WO1995007345A2 - Identification d'alleles de sequences repetees en tandem par hybridation - Google Patents
Identification d'alleles de sequences repetees en tandem par hybridation Download PDFInfo
- Publication number
- WO1995007345A2 WO1995007345A2 PCT/KR1994/000117 KR9400117W WO9507345A2 WO 1995007345 A2 WO1995007345 A2 WO 1995007345A2 KR 9400117 W KR9400117 W KR 9400117W WO 9507345 A2 WO9507345 A2 WO 9507345A2
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- WO
- WIPO (PCT)
- Prior art keywords
- dna
- alleles
- sample
- allele
- standard
- Prior art date
Links
- 108700028369 Alleles Proteins 0.000 title claims abstract description 47
- 238000009396 hybridization Methods 0.000 title claims abstract description 16
- 108091081062 Repeated sequence (DNA) Proteins 0.000 claims abstract description 7
- 108020004414 DNA Proteins 0.000 abstract description 34
- 238000003752 polymerase chain reaction Methods 0.000 abstract description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 abstract description 6
- 238000001502 gel electrophoresis Methods 0.000 abstract description 5
- 108090001008 Avidin Proteins 0.000 abstract description 4
- 108090000790 Enzymes Proteins 0.000 abstract description 4
- 102000004190 Enzymes Human genes 0.000 abstract description 4
- 239000002244 precipitate Substances 0.000 abstract description 4
- 229960002685 biotin Drugs 0.000 abstract description 3
- 235000020958 biotin Nutrition 0.000 abstract description 3
- 239000011616 biotin Substances 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 3
- 238000002965 ELISA Methods 0.000 abstract description 2
- 230000003321 amplification Effects 0.000 abstract description 2
- 230000029087 digestion Effects 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 239000007787 solid Substances 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 abstract description 2
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 238000004513 sizing Methods 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 208000005652 acute fatty liver of pregnancy Diseases 0.000 description 3
- 238000007894 restriction fragment length polymorphism technique Methods 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 108091092878 Microsatellite Proteins 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000003793 prenatal diagnosis Methods 0.000 description 2
- 238000005204 segregation Methods 0.000 description 2
- 108010008286 DNA nucleotidylexotransferase Proteins 0.000 description 1
- 102100033215 DNA nucleotidylexotransferase Human genes 0.000 description 1
- AHCYMLUZIRLXAA-SHYZEUOFSA-N Deoxyuridine 5'-triphosphate Chemical compound O1[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C=C1 AHCYMLUZIRLXAA-SHYZEUOFSA-N 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
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- 238000003745 diagnosis Methods 0.000 description 1
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- 238000012252 genetic analysis Methods 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
- C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6844—Nucleic acid amplification reactions
- C12Q1/6858—Allele-specific amplification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
Definitions
- Human DNA contains hypervariable sites caused by the varying number of repeated sequences (Nakamura et al., 1987; Weber and May, 1987). Each variety is an allele which can be recognized by different sizes of fragments. A few such loci used together can distinguish any two indivisuals who are not twins by generating an indivisual- specific allele combinations (Gill et al., 1985; Wong et al., 1987). The DNA profile obtained from such allele combinations revolutionized the art of human identification in forensic medicine (Kirby, 1990). The variable sequences are also useful in tagging a disease gene. The target gene, or more precisely a disease-causing allele, could be followed indirectly by the allele of the nearby hypervariable site (Antonarakis, 1989).
- RFLP restriction fragment length polymorphism
- AFLP or AMP-FLP amplified fragment length polymorphism
- HLA Human leucocyte antigen
- an allele of a tandemly repeated sequence such as NNTRs (variable number of tandem repeats) or STRs (short tandem repeats) do not hybridize to other alleles with different number of repeats under appropriate conditions.
- the major obligatory condition is that the alleles in hybridization must be flanked with unique sequences as in PCR ( Figure 1).
- the allele-specific hybridization could be easily detected by standard ELISA technology (For general immunological as well as molecular biological techniques, consult Ansubel et al., 1989). It will obviate the gel electrophoresis step, which is tedius and labor-intensive, in the traditional allele- identification of such hypervariable loci.
- the new method will greatly speed up the overall procedure and save efforts. Unlike in HLA, the number of applicable sites are numberous and most of the alleles can be discriminated.
- a set of standard DNA representing major alleles is to be prepared.
- the standard DNA is tagged at the 3 '-end, for example, with biotin-dUTP (black knob) using the terminal deoxynucleotidyl transferase.
- the sample DNA is amplified by PCR in the presence of any modified nucleotide, for example, digoxygenin-conjugated dUTP (circle), which provides the anchor for the enzyme as described below. For simplicity, only one strand is depicted. In the diagram, two hypothetical alleles, 1 and 9, are mixed with the standard allele 1.
- the DNA is then applied to a microtiter plate coated with avidin (large oval). Only allele 1 of the sample hybridizes to the standard allele 1 and the allele 9 DNA is washed away in the next stage. Therefore, although all standard DNA will be immobilized on the microtiter plate, only standard allele 1 and 9 can retain digoxygenin-labeled sample DNA.
- the anti-digoxygenin-antibody-conjugated horseradish peroxidase (Anti-Dig HRP) is added and attached to the sample allele. Unbound enzymes are washed away and the production of colored precipitate by the enzyme mark the location of the bound sample DNA, which is in turn the identity of the sample allele. In Figure 3, the color developed in the slots of allele 1 and 9 out of 12 hypothetical standard alleles suggesting that the imaginary sample had two alleles, 1 and 9.
- Figure 1 A diagram depicting allele-segregation on an agarose gel.
- lane 3 the two alleles, of lane 1 and lane 2, are mixed, denatured and renatured. It shows that the two alleles of a tandemly repeated sequence segregate during the hybridization.
- Figure 2 Procedure of the hybridization and subsequent detection on a solid support.
- the standard DNA is tagged with biotin (black knob) and the sample DNA is labeled with digoxygenin (circle).
- the standard and sample DNA is mixed, denatured, renatured and then applied to a avidin (large oval)-coated microtiter plate.
- the standard DNA and its hybridized sample DNA are immobilized to the well due to the biotin- avidin interaction.
- the horseradish peroxidase (gray square) anchored on the sample DNA via conjugated anti-digoxygenin antibody catalyzes the conversion of colorless substrate to colored precipitate.
- Figure 3 Allele-identification by hybridization to a set of standard DNA. On a hypothetical 12-allele set of a hypervariable locus, allele 1 and 9 of a sample are detected by the developed color precipitate.
- kits consisting of the standard DNA representing major alleles of the locus is prepared.
- the standard DNA is conjugated with biotin as described above. They are provided within a series of tubes representing the alleles.
- the kit may include all the necessary components for PCR like primers and reaction buffers as well as those for the hybridization and color development for optimal detection.
- kits can be made for all known DNA polymorphic sites due to tandem repeats. A few kits in combination will provide an efficient diagnostic tool for human identification in forensic and paternity test. The tracing of alleles for pre-natal diagnosis or carrier detection by the gel electrophoresis can be subsitituted with kits for the corresponding loci for better efficiency. Even new genes responsible for a disease can be pursued and mapped with a series of kits representing polymorphic sites nearby the disease gene.
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Analytical Chemistry (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
La région hypervariable de l'ADN humain, produite par l'ADN répété en tandem, peut être utilisée dans des tests d'identité en médecine légale et dans la génétique humaine. On a identifié les allèles de cet ADN en effectuant le classement en fonction de la taille par électrophorèse sur gel, soit après une digestion par une enzyme de restriction, soit après l'amplification par PCR. On a développé un procédé alternatif simple et fidèle permettant d'identifier les allèles d'ADN répété en tandem, basé sur l'hybridation spécifique des allèles et la technologie ELISA. Une partie aliquote d'un échantillon d'ADN amplifié par PCR et marqué par digoxygénine est mélangée à un ensemble d'ADN étalon marqué par biotine, après quoi le mélange est dénaturé et renaturé. Seuls, les ADN double-brin, composés d'un brin provenant de l'échantillon et d'un autre brin provenant de l'étalon, peuvent être immobilisés sur le support solide recouvert d'avidine et peuvent être fixés par l'enzyme conjuguée à l'anticorps et produisant un précipité visible. Les allèles présents dans l'échantillon sont déterminés en fonction de la position de développement de la couleur.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019930016881A KR970007025B1 (ko) | 1993-08-28 | 1993-08-28 | 잡종화에 의한 대립연쇄반복 dna의 동정방법 |
| KR1993-16881 | 1993-08-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1995007345A2 true WO1995007345A2 (fr) | 1995-03-16 |
| WO1995007345A3 WO1995007345A3 (fr) | 1995-04-06 |
Family
ID=19362175
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR1994/000117 WO1995007345A2 (fr) | 1993-08-28 | 1994-08-29 | Identification d'alleles de sequences repetees en tandem par hybridation |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR970007025B1 (fr) |
| WO (1) | WO1995007345A2 (fr) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997020070A1 (fr) * | 1995-11-29 | 1997-06-05 | The Anthony Nolan Bone Marrow Trust | Procedes pour separer et/ou identifier des molecules d'adn |
-
1993
- 1993-08-28 KR KR1019930016881A patent/KR970007025B1/ko not_active Expired - Fee Related
-
1994
- 1994-08-29 WO PCT/KR1994/000117 patent/WO1995007345A2/fr active Application Filing
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL ABSTRACTS, Vol. 118, No. 7, issued 1993, 15 February (Columbus, Ohio, USA), P.E. WARBURTON et al., "PCR Amplification of Tandemly Repeated DNA: Analysis of Intra- and Interchromosomal Sequence Variation and Homologous Unequal Crossing-over in Human alpha Satellite DNA", page 182, Abstract No. 53228s; & NUCLEIC ACIDS RESEARCH, 1992, 20(22), 6033-42. * |
| CHEMICAL ABSTRACTS, Vol. 120, No. 9, issued 1994, 28 February (Columbus, Ohio, USA), C.C. LIN et al., "Isolation and Identification of a Novel Tandemly Repeated DNA Sequence in the Centromeric Region of Human Chromosome 8", page 337, Abstract No. 97927q; & CHROMOSOMA, 1993, 102(5), 333-9. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997020070A1 (fr) * | 1995-11-29 | 1997-06-05 | The Anthony Nolan Bone Marrow Trust | Procedes pour separer et/ou identifier des molecules d'adn |
| US6994958B2 (en) | 1995-11-29 | 2006-02-07 | Anthony Nolan Bone Marrow Trust | Methods for separating and/or identifying DNA molecules |
Also Published As
| Publication number | Publication date |
|---|---|
| KR970007025B1 (ko) | 1997-05-02 |
| KR950005987A (ko) | 1995-03-20 |
| WO1995007345A3 (fr) | 1995-04-06 |
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