CN117402945A - Method for rapidly screening specific SNP probes based on quantum dot platform - Google Patents
Method for rapidly screening specific SNP probes based on quantum dot platform Download PDFInfo
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- 239000002096 quantum dot Substances 0.000 title claims abstract description 32
- 238000012216 screening Methods 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000009396 hybridization Methods 0.000 claims abstract description 35
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/588—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with semiconductor nanocrystal label, e.g. quantum dots
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Abstract
The invention provides a method for rapidly screening specific SNP probes based on a quantum dot platform, which comprises the steps of firstly designing and synthesizing two forward NH2 modified probes (wild type and mutant type) and two reverse biotin modified oligonucleotides (wild type and mutant type), then hybridizing the two probes with the oligonucleotides of the wild type and the mutant type respectively based on a quantum dot nucleic acid detection method, determining the specificity of the probes, and rapidly screening to obtain the specific SNP probes. The method has simple design, changes the conventional synthesis of long double-stranded DNA as a positive control into the short single-stranded oligonucleotide only containing SNP loci as the positive control, and reduces the synthesis period and the synthesis cost; meanwhile, the steps of PCR amplification, denaturation before nucleic acid hybridization and the like are omitted, so that the screening efficiency of SNP hybridization probes is greatly improved.
Description
Technical Field
The invention belongs to the field of molecular biology, and particularly relates to a method for rapidly screening specific SNP probes based on a quantum dot platform.
Background
A common method for screening SNP probes is to synthesize wild type and mutant type templates, amplify the templates by adopting an upstream primer F and a biotin modified downstream primer R, and then hybridize the single-stranded PCR product with biotin with the SNP probes, thereby achieving the purpose of screening specific probes. The disadvantage of this design is that it takes a lot of time and effort to synthesize long double-stranded DNA each time, perform PCR amplification, and perform denaturation detection of the PCR product.
Disclosure of Invention
Aiming at the problems in the background technology, the invention provides a method for rapidly screening specific SNP probes based on a quantum dot platform.
The invention adopts the following technical scheme:
a method for rapidly screening specific SNP probes based on quantum dot platform, firstly, designing and synthesizing two forward NH2 modified probes (wild type and mutant type) and two reverse biotin modified oligonucleotides (wild type and mutant type), wherein the two probes are hybridized with the wild type and mutant type oligonucleotides respectively; and then determining the specificity of the probe based on a quantum dot nucleic acid detection method, and screening to obtain the specific SNP probe. The method omits the steps of PCR amplification, denaturation before nucleic acid hybridization and the like, and can greatly improve the screening efficiency of SNP hybridization probes.
Quantum dot nucleic acid detection principle: the detection membrane strip is made of nylon membrane, and a certain concentration of NH2 modified capture probe is arranged on the activated nylon membrane. The nucleic acid amplification product with biotin label is hybridized with the probe on the detection membrane strip, then the biotin and the quantum dot coupled with streptavidin are combined, the detection membrane strip is observed by a fluorescence detection instrument to have no light signal at each site to judge whether the probe is hybridized with the nucleic acid product, and thus whether the sample contains relevant target nucleic acid is determined.
The beneficial effects of the invention are as follows:
the method has simple design, changes the conventional synthesis of long double-stranded DNA as a positive control into the short single-stranded oligonucleotide only containing SNP loci as the positive control, and reduces the synthesis period and the synthesis cost; meanwhile, the steps of PCR amplification, denaturation before nucleic acid hybridization and the like are omitted, so that the screening efficiency of SNP hybridization probes is greatly improved.
Drawings
FIG. 1 is a schematic diagram of a rapid screening principle of a specific SNP probe based on a quantum dot platform;
FIG. 2 is a schematic representation of hybridization of a probe to an oligonucleotide based on a quantum dot nucleic acid detection method;
FIG. 3 shows the results of quantum dot hybridization and the results of one-generation sequencing of wild-type and mutant SNP probes at the c.677C > T site of the MTHFR gene;
FIG. 4 shows the results of quantum dot hybridization and the sequencing of wild-type and mutant SNP probes at the c.1298A > C site of the MTHFR gene;
FIG. 5 shows the results of quantum dot hybridization and the results of first-generation sequencing of wild-type and mutant SNP probes at the c.66A > G site of the MTRR gene.
Detailed Description
Example 1
c.677C > T of 1MTHFR gene
Based on c.677C > T of MTHFR gene, one pair of reverse biotin-modified oligonucleotides (wild type and mutant) and two pairs of hybridization probes (wild type and mutant) were designed, respectively.
2 Quantum dot nucleic acid detection flow
2.1A detection membrane strip containing 677C1/677T1,677C2/677T2 probe was prepared in advance.
2.2 adding the oligonucleotides and the detection membrane strips into the hybridization solution respectively for hybridization (as shown in FIG. 1), wherein the hybridization time is 1h.
2.3 after hybridization, the detection membrane strip was transferred to a wash solution for washing for 0.5h.
2.4 after washing, the washing liquid is removed, and then added into an incubation liquid containing quantum dots, and incubated for 0.5h at room temperature.
2.5 after the incubation, the incubation liquid is removed, and a certain amount of washing liquid is added for washing, wherein the washing time is 0.5h.
2.6 after washing, the detection membrane strip is placed in a fluorescence instrument for fluorescence detection (see FIG. 2).
As a result of 3-quantum dot nucleic acid detection, 677T1 and 677C2 were selected as hybridization probes.
| Sample of | 677Cs | 677Ts |
| 677C1 | Positive and negative | Positive and negative |
| 677T1 | Negative of | Positive and negative |
| 677C2 | Positive and negative | Negative of |
| 677T2 | Positive and negative | Positive and negative |
4 comparison of conventional Quantum dot hybridization and sequencing results
4.1 sample sources: 5 cases of human throat swabs, labeled A, B, C, D, E, were collected, and genomic DNA was extracted using a magnetic bead extraction kit and quantified to 20 ng/. Mu.L.
4.2A first generation sequencing and 677T1/677C2 hybridization confirmation were performed simultaneously after amplification using the primer at position 677.
4.3 comparison of the two methods shows that the result of conventional quantum dot hybridization of the screened specific probe is consistent with the result of first-generation sequencing (as shown in FIG. 3).
Example 2
1MTHFR gene c.1298A > C
According to the MTHFR gene c.1298A > C, one pair of oligonucleotides (wild type and mutant) modified by reverse biotin and two pairs of hybridization probes (wild type and mutant) were designed respectively.
2 Quantum dot nucleic acid detection flow
2.1A detection membrane strip containing 298A1/1298C1,1298A2/1298C2 probes was prepared.
2.2 adding the oligonucleotides and the detection membrane strips into the hybridization solution respectively for hybridization, wherein the hybridization time is 1h.
2.3 after hybridization, the detection membrane strip was transferred to a wash solution for washing for 0.5h.
2.4 after washing, the washing liquid is removed, and then added into an incubation liquid containing quantum dots, and incubated for 0.5h at room temperature.
2.5 after the incubation, the incubation liquid is removed, and a certain amount of washing liquid is added for washing, wherein the washing time is 0.5h.
2.6 after the washing is finished, the detection membrane strip is placed in a fluorescent instrument for fluorescence detection.
3 quantum dot nucleic acid detection results: 1298A1 and 1298C2 were selected as hybridization probes
| Sample of | 1298As | 1298Cs |
| 1298A1 | Positive and negative | Negative of |
| 1298C1 | Positive and negative | Positive and negative |
| 1298A2 | Positive and negative | Positive and negative |
| 1298C2 | Negative of | Positive and negative |
4 comparison of conventional Quantum dot hybridization and sequencing results
4.1 sample sources: 5 cases of human throat swabs, labeled A, B, C, D, E, are collected, and the genome DNA is extracted by using a magnetic bead extraction kit and quantified to 20 ng/. Mu.L for later use.
4.2A primer of 1298 locus is used for amplification, and then one-generation sequencing and 1298A1/1298C2 hybridization confirmation result are carried out simultaneously.
4.3 comparison of the two methods shows that the result of conventional quantum dot hybridization of the screened specific probe is consistent with the result of first-generation sequencing (as shown in FIG. 4).
Example 3
1MTRR Gene c.66A > G
According to MTRR gene c.66A > G, one pair of oligonucleotides (wild type and mutant) modified by reverse biotin and two pairs of hybridization probes (wild type and mutant) were designed respectively.
2 Quantum dot nucleic acid detection flow
2.1 preparation of detection membrane strips containing 66A1/66G1,66A2/66G2 probes.
2.2 adding the oligonucleotides and the detection membrane strips into the hybridization solution respectively for hybridization, wherein the hybridization time is 1h.
2.3 after hybridization, the detection membrane strip was transferred to a wash solution for washing for 0.5h.
2.4 after washing, the washing liquid is removed, and then added into an incubation liquid containing quantum dots, and incubated for 0.5h at room temperature.
2.5 after the incubation, the incubation liquid is removed, and a certain amount of washing liquid is added for washing, wherein the washing time is 0.5h.
2.6 after the washing is finished, the detection membrane strip is placed in a fluorescent instrument for fluorescence detection.
3 quantum dot nucleic acid detection results: 66A1 and 66G1 were selected as hybridization probes
4 comparison of conventional Quantum dot hybridization and sequencing results
4.1 sample sources: 5 cases of human throat swabs, labeled A, B, C, D, E, are collected, and the genome DNA is extracted by using a magnetic bead extraction kit and quantified to 20 ng/. Mu.L for later use.
4.2 one generation of sequencing and 66A1/66G1 hybridization validation results were performed simultaneously after amplification with 66F and b66R primers.
4.3 comparison of the two methods shows that the result of conventional quantum dot hybridization of the screened specific probe is consistent with the result of first-generation sequencing (as shown in FIG. 5).
The three sites prove that the method can eliminate the steps of complicated PCR amplification, PCR product denaturation and the like, rapidly performs SNP-specific probe screening, and the detection sample result is completely consistent with the result of gold standard first-generation sequencing.
Claims (5)
1. The method for rapidly screening the specific SNP probe based on the quantum dot platform is characterized by comprising the following steps:
firstly, designing and synthesizing two forward NH2 modified probes and two reverse biotin modified oligonucleotides; wherein the two forward probes comprise wild-type and mutant probes and the two reverse biotin-modified oligonucleotides comprise wild-type and mutant oligonucleotides;
and then, carrying out molecular hybridization on the wild type and mutant type probes and the wild type and mutant type oligonucleotides, and determining the specificity of the probes based on a quantum dot nucleic acid detection method to finish the screening of SNP probes.
2. A specific SNP probe, wherein the specific SNP probe is obtained by screening by the method according to claim 1.
3. The specific SNP probe according to claim 2, wherein when used for detecting c.677c > T site of MTHFR gene, the specific SNP probe is specifically: the sequence of the wild-type probe was TTTTTTTTTTCTGCGGGAGTCGATTTCATCATC and the sequence of the mutant probe was TTTTTTTTTTTCTGCGGGAGCCGATTTCATC.
4. The specific SNP probe according to claim 2, wherein when used for detecting MTHFR gene c.1298a > C site, the specific SNP probe is specifically: the sequence of the wild-type probe was TTTTTTTTTTAGTGAAGaAAGTGTC and the sequence of the mutant probe was TTTTTTTTTTACCAGTGAAGcAAGTGTCTTT.
5. The specific SNP probe according to claim 2, wherein when used for detecting MTRR gene c.66a > G site, the specific SNP probe is specifically: the sequence of the wild-type probe was TTTTTTTTTTGAAGAAATaTGTGAGCAAG and the sequence of the mutant probe was TTTTTTTTTTGAAGAAATgTGTGAGCAAG.
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