Patent 5965362 Issued on October 12, 1999. Estimated Expiration Date: November 27, 2015. Estimated Expiration Date is calculated based on simple USPTO term provisions. It does not account for terminal disclaimers, term adjustments, failure to pay maintenance fees, or other factors which might affect the term of a patent.
435/6, Involving nucleic acid424/9.1, IN VIVO DIAGNOSIS OR IN VIVO TESTING435/91.2, Acellular exponential or geometric amplification (e.g., PCR, etc.)536/22.1, N-glycosides, polymers thereof, metal derivatives (e.g., nucleic acids, oligonucleotides, etc.)536/23.1, DNA or RNA fragments or modified forms thereof (e.g., genes, etc.)536/24.3, Probes for detection of specific nucleotide sequences or primers for the synthesis of DNA or RNA536/24.31, Probes for detection of animal nucleotide sequences536/24.32, Probes for detection of microbial nucleotide sequences536/24.33Primers
Disclosed are new methods comprising the use of in situ hybridization to detect abnormal nucleic acid sequence copy numbers in one or more genomes wherein repetitive sequences that bind to multiple loci in a reference chromosome spread are either substantially removed and/or their hybridization signals suppressed. The invention termed Comparative Genomic Hybridization (CGH) provides for methods of determining the relative number of copies of nucleic acid sequences in one or more subject genomes or portions thereof (for example, a tumor cell) as a function of the location of those sequences in a reference genome (for example, a normal human genome). The intensity(ies) of the signals from each labeled subject nucleic acid and/or the differences in the ratios between different signals from the labeled subject nucleic acid sequences are compared to determine the relative copy numbers of the nucleic acid sequences in the one or more subject genomes as a function of position along the reference chromosome spread. Amplifications, duplications and/or deletions in the subject genome(s) can be detected. Also provided is a method of determining the absolute copy numbers of substantially all RNA or DNA sequences in subject cell(s) or cell population(s).
Other References
Mariani-Costantini et al, "Genomic alterations in human breat cancer: a Review", Tumori, 75:311-320, 1989
Cherif et al, "Selection of cells with different chromosomal localizations of the amplified c-myc gene during in vivo and in vitro growth of the breast carcinoma cell line SW 613-S", Chromosoma 97:327-333, 1989
Alitalo et al, "Homogenously staining chromosomal regions contain amplified copies of an abundantly expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma", Proc. Natl. Acad. Sci. 80:1707-1711, Mar. 1983
Yoshida et al, "Human HST1 (HSTF1) gene maps to chromosome band 11q13 and coamplifies with the INT2 gene in human cancer", Proc. Natl. Acad. Sci. 85:4861-4864, Jul. 1988
Squire et al, "A detailed analysis of chromosomal changes in heritable and non-heritable retinoblastoma", Human Genetics 70:291-301, 1985
Sen et al, "Specific gene amplification associated with consistent chromosomal abnormality in independently established multi-drug resistant chinese hamster ovary cells", Chromosoma 95:117-125, 1987
Matthews, "Analytical strategies for the use of DNA probes", Anal. Biochem. 169:1-25, 1988
Mandahl et al, "Characteristic karyotypic anomalies identify subytpes of malignant fibrous histiocytoma", Genes Chromosomes Cancer 1(1):9-14, 1989
Wolman et al, "Genetic markers as prognostic indicators in breast cancer", Cancer 70(6):1765-1774, Sep. 1992
Cuneo et al, "Multipotent stem cell involvement in megakaryoblastic leukemia: cytologic and cytogenetic evidence in 15 patients", Blood 74(5):1781-1790, Oct. 1989
Nishida et al, "Nonrandom rearrangement of chromosome 14 at band q32.33 in human lymphoid malignancies with mature B-cell phenotype", Cancer Res. 49:1275-1281, Mar. 1989
Lakkala et al, "Comparison of DNA and karyotype aneuploidy in malignant lymphomas", Am. J. Clin. Pathol. 94:600-605, 1990
Burk et al, "Organization and Chromosomal Specificity of Autosomal Homologs of Human Y Chromosome Repeated DNA," Chromosoma, vol. 92, 1985, pp. 225-233
Cote et al, "Quantitation of in situ Hybridization of Ribosomal Ribonucleic Acids to Human Diploid Cells," Chromosoma, vol. 80, 1980, pp. 349-367
Cremer et al, "Preparative Dual-Beam Sorting of the Human Y Chromosome and In Situ Hybridization of Cloned DNA Probes," Cytometry, vol. 5, 1984, pp. 572-579
Davies, "The Application of DNA Recombinant Technology to the Analysis of the Human Genome and Genetic Disease," Human Genetics, vol. 58, 1981, pp. 351-357
Dennis et al, "Cytogenetics of the Parthenogenetic Grasshopper Warramaba virgo and Its Bisexual Relatives," Chromosoma, vol. 82, 1981, pp. 453-469
Gerhard et al, "Localization Of a Unique Gene By Direct Hybridization in situ," PNAS, vol. 78, 1981, pp. 3755-3759
Haase et al, "Detection of Two Viral Genomes in Single Cells By Double-Label Hybridization in Situ and Color Microradioautography," Science, vol. 227, 1985, pp. 189-192
Holden et al, "Amplified Sequences from Chromosome 15, Including Centromeres, Nucleolar Organizer Regions, and Centromeric Heterochromatin, in Homogeneously Staining Regions in the Human Melanoma Cell Line MeWo," Cancer Genet. & Cytogenet., vol. 14, 1985, pp. 131-146
Krumlauf et al, "Contruction and Characterization of Genomic Libraries From Specific Human Chromosomes," PNAS, vol. 79, 1982, pp. 2971-2975
Kunkel et al, "Organization and Heterogeneity of Sequences Within A Repeating Unit Of Human Y Chromosome Deoxyribonucleic Acid," Biochem., vol. 18, 1979, pp. 3343-3353
Malcom et al, "Chromosomal Localization Of A Single Copy Gene By in situ Hybridization--Human ଲ Genes On The Short Arm Of Chromosome 11," Ann. Hum. Genet., vol. 45, 1981, pp. 134-141
Pierce et al, "Analysis Of A Dispersed Repetitive DNA Sequence In Isogenic Lines of Drosophila," Chromosoma, vol. 82, 1981, pp. 471-492
Rabin, "Mapping Minimally Reiterated Genes On Diploid Chromosomes By In Situ Hybridization," thesis, Dept. of Biochemistry, Univ. III., 1982
Rabin et al, "Two Homoeo Box Loci Mapped In Evolutionarily Related Mouse And Human Chromosomes," Nature, vol. 314, 1985, pp. 175-178
Ruddle, "A New Era In Mammalian Gene Mapping: Somatic Cell Genetics And Recombinant DNA Methodologies," Nature, vol. 294, 1981, pp. 115-120
Siracusa et al, "Use of Repetitive DNA Sequences To Distinguish Mus musculus and Mus caroli Cells By in situ Hybridization," J Embryol. exp. Morph., vol. 73, 1983, pp. 163-178
Sondermeijer et al, "The Activity of Two Heat Shock Loci of Drosophila hydei In Tissue Culture Cells and Salivary Gland Cells as Analyzed by in situ Hybridization of Complementary DNA," Chromosoma, vol. 72, 1979, pp. 281-291
Steinemann, "Multiple Sex Chromosomes in Drosophila miranda: A System to Study the Degeneration of a Chromosome," Chromosoma, vol. 86, 1982, pp. 59-76
Szabo et al, "Quantitative in Situ Hybridization of Ribosomal RNA Species to Polytene Chromosomes of Drosophila melanogaster," J. Mol. Biol., vol. 115, 1977, pp. 539-563
Albertson, "Mapping Muscle Protein Genes by in situ Hybridization Using Biotin-Labeled Probes," EMBO J., vol. 4, No. 10, 1985, pp. 2493-2498
Albertson, "Localization of the Ribosomal Genes in Caenorhabditis elegans Chromosomes by in situ Hybridization Using Biotin-Labeled Probes," EMBO J., vol. 3, No. 6, 1984, pp. 1227-1234
Angerer et al, "In Situ Hybridization to Cellular RNAs," Genetic Engineering: Principles and Methods, Setlow and Hollaender, Eds., vol. 7, pp. 43-65, Plenum Press, New York (1985)
Ardeshir et al, "Structure of Amplified DNA in Different Syrian Hamster Cell Lines Resistant to N-(Phosphonacetyl)-L-Aspartate," Molecular and Cellular Biology, vol. 3, No. 11, Nov. 1983, pp. 2076-2088
Arnoldus et al, "Detection of the Philadelphia Chromosome in Interphase Nuclei (With 2 Color Plates)," Cytogenet. Cell Genet., vol. 54, 1990, pp. 108-111
Bar-Am et al, "Detection of Amplified DNA Sequences in Human Tumor Cell Lines by Fluorescence In Situ Hybridization," Genes, Chromosomes & Cancer, vol. 4, 1992, pp. 314-320
Bayer et al, "The Use of the Avidin-Biotin Complex as a Tool in Molecular Biology," Methods of Biochemical Analysis, vol. 26, pp. 1-45 (1980)
Benton et al, "Screening λgt Recombinant Clones by Hybridization to Single Plaques in situ," Science, vol. 196, 1977, pp. 180-182
Bergerheim et al, "Deletion Mapping in Human Renal Cell Carcinoma," Cancer Res., vol. 49, Mar. 1989, pp. 1390-1396
Bookstein et al, "Human Retinoblastoma Susceptibility Gene: Genomic Organization and Analysis of Heterozygous Intragenic Deletion Mutants," PNAS (USA), vol. 85, Apr. 1988, pp. 2210-2214
Boyle et al, "Differential Distribution of Long and Short Interspersed Element Sequences in the Mouse Genome: Chromosome Karyotyping by Fluorescence in situ Hybridization," PNAS Sci. USA, vol. 87, 1990, pp. 7757-7761
Brigati et al, "Detection of Viral Genomes in Cultured Cells and Paraffin-Embedded Tissue Sections Using Biotin-Labeled Hybridization Probes," Virology, vol. 126, pp. 32-50 (1983)
Brison et al, "General Method for Cloning Amplified DNA by Differential Screening with Genomic Probes," Molecular and Cellular Biology, vol. 2, No. 5, May 1982, pp. 578-587
Britten et al, "Analysis of Repeating DNA Sequences by Reassociation," Methods of Enzymology, vol. 29, 1974, pp. 363-418
Brock et al., "Quantitative in situ Hybridization Reveals Extent of Sequence Homology Between Related DNA Sequences in Drosophila melanogaster," Chromosoma, vol. 83, No. 2, 1981, pp. 159-168
Broker et al, "Electron Microscopic Visualization of tRNA Genes with Ferritin-Avidin: Biotin Labels," Nucleic Acids Research, vol. 5, No. 2, pp. 363-384 (1978)
Bufton et al, "A Highly Polymorphic Locus On Chromosome 16q Revealed By A Probe From A Chromosome-Specific Cosmid Library," Human Genetics, vol. 74, 1986, pp. 425-431
Bufton et al, "Four Restriction Fragment Length Polymorphisms Revealed By Probes From A Single Cosmid Map To Human Chromosome 19," Am J Hum Genet, vol. 38, 1986, pp. 447-460
Buongiorno-Nardelli et al, "Autoradiographic Detection of Molecular Hybrids between rRNA and DNA in Tissue Sections," Nature, vol. 225, Mar. 1970, pp. 946-948
Buroker et al, "Four Restriction Fragment Length Polymorphisms Revealed By Probes From A Single Cosmid Map To Human Chromosome 12q," Human Genetics, vol. 72, 1986, pp. 86-94
Cannizzaro et al, "In Situ Hybridization and Translocation Breakpoint Mapping II. Two Unusual t(21;22) Translocations," Cytogenet. Cell Genet., vol. 39, 1985, pp. 173-178
Cantor et al, "The Behavior of Biological Macromolecules, Part III," Biophysical Chemistry, Freeman & Co. 1980, pp. 1183, 1226-1228
Cohen et al, "Hereditary Renal-Cell Carcinoma Associated with a Chromosomal Translocation," N. Engl. J. Med., vol. 301, No. 11, Sep. 1979, pp. 592-595
Collins and Weissman, "Directional cloning of DNA fragments at a large distance from an initial probe: A circularization method", PNAS (USA), 81: 6812-6816 (Nov. 1984)
Connolly et al, "Chemical Synthesis of Oligonucleotides Containing A Free Sulphydryl Group and Subsequent Attachment of Thiol Specific Probes," Nucleic Acids Research, vol. 13, No. 12, pp. 4485-4502 (1985)
Cox et al, "Detection of mRNAs in Sea Urchin Embryos by in Situ Hybridization Using Asymmetric RNA Probes," Developmental Biology, vol. 101, 1984, pp. 485-502
Cremer et al, "Detection of Chromosome Aberrations in Metaphase and Interphase Tumor Cells by in situ Hybridization Using Chromosome-Specific Library Probes," Human Genetics, vol. 80, 1988, pp. 235-246
Cremer et al, "Detection of Chromosome Aberrations in the Human Interphase Nucleus by Visualization of Specific Target DNAs with Radioactive and Non-Radioactive in situ Hybridization Techniques: Diagnosis of Trisomy 18 with Probe L1.84," Human Genetics, vol. 74, 1986, pp. 346-352
Cremer et al, "Rapid Interphase and Metaphase Assessment of Specific Chromosomal Changes in Neuroectodermal Tumor Cells by in Situ Hybridization with Chemically Modified DNA Probes," Exp. Cell Res., vol. 176, 1988, pp. 199-220
Cremer et al, "Rapid Metaphase and Interphase Detection of Radiation-Induced Chromosome Aberrations in Human Lymphocytes by Chromosomal Suppression In Situ Hybridization," Cytometry, vol. 11, 1990, pp. 110-118
Devilee et al, "Detection of Chromosome Aneuploidy in Interphase Nuclei from Human Primary Breast Tumors Using Chromosome-specific Repetitive DNA Probes," Cancer Res., vol. 48, Oct. 1988, pp. 5825-5830
Durnam et al, "Detection of Species Chromosomes in Somatic Cell Hybrids," Sonomatic Cell and Molecular Genetics,vol. 11, No. 6, 1985, pp. 571-577
Dutrillaux et al, "Characterization of Chromosomal Anomalies in Human Breast Cancer--A Comparison of 30 Paradiploid Cases with Few Chromosome Changes," Cancer Genet. Cytogenet., vol. 49, 1990, pp. 203-217
Erikson et al, "Heterogeneity of Chromosome 22 Breakpoint in Philadelphia-positive (Ph+) Acute Lymphocytic Leukemia," PNAS, USA, vol. 83, Mar. 1986, pp. 1807-1811
Fisher et al, "Adhesive and Degradative Properties of Human Placental Cytotrophoblast Cells In Vitro," J. Cell Biol., vol. 109, No. 2, 1989, pp. 891-902
Fisher et al, "Molecular Hybridization Under Conditions of High Stringency Permits Cloned DNA Segments Containing Reiterated DNA Sequences to be Assigned to Specific Chromosomal Locations," PNAS, USA, vol. 81, Jan. 1984, pp. 520-524
Friend et al, "A Human DNA Segment with Properties of the Gene that Predisposes to Retinoblastoma and Osteosarcoma," Nature, vol. 323, Oct. 16, 1986, pp. 643-646
Fuscoe et al, "An Efficient Method for Selecting Unique-Sequence Clones from DNA Libraries and Its Application To Fluorescent Staining of Human Chromosome 21 Using in Situ Hybridization," Genomics, vol. 5, 1989, pp. 100-109
Fuscoe et al, "Construction of Fifteen Human Chromosome-Specific DNA Libraries from Flow-Purified Chromosomes," Cytogenetic Cell Genetics, vol. 43, pp. 79-86 (1986)
Gall et al, "Nucleic Acid Hybridization in Biological Preparations," Methods in Enzymology, vol. 21, pp. 470-480 (1981)
Gall et al, "Formation and Detection of RNA-DNA Hybrid Molecules in Cytological Preparations," PNAS (USA), vol. 63, 1969, pp. 378-383
Gray et al, "Flow Cytometric Detection of Chromosome Aberrations," (Abstract) Conference on Flow Cytometry in Cell Biology and Genetics, Clift Hotel, San Francisco, California, Jan. 15, 1985-Jan. 17, 1985
Gray et al, "Fluorescence Hybridization to Human Chromosome 21 Using Probes From A Charon 21 A Library," Cytometry, (Suppl. 1), 1987, Abst. 19, p. 4
Grunstein et al, "Colony Hybridization: A Method for the Isolation of Cloned DNAs That Contain A Specific Gene," PNAS, USA, vol. 72, No. 10, Oct. 1975, pp. 3961-3965
Harper et al, "Localization of Single Copy DNA Sequences on G-Banded Human Chromosomes by in situ Hybridization," Chromosoma (Berl.), vol. 83, 1981, pp. 431-439
Harper et al, "Localization of the Human Insulin Gene to the Distal End of the Short Arm of Chromosome 11," PNAS (USA), vol. 78, No. 7, Jul. 1981, pp. 4458-4460
Henderson, "Cytological Hybridization to Mammalian Chromosomes," International Review of Cytology, vol. 76, 1982, pp. 1-46
Herzenberg et al, "Fetal Cells in the Blood of Pregnant Women: Detection and Enrichment by Fluorescence-Activated Cell Sorting," PNAS (USA), vol. 76, No. 3, Mar. 1979, pp. 1453-1455
Hood et al, Molecular Biology of Eucaryotic Cells, W. A. Benjamin, Inc., Menlo Park, CA, pp. 47-51 (1975)
Houldsworth et al, "Comparative Genomic Hybridization: An Overview," Am. J. Pathology, vol. 145, No. 6, 1994, pp. 1253-1260
Jabs et al, "Characterization of a Cloned DNA Sequence that is Present at Centromeres of All Human Autosomes and the X Chromosome and Shows Polymorphic Variation," PNAS (USA), vol. 81, Aug. 1984, pp. 4884-4888
John et al, "RNA-DNA Hybrids at the Cytological Level," Nature, vol. 223, Aug. 1969, pp. 582-587
Kallioniemi et al, "Comparative Genomic Hybridization for Molecular Cytogenetic Analysis of Solid Tumors," Science, vol. 258, 1992, pp. 818-821
Kallioniemi et al, "Optimizing Comparative Genomic Hybridization for Analysis of DNA Sequence Copy Number Changes in Solid Tumors," Genes, Chromosomes & Cancer, vol. 10, 1994, pp. 231-243
Kao et al, "Assignment of the Structural Gene Coding for Albumin to Human Chromosome 4," Human Genetics, vol. 62, 1982, pp. 337-341
Kievits et al, "Direct Nonradioactive In Situ Hybridization of Somatic Cell Hybrid DNA to Human Lymphocyte Chromosomes," Cytometry, vol. 11, 1990, pp. 105-109
Kuhlmann, Immuno Enzyme Techniques in Cytochemistry, Verlag Chemie, Weinheim, Basel (1984) (table of contents only)
Landegent et al, "Use of Whole Cosmid Cloned Genomic Sequences for Chromosomal Localization of Non-Radioactive in situ Hybridization," Hum. Genet., vol. 77, 1987, pp. 366-370
Landegent et al, "Chromosomal Localization of a Unique Gene by Non-Autoradiographic in situ Hybridization," Nature, vol. 317, Sep. 1985, pp. 175-177
Landegent et al, "2-Acetylaminofluorene-Modified Probes for the Indirect Hybridocyto-chemical Detection of Specific Nucleic Acid Sequences," Exp. Cell Res., vol. 153, 1984, pp. 61-72
Landegent et al, "Fine Mapping Of The Huntington Disease Linked D4S10 Locus By Non-Radioactive In Situ Hybridization," Human Genetics, vol. 73, 1986, pp. 354-357
Landegren et al, "DNA Diagnostics--Molecular Techniques and Automation," Science, vol. 242, Oct. 1988, pp. 229-237
Langer-Safer et al, "Immunological Method for Mapping Genes on Drosophila Polytene Chromosomes," PNAS (USA), vol. 79, 1982, pp. 4381-4385
Lawn et al, "The Isolation and Characterization of Linked δ- and ଲ-Globin Genes from a Cloned Library of Human DNA," Cell, vol. 15, pp. 1157-1174 (1978)
Lawrence et al, "Sensitive, High-Resolution Chromatin and Chromosome Mapping In Situ: Presence and Orientation of Two Closely Integrated Copies of EBV in a Lymphoma Line," Cell, vol. 52, Jan. 1988, pp. 51-61
LeGrys et al, "Clinical Applications of DNA Probes in the Diagnosis of Genetic Diseases," CRC Crit. Rev. Clin. Lab. Sci., vol. 25, No. 4, 1987, pp. 255-274
Lewin, "Genetic Probes Become Ever Sharper--Rapid Detection of Multiple-Pathogen Infections, Including Major Drug-Resistance Genes, May be Possible Using a Newly Developed Technique," Science, vol. 221, No. 4616, Sep. 1983, p. 1167
Lewin B., (editor), Genes, (2nd Edition John Wiley & Sons, Inc. 1984), pp. 298-299 and 464-465
Lichter et al, "Delineation of Individual Human Chromosomes in Metaphase and Interphase Cells by in situ Suppression Hybridization Using Recombinant DNA Libraries," Human Genet., vol. 80, 1988, pp. 224-234
Lichter et al, "Rapid Detection of Human Chromosome 21 Aberrations by in situ Hybridization," PNAS Sci. USA, vol. 85, 1988, pp. 9664-9668
Lichter et al, "Fluorescence in situ Hybridization with Alu and L1 Polymerase Chain Reaction Probes for Rapid Characterization of Human Chromosomes in Hybrid Cell Lines," PNAS Sci. USA, vol. 87, 1990, pp. 6634-6638
Lichter et al, "High-Resolution Mapping of Human Chromosome 11 by in Situ Hybridization with Cosmid Clones," Science, vol. 247, Jan. 5, 1990, pp. 64-69
Lichter et al, "Is Non-Isotopic in situ Hybridization Finally Coming of Age?," Nature, vol. 345, May 1990, pp. 93-94
Litt et al, "A Highly Polymorphic Locus in Human DNA Revealed by Cosmid-Derived Probes," PNAS, USA, vol. 82, Sep. 1985, pp. 6206-6210
Litt et al, "A Highly Polymorphic Locus In Human DNA Revealed By Probes From Cosmid 1-5 Maps To Chromosome 2q35.fwdarw.37," Am J Hum Genet, vol. 38, 1986, pp. 288-296
Litt et al, "A Polymorphic Locus On The Long Arm Of Chromosome 20 Defined By Two Probes From A Single Cosmid," Human Genetics, vol. 73, 1986, pp. 340-345
LLNL, "Fluorescent Labeling of Human Chromosomes with Recombinant DNA Probes," Energy & Tech. Review, Jul. 1985, pp. 84-85
LLNL, "Chromosome-Specific Human Gene Libraries," Energy & Tech. Review, Jul. 1985, pp. 82-83
Lucas et al, "Rapid Translocation Analysis Using Fluorescence In Situ Hybridization: Applied to Long Term Biological Dosimetry", (UCRL 102265 Abstract), Radiation Research Meeting, New Orleans, Louisiana, Apr. 7, 1990-Apr. 12, 1990
Maniatis et al, "In Vitro Packaging of Bacteriophage λ DNA," Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, pp. 256-307 (1982)
Manuelidis, "Individual Interphase Chromosome Domains Revealed by In Situ Hybridization," Hum Genet, vol. 71, 1985, pp. 288-293
Manuelidis et al, "Chromosomal and Nuclear Distribution of the HindIII 1.9-kb Human DNA Repeat Segment," Chromosoma (Berl.), vol. 91, 1984, pp. 28-38
Manuelidis, "Different Central Nervous System Cell Types Display Distinct and Nonrandom Arrangements of Satellite DNA Sequences," PNAS (USA), vol. 81, May 1984, pp. 3123-3127
Marmur, "A Procedure for the Isolation of Deoxyribonucleic Acid from Micro-organisms," J. Mol. Biol., vol. 3, pp. 208-218 (1961)
McCormick, "The Polymerase Chain Reaction and Cancer Diagnosis," Cancer Cells, vol. 1, No. 2, Oct. 1989, pp. 56-61
Montgomery et al, "Specific DNA Sequence Amplification in Human Neuroblastoma Cells," PNAS Sci. USA, vol. 80, 1983, pp. 5724-5728
Nederlof et al, "Detection of Chromosome Aberrations in Interphase Tumor Nuclei by Nonradioactive In Situ Hybridation," Cancer Genet. Cytogenet., vol. 42, 1989, pp. 87-98
Nelson et al, "Genomic Mismatch Scanning: A New Approach To Genetic Linkage Mapping," Nature Genetics, vol. 4, 1993, pp. 11-18
Olsen et al, "Isolation of Unique Sequence Human X Chromosomal Deoxyribonucleic Acid," Biochemistry, vol. 19, 1980, pp. 2419-2428
Park et al, "Amplification, Overexpression, and Rearrangement of the erbB-2 Protooncogene in Primary Human Stomach Carcinomas," Cancer Res., vol. 49, 1989, pp. 6605-6609
Pinkel et al, "Cytogenetic Analysis Using Quantitative, High-Sensitivity, Fluorescence Hybridization," PNAS Sci. USA, vol. 83, 1986, p. 2934-2938
Pinkel et al, "Fluorescence in situ Hybridization with Human Chromosome-Specific Libraries: Detection of Trisomy 21 and Translocations of Chromosome 4," PNAS (USA), vol. 85, Dec. 1988, pp. 9138-9142
Pinkel et al, "Detection of Structural Chromosome Aberrations in Metaphase Spreads and Interphase Nuclei by in situ Hybridization High Complexity Probes Which Stain Entire Human Chromosomes," Am. J. Hum. Genet. (Supplement) vol. 43, No. 3, Sep. 1988, p. A118 (Abstract 0471: 11.5)
Pinkel et al, "Cytogenetic Analysis by In Situ Hybridization with Fluorescently Labeled Nucleic Acid Probes," Cold Spring Harbor Symposia on Quantitative Biology, vol. LI, 1986, pp. 151-157
Pinkel et al, "Genetic Analysis by Quantitative Microscopy and Flow Cytometry Using Fluorescence In Situ Hybridization with Chromosome-Specific Nucleic Acid Probes," Am. J. Hum. Genet. (Supplement), vol. 39, No. 3, Sep. 1986, p. A129 (379)
Pinkel et al, "Cytogenetic Analysis During Leukemia Therapy Using Fluorescence in situ Hybridization with Chromosome-Specific Nucleic Acid Probes," Am. J. Hum. Genet. (Supplement), vol. 41, No. 3, Sep. 1987, p. A34 (096; 12.12)
Pinkel et al, "Simplified Cytogenetics Using Biotin Labeled Nucleic Acid Probes and Quantitative Fluorescence Microscopy," Am. J. Hum. Genet. (Supplement), vol. 37, No. 4, Jul. 1985, pp. A112 (328; 17.2)
Pinkel et al, "Cytogenetics Using Fluorescent Nucleic Acid Probes and Quantitative Microscopic Measurement" (UCRL 93269 Abstract) Analytical Cytology X Conference, Hilton Head Resort, Hilton Head Island, S.C., Nov. 17, 1985-Nov. 22, 1985
Pinkel et al, "Rapid Quantitative Cytogenic Analysis Using Fluorescently Labeled Nucleic Acid Probes", (UCRL 93553 Abstract), U.S.--Japan Joint Environmental Panel Conf., Research Triangle Park, N.C., Oct. 21, 1985-Oct. 23, 1985
Pinkel et al, "Detection of Structural and Numerical Abnormalities in Metaphase Spreads and Interphase Nuclei Using In Situ Hybridization", Cancer Genet. and Cytogenet. (UCRL 101043 Abstract) 41:236 (Oct. 1989)
Pinkel et al, "Detection of Translocations and Aneuploidy in Metaphase Spreads and Interphase Nuclei by In Situ Hybridization with Probes Which Stain Entire Human Chromosomes," (UCRL 101042 Abstract) 21st Oak Ridge Conference on Advanced Conepts in the Clinical Laboratory, Apr. 13, 1989-Apr. 14, 1989
Rappold et al, "Sex Chromosome Positions in Human Interphase Nuclei as Studied by in situ Hybridization with Chromosome Specific DNA Probes," Human Genetics, vol. 67, 1984, pp. 317-322
Richardson et al, "Biotin and Fluorescent Labeling of RNA Using T4 RNA Ligase," Nucleic Acids Research, vol. 11, No. 18, pp. 6167-6184 (1983)
Ried et al, "Simultaneous Visualization of Seven Different DNA Probes by in situ Hybridization Using Combinatorial Fluorescence and Digital Imaging Microscopy," PNAS Sci. USA, vol. 89, 1992, pp. 1388-1392
Roelofs et al, "Gene Amplification in Human Cells May Involve Interchromosomal Transposition and Persistence of the Original DNA Region," The New Biologist, vol. 4, No. 1, (Jan. 1992), pp. 75-86
Saint-Ruf et al, "Proto-Oncogene Amplification and Homogeneously Staining Regions in Human Breast Carcinomas," Genes, Chromosomes & Cancer, vol. 2, 1990, pp. 18-26
Scalenghe et al, "Microdissection and Cloning of DNA from a Specific Region of Drosophila melanogaster Polytene Chromosomes," Chromosoma (Berl.), vol. 82, 1981, pp. 205-216
Schardin et al, "Specific Staining of Human Chromosomes in Chinese Hamster X Man Hybrid Cell Lines Demonstrates Interphase Chromosome Territories," Hum. Genet., vol. 71, 1985, pp. 281-287
Schmeckpeper et al, "Partial Purification and Characterization of DNA from the Human X Chromosome," PNAS (USA), vol. 76, No. 12, Dec. 1979, pp. 6525-6528
Sealey, et al, "Removal of Repeated Sequences from Hybridisation Probes," Nucleic Acid Research, vol. 13, No. 6, 1985, pp. 1905-1922
Selypes et al, "A Noninvasive Method for Determination of the Sex and Karyotype of the Fetus from the Maternal Blood," Hum. Genet., vol. 79, 1988, pp. 357-359
Smith et al, "Distinctive Chromosomal Structures Are Formed Very Early in the Amplification of CAD Genes in Syrian Hamster Cells," Cell, vol. 63, (Dec. 21, 1990), pp. 1219-1227
Smith et al, "The Synthesis of Oligonucleotides Containing an Aliphatic Amino Group at the 5' Terminus: Synthesis of Fluorescent DNA Primers For Use In DNA Sequence Analysis," Nucleic Acids Research, vol. 13, No. 7, pp. 2399-2412 (1985)
Sparkes et al, "Regional Assignment of Genes for Human Esterase D and Retinoblastoma to Chromosome Band 13q14," Science, vol. 208, May 30, 1988, pp. 1042-1044
Stewart et al, "Cloned DNA Probes Regionally Mapped to Human Chromosome 21 and Their Use in Determining the Origin of Nondisjunction," Nucleic Acids Research, vol. 13, No. 11, 1985, pp. 4125-4132
Straume et al, "Chromosome Translocation of Low Radiation Doses Quantified Using Fluorescent DNA Probes", (UCRL 93837 Abstract), Radiation Research Society Meeting, Las Vegas, Nevada, Apr. 12, 1986-Apr. 17, 1986
Szabo et al, "What's New With Hybridization in situ?," TIBS, vol. 7, No. 11, Dec. 1982, pp. 425-427
Tchen et al, "Chemically Modified Nucleic Acids as Immunodetectable Probes in Hybridization Experiments," PNAS, vol. 81, pp. 3466-3470 (1984)
Thompson et al, Thompson & Thompson: Genetics in Medicine, 5th ed., W.B. Saunders Co., Philadelphia, PA, pp. 38-39 (1991)
Trask et al, "The Proximity of DNA Sequences in Interphase Cell Nuclei Is Correlated to Genomic Distance and Permits Ordering of Cosmids Spanning 250 Kilobase Pairs," Genomics, vol. 5, 1989, pp. 710-717
Trask et al, "Detection of DNA Sequences in Nuclei in Suspension by In Situ Hybridization and Dual Beam Flow Cytometry" (UCRL 93372 Abstract)--Analytical Cytology X Conference, Hilton Head Resort, Hilton Head Island, S.C., Nov. 17, 1985-Nov. 22, 1985
Trask et al, "Early Dihydrofolate Reductase Gene Amplification Events in CHO Cells Usually Occur on the Same Chromosome Arm as the Original Locus," Genes & Development, vol. 3, (1989), pp. 1913-1925
Trent et al, "Report of the Committee on Structural Chromosome Changes in Neoplasia," Cytogenet. Cell Genet., vol. 51, 1989, pp. 533-562
Van Dilla et al, "Construction and Availability of Human Chromosome-Specific DNA Libraries From Flow Sorted Chromosomes: Status Report," Am. J. of Human Genetics, vol. 37 (R Supplement) Jul. 1985, p. A179
Wallace et al, "The Use of Synthetic Oligonucleotides as Hybridization Probes--II Hybridization of Oligonucleotides of Mixed Sequence to Rabbit ଲ Globin DNA," Nucleic Acids Research, vol. 9, No. 4, 1981, pp. 879-894
Weiss et al, "Organization and Evolution of the Class I Gene Family in the Major Histocompatibility Complex of the C57BL/10 Mouse," Nature, vol. 310, No. 23, Aug. 1984, pp. 650-655
Willard et al, "Isolation and Characterization of a Major Tandem Repeat Family from the Human X Chromosome," Nucleic Acids Research, vol. 11, No. 7, 1983, pp. 2017-2033
Windle et al, "A Central Role for Chromosome Breakage in Gene Amplification, Deletion Formation, and Amplicon Integration," Genes & Development, vol. 5, (1991), pp. 160-174
Yunis et al, "Localization of Sequences Specifying Messenger RNA to Light-Staining G-Bands of Human Chromosomes," Chromosoma (Berl.), vol. 61, 1977, pp. 335-34