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(12) Patent Application Publication (10) Pub. No.: US 2011/0160076 A1 Alexander Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0160076 A1 Alexander Et Al US 2011 016.0076A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0160076 A1 Alexander et al. (43) Pub. Date: Jun. 30, 2011 (54) METHODS FOR PRODUCING UNIQUELY Publication Classification SPECIFIC NUCLECACD PROBES (51) Int. Cl. C40B 30/04 (2006.01) (75) Inventors: Nelson Alexander, Marana, AZ C7H I/00 (2006.01) (US); Stacey Stanislaw, Tucson, CI2P 19/34 (2006.01) AZ (US); James Grille, Tucson, AZ C7H 2L/00 (2006.01) (US); Mark B. Leick, Washington, (52) U.S. Cl. ........... 506/9:536/25.3:435/91.5:536/24.3 DC (US) (57) ABSTRACT Disclosed herein are uniquely specific nucleic acid probes (73) Assignee: Ventana Medical Systems, Inc. and methods for their use and production. The disclosed probes have reduced or eliminated background signal while reducing or eliminating the use of blocking DNA during (21) Appl. No.: 12/930,172 hybridization. In one example, probes are produced by a method that includes joining at least a first binding region and (22) Filed: Dec. 30, 2010 a second binding region in a pre-determined order and orien tation, wherein the first binding region and second binding region are complementary to uniquely specific nucleic acid Related U.S. Application Data sequences, wherein the uniquely specific nucleic acid (60) Provisional application No. 61/291,750, filed on Dec. sequences are represented only once in a genome of an organ ism and wherein the first binding region and the second bind 31, 2009, provisional application No. 61/314,654, ing region include about 20% or less of a genomic target filed on Mar. 17, 2010. nucleic acid molecule. In particular examples, the binding regions (“uniquely specific binding regions') are comple mentary to non-contiguous portions of the genomic target (30) Foreign Application Priority Data nucleic acid. Methods of using the disclosed probes and kits including the probes and/or reagents for producing or using Dec. 30, 2010 (US) ................. PCT/US2O1 OFO62485 the probes are also disclosed. Patent Application Publication Jun. 30, 2011 Sheet 1 of 11 US 2011/016.0076 A1 8. : 3. : y : 8: 8, Patent Application Publication Jun. 30, 2011 Sheet 2 of 11 US 2011/016.0076 A1 . **************************************************;****************** Patent Application Publication Jun. 30, 2011 Sheet 3 of 11 US 2011/016.0076 A1 Patent Application Publication Jun. 30, 2011 Sheet 4 of 11 US 2011/016.0076 A1 C. A “Repeat ree” (v. 8 rate rigtsey Specific v 8 reas: G. 3 *Repeat ree” (SFR probes iniqueiy Specific i388 protes Patent Application Publication Jun. 30, 2011 Sheet 5 of 11 US 2011/016.0076 A1 G, SA (, ingfi pi *i;& {... 3 No pxA & Patent Application Publication Jun. 30, 2011 Sheet 6 of 11 US 2011/016.0076 A1 3.3 g fraxia. (S. 8) Patent Application Publication Jun. 30, 2011 Sheet 7 of 11 US 2011/016.0076 A1 §8383··· 38 uis *:::::::3:38& o Patent Application Publication Jun. 30, 2011 Sheet 8 of 11 US 2011/016.0076 A1 ? ??? 89'943 ? $3 -3&3. 8. x 8::8 w83 :8: gif :: Patent Application Publication Jun. 30, 2011 Sheet 9 of 11 US 2011/016.0076 A1 3|…39§§ -------------. arrassass-Xaa-XXXXXXXXXXXXww s X: 8 w xes 88:S w8: 33 388: 8 Patent Application Publication Jun. 30, 2011 Sheet 10 of 11 US 2011/016.0076 A1 G. A G. C. Patent Application Publication Jun. 30, 2011 Sheet 11 of 11 US 2011/016.0076 A1 US 2011/016.0076 A1 Jun. 30, 2011 METHODS FOR PRODUCING UNIQUELY 0005. The genome of many organisms contains repetitive SPECIFIC NUCLECACID PROBES nucleic acid sequences, which are series of nucleotides that are repeated multiple times, often in tandem arrays. The pres CROSS REFERENCE TO RELATED ence of Such repetitive sequences in a probe results in APPLICATIONS increased background staining and requires the use of block ing DNA during hybridization. “Repeat-free” probes which 0001. This claims the benefit of U.S. Provisional Applica lack Such repetitive sequences are often generated (for tion No. 61/291,750, filed Dec. 31, 2009, and U.S. Provi example using a computer algorithm) to reduce this problem. sional Application No. 61/314,654, filed Mar. 17, 2010, and However, even “repeat-free” probes require the use of sub claims priority to International Application No. PCT/ stantial amounts of blocking DNA in order to reduce back US2010/62485, filed Dec. 30, 2010, each of which are incor ground staining to acceptable levels. porated herein by reference in their entirety. SUMMARY FIELD 0006 Disclosed herein are uniquely specific nucleic acid 0002. This disclosure relates to the field of molecular probes and methods for their use and production. The dis detection of nucleic acid target sequences (e.g., genomic closed probes have reduced or eliminated background signal DNA or RNA). More specifically, this disclosure relates to while reducing or eliminating the use of blocking DNA dur methods of producing nucleic acid probes that include ing hybridization. In some examples, probes are produced by uniquely specific nucleic acid sequences which are repre a method that includes joining at least a first binding region sented only once in the haploid genome of an organism, and and a second binding region in a pre-determined order and probes generated by the disclosed methods. orientation, wherein the first binding region and second bind ing region are complementary to uniquely specific nucleic BACKGROUND acid sequences, wherein the uniquely specific nucleic acid sequences are represented only once in a genome of an organ 0003 Molecular cytogenetic techniques, such as fluores ism and wherein the first binding region and the second bind cence in situ hybridization (FISH), chromogenic in situ ing region include about 20% or less (for example 20%, 19%, hybridization (CISH) and silver in situ hybridization (SISH), 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, combine visual evaluation of chromosomes (karyotypic 7%, 6%. 5%, 4%. 3%, 2%, 1%, or less) of a genomic target analysis) with molecular techniques. Molecular cytogenetics nucleic acid molecule. In some examples, the first binding methods are based on hybridization of a nucleic acid probe to region and the second binding region include about 10% or its complementary nucleic acid within a cell. A probe for a less of a genomic target nucleic acid molecule. In particular specific chromosomal region will recognize and hybridize to examples, the binding regions ("uniquely specific binding its complementary sequence on a metaphase chromosome or regions') are complementary to non-contiguous portions of within an interphase nucleus (for example in a tissue sample). the genomic target nucleic acid. In some examples, the Probes have been developed for a variety of diagnostic and uniquely specific binding regions are at least about 20 base research purposes. For example, certain probes produce a pairs (bp) in length (for example, about 35-500 bp, such as chromosome banding pattern that mimics traditional cytoge about 100 bp). In some examples, the genomic target nucleic netic staining procedures and permits identification of indi acid is from a eukaryotic genome (such as a mammalian vidual chromosomes for karyotypic analysis. Other probes genome, for example a human genome). are derived from a single chromosome and when labeled can 0007. In particular embodiments, the uniquely specific be used as "chromosome paints' to identify specific chromo binding regions are generated by one or more of the follow somes within a cell. Yet other probesidentify particular chro ing: separating the genomic target nucleic acid into a plurality mosome structures, such as the centromeres or telomeres of of segments (for example, separating the genomic nucleic chromosomes. Additional probes hybridize to single copy acid sequence into segments, such as in silico); comparing DNA sequences in a specific chromosomal region or gene. each segment with a genome including the genomic target These are the probes used to identify the critical chromo nucleic acid (for example, using a computer algorithm, Such Somal region or gene associated with a syndrome or condition as BLAT); selecting at least two segments which are uniquely of interest. On metaphase chromosomes, such probes hybrid specific to the genomic target nucleic acid (Such as at least two ize to each chromatid, usually giving two small, discrete segments that are each represented only once each in the signals per chromosome. genomic target nucleic acid molecule); removing repetitive 0004) Hybridization of such chromosomal or gene-spe DNA sequences from the genomic target nucleic acid (for cific probes has made possible detection of chromosomal example, using a computer algorithm, such as Repeat abnormalities associated with numerous diseases and Syn Masker); and selecting at least two segments having a GC dromes, including constitutive genetic anomalies, such as nucleotide content between about 30% and 70%. microdeletion syndromes, chromosome translocations, gene 0008. In other embodiments, the uniquely specific binding amplification and aneuploidy syndromes, neoplastic dis regions are generated by one or more of the following: sepa eases, as well as pathogen infections. Most commonly these rating the genomic target nucleic acid into a plurality of techniques are applied to standard cytogenetic preparations segments (for example, separating the genomic nucleic acid on microscope slides. In addition, these procedures can be sequence into segments, such as in silico); synthesizing the used on slides of formalin-fixed tissue, blood or bone marrow plurality of nucleic acid segments; attaching the synthesized Smears, and directly fixed cells or other nuclear isolates. plurality of nucleic acid segments to an array; hybridizing the Chromosomal or gene-specific probes can also be used in array with total genomic DNA and blocking DNA; selecting comparative genomic hybridization (CGH) to determine at least two segments which are uniquely specific to the gene copy number in a genome.
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