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Methods and Compositions for Analyzing Nucleic Acids

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Methods and Compositions for Analyzing Nucleic Acids Europäisches Patentamt *EP000990047B1* (19) European Patent Office Office européen des brevets (11) EP 0 990 047 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C12Q 1/68 of the grant of the patent: 14.05.2003 Bulletin 2003/20 (86) International application number: PCT/US98/15008 (21) Application number: 98936928.5 (87) International publication number: (22) Date of filing: 22.07.1998 WO 99/005319 (04.02.1999 Gazette 1999/05) (54) METHODS AND COMPOSITIONS FOR ANALYZING NUCLEIC ACIDS BY MASS SPECTROMETRY VERFAHREN UND VERBINDUNGEN ZUR ANALYSIERUNG VON NUKLEINSAEUREN DURCH MASSENSPEKTROMETRIE PROCEDES ET COMPOSITIONS POUR L’ANALYSE DE MOLECULES D’ACIDES NUCLEIQUES AU MOYEN DE SPECTROMETRIE DE MASSE (84) Designated Contracting States: (56) References cited: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU WO-A-94/16101 WO-A-95/04160 MC NL PT SE WO-A-95/14108 WO-A-95/25737 WO-A-95/28640 WO-A-97/27325 (30) Priority: 22.07.1997 US 898180 WO-A-97/27327 WO-A-97/27331 22.07.1997 US 898564 US-A- 5 118 605 22.07.1997 US 898501 • JACOBSON K B ET AL: "APPLICATIONS OF (43) Date of publication of application: MASS SPECTROMETRY TO DNA SEQUENCING" 05.04.2000 Bulletin 2000/14 GENETIC ANALYSIS TECHNIQUES AND APPLICATIONS, vol. 8, no. 8, 1 December 1991, (73) Proprietor: Qiagen Genomics, Inc. pages 223-229, XP000271820 Bothell, Washington 98021 (US) • P.C.TOREN ET AL.: "Determination of Impurities in Nucleoside 3’-Phosphoramidites by Fast (72) Inventors: Atom Bombardment Mass Spectrometry" • VAN NESS, Jeffrey ANALYTICAL BIOCHEMISTRY, vol. 152, no. 2, Seattle, WA 98125 (US) 1986, pages 291-294, XP002094264 • TABONE, John, C. • B.B.BROWN ET AL.: "A Single-Bead Decode Bothell, WA 98011 (US) Strategy Using Electrospray Ionization Mass • HOWBERT, Jeffry Spectometry and a New Photolabile Linker : Bellevue, WA 98005 (US) 3-Amino-3-(2-nitrophenyl)Propionic Acid." • MULLIGAN, John, T. MOLECULAR DIVERSITY, vol. 1, 1995, pages Seattle, WA 98105 (US) 4-12, XP002094265 (74) Representative: Gowshall, Jonathan Vallance FORRESTER & BOEHMERT Pettenkoferstrasse 20-22 80336 München (DE) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 990 047 B1 Printed by Jouve, 75001 PARIS (FR) EP 0 990 047 B1 Description [0001] The present invention relates generally to methods and compositions for analyzing nucleic acid molecules, and more specifically to tags which may be utilized in a wide variety of nucleic acid reactions, wherein separation of 5 nucleic acid molecules based on size is required. BACKGROUND OF THE INVENTION [0002] Detection and analysis of nucleic acid molecules are among the most important techniques in biology. Such 10 techniques are at the heart of molecular biology and play a rapidly expanding role in the rest of biology. [0003] Generally, one type of analysis of nucleic acid reactions involves separation of nucleic acid molecules based on length. For example, one widely used technique, polymerase chain reaction (PCR) (see, U.S. Patent Nos. 4,683,195, 4,683,202, and 4,800,159) has become a widely utilized technique to both identify sequences present in a sample and to synthesize DNA molecules for further manipulation. 15 [0004] Briefly, in PCR, DNA sequences are amplified by enzymatic reaction that synthesizes new DNA strands in either a geometric or linear fashion. Following amplification, the DNA sequences must be detected and identified. Because of non-specific amplifications, which would otherwise confuse analysis, or the need for purity, the PCR reaction products are generally subjected to separation prior to detection. Separation based on the size (i.e.. length) of the products yields the most useful information. The method giving the highest resolution of nucleic acid molecules is 20 electrophoretic separation. In this method, each individual PCR reaction is applied to an appropriate gel and subjected to a voltage potential. The number of samples that can be processed is limited by the number of wells in the gel. On most gel apparatus, from approximately 10 to 64 samples can be separated in a single gel. Thus. processing large numbers of samples is both labor and material intensive. [0005] Electrophoretic separation must be coupled with some detection system in order to obtain data. Detection 25 systems of nucleic acids commonly, and almost exclusively, utilize an intercalating dye or radioactive label, and less frequently, a nonradioactive label. Intercalating dyes, such as ethidium bromide, are simple to use. The dye is included in the gel matrix during electrophoresis or, following electrophoresis, the gel is soaked in a dye-containing solution. The dye can be directly visualized in some cases, but more often, and for ethidium bromide in particular, is excited by light (e.g., UV) to fluoresce. In spite of this apparent ease of use, such dyes have some notable disadvantages. First, 30 the dyes are insensitive and there must be a large mass amount of nucleic acid molecules in order to visualize the products. Second, the dyes are typically mutagenic or carcinogenic. [0006] A more sensitive detection technique than dyes uses a radioactive (or nonradioactive) label. Typically, either a radiolabeled nucleotide or a radiolabeled primer is included in the PCR reaction. Following separation, the radiolabel is "visualized" by autoradiography. Although more sensitive, the detection suffers from film limitations, such as reci- 35 procity failure and non-linearity. These limitations can be overcome by detecting the label by phosphor image analysis. However, radiolabels have safely requirements, increasing resource utilization and necessitating specialized equip- ment and personnel training. For such reasons, the use of nonradioactive labels has been increasing in popularity. In such systems, nucleotides contain a label,; such as a fluorophore, biotin or digoxin, which can be detected by an antibody or other molecule (e.g., other member of a ligand pair) that is labeled with an enzyme reactive with a chro- 40 mogenic substrate. These systems do not have the safety concerns as described above, but use components that are often labile and may yield nonspecific reactions, resulting in high background (i.e., low signal-to-noise ratio). [0007] The present invention provides novel compositions and methods which may be utilized in a wide variety of nucleic acid reactions, and further provides other related advantages. [0008] US-A-5118605 relates to methods for assaying a nucleic acid analytic. WO-A-9504160 relates to a tag reagent 45 and assay method. SUMMARY OF THE INVENTION [0009] Briefly stated, the present invention provides compositions and methods which may be utilized in a wide 50 variety of ligand pair reactions wherein separation of molecules of interest, such as nucleic acid molecules, based on size is required. Representative examples of methods which may be enhanced given the disclosure provided herein include PCR, differential display, RNA fingerprinting, PCR-SSCP, oligo litations assays, nuclease digestion methods (e.g., exo- and endo- nuclease based assays), and dideoxy fingerprinting. The methods described herein may be utilized in a wide array of fields, including, for example, in the development of clinical or research-based diagnostics, 55 the determination of polymorphisms, and the development of genetic maps. [0010] Within one aspect of the present invention, there is provided a compound of the formula: 2 EP 0 990 047 B1 ms T -L-X wherein, 5 Tms is an organic group detectable by mass spectrometry, comprising carbon, at least one of hydrogen and fluoride, and optional atoms selected from oxygen, nitrogen, sulfur, phosphorus and iodine; L is an organic group which allows a unique Tms-containing moiety to be cleaved from the remainder of the com- pound, wherein the Tms-containing moiety comprises a functional group which supports a single ionized charge 10 state when the compound is subjected to mass spectrometry and is tertiary amine. quaternary amine or organic acid; and X is a functional group selected from phosphoramidite and H-phosphonate. [0011] In another aspect, the present invention provides a method for determining the presence of a single nucleotide 15 polymorphism in a nucleic acid target comprising: a) amplifying a sequence of a nucleic acid target containing a single nucleotide polymorphism; b) generating a single strand form of the target; c) combining a tagged nucleic acid probe having the structure Tms-L-X' with the amplified target nucleic acid mol- 20 ecules under conditions and for a time sufficient to permit hybridization of said tagged nucleic acid probe to com- plementary amplified selected target nucleic acid molecules, wherein said tag is correlative with a particular single nucleotide polymorphism and is detectable by spectrometry or potentiometry; d) separating unhybridized tagged probe from hybridized tagged probe by a sizing methodology; e) cleaving said tag from said probe: and 25 f) detecting said tag by spectrometry or potentiometry, and determining the presence of said single nucleotide polymorphism. [0012] In another aspect, the present invention provides a method for determining the presence of a single nucleotide polymorphism
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