Showing papers on "Chromosome 21 published in 1988"

Rapid detection of human chromosome 21 aberrations by in situ hybridization

Abstract: Plasmid clones containing up to 94 kilobases of single-copy DNA from band q22.3 of chromosome 21 and a complete pool of insert DNA from a chromosome 21 recombinant library have been used to rapidly detect numerical and structural aberrations of chromosome 21 by in situ hybridization in both metaphase and interphase cells. A trisomic karyotype, diagnostic of Down syndrome, is readily detected in nonmitotic cells because the majority of their nuclei exhibit three discrete foci of hybridization, in contrast to normal diploid cells, which show two foci. Chromosomal translocations involving chromosome 21 sequences were also detected with these probes, and the intranuclear location of 21q22.3 DNA sequences in "normal" human brain neurons was established with the plasmid DNA probe set. These results suggest that chromosome 21-specific probes may have utility in clinical diagnostics, especially by facilitating the direct analysis of interphase cells.

Absence of linkage of chromosome 21q21 markers to familial Alzheimer's disease

Abstract: Alzheimer's disease is the most common form of dementia among the elderly population. Although the etiology is unknown, inheritance plays a role in the pathogenesis of the disease. Recent work indicates that an autosomal dominant gene for Alzheimer's disease is located on chromosome 21 at band q21. In the present study of a group of autopsy-documented kindreds, no evidence for linkage was found between familial Alzheimer's disease (FAD) and chromosome 21q21 markers (D21S1/D21S72 and the amyloid beta gene). Linkage to the D21S1/D21S72 locus was excluded at recombination fractions (theta) up to 0.17. Linkage to the amyloid gene was excluded at theta = 0.10. Apparent recombinants were noted in two families for the amyloid gene and in five families for the D21S1/D21S72 locus. These data indicate that FAD is genetically heterogeneous.

Gene encoding the beta subunit of S100 protein is on chromosome 21: implications for Down syndrome.

Abstract: S100 protein is a calcium-binding protein found predominantly in the vertebrate nervous system. Genomic and complementary DNA probes were used in conjunction with a panel of rodent-human somatic cell hybrids to assign the gene for the beta subunit of S100 protein to the distal half of the long arm of human chromosome 21. This gene was identified as a candidate sequence which, when expressed in the trisomic state, may underlie the neurologic disturbances in Down syndrome.

Chromosomal localization of genes encoding guanine nucleotide-binding protein subunits in mouse and human

Abstract: A variety of genes have been identified that specify the synthesis of the components of guanine nucleotide-binding proteins (G proteins). Eight different guanine nucleotide-binding alpha-subunit proteins, two different beta subunits, and one gamma subunit have been described. Hybridization of cDNA clones with DNA from human-mouse somatic cell hybrids was used to assign many of these genes to human chromosomes. The retinal-specific transducin subunit genes GNAT1 and GNAT2 were on chromosomes 3 and 1; GNAI1, GNAI2, and GNAI3 were assigned to chromosomes 7, 3, and 1, respectively; GNAZ and GNAS were found on chromosomes 22 and 20. The beta subunits were also assigned--GNB1 to chromosome 1 and GNB2 to chromosome 7. Restriction fragment length polymorphisms were used to map the homologues of some of these genes in the mouse. GNAT1 and GNAI2 were found to map adjacent to each other on mouse chromosome 9 and GNAT2 was mapped on chromosome 17. The mouse GNB1 gene was assigned to chromosome 19. These mapping assignments will be useful in defining the extent of the G alpha gene family and may help in attempts to correlate specific genetic diseases with genes corresponding to G proteins.

Cloning and chromosomal localization of human genes encoding the three chains of type VI collagen.

Abstract: Type VI collagen is a heterotrimer composed of three polypeptide chains, alpha 1(VI), alpha 2(VI), and alpha 3(VI). By immunological screening of an expression cDNA library, human cDNAs specific for each chain were isolated and characterized. Major mRNA species encoding these chains have a size of 4.2 kb (alpha 1), 3.5 kb (alpha 2), and 8.5 kb (alpha 3). The cDNA clones were also used to map the genes on human chromosomes by somatic cell hybrid analysis and in situ hybridization. The alpha 1 (VI) and alpha 2(VI) collagen genes were both located on chromosome 21, in band q223. This represents a third example of a possible physical proximity of two collagen loci. The alpha 3(VI) collagen gene was localized to chromosome 2, in the region 2q37. The alpha 3(VI) collagen gene is the fifth extracellular matrix gene to be localized to 2q, as four other extracellular matrix genes--i.e., the alpha 1(III) and alpha 2(V) collagen genes, the elastin gene, and the fibronectin gene--have been previously mapped to the distal region of the long arm of chromosome 2.

Microcloning reveals a high frequency of repetitive sequences characteristic of chromosome 4 and the beta-heterochromatin of Drosophila melanogaster

Abstract: Microdissection and microcloning of the euchromatin-heterochromatin transition region of the Drosophila melanogaster polytene X chromosome and part of the euchromatin of chromosome 4 reveals that they share certain features characteristic of beta-heterochromatin, which is morphologically defined as the loosely textured material at the bases of some polytene chromosome arms. Both are mosaics of many different middle-repetitive DNA sequences interspersed with single-copy DNA sequences. Sixty percent of cloned inserts derived from division 20 and about 40 percent from subdivisions 19EF of the X chromosome harbor at least one repetitive DNA sequence in an average insert of 4.5 kilobases. No repeats have significant cross-hybridization to any of the eleven satellite DNAs, or to the clustered-scrambled sequences present in pDm1. The repetitive elements are, in general, confined to the beta-heterochromatic regions of polytene chromosomes, but some are adjacent to nomadic elements. Chromosome 4, however, has some repeats spread throughout its entire euchromatin. These data have implications for the structure of transition zones between euchromatin and heterochromatin of mitotic chromosomes and also provide a molecular basis for reexamining some of the unusual classical properties of chromosome 4.

Chromosomal location of the genes encoding the leukocyte adhesion receptors LFA-1, Mac-1 and p150,95. Identification of a gene cluster involved in cell adhesion.

Abstract: The adhesion receptors Mac-1, LFA-1, and p150,95 are cell surface alpha/beta heterodimers that play a key role in leukocyte adhesion processes. The genes for Mac-1, LFA-1, and p150,95 alpha subunits have been located to chromosome 16 by means of Southern blot analysis using a series of somatic cell hybrids. Chromosomal in situ hybridization has demonstrated that the genes for the three alpha subunits map to the short arm of chromosome 16, between bands p11 and p13.1, defining a cluster of genes involved in leukocyte adhesion. The gene encoding the LFA-1/Mac-1/p150,95 beta subunit, and defective in leukocyte adhesion deficiency, has been located on chromosome 21, band q22. The leukocyte adhesion receptor alpha and beta subunits are mapped to chromosomal regions that have been shown to be involved in cytogenetic rearrangements in certain patients with acute myelomonocytic leukemia and the blast phase of chronic myelogenous leukemia, respectively.

Expansions and contractions of the genetic map relative to the physical map of yeast chromosome III.

Abstract: To examine the relationship between genetic and physical chromosome maps, we constructed a diploid strain of the yeast Saccharomyces cerevisiae heterozygous for 12 restriction site mutations within a 23-kilobase (5-centimorgan) interval of chromosome III. Crossovers were not uniformly distributed along the chromosome, one interval containing significantly more and one interval significantly fewer crossovers than expected. One-third of these crossovers occurred within 6 kilobases of the centromere. Approximately half of the exchanges were associated with gene conversion events. The minimum length of gene conversion tracts varied from 4 base pairs to more than 12 kilobases, and these tracts were nonuniformly distributed along the chromosome. We conclude that the chromosomal sequence or structure has a dramatic effect on meiotic recombination.

Loss of alleles on chromosome 18 and on the short arm of chromosome 17 in polyploid colorectal carcinomas.

Abstract: The zygosity of 19 colorectal carcinomas (either near-diploid or polyploid) from patients known to be heterozygous for RFLPs located on chromosome 18 or on the short arm of chromosome 17 has been examined. In most cases, at least one allele was significantly under-represented. The reason for the absence of complete loss of heterozygosity was investigated for 5 polyploid tumors. It was shown that the diploid component which, in these tumors, is essentially composed of non-neoplastic cells, remains heterozygous as the polyploid component invariably loses heterozygosity. The results strongly suggest that many colorectal carcinomas originate from a single cell which had lost at least part of either chromosome 18 or of one short arm of chromosome 17, or both.

Chromosomal mapping of genes for transforming growth factors beta 2 and beta 3 in man and mouse: dispersion of TGF-beta gene family.

Abstract: Human cDNA probes for two new types of transforming growth factor-beta, TGF-beta 2 and TGF-beta 3, were used for mapping their cognate genes on human and mouse chromosomes by Southern blot analysis of somatic cell hybrid lines and, for the human loci, also by in situ chromosomal hybridization. For TGF-beta 2, a single site was found on the long arm of human chromosome 1, band 1q41, and on mouse chromosome 1, most likely in the known conserved syntenic region. For TGF-beta 3, the major site of hybridization, both on Southern filters and direct chromosome preparations, was at 14q24 in humans. This region is homologous in part to mouse chromosome 12, to which the murine beta 3 locus was mapped. These results indicate a wide dispersion of the TGF-beta gene family, with genes for TGF-beta 1 previously mapped by us to human chromosome 19q and mouse chromosome 7 and for inhibins alpha, beta B and beta A to human chromosomes 2q33-qter, 2cen-q13 and 7p15-p13, respectively.

Homologous alpha satellite sequences on human acrocentric chromosomes with selectivity for chromosomes 13, 14 and 21: implications for recombination between nonhomologues and Robertsonian translocations

Abstract: We report a new subfamily of alpha satellite DNA (pTRA-2) which is found on all the human acrocentric chromosomes. The alphoid nature of the cloned DNA was established by partial sequencing. Southern analysis of restriction enzyme-digested DNA fragments from mouse/human hybrid cells containing only human chromosome 21 showed that the predominant higher-order repeating unit for pTRA-2 is a 3.9 kb structure. Analysis of a "consensus" in situ hybridisation profile derived from 13 normal individuals revealed the localisation of 73% of all centromeric autoradiographic grains over the five acrocentric chromosomes, with the following distribution: 20.4%, 21.5%, 17.1%, 7.3% and 6.5% on chromosomes 13, 14, 21, 15 and 22 respectively. An average of 1.4% of grains was found on the centromere of each of the remaining 19 nonacrocentric chromosomes. These results indicate the presence of a common subfamily of alpha satellite DNA on the five acrocentric chromosomes and suggest an evolutionary process consistent with recombination exchange of sequences between the nonhomologues. The results further suggests that such exchanges are more selective for chromosomes 13, 14 and 21 than for chromosomes 15 and 22. The possible role of centromeric alpha satellite DNA in the aetiology of 13q14q and 14q21q Robertsonian translocations involving the common and nonrandom association of chromosomes 13 and 14, and 14 and 21 is discussed.

A spontaneously opened ring chromosome of Drosophila melanogaster has acquired He-T DNA sequences at both new telomeres.

Abstract: Ring chromosomes that have been opened to give linear chromosomes offer an opportunity to study the DNA sequences associated with new chromosome ends. The Drosophila melanogaster chromosome C(1)A was originally a ring chromosome, consisting of two linked X chromosomes, and thus had no telomeres. This chromosome has spontaneously opened in polytene region 13, a region near the middle of the euchromatic arm of the X chromosome. The opening of the ring has produced two new telomeres on the C(1)A chromosome. Each of the new telomeres has acquired He-T DNA sequences. He-T DNA is a complex family of repeated sequences found in the telomeric and pericentric heterochromatin of D. melanogaster chromosomes. He-T DNA sequences are detected, at various levels, in the most distal band on the end of each polytene chromosome in all D. melanogaster stocks. To our knowledge, these sequences have never been detected within the euchromatic chromosomal regions in any stock. The strong correlation between He-T DNA sequences and telomeric regions suggests that He-T sequences may have a role in organizing or maintaining the ends of chromosomes. The association of He-T DNA with newly acquired telomeres in a formerly euchromatic region, polytene region 13, strengthens this correlation.

Partial physical map of human chromosome 21.

Abstract: The long arm of human chromosome 21 has been analyzed with unique sequence DNA probes, using an expanded panel of somatic cell hybrids containing defined regions of the chromosome, and both standard and pulsed field gel electrophoresis. Each member of the hybrid cell panel contains either a normal chromosome 21, or one of 11 different translocations or deletions within the long arm. Together, these now include 11 breakpoints, defining 11 long arm regions. Thirty-two unique sequence probes have been localized to these regions by standard gel electrophoresis. Analysis by pulsed field gels indicates that 27 of these identify a total of 18 Not1 restriction fragments, which together account for approximately 17 million base pairs, over half the long arm. Five physical linkage groups have been identified, as well as patterns in the distribution of unique sequences and GC-rich chromosomal regions. This information can be correlated with that obtained by other methods and contributes to the construction of a detailed physical map of this chromosome.

Comparative mapping of DNA markers from the familial Alzheimer disease and Down syndrome regions of human chromosome 21 to mouse chromosomes 16 and 17

Abstract: Mouse trisomy 16 has been proposed as an animal model of Down syndrome (DS), since this chromosome contains homologues of several loci from the q22 band of human chromosome 21. The recent mapping of the defect causing familial Alzheimer disease (FAD) and the locus encoding the Alzheimer amyloid beta precursor protein (APP) to human chromosome 21 has prompted a more detailed examination of the extent of conservation of this linkage group between the two species. Using anonymous DNA probes and cloned genes from human chromosome 21 in a combination of recombinant inbred and interspecific mouse backcross analyses, we have established that the linkage group shared by mouse chromosome 16 includes not only the critical DS region of human chromosome 21 but also the APP gene and FAD-linked markers. Extending from the anonymous DNA locus D21S52 to ETS2, the linkage map of six loci spans 39% recombination in man but only 6.4% recombination in the mouse. A break in synteny occurs distal to ETS2, with the homologue of the human marker D21S56 mapping to mouse chromosome 17. Conservation of the linkage relationships of markers in the FAD region suggests that the murine homologue of the FAD locus probably maps to chromosome 16 and that detailed comparison of the corresponding region in both species could facilitate identification of the primary defect in this disorder. The break in synteny between the terminal portion of human chromosome 21 and mouse chromosome 16 indicates, however, that mouse trisomy 16 may not represent a complete model of DS.

Mapping of the gene encoding the beta-amyloid precursor protein and its relationship to the Down syndrome region of chromosome 21.

Abstract: The gene encoding the beta-amyloid precursor protein has been assigned to human chromosome 21, as has a gene responsible for at least some cases of familial Alzheimer disease. Linkage studies strongly suggest that the beta-amyloid precursor protein and the product corresponding to familial Alzheimer disease are from two genes, or at least that several million base pairs of DNA separate the markers. The precise location of the beta-amyloid precursor protein gene on chromosome 21 has not yet been determined. Here we show, by using a somatic-cell/hybrid-cell mapping panel, in situ hybridization, and transverse-alternating-field electrophoresis, that the beta-amyloid precursor protein gene is located on chromosome 21 very near the 21q21/21q22 border and probably within the region of chromosome 21 that, when trisomic, results in Down syndrome.

Identification and regional localization of DNA markers on chromosome 7 for the cloning of the cystic fibrosis gene.

Abstract: To facilitate mapping of the cystic fibrosis locus (CF) and to isolate the corresponding gene, we have screened a flow-sorted chromosome 7-specific library for additional DNA markers in the 7q31-q32 region. Unique ("single-copy") DNA segments were selected from the library and used in hybridization analysis with a panel of somatic cell hybrids containing various portions of human chromosome 7 and patient cell lines with deletion of this chromosome. A total of 258 chromosome 7-specific single-copy DNA segments were identified, and most of them localized to subregions. Fifty three of these corresponded to DNA sequences in the 7q31-q32 region. Family and physical mapping studies showed that two of the DNA markers, D7S122 and D7S340, are in close linkage with CF. The data also showed that D7S122 and D7S340 map between MET and D7S8, the two genetic markers known to be on opposite sides of CF. The study thus reaffirms the general strategy in approaching a disease locus on the basis of chromosome location.

Down syndrome, Alzheimer's disease and the somy 16 mouse

Abstract: Joseph T. Coyle, Mary Lou Oster-Granite, Roger H. Reeves and John D. Gearhart Joseph T. Coyle, Mary Lou Oster.Granite, Roger H. Reeves and John D. Oearhart are at the Departments of Psychiatry, Neuroscience, Physiology, Cell Biology and Anatomy, Gynecology and Obstetrics and the Developmental Genetics Laboratory, The Johns Hopkins University Sehool of Medicine, Baltimore, MD 21205, USA. Recent findings have implicated genes on human chromosome 21 as important in the pathophysiology of Alzheimer's disease (ADJ. These include the high incidence of the pathological features characteristic of AD in individuals with Down syndrome (trisomy 21) and the localization of both a familial AD gene and the gene encoding amyloid precursor protein on chromo- some 21. Substantial genetic homology exists between human chromosome 21 and mouse chromosome 16, including the gene encoding the amyloid precursor protein. Mice that are trisomic for chromosome 16 offer a genetic model.for studies relevant to Down syndrome that may also help to clarify molecular mechanisms involved in Alzheimer's disease. An understanding of the pathophysiology of Alzheimer's disease (AD) has been hindered by the lack of suitable animal models that could be subjected to rigorous molecular and cellular biological studies since such studies currently are not feasible with humans. While the cognitive impairments observed in aged rodents and primates may reflect compromised central cholinergic function 1, it is generally agreed that AD is a disease process with specific pathological features. Furthermore, the synaptic neurochemical abnormalities of AD can be distinguished from those associated with simple aging 2. Lesion-induced deficits of basal forebrain cholinergic neurons in animals have been informative about the behavioral role and synap- tic pharmacology of this particularly vulnerable neur- onal pathway in AD, but do not recreate the other characteristic pathological features a. Several other neurotransmitter systems, including noradrenergic and somatostatin-containing neurons, are also affected in AD 4's. To date, only humans are known to develop spontaneously the neuropathological and cognitive manifestations of AD. Genetics of Alzheimer's disease Recent studies have provided four lines of evidence that genetic factors are involved in the etiology of AD. First, as discussed in greater detail below, most individuals with Down syndrome (DS; trisomy 21) develop the pathological features of AD by the fourth

cDNA cloning and assignment to chromosome 21 of IFI-78K gene, the human equivalent of murine Mx gene.

Abstract: Recently we have purified to homogeneity and characterized an interferon-induced human protein (p78 protein) which is the equivalent of the interferon-induced murine Mx protein responsible for a specific antiviral state against influenza virus infection. A cDNA library was constructed using mRNAs from interferon-induced human diploid fibroblasts. cDNA clones coding for the human p78 protein were identified and used to determine the chromosomal location of the corresponding gene (termed IFI-78K gene) by hybridization to DNA from a panel of human x rodent somatic cell hybrids. The newly identified gene is located on chromosome 21. This has been confirmed by the observation of a gene dosage effect using chromosome 21 trisomic cells (fibroblasts derived from Down's syndrome patients). Among all interferon-inducible genes mapped so far, the IFI-78K gene is the only one located on chromosome 21, together with the gene for the receptor of type I interferon. Our results also provide further evidence for homology between human chromosome 21 and mouse chromosome 16, since the gene encoding the mouse Mx protein (the presumed mouse homolog protein of human p78 protein) has been assigned to chromosome 16.

Detection of submicroscopic deletions in band 17p13 in patients with the Miller-Dieker syndrome.

Abstract: The Miller-Dieker syndrome (MDS), a syndrome with lissencephaly, distinctive craniofacial features, growth impairment, and profound developmental failure, has been associated with a deletion of the distal part of chromosome band 17p13. A minority of patients with the syndrome do not have a deletion detectable with current cytogenetic techniques. Using three highly polymorphic DNA probes (pYNZ22, pYNH37.3, and p144D6) we have detected microdeletions in three MDS patients, two of whom had no visible abnormalities of chromosome 17. Loci defined by two of the DNA probes, pYNZ22 and pYNH37.3, were deleted in all three patients. The most distal locus, defined by p144D6, was present in one MDS patient, possibly defining the distal limits of the MDS region in band 17p13.3. None of these loci were absent in one case of lissencephaly without MDS.

Genetic mapping of the Mx influenza virus resistance gene within the region of mouse chromosome 16 that is homologous to human chromosome 21.

Abstract: A total of 318 progeny from four backcrosses involving different laboratory strains and subspecies of Mus musculus were analyzed to map the Mx gene to the region of mouse chromosome 16 (MMU 16) which is homologous to human chromosome 21 (HSA 21). This result suggests that Mx will be found in the region of HSA 21 which has been implicated in Down syndrome when inherited in three copies.