The GDB Human Genome Data Base Anno 1992.
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Chromosomes, Human↗
Biomedical subjects
P L Pearson
Publications and source records attributed to P L Pearson.
Analysis of reciprocal translocations by chromosome painting: applications and limitations of the technique.
Fluorescent in situ hybridization with chromosome-specific DNA libraries (chromosome painting) is an important new method for assessing chromosome rearrangements. In the research presented in this paper, two familial reciprocal translocations have been studied in the balanced and unbalanced forms, using both traditional G-banding techniques and chromosome painting. Although for each case two chromosomes were involved in the rearrangement, we found that only one chromosome library was suitable for detecting the translocation. These findings illustrate both the potential and the limitations of chromosome painting as a diagnostic tool in cytogenetics.
Adult↗
The human genome initiative--do databases reflect current progress?
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Base Sequence↗
Presymptomatic, prenatal, and exclusion testing for Huntington disease using seven closely linked DNA markers.
Presymptomatic, testing, prenatal diagnosis, or exclusion testing are now available for persons at risk for Huntington disease. These tests will reduce uncertainty, assist in life planning, and prevent the birth of potentially affected children. We present the results of presymptomatic tests for 37 applicants including two prenatal and one exclusion test in 23 families. We initially used the markers G8, H5.52, F5.53, and pTV20 (D4S10), p8 (D4S62), and pRB1.6 (D4S81) and extended the informativity of the test at a later stage with the markers pKP1.65, C4H, S1.5 (D4S43), 674 (D4S95), 157.9 (D4S111), and YNZ32 (D4S125). Applicants with an unsuitable family structure were not admitted to the test. Of the 37 applicants, 33 were informative. In our hands the most efficient strategy is first to use the markers H5.52 (D4S10), pRB1.6 (D4S81), 674 (D4S95), pKP1.65 (D4S43), 157.9 (D4S111), YNZ32 (D4S125), and 252.3 (D4S115). The overall informativity in our data set was 84% and in the most recent test we achieved a 90-95% informativity. The other markers are used only when the first set is not informative.
DNA↗
The genome data base (GDB)--a human gene mapping repository.
The types of gene mapping data and its organization in the Genome Data Base (GDB) recently established at Johns Hopkins Medical School are described. The database provides a continuous online environment for data perusal and editing and is used as the informatics core for running the human gene mapping workshops. Current development is primarily concentrated on extending the types of map object, means of defining map location, map storage and representation. Experimental data structures have been created that permit storage of any type of map information, physical or genetic.
Baltimore↗
Frequent somatic imbalance of marker alleles for chromosome 1 in human primary breast carcinoma.
Loss of heterozygosity at particular chromosomal loci in the tumor cell, as evidenced by restriction fragment length polymorphism analysis, has been taken as a hallmark of the presence of tumor suppressor genes. Recent studies of breast carcinoma have suggested that such genes might be located on the short as well as on the long arm of chromosome 1. We report here that comparison of constitutional and tumor genotypes of 84 breast tumors at 7 polymorphic chromosome 1 loci indicates a frequent imbalance of alleles on both 1p (12 of 61 informative patients) and 1q (37 of 71 informative patients). In about one-half of these cases, however, this imbalance was consistent with a gain in copy number of one allele in tumor DNA relative to normal DNA, rather than loss of the other. In 10 tumors we performed chromosome 1 enumeration in the interphase nucleus using in situ hybridization with a probe detecting the heterochromatin region at 1q12. These experiments confirmed the supernumerary presence of region 1q12 in those tumors showing an allelic copy number gain of 1q. We suggest that there are several genes on chromosome 1 serving as targets for these changes, some of them associated with breast cancer development through their deletion and others through an increase in copy number.
Alleles↗
Origin of chromosome rearrangements in two long-lived human keratinocyte lines.
We have determined the origin of the extra chromosomal material in the karyotypes of two spontaneously-occurring long-lived human keratinocyte lines, HKC-N2 and HKC-N6. In each case the extra material was derived from the chromosome on which it was located. Possible relationships between the triplication of chromosomal material and the overcoming of cell senescence are discussed.
Cell Line↗
Genome mapping databases: data acquisition, storage and access.
The introduction of the genome database to the human gene mapping community in September 1990 heralded the advent of a new generation of databases to serve the needs of the human genome initiative over the coming years. The databases will act as a fulcrum around which the activities of the human genome initiative can be coordinated at an international level.
Animals↗
Allelotype of human breast carcinoma: a second major site for loss of heterozygosity is on chromosome 6q.
Loss of heterozygosity (LOH), which is detected with polymorphic DNA markers by comparing constitutional and tumor genotypes, has been observed at a number of different chromosome arms in primary breast tumors. These include 1p, 1q, 3p, 11p, 13q, 17p and 18q. We present here the results of a screening of all non-acrocentric chromosome arms, including those of the X chromosome, with at least one polymorphic marker per arm, in a total of 86 breast carcinomas. This dataset, termed an allelotype, indicates that in addition to the chromosome regions listed above, allelic loss may be observed in more than 30% of informative cases on 6q, 8q, 9q, 15q, and 16q. Multiple LOH involving at least two different chromosomes in a single tumor was observed in approximately 75% of the investigated tumors, and revealed complex chromosome involvement. Six different combinations of concurrent LOH at two different chromosome arms were found to be significantly correlated (r greater than 0.45; P less than 0.01). Tumors showing LOH at 3p or 17p were preferentially aneuploid, while LOH at 6q and 17q was inversely correlated with the number of positive lymph nodes and age respectively.
Alleles↗
Somatic genetic changes on chromosome 18 in breast carcinomas: is the DCC gene involved?
Recently, a gene has been isolated from the long arm of chromosome 18 which was shown to be frequently deleted in colorectal carcinomas and hence designated the DCC gene (Fearon et al., 1990). To explore the possible involvement of this gene in breast cancer, we have used 5 polymorphic DNA markers (one for 18p, and four for 18q) to examine the status of chromosome 18 in 49 primary breast carcinomas by comparing the genotypes of lymphocyte and tumour DNA samples. Imbalance of alleles, resulting in allelic loss of duplication, was observed in 17 cases (38% of informative cases). In 13 of these, this imbalance included the locus D18S8 located within the DCC gene region. In the remaining 4 cases this locus was not involved, with the affected chromosome region mapping proximally of D18S8 in 3 cases, and distally in 1 case. These results indicate that chromosome 18 is rearranged in breast cancer more frequently than is expected on the basis of cytogenetic data alone, and warrant a closer inspection of the DCC gene in this tumour.
Alleles↗
[Procedure and initial results of presymptomatic DNA studies in Huntington's chorea].
The availability of DNA-markers more tightly linked to the Huntington's disease locus made presymptomatic and exclusion testing possible with an accuracy of up to 98%. The testing programme started in Leiden in August 1987. In 56 adults with 25% and 50% risks presymptomatic tests were performed. In 8 persons the risk was increased to 98%, in 17 it was decreased to less than 5%. In two instances the test was not informative. The remaining 29 persons have not yet been tested for different reasons. So far 3 exclusion tests were requested: one showed a decreased risk, one has not yet been performed and one request was rejected. The results and the reactions to the test are discussed.
Adolescent↗
P9 (DXYS75) detects a VNTR-type RFLP in the pseudoautosomal region.
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Chromosome Deletion↗
Direct nonradioactive in situ hybridization of somatic cell hybrid DNA to human lymphocyte chromosomes.
Biotinylated DNA from various human-rodent hybrids was hybridized to human lymphocyte spreads after preannealing of the repeated sequences with sonicated total human DNA. Fluorescent labeling was achieved by successive treatments with fluorescein-labeled avidin and biotinylated antiavidin antibody. The use of labeled total DNA from hybrids with known chromosome composition permits the fluorescent staining-("painting") of specific chromosomes, or parts thereof, in human lymphocyte metaphases. Alternatively, the human chromosome content of cell hybrids with unknown chromosome composition is directly assessed from the labeling pattern of human lymphocyte spreads using the total hybrid DNA as probe.
Animals↗
Somatic origin of inherited haemophilia A.
We found a partial deletion of the clotting factor VIII gene of about 2000 bp, spanning exon 5 and part of intervening sequence 4 and 5 in an isolated patient with severe haemophilia A. The mother of the patient, who appeared to be a non-carrier on the basis of coagulation assays and restriction fragment length polymorphism analysis in the family, turned out to be a mosaic for the deletion, not only in her germ cells, but also in various somatic cells. These findings suggest that the mutation is the result of an event in early embryogenesis. If mosaicism for a mutation, either gonadal or somatic, proves to be a common phenomenon in human genetics, it is imperative to reconsider genetic risks for (future) sibs of any apparently new mutant of a hereditary disease.
Chromosome Deletion↗
Two step procedure for early diagnosis of polycystic kidney disease with polymorphic DNA markers on both sides of the gene.
Polymorphic DNA markers can now be used for presymptomatic and prenatal diagnosis of the autosomal dominant form of polycystic kidney disease (PKD). A detailed map is known for the chromosomal region around the PKD1 gene on the short arm of chromosome 16. We present here a simple, two step procedure for diagnosis of PKD1 by family studies. Using this approach, at least 92% of random subjects are informative for polymorphic DNA markers bracketing the PKD1 gene. The recombination rate between these flanking markers is on average 10%. In non-recombinants (90% of family members), the accuracy of diagnosis using DNA markers is greater than 99%. We conclude that sufficient well defined DNA markers are now available for routine diagnosis of PKD1. We recommend, however, that prenatal diagnosis of PKD by chorionic villi sampling should be attempted only after the linkage phase of the DNA markers has been established by haplotyping the index family. Since autosomal dominant PKD has been found to be genetically heterogeneous, families should be of sufficient size to rule out the rare form of PKD not caused by a mutation on the short arm of chromosome 16.
Chromosomes, Human, Pair 16↗
Loss of heterozygosity on 17p in human breast carcinomas: defining the smallest common region of deletion.
The marker D17S5, mapping to the short arm of chromosome 17, was recently reported by us and others to undergo frequent heterozygous deletion in human primary breast carcinomas, implicating the presence of a tumor suppressor gene in this region. To narrow down the location of this gene more precisely, we have performed a deletion-mapping study in an extended series of 78 breast carcinomas, using nine polymorphic markers for the short arm and two polymorphic markers for the long arm of chromosome 17. Partial allele losses on 17p were observed in nine cases, which, taken together, suggest that the target gene for the deletions maps to the region extending between the markers D17S5 (17p13.3) and D17S67 (17p12).
Breast Neoplasms↗
Rapid detection of chromosome 16 inversion in acute nonlymphocytic leukemia, subtype M4: regional localization of the breakpoint in 16p.
The pericentric inversion of chromosome 16 characteristic for acute nonlymphocytic leukemia, subtype M4, was detected in five patients by means of nonradioactive in situ hybridization of complete cosmids. First, five cosmids situated along the short arm of chromosome 16 were used to map the breakpoint of the inversion distal to the rare folate-sensitive fragile site FRA16A. Then, the use of two cosmids on either side of the breakpoint, combined with a probe specific for the centromeric region of chromosome 16, readily detected the inversion, even in poor metaphase spreads.
Chromosome Inversion↗
Rapid subchromosomal localization of cosmids by nonradioactive in situ hybridization.
A rapid method for localizing large numbers of complete cosmids by nonradioactive in situ hybridization is described. The cosmids are nick translated in the presence of biotin-16-dUTP, incubated with an excess of sonicated human DNA, and used as a probe for in situ hybridization. Sites of hybridization are detected by successive treatments with FITC-labeled avidin and biotinylated anti-avidin antibody. Fifty-two cosmids were localized on chromosome 16 in 5 d relative to translocation breakpoints contained in two cell lines. Rapid identification of chromosome 16 was achieved by cohybridization with a chromosome 16-specific centromeric repeat probe.
Cell Line, Transformed↗