Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-06-30
2001-08-07
Myers, Carla J. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S024310
Reexamination Certificate
active
06270971
ABSTRACT:
PRIORITY
This application claims priority to British Patent Application No. 9704054.7, filed on Feb. 27, 1997, the content of which is explicitly incorporated by reference in its entirety.
FIELD OF THE INVENTION
This invention relates to an assay for the detection and identification of chromosomal aberrations.
BACKGROUND TO THE INVENTION
The identification and analysis of chromosome preparations has previously depended on staining methods which produce characteristic chromosome banding patterns unique for every chromosome. The resolution of the method is low, and small rearrangements, including some deletions and duplications, are undetectable. This has led to the introduction of fluorescence in situ hybridization (FISH) techniques using DNA probes which can anneal to complementary sequences on chromosomes and thus act as specific markers. The probes annealed in this way are commonly labeled by haptens and detected indirectly by fluorescent-antibodies, or detected directly by fluorochromes incorporated into the probe itself. The specificity of the probe depends on its DNA sequence and the size of the signal depends on the length of the sequence. Many types of DNA probe are cloned in plasmid, cosmid, yeast artificial chromosome or other vector.
Another class of DNA probe uses total genomic DNA from either complete nuclear DNA or from fractions of nuclear DNA, which can be generated from a variety of sources including whole cells and specific chromosomes. The usual method of preparing these complex probes is by DNA amplification using the polymerase chain reaction (PCR) and random DNA primers. The label is incorporated during the amplification procedure or by nick-translation following amplification. Hybridization of these probes to chromosomes results in a more or less uniform series of fluorescent signals throughout the length of the chromosome. This has been referred to as “chromosome painting” and the probes producing this effect have been termed chromosome paints.
Paints corresponding to individual chromosomes (chromosome-specific paints) can be prepared from PCR amplification of flow sorted chromosomes. They have proved to be useful in the detection and identification of chromosome aberrations beyond the resolution of standard cytogenetic banding methods. Several chromosome specific paints can be used together to detect multiple target chromosomes provided different fluorochromes are used for labeling the probes derived from different chromosomes. For a more detailed description of modern cytogenetic techniques see Ferguson-Smith and Andrews. 1996, “Cytogenetic Analysis,” Chapter 12 in Emery & Rimoin's P
RINCIPLES
& P
RACTICE OF
M
EDICAL
G
ENETICS
, edited by D. L. Rimoin et al., Churchill-Livingstone, London. In addition, human chromosome specific paints have been used to identify homologies in non-human species by comparative genome analysis (Wienberg & Stanyon, 1995,
Curr. Opin. Gen.
&
Dev.
5:792-97).
SUMMARY OF THE INVENTION
In one aspect. the present invention provides a method for detecting a chromosomal aberration in an animal, by hybridizing at least one detectably-labeled chromosome-specific probe from a first animal species to one or more chromosomes of a second animal species; detecting a banding pattern resulting from the hybridization; and comparing the banding pattern detected to a banding pattern for the corresponding non-aberrant chromosome(s) of the second species. In one embodiment of this method, a plurality (at least two) of detectably-labeled chromosome-specific probes from the first animal species are hybridized to one or more chromosomes of a second animal species, and at least a two of the chromosome-specific probes are differently labeled.
In one embodiment of the invention, both animal species are vertebrate. In various embodiments, the first animal species is a non-human primate, for example a non-human primate of the genus Hylobates, such as
Hylobates concolor
and/or
Hylobates syndactylus.
In one embodiment of the invention, the second species is a human. The hybridization may be to the complete karyotype of the second animal.
The probes of the invention may be detectably labeled probes with one or more hapten species, a fluorochrome, or both. In certain embodiments, the hapten is biotin, digoxigenin, or fluorescein-isothiocyanate (FITC). Examples of fluorochromes are FITC, Cyanine-2, Cyanine-3, Cyanine-3.5, Cyanine-5, Cyanine-7, fluorescein, Texas red, rhodamine, lissamine and phycoerythrin. Chromosome-specific probes of the invention may be labeled with more than one label (e.g., 2, 3 or more haptens, fluorochromes, or combinations of haptens and fluorochromes).
In a related aspect, the invention is directed to compositions of detectably-labeled chromosome-specific probes from at least two different animal species. The species may be vertebrates such as non-human primates (e.g., species from the genus Hylobates, such as
Hylobates concolor
and
Hylobates syndactylus
).
In another related aspect, the invention provides kits useful for detecting chromosome aberrations. In one embodiment, the kit contains one or more detectably labeled chromosome-specific probes from a non-human animal species, and a photograph or drawing of a normal human karyotype stained with the probes. In one embodiment, the kit of the invention contains detectably labeled chromosome-specific probes from two different species in the same container. In a particular embodiment, both species are non-human primates such as primates of genus Hylobates.
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Ahern, “Biochemical, reagent kits offer scientists good return on investment”The Scientist, 9(15):20 (1995).
Arnold et al., “Identification of complex chromosome rearrangement in the gibbon by fluorescent in situ hybridization (FISH) of a human chromosome 2q specific microlibrary, yeast artificial chromosomes, and reciprocal chromosome painting”Cytogenet. Cell Genet., 74:80-85 (1996).
Cambio Ltd. Catalog, pp. 1, 19, 20 Star*Fish™ Chromosome Painting. Undated.
Ferguson-Smith, “Genetic analysis by chromosome sorting and painting: Phylogenetic and diagnostic applications,”Eur. J. Hum. Genet., 5:253-265 (1997).
Ferguson-Smith, “Applications of cross-species color banding,” (Abstract), 47thASHG Annual Meeting, Baltimore, Maryland, (Oct. 29, 1997).
Goureau, A. et al., “Human and porcine correspondence of chromosome segments using bidirectional chromosome painting,”Genomics, 36(2): 252-262 (1996).
Hoebee, B. et al., “Isolation of rat chromosome-specific paint probes by bivariate flow sorting followed by degenerate oligonucleotide primed-PCR,”Cytogenet. Cell Genet., 66:277-282 (1994).
Jauch et al., “Reconstruction of genomic rearrangements in great apes and gibbons by chromosome painting,”Proc. Natl. Acad. Sci. USA, 89:8611-8615 (1992).
Koehler et al., “Genomic reorganization and disrupted chromosomal synteny in the siamang (Hylobates Syndactylus) revealed by fluorescence in situ hybridization,”American Journal of Physical Anthropolocy, 97:37-47 (1995).
Koehler et al., “Genomic reorganization in the concolor gibbon (Hylobates Concolor) revealed by chromosome painting,”Genomics30:287-292 (1995).
Lengauer C. et al., “Chromosomal bar codes produced by multicolor fluorescence in situ hybridization with multiple YAC clones and whole chromosome painting probes,”Hum Mol Genet, 2(5):505-12 (1993).
Müller et al., “A novel source of highly specific chromosome painting probes for human karyotype analysis derived from primate homologues,”Hum. Genet., 101:149-153 (1997).
Müller, S. et al., Toward a multicolor chromosome bar code for the entire human karyotype of fluorescence in situ hybridization,Hum. Genet., 100:271-278 (1997).
Müller, “Cross-species color bonding (CSC-Banding): Te
Ferguson-Smith Malcolm A
Muller Stefan
Wienberg Johannes F
Applied Imaging Corporation
Johannsen Diana
Myers Carla J.
Townsend and Townsend and Crew LLP.
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