CN1313621C - Electronic gene chip detecting method - Google Patents
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- CN1313621C CN1313621C CNB011291044A CN01129104A CN1313621C CN 1313621 C CN1313621 C CN 1313621C CN B011291044 A CNB011291044 A CN B011291044A CN 01129104 A CN01129104 A CN 01129104A CN 1313621 C CN1313621 C CN 1313621C
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Abstract
The present invention relates to an electronic gene chip detecting method which is characterized in that a gene chip with an electrochemical active group and a sample DNA are hybridized; then, an electronic detector which replaces a fluorescent scanner is used for detecting the variation of electric signals before and after gene chip hybridization; whether a detected sample contains a DNA fragment with specificity to be detected is judged. In a hybridization process of the present invention, the sample DNA does not need to be processed by fluorescent, and can be directly denatured. A detection device is cheap. Thus, the electronic gene chip detecting method having the advantages of convenient operation, low cost and high detection sensitivity and reliability is provided for people, and can be popularized and applied in large scale.
Description
The invention belongs to DNA hybridization detection technique field, specifically is a kind of detection method of electronic gene chip.
In the prior art, gene chip conventional sense method-fluorescence scanning method need carry out pre-treatment with sample DNA, promptly sample is carried out fluorescent mark, making the said gene chip then is that fluorescently-labeled sample DNA is hybridized with having the fluorescent scanning signal, with the fluorescent scanning instrument fluorescent signal after hybridizing is detected then, judge whether contain dna fragmentation to be detected in the detected sample.
Yet, above-mentioned existing gene chip conventional sense method-fluorescence scanning method also only rests on laboratory stage owing to following reason makes it, be confined to scientific research field, also have sizable distance from formal input application: it is very high 1, to detect cost, generally has only big drug firm and the scientific research institutions that have sufficient funds just can bear.One commercial gene chip signal detection of cover and analytical system, comprise fluorescent scanning instrument, computer and software thereof etc., approximately be worth 200,000 dollars, such as U.S. Affymetrix the international market price of cover chip system (comprising 5 oligonucleotides and 1 cDNA chip) above 150,000 dollars.With regard to applied gene chip such as diagnosing chip, a very common transmissible disease detection chip single detection cost will be about 200 yuans.Because can cost be the matter of utmost importance that realize widespread use, institute is so that the difficulty of its popularization application is very big.2, existing detection method must be carried out complicated pretreatment to sample DNA, and mainly showing as needs sample is carried out fluorescent mark.For monochromatic fluorescent mark,, can not obtain good signal though preprocessing process is simple relatively; Though and four look fluorescent mark signals are better, the preprocessing process relative complex.This treating processes needs the professional can finish through special training.3, the said gene chip with have fluorescently-labeled sample DNA and hybridize resulting fluorescent signal and can only think a kind of qualitative or semiquantitative signal results, and can not directly carry out the exact figure fractional analysis.The further analysis that this large number of biological that on the one hand gene chip is obtained is learned data brings very big inconvenience, has also reduced the sensitivity and the reliability of signal detection simultaneously.
The present invention seeks in order to remedy the defective of prior art, for people provide a kind of easy to operate, cost is low, the sensitivity and the reliability height that detect, the detection method of the electronic gene chip of popularization application on a large scale.
The objective of the invention is to realize by following technical proposals.
The detection method of electronic gene chip of the present invention, be that the gene chip and the sample DNA that will have electrochemical active group hybridized, detect with of the variation of electronic detectors replacement fluorescent scanning instrument then, judge whether contain DNA fragment specific to be detected in the detected sample electrical signal before and after the gene chip hybridization.
In the such scheme, described crossover process is:
A. sample DNA does not need the fluorescence pre-treatment directly to carry out sex change: the sample water-bath is heated to boiling, keeps more than 1 minute; From boiling water, take out, put immediately to cooling extremely fully on ice.At this moment, sample DNA fully sex change be strand.
B. sample DNA hybridization: denatured DNA sample (liquid) is mixed with probe on the chip basic point, and 20 ℃-45 ℃ (with different dna probe sequence changes) are incubated 1-24 hour, hybridize.
C. the wash-out of chip: after hybridization is finished, with the hybridization solution that does not contain the DNA sample chip is carried out rinsing for several times, temperature is controlled at 20 ℃-55 ℃ (changing with different dna probe sequences), time remaining is more than half an hour, the sample DNA on flush away fails to hybridize and the non-specific adsorption of probe.
In the such scheme, better be the dna probe that has following structure on the gene chip of described electrochemical active group:
5′-NH
2-(CH
2)
n-
********+++++++++++++++++
********-(CH
2)n-SH-
Wherein,
* * * * * * *Be depicted as two sections can complementary pairing the dna sequence dna of (A and T pairing, G and C match); ++ ++ ++ ++ ++ ++ ++ +++be depicted as DNA fragment specific to be detected in the crossover process (10-30 base); Methyl (the CH at described two ends
2) quantity n is 0～10.
In the such scheme, described electrochemical active group can be a kind of group that can produce electrochemical signals of arbitrary structures.
In the such scheme, described electrochemical active group can be carboxyl ferrocene or other methyl violet carboxy derivatives class electrochemical active group.
In the such scheme, described electronic detectors can be electrochemical workstation or other electron detection device.Detect with of the variation of sensitive alternating voltammetry, thereby judge whether contain DNA fragment specific to be detected in the detected sample electrical signal before and after the hybridization.
Under the normal circumstances, there is electrical signal on the basic point before the hybridization.If contain probe sequence (DNA fragment specific to be detected) in the test sample, then the electrical signal on the basic point of hybridization back disappears; Otherwise then electrical signal still exists.
Visible Fig. 2 of characterization processes flow process of electronic gene chip of the present invention.
The principle of technical solution of the present invention is: before hybridization, because one section paired dna sequence dna is fully contained at the dna probe two ends, under free state, can form footpath ring structure (stemloop).At this moment, 5 ' end of probe is close with 3 ' end, and 3 ' terminal entrained electrochemical active group can produce the electrical signal of an energy with the electrochemical workstation detection near the Au surface time.After hybridization is finished, owing to be positioned at the DNA fragment specific and the sample in probe stage casing the DNA complementary pairing having taken place, formed normal dna double spirane structure, thereby has destroyed the footpath ring structure.At this moment, 5 ' end of probe is no longer close with 3 ' end, has caused the forfeiture of original electrochemical signals.Utilize this principle, can detect DNA and whether finish the hybridization pairing, also promptly can detect the hybridization signal of DNA on designed gene chip.For further understanding above-mentioned principle, can be referring to accompanying drawing 1.
The detection method of electronic gene chip of the present invention can be carried out detection by quantitative to the variation that electrical signal in the DNA crossover process produces.This technology is applied to sophisticated microelectronics on the gene chip, maintains the leading position in the whole world at present.
This technology uses electronic detectors to detect the signal of gene chip, the mature technology and the achievement of microelectronics industry have directly been used, compare with existing gene chip, the art of this patent has the following advantages: 1, the test set cost reduces significantly, electronic detectors such as electrochemical workstation as signal detection, the fluorescent scanning instrument that its cost is used well below existing technology, thus help realizing popular, enter wide application field; 2, in the above-mentioned crossover process of the present invention to sample to be detected without any need for mark, having saved complicated fluorescent mark preprocessing process only need be through simple training with, preprocessing process of the present invention, anyone can both finish.3, the electric scanning signal that obtains of method of the present invention is a kind of quantitative signal results, can carry out the exact figure fractional analysis.This further analysis that makes the large number of biological that gene chip is obtained learn data becomes possibility, has also improved the sensitivity and the reliability of signal detection simultaneously greatly.Table 1 is the contrast situation of the present invention and existing detection method.
The contrast situation of table 1 and existing detection method
| Existing detection method | Detection method of the present invention | |
| Sample pretreatment | Extract DNA, and carry out fluorescent mark | Extract DNA |
| Crossover process | Conventional solid-liquid crossover process | Conventional solid-liquid crossover process |
| Detection signal | Fluorescent signal | Digital signal |
| Test set | The confocal fluorescent flying-spot microscope | Electrochemical workstation or other electrical signal detection equipment |
Accompanying drawing 1 is a technical schematic diagram.
Among the figure: 1, loop-stem structure; 2, Au surface; 3, produce electrical signal; 4, electrical signal disappears; 5, with foreign DNA hybridization pairing.Be embodiments of the invention below, the present invention is not limited only to described embodiment.
Embodiment one
At first, with the dna probe structure be 5 '-NH
2-(CH
2)
3-GCG AG-
-CT CGC-(CH
2)
6-SH-3 ', charged chemical group be the carboxyl ferrocene electrical signal detection gene chip (wherein
Being the specific DNA sequences of selecting for use in this experiment, is a section on the pUC18 carrier, and correspondingly, the DNA that is used to hybridize selects the pUC18 carrier for use) take out, measure the electrical signal of basic point with electrochemical workstation, for 9uA (to Ag/AgCl, 200mv).Hybridization in order to this routine following sample DNA is required.The gene chip preparation method of described electrical signal detection can be referring to other patent.
The crossover process of the sample DNA that this is routine is:
A. the sex change of sample DNA: extract pUC18 plasmid DNA (10uL, about 1ug), boiling water bath 5 minutes places rapidly on ice, makes the DNA sex change, and at this moment, sample DNA sex change fully is a strand.
B. sample DNA hybridization: the probe on the gene chip basic point of denatured DNA sample (liquid) and above-mentioned institute power backup signal detection is mixed, the pUC18 plasmid point that is about to sex change is on basic point, 20 ℃-45 ℃ (changing with different dna probe sequences) are incubated 1-24 hour, hybridize, this example is 37 ℃ of insulations 2 hours.
C. the wash-out of chip: chip is carried out rinsing for several times with the hybridization solution that does not contain the DNA sample, temperature is controlled at 20 ℃-55 ℃ (changing with different dna probe sequences), time remaining is more than half an hour, the sample DNA on flush away fails to hybridize and the non-specific adsorption of probe.After the hybridization of this example is finished, clean chip, and chip is placed 45 ℃ distilled water rinsing several, about 30 minutes with distilled water.
Take out chip, measure the electrical signal of basic point once more with electrochemical workstation, be 2uA (to Ag/AgCl, 200mv, this signal detect background signal).Because the destruction of loop-stem structure, the electrical signal group is away from the Au surface on the proof chip, and caused the disappearance of electrochemical signals.Contain and dna probe sequence paired dna sequence dna in the proof sample, promptly contain the pUC18 plasmid.
Embodiment two
This example is bought or the synthetic dna probe that contains following structure, charged chemical group be the gene chip of the electrical signal detection of carboxyl ferrocene:
5 '-NH
2-(CH
2)
3-ATGCGT-
-ACGCAT-(CH
2)
6-SH-3 '
Be the specific DNA sequences of selecting for use in this experiment, identical with embodiment one, be a section on the pUC18 carrier, correspondingly, the DNA that is used to hybridize selects the pUC18 carrier for use.
Chip is taken out, measures the electrical signal of basic point with electrochemical workstation, for 8.7uA (vs.Ag/AgCl, 200mv).
Extract pUC18 plasmid DNA (10uL, about 1ug), boiling water bath 5 minutes places rapidly on ice, makes the DNA sex change.
With the pUC18 plasmid point of sex change on basic point, 37 ℃ of insulations 2 hours.
Use ddH
2O cleans chip, and chip is placed 45 ℃ ddH
2Rinsing several among the O, about 30 minutes.DdH
2O is a distilled water.
Take out chip, measure the electrical signal of basic point once more with electrochemical workstation, be 2uA (to Ag/AgCl, 200mv, this signal detect background signal).Because the destruction of loop-stem structure, the electrical signal group is away from the Au surface on the proof chip, and caused the disappearance of electrochemical signals.Contain and dna probe sequence paired dna sequence dna in the proof sample, promptly contain the pUC18 plasmid.
Present embodiment is compared with embodiment one, only changes in the sequence that forms loop-stem structure, and the result shows that the dna sequence dna in the loop-stem structure zone in this patented method can change.
Embodiment three
This example is bought or the synthetic dna probe that contains following structure, charged chemical group be the gene chip of the electrical signal detection of carboxyl ferrocene:
5′-NH
2-(CH
2)
3-GCG AG-
-CTCGC-(CH
2)
6-SH-3′
Being the specific DNA sequences of selecting for use in this experiment, is a section in the bacillus pumilus alkaline protease gene, and correspondingly, the DNA that is used to hybridize selects the plasmid vector that contains this fragment gene for use.
Chip is taken out, measures the electrical signal of basic point with electrochemical workstation, for 10uA (vs.Ag/AgCl, 200mv).
Extraction contains the plasmid DNA (10uL, about 1ug) of bacillus pumilus alkaline protease gene, and boiling water bath 5 minutes places rapidly on ice, makes the DNA sex change.
With the plasmid point of sex change on basic point, 37 ℃ of insulations 2 hours.
Use ddH
2O cleans chip, and chip is placed 45 ℃ ddH
2Rinsing several among the O, about 30 minutes.
Take out chip, measure the electrical signal of basic point once more with electrochemical workstation, be 2uA (to Ag/AgCl, 200mv, this signal detect background signal).Because the destruction of loop-stem structure, the electrical signal group is away from the Au surface on the proof chip, and caused the disappearance of electrochemical signals.Contain and dna probe sequence paired dna sequence dna in the proof sample, promptly contain the bacillus pumilus alkaline protease gene.
Present embodiment is compared with embodiment one, only changes at specific DNA sequences to be detected, and the result shows that the sequence in the specific DNA zone in this patented method can change, and promptly this patented method can be used for detecting the existence of multiple specific DNA.
Embodiment four
This example is the embodiment of the whole process of the preparation of electronic gene chip and detection.
At first, get chip matrix and select sheet glass for use, silicon chip and ceramic plate are tested.Mask on these three kinds of matrix cover (on an aperture is arranged and derive circuit) from this hole, the titanium of the about 10nm of vacuum evaporating last layer, and then the about 300nm gold of spraying plating last layer, the immobilization surface and the circuit of formation dna probe.Detect surface flatness.After testing, on the silicon chip gold-plated after, the surface is the most smooth.Select for use silicon chip matrix to continue test.
Handle gold-plated silicon chip with following three kinds of methods:
The a Cement Composite Treated by Plasma places ethanolic soln then rapidly;
B handles with ultraviolet-ozonize case, handles with saturated KOH again;
C handles 30min with piranha solution (70% vitriol oil/30% hydrogen peroxide), electrochemistry cleaning in 0.5M KOH solution under certain potentials then.
The result shows, more than three kinds of methods be the feasible notable difference of not seeing.Chip after the cleaning is stored in the ethanol standby.
The dna sequence dna that composite structure is as follows:
5′-NH
2-(CH
2)
3-GCG AG-
-CTCGC-(CH
2)
6-SH-3′
Being the specific DNA sequences of selecting for use in this experiment, is a section in the bacillus pumilus alkaline protease gene, and correspondingly, the DNA that is used to hybridize selects the PCR product that contains this fragment gene for use.
Manually with the dna probe for preparing (1uL, 1mM) on basic point, ambient temperature overnight behind the covering surfaces.
To contain 5uL, the solution point of 3mM electrochemistry group (carboxyl ferrocene) adds 10mM EDC/10mM NHS again on fixed DNA surface, reaction 1h.
Silicon chip is dipped in the SH-(CH of 10mM
2)
6In-OH the ethanolic soln, wait for hybridization.The gene chip that is used for electrical signal detection completes.
Chip is taken out, measures the electrical signal of basic point with electrochemical workstation, for 10uA (vs.Ag/AgCl, 200mv).
With PCR product (5uL, the about 0.5ug) boiling water bath of bacillus pumilus alkaline protease gene 5 minutes, place rapidly on ice, make the DNA sex change.
With the pUC18 plasmid point of sex change on basic point, 37 ℃ of insulations 2 hours.
Use ddH
2O cleans chip, and chip is placed 45 ℃ ddH
2Rinsing several among the O, about 30 minutes.
Take out chip, measure the electrical signal of basic point once more with electrochemical workstation, be 2uA (to Ag/AgCl, 200mv, this signal detect background signal).Because the destruction of loop-stem structure, the electrical signal group is away from the Au surface on the proof chip, and caused the disappearance of electrochemical signals.Contain and dna probe sequence paired dna sequence dna in the proof sample, promptly contain the bacillus pumilus alkaline protease gene.
Present embodiment is compared with embodiment three, only changes in the source of sample, and the plasmid DNA of sample for extracting among the embodiment three, sample is the product of PCR in the present embodiment.The result shows that the required sample of this patented method can be from multiple diverse ways.
Claims (7)
1, a kind of detection method of electronic gene chip, it is characterized in that it being that gene chip and sample DNA with having electrochemical active group hybridized, detect with of the variation of electronic detectors replacement fluorescent scanning instrument then, judge whether contain DNA fragment specific to be detected in the detected sample electrical signal before and after the gene chip hybridization.
2, the detection method of electronic gene chip according to claim 1 is characterized in that on the gene chip of described electrochemical active group be the dna probe that has following structure:
5′-NH
2-(CH
2)n-********+++++++++++++++++********-(CH
2)n-SH-
Wherein, * * * * * * * * be depicted as two sections can complementary pairing the dna sequence dna of (A and T pairing, G and C match); ++ ++ ++ ++ ++ ++ ++ +++be depicted as DNA fragment specific to be detected in the crossover process (10-30 base); Methyl (the CH at described two ends
2) quantity n is 0～10.
3, the detection method of electronic gene chip according to claim 1 is characterized in that described crossover process is:
A. sample DNA directly carries out sex change: the sample water-bath is heated to boiling, keeps more than 1 minute; Take out from boiling water, put immediately to cooling extremely fully on ice, at this moment, sample DNA sex change fully is a strand;
B. sample DNA hybridization: the denatured DNA liquid sample is mixed with probe on the chip basic point, and 20 ℃-45 ℃ are incubated 1-24 hour, hybridize;
C. the wash-out of chip: after hybridization is finished, also chip is carried out rinsing for several times with the hybridization that does not contain the DNA sample, temperature is controlled at 20 ℃-55 ℃, and time remaining is more than half an hour, the sample DNA on flush away fails to hybridize and the non-specific adsorption of probe.
4, the detection method of electronic gene chip according to claim 1 is characterized in that described electrochemical active group is a kind of group that can produce electrochemical signals of arbitrary structures.
5, the detection method of electronic gene chip according to claim 4 is characterized in that described electrochemical active group is carboxyl ferrocene or other methyl violet carboxy derivatives class electrochemical active group.
6, the detection method of electronic gene chip according to claim 1 is characterized in that described electronic detectors are electrochemical workstation or other electron detection device.
7, the detection method of electronic gene chip according to claim 1 is characterized in that described testing process is: a. sample pretreatment, extract DNA; B. sample DNA sex change; C. and chip hybridization; D. the cleaning of chip; E. the detection of electrical signal; F. post-digital signal analysis.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011291044A CN1313621C (en) | 2001-11-23 | 2001-11-23 | Electronic gene chip detecting method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011291044A CN1313621C (en) | 2001-11-23 | 2001-11-23 | Electronic gene chip detecting method |
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|---|---|
| CN1422961A CN1422961A (en) | 2003-06-11 |
| CN1313621C true CN1313621C (en) | 2007-05-02 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8003374B2 (en) | 2003-03-25 | 2011-08-23 | The Regents Of The University Of California | Reagentless, reusable, bioelectronic detectors |
| US7803542B2 (en) | 2005-11-29 | 2010-09-28 | The Regents Of The University Of California | Signal-on architecture for electronic, oligonucleotide-based detectors |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1273364A (en) * | 1999-05-06 | 2000-11-15 | 杨梦甦 | Method for testing DNA chip dedicated for diagnosing pathogenic bacteria and disease-correlative gene mutation |
| JP2001194298A (en) * | 1999-10-28 | 2001-07-19 | Nippon Telegr & Teleph Corp <Ntt> | Surface plasmon resonance enzyme sensor and method for measuring surface plasmon resonance |
-
2001
- 2001-11-23 CN CNB011291044A patent/CN1313621C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1273364A (en) * | 1999-05-06 | 2000-11-15 | 杨梦甦 | Method for testing DNA chip dedicated for diagnosing pathogenic bacteria and disease-correlative gene mutation |
| JP2001194298A (en) * | 1999-10-28 | 2001-07-19 | Nippon Telegr & Teleph Corp <Ntt> | Surface plasmon resonance enzyme sensor and method for measuring surface plasmon resonance |
Non-Patent Citations (4)
| Title |
|---|
| DNA芯片制作原理及其杂交信号检测方法 生物工程进展，第20卷第2期 2000 * |
| DNA芯片制作原理及其杂交信号检测方法 生物工程进展，第20卷第2期 2000;Preparation and hybridization analysis of DNA/RNA fromE.coli on microfabricated bioelectronic chip. Nature Biotechnology,Vol.16 No.6 1998;生物芯片技术的发展及应用 科学通报，第44卷第24期 1999 * |
| Preparation and hybridization analysis of DNA/RNA fromE.coli on microfabricated bioelectronic chip. Nature Biotechnology,Vol.16 No.6 1998 * |
| 生物芯片技术的发展及应用 科学通报，第44卷第24期 1999 * |
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