WO1996023213A1 - Analyse de molecules biologiques - Google Patents

Analyse de molecules biologiques Download PDF

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Publication number
WO1996023213A1
WO1996023213A1 PCT/US1996/001613 US9601613W WO9623213A1 WO 1996023213 A1 WO1996023213 A1 WO 1996023213A1 US 9601613 W US9601613 W US 9601613W WO 9623213 A1 WO9623213 A1 WO 9623213A1
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WO
WIPO (PCT)
Prior art keywords
nucleic acid
molecules
labeled
gel matrix
light
Prior art date
Application number
PCT/US1996/001613
Other languages
English (en)
Inventor
Anthony J. Murray
Josef Stegemann
Wilhelm Ansorge
Original Assignee
Murray Anthony J
Josef Stegemann
Wilhelm Ansorge
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Murray Anthony J, Josef Stegemann, Wilhelm Ansorge filed Critical Murray Anthony J
Priority to EP96905389A priority Critical patent/EP0805974A1/fr
Priority to JP8523084A priority patent/JPH10513553A/ja
Publication of WO1996023213A1 publication Critical patent/WO1996023213A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/44756—Apparatus specially adapted therefor
    • G01N27/44773—Multi-stage electrophoresis, e.g. two-dimensional electrophoresis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/44704—Details; Accessories
    • G01N27/44717—Arrangements for investigating the separated zones, e.g. localising zones
    • G01N27/44721—Arrangements for investigating the separated zones, e.g. localising zones by optical means

Definitions

  • the labeled-DNA fragments which are a product of either procedure are separated according to size by high resolution gel electrophoresis and a so-called "sequence ladder" is thus generated upon visualization of the gel by exposure to photographic film or other image storage means.
  • Gel electrophoresis usually involves loading the labeled-DNA fragments onto one end of a polyacrylamide gel formed between two glass plates in such a way that, at one end, it contains slots or wells for the placement of samples.
  • Patent No. 4,707,235 issued to Englert and Wheeler on November 17, 1987 describes a method and apparatus for determining the nucleotide sequence of labeled DNA fragments.
  • samples containing radioactively-labeled DNA fragments are electrophoresed through a gel matrix.
  • the labeled fragments migrate to the bottom of the gel, they pass the window of a detector.
  • Ionizing radiation from the radiolabeled fragments of sufficient energy passes through the window, producing free electrons in the gaseous environment of the detector.
  • the free electrons are accelerated towards an anode wire which, in response, produces electronic signals.
  • the electronic signals so generated are ultimately stored and interpreted by means of a computer.
  • the latter method of labeling utilizes labeled deoxynucleoside triphosphates e.g. deoxyadenosine triphosphate (dATP) , and is particularly advantageous in that it allows the use of unlabeled primer.
  • dATP deoxyadenosine triphosphate
  • fragment labeling with fluorescent dATP enables sequence information to be read beyond 1000 bases from a single lane or group of four lanes after electrophoresis of the labeled DNA fragments through a gel matrix.
  • the increased amount of sequence data that can be obtained from a single gel is due, in part, to the increased efficiency of DNA fragment labeling disclosed in the Ansorge and Voss protocol.
  • diode/amplifier-based detection systems have been incorporated into the design of a number of automated DNA sequencing systems, their utility has been limited by physical constraints. In such DNA sequencing machines, each lane on the gel must correspond to a discrete diode which is separately combined with a signal amplifier. In the discrete diode/amplifier detection systems, any increase in the number of lanes on the gel must be accompanied by a concomitant increase in the number of diodes. Recent innovations such as those which have allowed the integration of multiple amplifiers and diodes into a single unit have enabled diode/amplifier-array-based fluorescence detection systems to overcome some of the disadvantages associated with their use.
  • the commercially available automated DNA sequencing machines can be divided into two types - those which use a scanning laser means to excite fluorescence and those which use fixed laser means to achieve this goal. Scanning Fluorescence Detection
  • Another significant disadvantage of the apparatus described in the '218 patent involves the integration time for the information contained in the lanes of the gel which are scanned.
  • a band on a gel containing a labeled fragment is examined for a shorter time in a laser scanning excitation system than in a static laser excitation system.
  • This shorter scanning time results in a shorter detector integration time because the laser must not only scan each lane but also scan at different emission wavelengths to collect sufficient data points in order to make a base determination.
  • the use of mechanical means for scanning causes a reduction in the system's overall reliability.
  • the fixed detection system used in DNA sequencing machines is exemplified by the automated apparatus described by Ansorge et.al. (1986), cited above; and Ansorge et.al.. FRG Patent Application Nr. P36.18.605.B (1986).
  • This apparatus consists of a laser, light from which passes through the entire width of a gel, inducing fluorescence from fluorophore-labeled DNA fragments migrating within the gel matrix, and a system for detecting and monitoring the emission of fluorescence from all four lanes.
  • U.S. Patent No. 4,675,095 issued to Kambara et.al. on 23 June, 1987 describes an automated DNA sequencing apparatus consisting of a laser as a source of fluorescence-inducing electromagnetic radiation, a fluorescence detection system and a computerized data storage and interpretation system.
  • the light from the laser is launched horizontally into the gel from the side, i.e. in a direction which is perpendicular to the migration of the DNA bands.
  • the fluorescence detector consists of an imaging lens; a bandpass filter attached to the distal end of the imaging lens; a solid state imaging device such as a photodiode, CCD sensor or MOS linear image sensor in alignment with the optical axis of the imaging lens; and a Peltier device which provides cooling to the solid state imaging de-ice.
  • the fluorescence detected from each lane on the gel is condensed onto an image intensifier.
  • the amplified image is converted to an electrical signal by a photodiode array.
  • the electrical signal produced in this manner is processed with the aid of a computer into readable DNA sequence data.
  • the manner described by the '095 and '323 patents for launching light from the laser into the gel allows DNA sequence information to be generated using a low power laser. This therefore offers a significant cost saving in the manufacture of the machine.
  • the use of a static laser excitation system results in a higher accuracy at faster separation speeds.
  • the characteristic brightness of the SLA is given by the numerical aperture (NA) .
  • the SLA can operate in two modes - a field or line scanning mode.
  • the NA of the line scanning mode is always higher than that of the field scanning mode.
  • the SLA When used with the CCD-based detector system, the SLA operates in a line scanning mode. Due to the small pixel size of the CCD, e.g. 50 urn, the detector "sees" only a line.
  • the SLA when used in conjunction with the diode/amplifier array, it uses the field scanning mode. This, again, is a function of pixel size because the diode has a much larger pixel size than the CCD, e.g. 3 mm, the detector thus "sees" a greater area.
  • GRIN lenses such as the SLA are typically composed of one or more rows of SELFOC graded-index micro lenses, each with equal dimensions and identical optical properties.
  • the individual lenses which make up the SLA are aligned between two fiberglass-reinforced plastic plates.
  • the interstices are filled with black silicone.
  • black silicone not only protects the individual lenses, but also prevents flare or crosstalk between the lenses.
  • a continuous 1:1 image is formed by overlapping the images from the adjacent lens elements in the SLA.
  • One advantage of the SLA-CCD detector combination is the ability of the CCD to function efficiently without the inclusion of cooling means in the apparatus.
  • the SLA allows for significantly increased amounts of light to be focused on the CCD, the signal to noise ratio of the CCD remains within acceptable limits without the need to provide cooling. Provision of cooling means leads to a further improvement in the signal to noise ratio. The fact that acceptable results can be obtained without the requirement for cooling affords reductions in the cost and complexity of manufacturing the DNA sequencing machine.
  • the better quantitation of DNA in individual bands which is obtained from the combination can be used to provide data on the efficiency of the enzyme utilized in the sequencing reaction as well as data regarding the local structure of the DNA strand being sequenced.
  • Such information can be employed by modern data analysis algorithms to further enhance the efficiency of methods used to decipher stretches of ambiguity in the base sequence as read from the electrophoresis of labeled DNA fragments through a gel matrix.
  • Other areas where the data generated by the system of the present invention are invaluable are those involving allele analysis and fragment mapping, detection of heterozygotes and analysis of viral mutations and populations.
  • the system therefore has numerous applications in a variety of areas including, but not limited to, paternity testing procedures, forensic medicine, clinical evaluation of disease and cancer-inducing mutations in genes, evaluation of anti ⁇ viral drug resistance-inducing mutations during treatment regimens, protein/DNA interaction analysis, and bacterial fingerprinting, in addition to de novo DNA sequencing.
  • the CCD becomes the limiting aperture in the system (typically this is a function of the CCD pixel size which is of the order of 50 urn in the vertical dimension) .
  • the laser must be precisely aligned to the detector by, for example, the use of an actuated mirror at the entrance to the gel.
  • An alignment error signal can be derived either from pixels at each end of the CCD or through diodes dedicated for this purpose.
  • the tendency of the laser to wander is a major factor in determining whether alignment must be an ongoing process during electrophoretic separation of the labeled DNA fragments.
  • Laser wandering can be a function of gel composition and/or the laser/dye combination. When using lasers at the red end of the spectrum, for example, an initial adjustment at the beginning of the electrophoresis separation is all that is required.
  • light from two or more laser light excitation sources 19' , 19' ' , 19 • ' ' can be combined in a beam combining element 47, so that the combined beam strikes the gel electrolyte layer 16 situated between two electrophoresis plates 17' , 17' ' at a single predetermined linear irradiation region 48.
  • Fluorescent light emitted by the excited fluorophore-labeled DNA fragments 23 is collected and focused by a light collection and focusing lens array 24 and is focused through a multiple notch light filter 52 and then onto a single CCD element 26.
  • the CCD element can be cooled by Peltier device 33 and associated heat-sink 34.
  • the light collection and focusing lens array 24 consists of an array of gradient index lenses composed of individual SELFOC graded-index micro lenses 28 of substantially equal dimension and substantially identical optical properties.
  • the individual lenses 28 are aligned between two fiberglass- reinforced plastic plates 29, 30.
  • the interstices 31 are filled with black silicone.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Electrochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

Appareil (12) et procédé de détection et de séparation de molécules biologiques qui sont marquées avec une étiquette photosensible. Les molécules sont séparées par dimension, à la fois dans le plan horizontal et dans le plan vertical, dans des chemins électrophorétiques parrallèles (18) dans une matrice de gel (16). Un potentiel électrique est appliqué à la matrice de gel (16) pendant qu'une lumière laser excite les molécules pendant que celles-ci migrent dans une direction prédéterminée. Les signaux de lumière de sortie émis par les molécules excitées sont détectés, collectés, stockés et analysés à l'aide d'un monitor (36), d'un dispositif de commande (35) et d'un processor de données numériques (37).
PCT/US1996/001613 1995-01-23 1996-01-23 Analyse de molecules biologiques WO1996023213A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP96905389A EP0805974A1 (fr) 1995-01-23 1996-01-23 Analyse de molecules biologiques
JP8523084A JPH10513553A (ja) 1995-01-23 1996-01-23 生物学的分子の分析

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US37685395A 1995-01-23 1995-01-23
US08/376,853 1995-01-23

Publications (1)

Publication Number Publication Date
WO1996023213A1 true WO1996023213A1 (fr) 1996-08-01

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/001613 WO1996023213A1 (fr) 1995-01-23 1996-01-23 Analyse de molecules biologiques

Country Status (3)

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EP (1) EP0805974A1 (fr)
JP (1) JPH10513553A (fr)
WO (1) WO1996023213A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0840115A2 (fr) * 1996-11-05 1998-05-06 Hitachi Electronics Engineering Co., Ltd. Séquenceur de bases d'ADN
EP0911630A1 (fr) * 1997-08-07 1999-04-28 Hitachi Electronics Engineering Co., Ltd. Détecteur de fluorescence
WO1999058963A1 (fr) * 1998-05-14 1999-11-18 Zeptosens Ag Unite de detection equipee d'un guidage de lumiere de detection separe
WO2000065325A2 (fr) * 1999-04-27 2000-11-02 Carl Zeiss Jena Gmbh Dispositif pour l'evaluation optique d'un ensemble d'objets
WO2001007150A2 (fr) * 1999-07-26 2001-02-01 Kahl Johan Valentin Procedes et dispositifs de separation electrophoretique de particules, en particulier de macromolecules
WO2001025779A2 (fr) * 1999-10-07 2001-04-12 Europäisches Laboratorium für Molekularbiologie (EMBL) Dispositif d'electrophorese pour l'analyse de molecules marquees, en particulier de molecules biologiques
EP1186886A2 (fr) * 2000-09-04 2002-03-13 Fuji Photo Film Co., Ltd. Méthode d'analyse biochimique et appareil pour utiliser cette méthode
EP1223421A2 (fr) * 2001-01-10 2002-07-17 Yokogawa Electric Corporation Lecteur de biopuce
WO2003048749A1 (fr) * 2001-11-29 2003-06-12 Amersham Biosciences Uk Limited Emetteurs detecteurs de rayonnement electromagnetique, en particulier de substances marquees par un fluorophore
EP1432966A1 (fr) * 2001-08-28 2004-06-30 The Baylor College Of Medicine Excitation a lignes multiples par impulsions pour detection par fluorescence non chromatisee
US8361299B2 (en) 2008-10-08 2013-01-29 Sage Science, Inc. Multichannel preparative electrophoresis system
US8361298B2 (en) 2008-10-08 2013-01-29 Sage Science, Inc. Multichannel preparative electrophoresis system
US10131901B2 (en) 2014-10-15 2018-11-20 Sage Science, Inc. Apparatuses, methods and systems for automated processing of nucleic acids and electrophoretic sample preparation
US10175172B2 (en) 2015-02-03 2019-01-08 Hitachi High-Technologies Corporation Multicolor detection device
US10473619B2 (en) 2012-10-12 2019-11-12 Sage Science, Inc. Side-eluting molecular fractionator
US10908083B2 (en) 2015-02-02 2021-02-02 Hitachi High-Tech Corporation Multicolor fluorescence analysis device
WO2021221665A1 (fr) * 2020-04-30 2021-11-04 Promega Corporation Techniques d'éclairage laser pour électrophorèse capillaire
US11542495B2 (en) 2015-11-20 2023-01-03 Sage Science, Inc. Preparative electrophoretic method for targeted purification of genomic DNA fragments
US11867661B2 (en) 2017-04-07 2024-01-09 Sage Science, Inc. Systems and methods for detection of genetic structural variation using integrated electrophoretic DNA purification

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7329658B2 (ja) * 2020-10-07 2023-08-18 株式会社日立ハイテク 発光検出装置

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987007719A1 (fr) * 1986-06-03 1987-12-17 Europäisches Laboratorium Für Molekularbiologie (E Appareil pour detecter les substances pouvant etre excitees en vue d'une emission photonique
US4971677A (en) * 1988-02-24 1990-11-20 Hitachi, Ltd. Fluorescence detection type electrophoresis apparatus
EP0645622A2 (fr) * 1993-09-28 1995-03-29 Hitachi Electronics Engineering Co., Ltd. Analyseur des bases de l'ADN

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987007719A1 (fr) * 1986-06-03 1987-12-17 Europäisches Laboratorium Für Molekularbiologie (E Appareil pour detecter les substances pouvant etre excitees en vue d'une emission photonique
US4971677A (en) * 1988-02-24 1990-11-20 Hitachi, Ltd. Fluorescence detection type electrophoresis apparatus
EP0645622A2 (fr) * 1993-09-28 1995-03-29 Hitachi Electronics Engineering Co., Ltd. Analyseur des bases de l'ADN

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0840115A3 (fr) * 1996-11-05 1999-08-25 Hitachi Electronics Engineering Co., Ltd. Séquenceur de bases d'ADN
EP0840115A2 (fr) * 1996-11-05 1998-05-06 Hitachi Electronics Engineering Co., Ltd. Séquenceur de bases d'ADN
EP0911630A1 (fr) * 1997-08-07 1999-04-28 Hitachi Electronics Engineering Co., Ltd. Détecteur de fluorescence
US6039925A (en) * 1997-08-07 2000-03-21 Hitachi Electronics Engineering Co., Ltd. Fluorescence detector
WO1999058963A1 (fr) * 1998-05-14 1999-11-18 Zeptosens Ag Unite de detection equipee d'un guidage de lumiere de detection separe
US6437345B1 (en) 1998-05-14 2002-08-20 Zeptosens Ag Sensing unit provided with separated detection light guiding
US7812944B1 (en) 1999-04-27 2010-10-12 Carl Zeiss Jena Gmbh Array for optical evaluation of an object array
WO2000065325A2 (fr) * 1999-04-27 2000-11-02 Carl Zeiss Jena Gmbh Dispositif pour l'evaluation optique d'un ensemble d'objets
WO2000065325A3 (fr) * 1999-04-27 2001-04-26 Zeiss Carl Jena Gmbh Dispositif pour l'evaluation optique d'un ensemble d'objets
WO2001007150A2 (fr) * 1999-07-26 2001-02-01 Kahl Johan Valentin Procedes et dispositifs de separation electrophoretique de particules, en particulier de macromolecules
WO2001007150A3 (fr) * 1999-07-26 2001-07-26 Kahl Johan Valentin Procedes et dispositifs de separation electrophoretique de particules, en particulier de macromolecules
US7204922B1 (en) 1999-07-26 2007-04-17 Johan-Valentin Kahl Method and device for the electrophoretic separation of particles, especially of macromolecules, by electrophoresis
WO2001025779A3 (fr) * 1999-10-07 2002-02-28 Europ Lab Molekularbiolog Dispositif d'electrophorese pour l'analyse de molecules marquees, en particulier de molecules biologiques
WO2001025779A2 (fr) * 1999-10-07 2001-04-12 Europäisches Laboratorium für Molekularbiologie (EMBL) Dispositif d'electrophorese pour l'analyse de molecules marquees, en particulier de molecules biologiques
EP1186886A3 (fr) * 2000-09-04 2004-01-07 Fuji Photo Film Co., Ltd. Méthode d'analyse biochimique et appareil pour utiliser cette méthode
EP1186886A2 (fr) * 2000-09-04 2002-03-13 Fuji Photo Film Co., Ltd. Méthode d'analyse biochimique et appareil pour utiliser cette méthode
EP1223421A3 (fr) * 2001-01-10 2002-07-24 Yokogawa Electric Corporation Lecteur de biopuce
EP1223421A2 (fr) * 2001-01-10 2002-07-17 Yokogawa Electric Corporation Lecteur de biopuce
EP1432966A1 (fr) * 2001-08-28 2004-06-30 The Baylor College Of Medicine Excitation a lignes multiples par impulsions pour detection par fluorescence non chromatisee
EP1432966A4 (fr) * 2001-08-28 2011-05-04 Baylor College Medicine Excitation a lignes multiples par impulsions pour detection par fluorescence non chromatisee
US8089628B2 (en) 2001-08-28 2012-01-03 Baylor College Of Medicine Pulsed-multiline excitation for color-blind fluorescence detection
WO2003048749A1 (fr) * 2001-11-29 2003-06-12 Amersham Biosciences Uk Limited Emetteurs detecteurs de rayonnement electromagnetique, en particulier de substances marquees par un fluorophore
US6992303B2 (en) 2001-11-29 2006-01-31 Amersham Biosciences Uk Limited Detecting emitters of electromagnetic radiation, in particular fluorophore labeled substances
US9719961B2 (en) 2008-10-08 2017-08-01 Sage Science, Inc. Multichannel preparative electrophoresis system
US8361298B2 (en) 2008-10-08 2013-01-29 Sage Science, Inc. Multichannel preparative electrophoresis system
US8361299B2 (en) 2008-10-08 2013-01-29 Sage Science, Inc. Multichannel preparative electrophoresis system
US10473619B2 (en) 2012-10-12 2019-11-12 Sage Science, Inc. Side-eluting molecular fractionator
US10131901B2 (en) 2014-10-15 2018-11-20 Sage Science, Inc. Apparatuses, methods and systems for automated processing of nucleic acids and electrophoretic sample preparation
US10738298B2 (en) 2014-10-15 2020-08-11 Sage Science, Inc. Apparatuses, methods and systems for automated processing of nucleic acids and electrophoretic sample preparation
US10908083B2 (en) 2015-02-02 2021-02-02 Hitachi High-Tech Corporation Multicolor fluorescence analysis device
US10175172B2 (en) 2015-02-03 2019-01-08 Hitachi High-Technologies Corporation Multicolor detection device
US10753873B2 (en) 2015-02-03 2020-08-25 Hitachi High-Tech Corporation Multicolor detection device
US11542495B2 (en) 2015-11-20 2023-01-03 Sage Science, Inc. Preparative electrophoretic method for targeted purification of genomic DNA fragments
US11867661B2 (en) 2017-04-07 2024-01-09 Sage Science, Inc. Systems and methods for detection of genetic structural variation using integrated electrophoretic DNA purification
WO2021221665A1 (fr) * 2020-04-30 2021-11-04 Promega Corporation Techniques d'éclairage laser pour électrophorèse capillaire

Also Published As

Publication number Publication date
JPH10513553A (ja) 1998-12-22
EP0805974A1 (fr) 1997-11-12

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