than the result of these chromosome rearrangements. 相似文献
13.
We extract 11 genome-wide sets of breakpoint positions from databases on reciprocal translocations, inversions and deletions in neoplasms, reciprocal translocations and inversions in families carrying rearrangements and the human-mouse comparative map, and for each set of positions construct breakpoint distributions for the 44 autosomal arms. We identify and interpret four main types of distribution: (i) a uniform distribution associated both with families carrying translocations or inversions, and with the comparative map, (ii) telomerically skewed distributions of translocations or inversions detected consequent to births with malformations, (iii) medially clustered distributions of translocation and deletion breakpoints in tumor karyotypes, and (iv) bimodal translocation breakpoint distributions for chromosome arms containing telomeric proto-oncogenes. 相似文献
14.
Summary This study describes 12 examples of translocations between chromosomes 7 and 14 in short-term peripheral blood lymphocyte cultures from 10 patients investigated in a routine cytogenetic series. Only one constant breakpoint was found on 14q, and chromosome 7 had two constant breakpoints, one on 7p and the other on 7q. The cause and true significance of such nonrandom in vitro chromosome translocations is not known at present, but one may speculate as to their possible indication of heterozygosity for a chromosome instability syndrome and thus a predilection for the development of lymphoid or other malignancy. 相似文献
15.
Localization of the restriction fragment length polymorphism D14S1 (pAW-101) to chromosome 14q32.1 leads to 32.2 by in situ hybridization 总被引:8,自引:1,他引:7
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The restriction fragment length polymorphism D14S1 is delineated by the cloned, single-copy DNA fragment pAW-101. This cloned fragment can therefore serve as a useful marker for gene linkage studies, and the exact location on the gene map is of great interest. pAW-101 was 3H-labeled and hybridized in situ to normal, prometaphase chromosome preparations. Analysis of the grain distribution shows this fragment to be localized to the long arm of chromosome 14 at band q32. Using lymphoid cell lines with 8;14 reciprocal translocations (q24.1;q32.3) from patients with Burkitt lymphoma, we found that the DNA fragment hybridizes to the rearranged chromosome 14 proximal to the breakpoint. These results localize D14S1 to the region 14q32.1 leads to 32.2 This is consistent with localization of this fragment utilizing somatic cell hybrids and family studies. 相似文献
16.
Closing in on the Rieger syndrome gene on 4q25: mapping translocation breakpoints within a 50-kb region. 总被引:2,自引:1,他引:1
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N. A. Datson E. Semina A. A. van Staalduinen H. G. Dauwerse E. J. Meershoek J. J. Heus R. R. Frants J. T. den Dunnen J. C. Murray G. J. van Ommen 《American journal of human genetics》1996,59(6):1297-1305
Rieger syndrome (RGS) is an autosomal dominant disorder of morphogenesis affecting mainly the formation of the anterior eye chamber and of the teeth. RGS has been localized to human chromosome 4q25 by linkage to epidermal growth factor (EGF). We have constructed a detailed physical map and a YAC contig of the genomic region encompassing the EGF locus. Using FISH, several YACs could be shown to cross the breakpoint in two independent RGS patients with balanced 4q translocations. Alu- and LINE-fragmentation of a 2.4-Mb YAC generated a panel of shorter YACs ranging in size from 2.4 Mb to 75 kb. Several fragmentation YACs were subcloned in cosmids, which were mapped to specific subregions of the original YAC by hybridization to the fragmentation panel to further refine the localization of the translocation breakpoints, allowing mapping of the breakpoints to within the most-telomeric 200 kb of the original 2.4-Mb YAC. FiberFISH of cosmids located in this 200-kb region mapped the two translocation breakpoints within a 50-kb region approximately 100-150 kb centromeric to D4S193, significantly narrowing down the candidate region for RGS. The mapping data and resources reported here should facilitate the identification of a gene implicated in Rieger syndrome. 相似文献
17.
Abnormalities involving chromosome 13 have been reported as the only cytogenetic change in B-cell chronic lymphocytic leukemia (BCLL). Deletions are the most common cytogenetic abnormality and always involve 13q14, but when translocations are seen, the consistent breakpoint is always in 13q14. It is now established that deletions, distal to the RB1 gene in 13q14, are invariably associated with these translocations. We have recently described the smallest such deletion from a series of rearrangements from these tumors isolated in somatic cell hybrids, which spans approximately 1 Mb. In this report, we present the results of a series of a chromosome walking experiments using YACs and have been able to span this small deletion, which must contain the gene that is frequently deleted in BCLL. Four probes from 13q14 (RBI-mgg15-D13S25-D13S31) were used to isolate corresponding YACs for each of the markers. The chromosomal location of these YACs was verified using FISH, which also demonstrated their nonchimeric nature. Vectorette end rescue was then used to demonstrate the overlap of the YACs and to isolate new clones to complete the contig. The extremes of the contig were shown to cross the chromosome 13 translocation breakpoints isolated in somatic cell hybrids that carry the derivatives of chromosome 13 involved in the smallest BCLL deletion. This YAC contig covers the entire deletion and will prove a valuable resource to begin isolating genes from this region. In addition, we have isolated YACs corresponding to the RB1 locus, which extends the contig over a 3.8-cM distance on the chromosome. 相似文献
18.
Germ line insertion of mtDNA at the breakpoint junction of a reciprocal constitutional translocation 总被引:6,自引:0,他引:6
Constitutional chromosomal translocations are relatively common causes of human morbidity, yet the DNA double-strand break (DSB) repair mechanisms that generate them are incompletely understood. We cloned, sequenced and analyzed the breakpoint junctions of a familial constitutional reciprocal translocation t(9;11)(p24;q23). Within the 10-kb region flanking the breakpoints, chromosome 11 had 25% repeat elements, whereas chromosome 9 had 98% repeats, 95% of which were L1-type LINE elements. The breakpoints occurred within an L1-type repeat element at 9p24 and at the 3'-end of an Alu sequence at 11q23. At the breakpoint junction of derivative chromosome 9, we discovered an unusually large 41-bp insertion, which showed 100% identity to 12S mitochondrial DNA (mtDNA) between nucleotides 896 and 936 of the mtDNA sequence. Analysis of the human genome failed to show the preexistence of the inserted sequence at normal chromosomes 9 and 11 breakpoint junctions or elsewhere in the genome, strongly suggesting that the insertion was derived from human mtDNA and captured into the junction during the DSB repair process. To our knowledge, these findings represent the first observation of spontaneous germ line insertion of modern human mtDNA sequences and suggest that DSB repair may play a role in inter-organellar gene transfer in vivo. Our findings also provide evidence for a previously unrecognized insertional mechanism in human, by which non-mobile extra-chromosomal fragments can be inserted into the genome at DSB repair junctions. 相似文献
19.
A detailed analysis of chromosomal changes in heritable and non-heritable retinoblastoma 总被引:7,自引:0,他引:7
Summary Full cytogenetic analysis of 27 different retinoblastoma tumors is presented. Gross aneuploidy of chromosome arms 6p and 1q were very common, being observed in 15/27 and 21/27 tumors, respectively. However, we found that chromosome 13 was rarely missing: only 3/27 had a detectable monosomy affecting 13q14. Monosomy of chromosome 13 by small deletion or rearrangement was also not observed in any of 12 retinoblastoma tumor lines analyzed detail at the 300–400 chromosome band level. A novel observation in retinoblastoma was the discovery of non-random translocations at three specific breakpoints, 14q32 (4/12), 17p12 (5/12), and 10q25 (3/12). Genomic rearrangements similar to those described involving C-myc in Burkitt lymphoma 14q+ cells could not be demonstrated in the four 14q+ retinoblastoma lines using molecular techniques, and a probe mapping to the site implicated to have an activating role in lymphoma. These data suggest that there is a target for rearrangement at 14q32 but it is not the same sequence used in some Burkitt lymphomas. Two other breakpoints (2p24 and 8q24) coincided with the mapped position of cellular oncogenes, but also failed to show a molecular rearrangement with the oncogene probes. The breakpoints, 10q25 and 17p12, are constitutional fragile sites which may predispose these regions to act as acceptors of translocations in malignant cells. One line had double minute chromosomes, and was the only one of 16 (6%) tested with the N-myc probe which had an amplification. Different tumors from single patients with multifocal heritable retinoblastoma showed independent karyotype evolution. Unilateral non-heritable tumors exhibited a high level of karyotype stability throughout both in vivo and in vitro growth. The various common patterns of aneuploidy and translocations probably confer an early selective advantage to malignant cells, rather than induce malignant transformation. 相似文献
20.
Lahortiga I Vázquez I Belloni E Román JP Gasparini P Novo FJ Zudaire I Pelicci PG Hernández JM Calasanz MJ Odero MD 《Human genetics》2005,116(6):476-485
Rearrangements in the distal region of the short arm of chromosome 1 are recurrent aberrations in a broad spectrum of human neoplasias. However, neither the location of the breakpoints (BP) on 1p36 nor the candidate genes have been fully determined. We have characterized, by fluorescence in situ hybridization (FISH), the BP in 26 patients with hematological neoplasias and 1p36 rearrangements in the G-banding karyotype. FISH allowed a better characterization of all samples analyzed. Nine cases (35%) showed reciprocal translocations, 15 (58%) unbalanced rearrangements, and two (7%) deletions. We describe two new recurrent aberrations. In 18 of the 26 cases analyzed the BP were located in band 1p36, which is 25.5 Mb long. In 14 of these 18 cases (78%) and without distinction between myeloid and lymphoid neoplasias, the BP clustered in a 2.5 Mb region located between 1p36.32 and the telomere. Interestingly, this region is contained in the 10.5 Mb cluster on 1p36.22-1pter defined in cases with 1p36 deletion syndrome. The 2.5 Mb region, located on 1p36.32-1pter, has a higher frequency of occurrence of tandem repeats and segmental duplications larger than 1 kb, when compared with the 25.5 Mb of the complete 1p36 band. This could explain its proneness for involvement in chromosomal rearrangements in hematological neoplasias. 相似文献