CN1341749A - Nucleic acid target molecule fragment selection and amplification method - Google Patents
Nucleic acid target molecule fragment selection and amplification method Download PDFInfo
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- CN1341749A CN1341749A CN 01127536 CN01127536A CN1341749A CN 1341749 A CN1341749 A CN 1341749A CN 01127536 CN01127536 CN 01127536 CN 01127536 A CN01127536 A CN 01127536A CN 1341749 A CN1341749 A CN 1341749A
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- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
The present invention relates to a method for selecting and amplifying nucleic acid target molecule fragment, and is characterized by that in the described non-speific primer the nucleotidoid is contained, the specific primer possesses exogeneous series, and the target molecule fragment can be amplfiied by means of reaction of the described exogenous sequence or exogeneous sequence obtained by repairing and modifying non-specific primer sequence. Said invention possesses the following advantages: it can select and modify lots of target molecules simultaneously, then uses small amount of primers to implement amplification of large amount of target molecule fragments, and can simplify detection process of molecules.
Description
The present invention relates to the method that a kind of nucleic acid target molecule fragment is selected and increased.
Nucleic acid comprises Yeast Nucleic Acid (RNA) and thymus nucleic acid (DNA).The fundamental unit of nucleic acid is the Nucleotide that contains base.Base in the dna molecular has four kinds, represents with English alphabet A.C.G.T respectively, and U replaces T in RNA, and all the other still are A.C.G.Base A and T or U pairing (complementation) in nucleic acid, G and C pairing.The base derivative also has the characteristic identical or close with above-mentioned base.For example base I (Inosine) is present in the organism, the base I in the nucleic acid molecule chain can with multiple base pairing.The normal base A.C.G.T (U) in DNA and RNA, the unusual base of base I also can find or synthetic by chemical process at nature, as other derivative of the base and the normal base of biotin labeled base and fluorescent substance mark.At nature or can produce the class Nucleotide of lixiviating base with chemical process.Another integral part of Nucleotide is a ribose, the structure of ribose can change with chemical process and produce bi-deoxyribose nucleic acid (ddNTP), dicyclic ring ribosomal ribonucleic acid (LNA) etc., general nucleic acid connects monomer whose by phosphodiester bond, when phosphodiester bond is replaced by peptide bond, its formed nucleic acid is called peptide chain nucleic acid (PNA), when the Sauerstoffatom of phosphate group is replaced by sulphur atom in addition, formed DNA is called sulfo-thymus nucleic acid (S-DNA), can produce multiple nucleotide derivative by above structure, or claiming class Nucleotide, Nucleotide can change the physics of nucleic acid chains, chemistry and biochemical characteristic.When two nucleic acid molecule chains had the arrangement of successive complementary base, under suitable condition, their can form stable duplex molecule by a plurality of base pairings, and this process is molecular hybridization.Under high temperature or low salinity or high and extremely low potential of hydrogen condition, double-strandednucleic acid also can split into single-stranded structure, and this process is sex change.When a known single stranded nucleic acid molecule is a molecular probe when making nucleic acid molecular hybridization in the biological sample becomes duplex molecule, this biological sample of deducibility has and known molecular complementary nucleotide sequence mutually.When a long molecular chain formed hybrid molecule with a short molecular chain, archaeal dna polymerase can be a primer with short molecular chain,, copied and template complementary molecular chain mutually as template with the molecular chain of length.The complementary template that can become the template reparation of containing base analog the template of class Nucleotide or remove class Nucleotide with primer hybridization and known biochemical reaction.In biochemical reaction, used primer can be to treat the analysis of nucleic acids sequence to have narrow spectrum complementary relationship, thereby nucleic acid sequence fragments to be analyzed is called target molecule fragment, to its primer that single-minded complementary relationship is arranged the specificity primer, as primer the sequence beyond the target molecule is also had complementarity, then this primer is non-characteristic (non-specificity) primer.When the genome of a primer and the biological object studied did not have complementary relationship, then this group sequence was called exogenous array.When nucleic acid is comprised that DNA and RNA carry out Molecular Detection, need the target molecule in the nucleic acid samples is selectively increased (copying a plurality of same a part).Target molecule is the nucleic acid fragment that must detect, the hereditary feature of organism under its constitutional features can be represented.Target molecule can be DNA, RNA or at the external cDNA that is become by the RNA reverse transcription.To the nucleic acid molecule general polymerase chain reaction (PCR) that adopts that increases, a dna molecular can be increased into same a part of enormous amount with PCR.RNA is after reverse transcription becomes cDNA, and also available PCR increases.When carrying out PCR, need there be two to the narrow spectrum primer of target molecule tool (primer to).The effect of primer is and target molecule hybridization, and is starting point with its 3 ' end, duplicates target molecule, and this process just can realize the amplification of target molecule repeatedly.The method of another kind of molecular cloning is that double-stranded dna molecular is connected with promotor, with ribonucleic acid polymerase DNA is transcribed into the RNA of strand then.Can become a large amount of RNA to DNA cloning with the method for transcribing, can carry out intramolecular labelling to RNA simultaneously, but the amplification ability of dubbing method be generally about hundreds of times.The dna molecular that extracts from organism is generally double-stranded macromolecular structure, is made up of thousands of above base units.With physical method such as ultrasonic wave or biochemical method such as restriction enzyme, deoxyribonuclease, can make dna degradation is short and small molecule fragment, and this is converted into a plurality of micromolecular processes fragmentation by macromole.Ligase enzyme can link together a plurality of dna fragmentations and reach terminal purpose of extending under suitable condition, the dna molecular fragment also makes 3 ' terminal the extension under the effect of transferring enzyme endways, archaeal dna polymerase also can utilize the DNA chain as template another molecular chain to be carried out 3 ' terminal the extension, the DNA excision enzyme can be removed part dna molecular sequence in addition, and therefore end modified Bottoming and the end of comprising extends.Several different methods can be used for the target molecule fragment that is amplified is tested, and comprises the length of measuring molecular chain, the plasticity-of the quality of molecule and the stability of molecular hybridization and molecule, and molecule is to susceptibility of enzyme etc.Molecular modification also comprises end modified and intramolecularly is modified, and the result of modification changes molecular weight, change optics, chemistry and biochemical reaction characteristic.Inspection technology commonly used comprises molecule electrophoresis, mass spectroscopy and gene chip hybridization, and gene chip is a kind of device that is equipped with a large amount of nucleic acid molecular probes in the plane.Know that now causing a kind of gene polymorphic site of inherited disease to change can be more than one, in the time of detecting one or more inherited diseases, the target molecule kind number of required amplification can reach hundreds of more than.Described gene locus is meant base position specific in the nucleic acid construct, and the base substitution of base position claims nucleotide polymorphisms.With molecular hybridization and polymeric enzyme reaction target molecule being carried out single-basic extension (SBE) also is a kind of common method of measuring polymorphic nucleic acid.Gene is the division of nucleic acid function or has certain functional nucleic acid fragment, has the certain structure feature.As with conventional PCR method, need synthetic a large amount of primer when carrying out Molecular Detection, and respectively target molecule is screened and increase with a large amount of reactions.With molecular hybridization and polymeric enzyme reaction target molecule being carried out single-basic extension (SBE) also is a kind of common method of measuring polymorphic nucleic acid.Needed human and material resources and expense are all very big.As a plurality of combination of primers in a PCR, the interaction between these primers can produce by product, thereby influences the amplification of target molecule.
The purpose of this invention is to provide and a kind of a plurality of different nucleic acid target molecules are optionally modified, the method that is increased then, it can overcome the above-mentioned deficiency of prior art.
The method that a kind of nucleic acid target molecule fragment is selected and increased, comprise with non-specificity primer and specificity primer the target molecule fragment sequence in the sample nucleic acid is duplicated, then the product that is replicated is increased, it is characterized in that containing class Nucleotide in the described non-specificity primer, the specificity primer has external source series, and target molecule fragment increases by described exogenous array or through the exogenous array reaction of repairing or modifying non-specificity primer sequence gained.
Advantage of the present invention is simultaneously a large amount of target molecules to be selected and to modify, increase with the target molecule fragment of a small amount of several universal primers then to a large amount of kinds, can simplify the Molecular Detection process, save human and material resources, reduce the cost that utilizes nucleic acid to detect.After with present method target molecule fragment being increased, the constitutional features of target molecule can be by hybridization, sequencing, single-basic extension, molecular mass, molecular length size, the quantity of electric charge and molecular weight ratio etc. are measured, and are specially adapted to the specimen preparation in the biochip use.What of the genotype of animal, plant, microorganism and virus or its nucleic acid amount are present method can be used for measuring.Utilize present method can make the test kit of commercial value or be engaged in the molecular diagnosis service.
Below by embodiment the present invention is described.
500 relevant with inherited disease in one patient dna sample gene polymorphic points are selected and increased.Before the amplification DNA is purified, 500 DNA sample hybridization to narrow spectrum primer of target molecule fragment (polymorphic bands) tool and purification, and copy corresponding target molecule fragment selectively, 5 ' terminal portions of 500 used special-primers is the exogenous array of 20 bases, exogenous array in this reaction can be one or more, carries out replication reaction under archaeal dna polymerase and required Nucleotide and other reactant.Remove single-chain nucleic acid then, after this, add non-specificity primer, non-specificity primer is 15 base structures, and its preceding 10 bases (3 ' end) are synthetic structure at random, and its 11st base position is derive base or class Nucleotide, the the 12nd to 15 base (5 ' end) is a known array, this non-specificity primer is many combination of primers, and under polysaccharase and required condition, non-specificity primer duplicates and forms new duplex structure with selecteed target molecule.Under the effect of the 5 prime excision enzyme activity of polysaccharase, with the corresponding molecular end of non-single-minded primer be single-stranded structure.Behind the new duplex structure that forms of purifying, the sequence of external source and terminal single-stranded structure hybridization and coupled.The result of this molecule reparation and modification is that the two ends of target molecule all have exogenous array, uses at last with the corresponding primer of exogenous array the target molecule fragment sequence is increased.Target molecule to amplification carries out fluorescent mark, and uses the gene chip hybridization analysis, judges this patient's hereditary property at last according to the result.
The used amplification of present method comprises the combination of polymerase chain reaction, responsive transcription and reverse transcription reaction or these reactions.
Modification that present method is used or reparation reaction are the combination of ligase enzyme coupling reaction, terminal enzyme (DNA) reaction, excision enzyme reaction, polymeric enzyme reaction or these reactions.
The used target molecule analytical procedure of present method comprises the combination of single-basic extension method (SBE), method for gene chip, mass spectrometry method, electrophoresis method, fluorescent method or radiometric method and these methods.
Used contained derivatized nucleotide or the class Nucleotide of non-specificity primer of present method comprises peptide bond Nucleotide, thio nucleotides, the acid of lixiviating yl nucleosides, and the class Nucleotide that contains nature or non-natural kind base.
Can be made into test kit according to present method principle, test kit comprises the used primer of the primer, the pcr amplification that are used for that target molecule is selected and modify, required enzyme and buffer reagent.
It is fixed that present method can be used for the He Suan Monitoring of animal and plant and microorganism, comprises that Wu Zhong Monitoring is fixed, polymorphism mensurations, nucleic acid molecule quantitative measurement, hereditary feature mensuration.
Claims (3)
1, the method for a kind of nucleic acid target molecule fragment selection and amplification, comprise with non-specificity primer and specificity primer the target molecule fragment sequence in the sample nucleic acid is duplicated, then the product that is replicated is increased, it is characterized in that containing class Nucleotide in the described non-specificity primer, the specificity primer has external source series, and target molecule fragment increases by described exogenous array or through the exogenous array reaction of repairing and modifying non-specificity primer sequence gained.
2, the method for claim 1 is characterized in that described modification or repairs the combination of reaction for ligase enzyme coupling reaction, terminal enzyme (DNA) reaction, excision enzyme reaction, polymeric enzyme reaction or these reactions.
3, the method for claim 1 is characterized in that described amplification comprises the combination of polymerase chain reaction, responsive transcription and reverse transcription reaction or these reactions.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 01127536 CN1341749A (en) | 2001-10-04 | 2001-10-04 | Nucleic acid target molecule fragment selection and amplification method |
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| CN 01127536 CN1341749A (en) | 2001-10-04 | 2001-10-04 | Nucleic acid target molecule fragment selection and amplification method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100396775C (en) * | 2002-12-31 | 2008-06-25 | 徐定邦 | PCR method of universal primer and its reaction liquid and application in multiple PCR |
| CN111549110A (en) * | 2019-03-22 | 2020-08-18 | 健生生物技术有限公司 | Primer group, kit and detection method for detecting nonspecific amplification in qPCR (quantitative polymerase chain reaction) process |
-
2001
- 2001-10-04 CN CN 01127536 patent/CN1341749A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100396775C (en) * | 2002-12-31 | 2008-06-25 | 徐定邦 | PCR method of universal primer and its reaction liquid and application in multiple PCR |
| CN111549110A (en) * | 2019-03-22 | 2020-08-18 | 健生生物技术有限公司 | Primer group, kit and detection method for detecting nonspecific amplification in qPCR (quantitative polymerase chain reaction) process |
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