scispace - formally typeset
Search or ask a question

Showing papers on "Chromosome 21 published in 1990"


Journal ArticleDOI
12 Oct 1990-Science
TL;DR: The RH procedure was used to map 14 DNA probes from a region of human chromosome 21 spanning 20 megabase pairs, demonstrating the effectiveness of RH mapping for constructing high-resolution, contiguous maps of mammalian chromosomes.
Abstract: Radiation hybrid (RH) mapping, a somatic cell genetic technique, was developed as a general approach for constructing long-range maps of mammalian chromosomes. This statistical method depends on x-ray breakage of chromosomes to determine the distances between DNA markers, as well as their order on the chromosome. In addition, the method allows the relative likelihoods of alternative marker orders to be determined. The RH procedure was used to map 14 DNA probes from a region of human chromosome 21 spanning 20 megabase pairs. The map was confirmed by pulsed-field gel electrophoretic analysis. The results demonstrate the effectiveness of RH mapping for constructing high-resolution, contiguous maps of mammalian chromosomes.

628 citations


Journal ArticleDOI
13 Sep 1990-Nature
TL;DR: The inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedi-grees with familial Alzheimer's disease suggests that Alzheimer's Disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors.
Abstract: Alzheimer's disease, a fatal neurodegenerative disorder of unknown aetiology, is usually considered to be a single disorder because of the general uniformity of the disease phenotype. Two recent genetic linkage studies revealed co-segregation of familial Alzheimer disease with the D21S1/S11 and D21S16 loci on chromosome 21. But two other studies, one of predominantly multiplex kindreds with a late age-of-onset, the other of a cadre of kindreds with a unique Volga German ethnic origin, found absence of linkage at least to D21S1/S11. So far it has not been possible to discern whether these conflicting reports reflect aetiological heterogeneity, differences in methods of pedigree selection, effects of confounding variables in the analysis (for example, diagnostic errors, assortative matings), or true non-replication. To resolve this issue, we have now examined the inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedigrees with familial Alzheimer's disease. Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors.

415 citations


Journal ArticleDOI
15 Sep 1990-Blood
TL;DR: The most important predictive factor for a favorable response to intensive antileukemic chemotherapy in overt leukemia was the absence of a preceding myelodysplastic phase.

279 citations


Journal Article
TL;DR: Except for a possible phenotypic contribution from the deletion of chromosome band 4q35, these data provide a molecular definition of the minimal region of chromosome 21 which, when duplicated, generates the facial features, heart defect, a component of the mental retardation, and probably several of the dermatoglyphic changes of DS.
Abstract: Down syndrome (DS) is a major cause of mental retardation and heart disease. Although it is usually caused by the presence of an extra chromosome 21, a subset of the diagnostic features may be caused by the presence of only band 21q22. We now present evidence that significantly narrows the chromosomal region responsible for several of the phenotypic features of DS. We report a molecular and cytogenetic analysis of a three-generation family containing four individuals with clinical DS as manifested by the characteristic facial appearance, endocardial cushion defect, mental retardation, and probably dermatoglyphic changes. Autoradiograms of quantitative Southern blots of DNAs from two affected sisters, their carrier father, and a normal control were analyzed after hybridization with two to six unique DNA sequences regionally mapped on chromosome 21. These include cDNA probes for the genes for CuZn-superoxide dismutase (SOD1) mapping in 21q22.1 and for the amyloid precursor protein (APP) mapping in 21q11.2-21.05, in addition to six probes for single-copy sequences: D21S46 in 21q11.2-21.05, D21S47 and SF57 in 21q22.1-22.3, and D21S39, D21S42, and D21S43 in 21q22.3. All sequences located in 21q22.3 were present in three copies in the affected individuals, whereas those located proximal to this region were present in only two copies. In the carrier father, all DNA sequences were present in only two copies. Cytogenetic analysis of affected individuals employing R and G banding of prometaphase preparations combined with in situ hybridization revealed a translocation of the region from very distal 21q22.1 to 21qter to chromosome 4q. Except for a possible phenotypic contribution from the deletion of chromosome band 4q35, these data provide a molecular definition of the minimal region of chromosome 21 which, when duplicated, generates the facial features, heart defect, a component of the mental retardation, and probably several of the dermatoglyphic changes of DS. This region may include parts of bands 21q22.2 and 21q22.3, but it must exclude the genes S0D1 and APP and most of band 21q22.1, specifically the region defined by S0D1, SF57 and D21S47.

237 citations


Journal Article
TL;DR: The data from case 11 of the series suggests that the meningioma and the neurofibromatosis-2 loci are separate entities, which may suggest that tumors of males have preferentially smaller rearrangements on chromosome 22q than those of females or that the male and female cases with no detected aberrations have another mechanism of oncogenesis.
Abstract: Constitutional and tumor tissue genotypes from 81 unrelated patients with meningioma were compared at 25 polymorphic loci (restriction fragments length alleles) on chromosome 22. Thirty tumors (37%) retained the constitutional genotype along chromosome 22, a finding consistent with no detectable aberrations on chromosome 22 as studied. Forty-two tumors (52%) showed loss of one allele at all informative loci consistent with monosomy 22 in the tumor DNA. The remaining 9 tumors (11%) showed retained constitutional heterozygosity in the tumor DNA at one or more centromeric loci and loss of the heterozygosity at other telomeric loci, which is consistent with variable terminal deletions of one chromosome 22q in the tumor DNA. The localization of breakpoints in these 9 cases with deletions suggests that a meningioma locus is localized distal to myoglobin locus, within 22q12.3-qter. The male cases showed a higher percentage of tumors with no detectable aberrations on chromosome 22, a finding which may suggest that tumors of males have preferentially smaller rearrangements on chromosome 22q than those of females or that the male and female cases with no detected aberrations have another mechanism of oncogenesis. In view of the recent findings on the localization of the neurofibromatosis-2 gene on chromosome 22, the data from case 11 of our series suggests that the meningioma and the neurofibromatosis-2 loci are separate entities.

173 citations


Journal Article
TL;DR: An allelotype analysis of 41 malignant astrocytoma patients showed that loss of broad regions of chromosome 10 was a common event, particularly in glioblastoma multiforme, indicating an even greater complexity of genomic alterations than reported previously.
Abstract: Astrocytoma, the most common brain tumor in humans, is usually malignant and virtually incurable. Two types of malignant astrocytomas can be distinguished histopathologically: anaplastic astrocytoma and glioblastoma multiforme. Studies using DNA markers that detect restriction fragment length polymorphisms have shown that loci on chromosomes 10 and 17p are lost frequently in tumor DNA from malignant astrocytoma patients, suggesting that tumor suppressor genes important in astrocytoma tumorigenesis may be present on 2 different chromosomes. To identify additional regions of chromosome loss, we carried out an allelotype analysis of 41 malignant astrocytoma patients using restriction fragment length polymorphism markers for each arm of every human autosome. Loss of heterozygosity was found for every autosome except chromosome 21, indicating an even greater complexity of genomic alterations than reported previously. Many tumors showed loss of heterozygosity for multiple chromosomes and the number of chromosomes involved correlated with tumor histopathology. A high-resolution restriction fragment length polymorphism study of chromosome 10 loci in these patients showed that loss of broad regions of chromosome 10 was a common event, particularly in glioblastoma multiforme. An allelotype analysis has been carried out on only one other tumor, human colorectal carcinoma. Different profiles of allele loss were observed in malignant astrocytoma and colorectal carcinoma, suggesting that the genetic events leading to these 2 human cancers may proceed along different pathways.

165 citations


Journal ArticleDOI
TL;DR: Human chromosome 21 has been analyzed by pulsed‐field gel electrophoresis using somatic cell hybrids containing limited regions of the chromosome and greater than 60 unique sequence probes, providing information to guide the rapid investigation of the biology of chromosome 21.
Abstract: Human chromosome 21 has been analyzed by pulsed-field gel electrophoresis using somatic cell hybrids containing limited regions of the chromosome and greater than 60 unique sequence probes. Thirty-three independent NotI fragments have been identified, totalling 43 million bp. This must account for essentially the entire long arm, and therefore gaps remaining in the map must be small. The extent of the pulsed-field map has allowed the direct correlation of the physical map with the cytogenetic map: translocation breakpoints can be unambiguously positioned along the long arm and the distances between them measured in base pairs. Three breakpoints have been identified, providing physical confirmation of cytogenetic landmarks. Information on sequence organization has been obtained: (i) 60% of the unique sequence probes are located within 11 physical linkage groups which can be contained in only 20% of the long arm; (ii) 9/21 genes are clustered within 4%; (iii) translocation breakpoints appear to occur within CpG island regions, making their identification difficult by pulsed-field techniques. This analysis contributes to the human genome mapping effort, and provides information to guide the rapid investigation of the biology of chromosome 21.

162 citations


Journal ArticleDOI
TL;DR: The CTF1 gene, identified in a screen for mutants with decreased chromosome transmission fidelity and shown to correspond to the previously identified chl1 mutation, is analyzed and mutants lacking the CHL1 gene product are viable and display two striking, and perhaps interrelated, phenotypes.
Abstract: We have analyzed the CTF1 gene, identified in a screen for mutants with decreased chromosome transmission fidelity and shown to correspond to the previously identified chl1 mutation Chl1 null mutants exhibited a 200-fold increase in the rate of chromosome III missegregation per cell division, and near wild-type rates of marker homozygosis on this chromosome by mitotic recombination Analysis of the segregation of a marker chromosome indicated that sister chromatid loss (1:0 segregation) and sister chromatid non-disjunction (2:0 segregation) contributed equally to chromosome missegregation A genomic clone of CHL1 was isolated and used to map its physical position on chromosome XVI Nucleotide sequence analysis of CHL1 revealed a 26 kb open reading frame with a 99 kd predicted protein sequence that contained two PEST sequences and was 23% identical to the coding region of a nucleotide excision repair gene, RAD3 Domains of homology between these two predicted protein sequences included a helix-turn-helix motif and an ATP binding site containing a helicase consensus Mutants lacking the CHL1 gene product are viable and display two striking, and perhaps interrelated, phenotypes: extreme chromosome instability and a delay in cell cycle progression in G2/M This delay is independent of the cell cycle checkpoint that requires the function of the RAD9 gene

137 citations


Journal ArticleDOI
TL;DR: The identification of homologous chromosomes gives valuable insight into the organization of the trypanosome genome, will facilitate the genetic analysis of T. brucei, and suggests the presence of haploid gametes.
Abstract: The genome of the protozoan Trypanosoma brucei is known to be diploid. Karyotype analysis has, however, failed to identify homologous chromosomes. Having refined the technique for separating trypanosome chromosomes (L. H. T. Van der Ploeg, C. L. Smith, R. I. Polvere, and K. Gottesdiener, Nucleic Acids Res. 17:3217-3227, 1989), we can now provide evidence for the presence of homologous chromosomes. By determining the chromosomal location of different genetic markers, most of the chromosomes (14, excluding the minichromosomes), could be organized into seven chromosome pairs. In most instances, the putative homologs of a pair differed in size by about 20%. Restriction enzyme analysis of chromosome-sized DNA showed that these chromosome pairs contained large stretches of homologous DNA sequences. From these data, we infer that the chromosome pairs represent homologs. The identification of homologous chromosomes gives valuable insight into the organization of the trypanosome genome, will facilitate the genetic analysis of T. brucei, and suggests the presence of haploid gametes.

111 citations


Journal ArticleDOI
01 Nov 1990-Genomics
TL;DR: A detailed molecular genetic linkage map of mouse chromosome 7 is established that will be useful as a framework for determining linkage relationships of additional molecular markers and for identifying homologous disease genes in mice and humans.

106 citations


Journal ArticleDOI
TL;DR: Through a combination of chromosome jumping, long-range mapping, and chromosome walking, the chromosome 9 breakpoints of several t(6;9) ANLL patients were localized within a defined region of 8 kilobases (kb), 360 kb telomeric of c-abl, suggesting a direct involvement of the translocation in the leukemic process of t( 6;9).
Abstract: The specific (6;9)(p23;q34) chromosomal translocation is associated with a defined subtype of acute nonlymphocytic leukemia (ANLL). The 9q34 breakpoint is located at the telomeric side of the c-abl gene. Through a combination of chromosome jumping, long-range mapping, and chromosome walking, the chromosome 9 breakpoints of several t(6;9) ANLL patients were localized within a defined region of 8 kilobases (kb), 360 kb telomeric of c-abl. Subsequent cDNA cloning revealed that this region represented an intron in the middle of a gene, called Cain (can), encoding a 7.5-kb transcript. Disruption of the can gene by the translocation resulted in the expression of a new 5.5-kb can mRNA from the 6p- chromosome. Isolation of chromosome 6 sequences showed that breakpoints on 6p23 also clustered within a limited stretch of DNA. These data strongly suggest a direct involvement of the translocation in the leukemic process of t(6;9) ANLL.

Journal ArticleDOI
01 Aug 1990-Genetics
TL;DR: The locations of the genes mapped in this study extend the known regions of synteny between mouse chromosomes 10 and human chromosomes 6, 10, 12 and 21, and reveal a novel homology segment between mouse chromosome 10 andhuman chromosome 22.
Abstract: Interspecific mouse backcross analysis was used to generate a molecular genetic linkage map of mouse chromosome 10. The map locations of the Act-2, Ahi-1, Bcr, Braf, Cdc-2a, Col6a-1, Col6a-2, Cos-1, Esr, Fyn, Gli, Ifg, Igf-1, Myb, Pah, pgcha, Ros-1 and S100b loci were determined. These loci extend over 80% of the genetic length of the chromosome, providing molecular access to many regions of chromosome 10 for the first time. The locations of the genes mapped in this study extend the known regions of synteny between mouse chromosome 10 and human chromosomes 6, 10, 12 and 21, and reveal a novel homology segment between mouse chromosome 10 and human chromosome 22. Several loci may lie close to, or correspond to, known mutations. Preferential transmission of Mus spretus-derived alleles was observed for loci mapping to the central region of mouse chromosome 10.

Journal ArticleDOI
TL;DR: The data suggest duplication of a chromosome region including the precursors of the genes for BCM1, CD2, and LFA3, and the ATPase genes to give rise to the linkage groups now observed.
Abstract: The mouse BCM1 (OX45, Blast-1) antigen has been cDNA cloned and sequenced to provide data supporting the view that BCM1, LFA3, and CD2 constitute a subgroup within the Ig superfamily. Mouse BCM1 is widely expressed on leukocytes and is likely to be anchored to the cell surface by a glycosyl-phosphatidylinositol anchor, as is the case for rat and human BCM1 antigen. Genetic linkage studies by recombination and pulse field analysis showed the BCM1 locus (Bcm-1) to be on distal mouse chromosome 1 and to be linked within 1,600 kb to the locus for an ATPase alpha chain gene (Atpa-3). A similar relationship was established between the human BCM1 locus (BCM1) and ATP1A2, and other markers on chromosome 1q. Conservation of genomic organization within a segment of human chromosome 1q and mouse chromosome 1 was demonstrated. A similar situation is seen in the region of the CD2 and LFA3 genes between mouse chromosome 3 and human chromosome 1p. Furthermore, the CD2/LFA3 genes are linked within 580 kb to Atpa-1/ATP1A1 genes to provide a parallel situation to the linkage between Bcm-1/BCM1 and Atpa-3/ATP1A2 on chromosomes 1 (mouse) and 1q (human). Taken together, the data suggest duplication of a chromosome region including the precursors of the genes for BCM1, CD2, and LFA3, and the ATPase genes to give rise to the linkage groups now observed. The duplicated regions may have stayed together on chromosome 1 in the human (with the insertion of a centromere), while in the mouse, the genetic regions are proposed to have become dispersed in the formation of chromosomes 1 and 3. CD2 and LFA3 are more dissimilar in sequence than BCM1 and LFA3, and if the precursors of the CD2 and LFA3 loci formed before the proposed chromosome segment duplication, then a gene encoding a recognizer molecule for BCM1 may exist in linkage with Bcm-1/BCM1 on chromosome 1 (mouse) and 1q (human).

Journal Article
TL;DR: Two apparent deletions of the short arm of chromosome 16 were studied by in situ hybridisation using biotinylated DNA from a chromosome 16 specific cosmid library (chromosome painting).
Abstract: Two apparent deletions of the short arm of chromosome 16 were studied by in situ hybridisation using biotinylated DNA from a chromosome 16 specific cosmid library (chromosome painting). One abnormality was delineated as a t(1;16)(p36;p12) and the other as a ins(11;16)(q13;p13.13p13.3). Apparently unbalanced de novo abnormalities detected by classical cytogenetic procedures should be interpreted with caution. In situ hybridization using DNA from chromosome specific libraries provides the appropriate technology to delineate such abnormalities.

Journal ArticleDOI
01 Sep 1990-Yeast
TL;DR: An ordered clone bank is constructed that covers almost the whole of chromosome III with a single gap of several kilobases in length and it is found that the genes located near both termini are expressed only at low levels and that highly expressed genes are rather scattered over the chromosome.
Abstract: Using λ phage vector EMBL4, we isolated 344 clones containing segments of chromosome III of Saccharomyces cerevisiae, analysed their physical structure with eight restriction enzymes and sorted the data in contiguous groups with computer programmes. Furthermore, we performed Southern hybridizations between the sorted contiguous clone groups and interrelated them into larger groups. In this way, we constructed an ordered clone bank that covers almost the whole of chromosome III with a single gap of several kilobases in length. The consensus physical map thus obtained totals 334·6 kb, which is in good agreement with the size of this chromosome estimated by pulsed-field gel electrophoresis. Southern hybridization analysis with the DNA probes containing telomere-specific sequences showed that the bank contained a telomere at a position corresponding to the right arm terminus of chromosome III. Also, five Ty elements were found to be present. To estimate the number of genes on this chromosome and to analyse their levels of expression, we performed a series of Northern hybridization experiments using total poly(A)+ RNA from vegetatively growing cells and appropriate restriction enzyme fragments from the bank. Thus, we identified a total of 156 transcripts on chromosome III, indicating, on an average, one gene in every 2 kb on this chromosome. The transcripts were visually categorized into five groups according to their apparent levels of expression. It was found that the genes located near both termini are expressed only at low levels and that highly expressed genes are rather scattered over the chromosome.

Journal Article
TL;DR: The delineation of flanking markers for NF2 should permit accurate presymptomatic and prenatal diagnosis for the disorder and greatly facilitate efforts to isolate the defective gene on the basis of its location.
Abstract: Neurofibromatosis 2 or bilateral acoustic neurofibromatosis (NF2) is a severe autosomal dominant disorder characterized by the development of multiple tumors of the nervous system, including meningiomas, gliomas, neurofibromas, ependymomas, and particularly acoustic neuromas Polymorphic DNA markers have revealed frequent loss of one copy of chromosome 22 in the tumor types associated with NF2 Family studies have demonstrated that the primary defect in NF2 is linked to DNA markers on chromosome 22, suggesting that it involves inactivation of a tumor suppressor gene We have employed a combination of multipoint linkage analysis and examination of deletions in primary tumor specimens to precisely map the NF2 locus between flanking polymorphic DNA markers on chromosome 22 The 13-cM region bracketed by these markers corresponds to 13% of the genetic length of the long arm of chromosome 22 and is expected to contain less than 5 x 10(6) bp of DNA The delineation of flanking markers for NF2 should permit accurate presymptomatic and prenatal diagnosis for the disorder and greatly facilitate efforts to isolate the defective gene on the basis of its location

Journal ArticleDOI
01 Sep 1990-Neuron
TL;DR: It is demonstrated that a specific spliced form of mRNA that is transcribed from the APP gene and that lacks the beta/A4 sequence is elevated in the nucleus basalis, occipitotemporal cortex, and parahippocampal gyrus in Alzheimer's disease brain relative to controls.

Journal ArticleDOI
TL;DR: Lack of evidence of heterozvgosity for this distal portion of 3p suggests that a copy of the 3p homologue is involved in the translocation and therefore does not explain allelic loss of the other homologue.
Abstract: We have used 14 DNA probes, which detect 19 different restriction enzyme length polymorphisms, to search for heterozygosity on chromosome 3 in five cell lines isolated from patients with small cell lung carcinoma. The cell lines on karyotype analysis did not show the deletion in chromosome 3 characteristic of this disease. Our objective was to determine if allelic loss had occurred by some chromosomal mechanism other than deletion. Two of the cell lines are consistent with allelic loss having occurred by whole chromosome loss and reduplication. The third may have lost only the short arm due to i(3q) formation. The fourth cell line has an i(3q) chromosome, together with a translocation product involving the distal portion of the short arm of chromosome 3. Lack of evidence of heterozygosity for this distal portion of 3p suggests that a copy of the 3p homologue is involved in the translocation and therefore does not explain allelic loss of of the other homologue. The fifth, while also likely to have lost one chromosome homologue, has a submicroscopic deletion on all chromosome 3s, only detectable by RFLP analysis. Such homozygous deletions have recently proved useful in the isolation of tumour suppressor genes.

Journal ArticleDOI
01 Jun 1990-Genomics
TL;DR: These sequences should be useful for the construction of centromere-based genetic linkage maps for human chromosome 15 and, in conjunction with the other alphoid sequences already reported for chromosomes 13, 14, 21, and 22, should allow a concerted analysis of the evolution and the possible etiological role of these DNAs in aberrations commonly seen in these chromosomes.

Journal ArticleDOI
TL;DR: A cosmid containing the human sequence (HOX7) homologous to the mouse homeogene Hox-7 was isolated from a genomic cosmid library, and analysis of chromosomes from two patients with Wolf-Hirschhorn syndrome indicates that the HOX7 locus is deleted.
Abstract: A cosmid containing the human sequence (HOX7) homologous to the mouse homeogene Hox-7 was isolated from a genomic cosmid library. There is only one highly conserved homologous gene in the human genome. The C-terminal two-thirds of the HOX7 homeobox DNA sequence has been determined; there are no predicted amino acid changes from the mouse sequence. Data from mouse/human hybrid cell lines show that HOX7 maps to human chromosome 4p16.1, a region that is syntenic with part of mouse chromosome 5, the site of the murine Hox-7 gene. Analysis of chromosomes from two patients with Wolf-Hirschhorn syndrome, which is characterised by profound dysmorphologies, indicates that the HOX7 locus is deleted. Although not all Wolf-Hirschhorn syndrome patients analysed were deleted for HOX7, the combination of positional data and functional correlation with mouse expression implicates HOX7 as a candidate gene for this syndrome.

Journal ArticleDOI
TL;DR: It is concluded that the long arm of the human X chromosome represents a highly conserved region that formed part of the X chromosome in a mammalian ancestor at least 150 million years ago.
Abstract: Eight genes, located on the long arm of the human X chromosome and present on the marsupial X chromosome, were mapped by in situ hybridization to the chromosomes of the platypus Ornithorhynchus anatinus, one of the three species of monotreme mammals. All were located on the X chromosome. We conclude that the long arm of the human X chromosome represents a highly conserved region that formed part of the X chromosome in a mammalian ancestor at least 150 million years ago. Since three of these genes are located on the long arm of the platypus X chromosome, which is G-band homologous to the Y chromosome and apparently exempt from X chromosome inactivation, the conservation of this region has evidently not depended on isolation by X-Y chromosome differentiation and X chromosome inactivation.

Journal ArticleDOI
01 Sep 1990-Genomics
TL;DR: Recombination frequencies (RFs) in four intervals defined by five loci in the HSA21-homologous region of MMU16 were analyzed in up to 895 progeny of eight different backcrosses and considerable variation in RF was observed between crosses involving different strains.

Journal ArticleDOI
TL;DR: DNA fragments known to detect restriction fragment length polymorphisms along 5p were used to establish whether the paternal or the maternal chromosome had suffered the deletion, and the deleted chromosome 5 was of paternal origin in 20/25 cases.
Abstract: The parental origin of de novo deletions leading to the cri-du-chat syndrome has been investigated. Since the cri-du-chat syndrome is correlated with deletions involving the short arm of chromosome 5 (5p), DNA fragments known to detect restriction fragment length polymorphisms (RFLPs) along 5p were used to establish whether the paternal or the maternal chromosome had suffered the deletion. In cases where only one parent was available, somatic cell hybrids were used in conjunction with RFLP analysis to determine the origin of the deleted chromosome. The deleted chromosome 5 was of paternal origin in 20/25 cases.

Journal ArticleDOI
01 Mar 1990-Genomics
TL;DR: The Prader-Willi syndrome chromosome region on the long arm of human chromosome 15 was microdissected and microcloned from 20 GTG-banded metaphase chromosomes, and 5000 recombinant clones were obtained to identify single-copy human DNA sequences.

Journal ArticleDOI
Erwin Schurr1, Emil Skamene1, Kenneth Morgan1, Mon-Li Chu, Philippe Gros1 
01 Nov 1990-Genomics
TL;DR: The available map information for human chromosome 2q markers and mouse chromosome 1 markers presented here tentatively identifies Col3a1 and Col6a3 as the border markers that define the limits of the syntenic chromosome segment.

Journal Article
TL;DR: Analysis of DNA polymorphisms in 10 families with Down syndrome found that in two of 10 families the dup(21q) chromosome appeared to be the result of a Robertsonian translocation t( 21q; 21q) (maternal in origin in both cases).
Abstract: Down syndrome is rarely due to a de novo duplication of chromosome 21 [dup(21q)]. To investigate the origin of the dup(21q) and the nature of this chromosome, we used DNA polymorphisms in 10 families with Down syndrome due to de novo dup(21q). The origin of the extra chromosome 21q was maternal in six cases and paternal in four cases. Furthermore, the majority (eight of 10) of dup(21q) chromosomes were isochromosomes i(21q) (four were paternal in origin, and four were maternal in origin); however, in two of 10 families the dup(21q) chromosome appeared to be the result of a Robertsonian translocation t(21q;21q) (maternal in origin in both cases).

Journal ArticleDOI
TL;DR: This result, along with the genetic and cytogenetic data, suggests that the alleles of ld and a in this radiation-induced mutation were associated with DNA breaks caused by an inversion of an interstitial segment in the 2(17) chromosome.
Abstract: Molecular characterization of mutations in the mouse, particularly those involving agent-induced major structural alterations, is proving to be useful for correlating the structure and expression of individual genes with their function in the whole organism. Here we present the characterization of a radiation-induced mutation that simultaneously generated distinct alleles of both the limb deformity (ld) and agouti (a) loci, two developmentally important regions of chromosome 2 normally separated by 20 centimorgans. Cytogenetic analysis revealed that an interstitial segment of chromosome 17 (17B- 17C; or, possibly, 17A2-17B) had been translocated into the distal end of chromosome 2, resulting in a smaller-than-normal chromosome 17 (designated 17del) and a larger form of chromosome 2 (designated 2(17). Additionally, a large interstitial segment of the 2(17) chromosome, immediately adjacent and proximal to the insertion site, did not match bands 2E4-2H1 at corresponding positions on a normal chromosome 2. Molecular analysis detected a DNA rearrangement in which a portion of the ld locus was joined to sequences normally tightly linked to the a locus. This result, along with the genetic and cytogenetic data, suggests that the alleles of ld and a in this radiation-induced mutation, designated ldIn2 and ajIn2, were associated with DNA breaks caused by an inversion of an interstitial segment in the 2(17) chromosome.

Journal ArticleDOI
01 May 1990-Genomics
TL;DR: A (GT)n repeat in intron 4 of the functional human HMG14 gene on chromosome 21 was used as polymorphic marker to map this gene relative to the genetic linkage map of human chromosome 21.

Journal ArticleDOI
TL;DR: The construction and characterization of DNA libraries for the Langer-Giedion syndrome chromosome region (LGCR, 8q23–24), Wilms tumor chromosome region 1 (WT1, 11p13), Prader-Willi syndrome/Angelman syndrome chromosomes region (PWCR/ANCR, 15q11.2–12), meningioma chromosome region [MGCR, 22q12–13, and fragile X chromosome region] are described.
Abstract: A universally primed polymerase chain reaction was developed to amplify DNA dissected from GTG-banded human chromosomes. The amplification products are cloned into plasmid vectors, which allow the rapid characterization of recombinant clones. Starting from 20–40 chromosome fragments, several thousand independent clones detecting single-copy sequences can be obtained. Although these libraries comprise only a few percent of the dissected DNA, they provide narrowly spaced anchor clones for the molecular characterization of chromosome bands and the identification of gene sequences. Here we describe the construction and characterization of DNA libraries for the Langer-Giedion syndrome chromosome region (LGCR, 8q23–24.1), Wilms tumor chromosome region 1 (WT1, 11p13), Prader-Willi syndrome/Angelman syndrome chromosome region (PWCR/ANCR, 15q11.2–12), meningioma chromosome region (MGCR, 22q12–13), and fragile X chromosome region (FRAXA, Xq27.3).

Journal Article
TL;DR: Results show that elevation of CuZnSOD activity interferes with the transport of biogenic amines into chromaffin granules, which may contribute to the neurobiological abnormalities of Down's syndrome.
Abstract: Down syndrome (DS), the phenotypic expression of human trisomy 21, is presumed to result from overexpression of certain genes residing on chromosome 21 at the segment 21q22-the Down locus The "housekeeping" enzyme CuZn-superoxide dismutase (CuZnSOD) is encoded by a gene from that region and its activity is elevated in DS patients To investigate the possible involvement of CuZnSOD gene dosage in the etiology of the syndrome we have developed both cellular and animal models which enabled us to investigate the physiological consequences resulting from overexpression of the CuZnSOD gene 1 Rat PC12 cells expressing elevated levels of transfected human CuZnSOD gene were generated These transformants (designated PC12-hSOD) closely resembled the parental cells in their morphology, growth rate, and response to nerve growth factor, but showed impaired neurotransmitter uptake The lesion was localized to the chromaffin granule transport mechanism We found that the pH gradient (delta pH) across the membrane, which is the main driving force for amine transport, was diminished in PC12-hSOD granules These results show that elevation of CuZnSOD activity interferes with the transport of biogenic amines into chromaffin granules Since neurotransmitter uptake plays an important role in many processes of the central nervous system, CuZnSOD gene-dosage may contribute to the neurobiological abnormalities of Down's syndrome 2 As an approach to the development of an animal model for Down syndrome, several strains of transgenic mice that carry the human CuZnSOD gene have been prepared These animals express the transgene in a manner similar to that of humans, with 09 and 07-kilobase transcripts in a 1:4 ratio, and synthesize the human enzyme in an active form capable of forming human-mouse enzyme heterodimers CuZnSOD activity is increased from 16 to 60-fold in the brains of four transgenic strains and to an equal or lesser extent in several other tissues 3 To investigate the possible involvement of CuZnSOD gene dosage in the neuropathological symptoms of Down's syndrome, we analyzed the tongue muscle of the transgenic mice that express elevated levels of human CuZnSOD The tongue neuromuscular junctions (NMJ) in the transgenic animals exhibited significant pathological changes, namely, withdrawal and destruction of some terminal axons and the development of multiple small terminals The ratio of terminal axon area to postsynaptic membrane decreased, and secondary folds were often complex and hyperplastic The morphological changes in the transgenic NMJ were similar to those previously seen in muscles of aging mice and rats as well as in tongue muscle of patients with Down's syndrome(ABSTRACT TRUNCATED AT 400 WORDS)