【０００１】[0001]
【産業上の利用分野】本発明は、ＤＮＡなどの塩基配列
決定装置であって、更に詳しくは蛍光ラベルをしたＤＮ
Ａ断片をゲル電気泳動させ、泳動方向と交わる方向に蛍
光の励起・受光光学系を配置し、ＤＮＡ断片の泳動パタ
ーンを検出するものに関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a base sequence determination device for DNA and the like, and more particularly to a fluorescently labeled DN.
The present invention relates to a method in which the A fragment is subjected to gel electrophoresis, a fluorescence excitation / light receiving optical system is arranged in a direction intersecting the migration direction, and the migration pattern of the DNA fragment is detected.
【０００２】[0002]
【従来の技術】プライマー部又はダイオキシ部に蛍光ラ
ベルを付し、サンガーの方法で調整したＤＮＡ断片をゲ
ル電気泳動を行い、得られる展開パターンを解析してＤ
ＮＡの塩基配列を決定する塩基配列決定装置が知られて
いる。2. Description of the Related Art A DNA fragment prepared by Sanger's method with a fluorescent label attached to a primer portion or a dioxy portion is subjected to gel electrophoresis, and the resulting development pattern is analyzed to obtain D.
A base sequence determination device that determines the base sequence of NA is known.
【０００３】代表的な塩基配列決定装置としては、例え
ば特開昭６３−３１３０３５号公報に記載にものを挙げ
ることができる。この装置は、図６に示されるものであ
り、ガラス板に挟まれて図で紙面垂直方向に延びる泳動
ゲル１０４に蛍光ラベルしたサンプルが紙面垂直方向に
泳動する。As a typical base sequence determination device, for example, the one described in JP-A-63-313035 can be mentioned. This apparatus is shown in FIG. 6, and a sample fluorescent-labeled on an electrophoretic gel 104 sandwiched between glass plates and extending in the direction perpendicular to the paper surface in the figure migrates in the direction perpendicular to the paper surface.
【０００４】ステージ２３９はガイドレール２３３に案
内され、モータ２３７で駆動される棒ネジ２５２の回転
によって泳動方向と直交する図の上下方向に走査され
る。ステージ２３９には集光レンズ２６０が設けられ、
励起光であるレーザビーム２５０がミラー２５１で反射
されてレンズ２６０に入射し、ステージ２３９上のミラ
ー２５５で反射されて泳動ゲル１０４の測定部分を照射
する。The stage 239 is guided by a guide rail 233 and is scanned by the rotation of a rod screw 252 driven by a motor 237 in the vertical direction of the drawing, which is orthogonal to the migration direction. A condenser lens 260 is provided on the stage 239,
The laser beam 250, which is the excitation light, is reflected by the mirror 251 and enters the lens 260, and is reflected by the mirror 255 on the stage 239 to irradiate the measurement portion of the electrophoretic gel 104.
【０００５】その測定部分から出た蛍光はステージ２３
９に設けられた集光レンズ２２１で集光され、干渉フィ
ルタ２２３で分光されてレンズ２２５を通り、光電子増
倍管２２９で検知される。The fluorescence emitted from the measurement portion is the stage 23.
The light is condensed by the condenser lens 221 provided on the optical axis 9, is separated by the interference filter 223, passes through the lens 225, and is detected by the photomultiplier tube 229.
【０００６】[0006]
【発明が解決しようとする課題】しかし、図６の装置で
は、励起・受光光学系をステージ２３９に載せ走査して
いるため、高速で各泳動レーンの信号をサンプリングし
ようとすれば、ステージ２３９を高速駆動するための特
別な駆動機構を必要とし、装置全体の大型化を招いてい
た。However, in the apparatus of FIG. 6, since the excitation / reception optical system is mounted on the stage 239 for scanning, if the signals of each migration lane are to be sampled at high speed, the stage 239 will not be operated. A special drive mechanism for driving at high speed is required, which leads to an increase in size of the entire device.
【０００７】また、図６の装置では、泳動ゲル１０４と
走査方向（ネジ２５２とガイドレール２３３で決ま
る）、及び集光レンズ２６０への励起光の入射方向の三
者が全く平行で、かつ泳動ゲル１０４の位置は走査のど
の場所でも全く一致していなければならないが、図７に
示すような状態になっている場合がある。すなわち、走
査のある場所Ａでは励起光２５０により照明されたゲル
部分は正しく受光光学系の光軸上にあり、強い信号が得
られるが、ゲル１０４が挟まれているガラス板の厚さが
変化したり、ゲル１０４とネジ２５２の平行度が不十分
な場合など、走査の別の場所Ｂでは図のように励起光２
５０により照明されたゲル部分と受光光学系の光軸との
間にずれが生じ、信号強度が弱くなり、はなはだしい場
合には信号が検出されなくなった。Further, in the apparatus shown in FIG. 6, the electrophoretic gel 104, the scanning direction (determined by the screw 252 and the guide rail 233), and the incident direction of the excitation light to the condenser lens 260 are completely parallel to each other, and the migration is performed. The position of the gel 104 must be exactly the same at every scanning position, but it may be in the state shown in FIG. 7. That is, at the scanning position A, the gel portion illuminated by the excitation light 250 is correctly on the optical axis of the light receiving optical system, and a strong signal is obtained, but the thickness of the glass plate sandwiching the gel 104 changes. If the parallelism between the gel 104 and the screw 252 is insufficient, the excitation light 2 is emitted at another scanning position B as shown in the figure.
The gel portion illuminated by 50 and the optical axis of the light receiving optical system were displaced from each other, the signal intensity was weakened, and in the worst case, no signal was detected.
【０００８】そこで、本発明は、上記に鑑みなされたも
ので、励起・受光光学系の走査及び複雑な光軸調整が不
要で、しかも光利用率が高くＳ／Ｎ比の良くなる塩基配
列決定装置を提供することを目的とする。Therefore, the present invention has been made in view of the above, and it does not require scanning of the excitation / reception optical system and complicated optical axis adjustment, and has a high light utilization rate and a good S / N ratio. The purpose is to provide a device.
【０００９】[0009]
【課題を解決するための手段】本発明は、上記課題を解
決するため、蛍光ラベルしたＤＮＡ断片を複数のレーン
でゲル電気泳動させ、泳動方向と交わる方向に蛍光の励
起・受光光学系を配置し、ＤＮＡ断片の泳動パターンを
検出する塩基配列決定装置において、前記励起・受光光
学系を一体化して、各泳動レーン毎に配置したことを特
徴とする。In order to solve the above problems, the present invention performs gel electrophoresis of fluorescently labeled DNA fragments in a plurality of lanes, and arranges an excitation / reception optical system for fluorescence in a direction intersecting the migration direction. In the base sequence determination device for detecting the migration pattern of the DNA fragment, the excitation / light receiving optical system is integrated and arranged in each migration lane.
【００１０】ここで、励起・受光光学系とは、ＤＮＡ断
片の蛍光ラベルに励起光を照射する光源、発した蛍光を
受光する検出器を少なくとも備えたもので、光源として
は、ＬＥＤ、検出器としてはフォトダイオードを用いる
のが小形化の点で特に好ましいが、これに限定されな
い。また、フォトダイオードとしては、感度を考慮する
と高感度検出が可能なアバランシェ・フォトダイオード
を用いるのが好ましい。なお、アバランシェフォト・ダ
イオードとは、ｐｎ接合に逆方向バイアスを十分印加
し、空乏層を広げ、空乏層の高電界でそこで発生したキ
ャリアを発生させ、原子との衝突によって新たな電子正
孔対を発生させるものである。Here, the excitation / reception optical system includes at least a light source for irradiating a fluorescent label of a DNA fragment with excitation light and a detector for receiving emitted fluorescence. The light source is an LED or a detector. It is particularly preferable to use a photodiode in terms of downsizing, but the present invention is not limited to this. Further, as the photodiode, it is preferable to use an avalanche photodiode capable of high-sensitivity detection in consideration of sensitivity. An avalanche photo diode is a reverse bias sufficiently applied to a pn junction to widen a depletion layer, generate carriers generated in the high electric field of the depletion layer, and generate new electron-hole pairs by collision with atoms. Is generated.
【００１１】励起・受光光学系には、必要に応じ光源か
らの励起光をＤＮＡ断片の蛍光ラベルにスポット照射す
るための集光レンズ、発した蛍光を検出器に集めるため
の集光レンズ等も含まれる。The excitation / reception optical system also includes a condenser lens for spot-irradiating the excitation label from the light source onto the fluorescent label of the DNA fragment, a condenser lens for collecting the emitted fluorescence in the detector, and the like. included.
【００１２】励起・受光光学系の一体化は、例えば、鏡
筒の中に光源、検出器などを収容することにより行う
が、これに限定されない。The excitation / light-receiving optical system is integrated, for example, by accommodating a light source, a detector and the like in a lens barrel, but is not limited to this.
【００１３】一体化された励起・受光光学系を、ゲル電
気泳動板に設置するときは、光学系の焦点が泳動レーン
にくるようにすることは勿論である。設置は、例えばマ
ウント部材に励起・受光光学系を泳動レーンの間隔毎に
複数個並べて、そのマウント部材を電気泳動板に嵌め合
わせるようにすることが考えられるが、これに限定され
ず励起・受光光学系を直接ゲル電気泳動板の泳動レーン
に設置しても良い。設置方向も励起光がゲルに垂直に入
射する方向には限定されず、斜入射する方向でも良い。When the integrated excitation / reception optical system is installed on the gel electrophoresis plate, it goes without saying that the focus of the optical system is on the migration lane. For installation, for example, a plurality of excitation / light reception optical systems may be arranged on the mount member at intervals of migration lanes, and the mount members may be fitted to the electrophoretic plate, but not limited to this. The optical system may be installed directly in the migration lane of the gel electrophoresis plate. The installation direction is not limited to the direction in which the excitation light is vertically incident on the gel, and may be the direction in which the excitation light is obliquely incident.
【００１４】なお、本発明で使用する蛍光ラベルとして
は、例えば、イソチオシアン酸フルオレセイン（ＦＩＴ
Ｃ）、イソチオシアン酸エオシン（ＥＩＴＣ）、イソチ
オシアン酸テトラメチルローダミン（ＴＭＩＲＴＣ）、
置換イソチオシアン酸ローダミン（ＸＲＩＴＣ）、テキ
アスレッドなどを挙げることができる。また、蛍光ラベ
ルは塩基の種類、Ａ（アデニン）、Ｃ（シトシン）、Ｔ
（チミン），Ｇ（グアニン）毎に異なるものを用いても
良いし、同一のものを用いてもよい。もし、塩基の種類
毎に蛍光ラベルを異なえる場合（４種類の蛍光ラベルを
用いる場合）は、一つの泳動レーンで４種類の塩基の測
定が可能となる。The fluorescent label used in the present invention is, for example, fluorescein isothiocyanate (FIT).
C), eosin isothiocyanate (EITC), tetramethylrhodamine isothiocyanate (TMIRTC),
Examples thereof include substituted rhodamine isothiocyanate (XRITC) and Texia red. In addition, fluorescent labels include base types, A (adenine), C (cytosine), and T.
Different (thymine) and G (guanine) may be used, or the same may be used. If different fluorescent labels are used for each type of base (when four types of fluorescent labels are used), it is possible to measure four types of bases in one migration lane.
【００１５】また、ゲル電気泳動には、キャピラリー
型、平板型の両者を含む。Gel electrophoresis includes both capillary type and flat plate type.
【００１６】[0016]
【作用】本発明によれば、励起・受光光学系を一体化
し、その光学系焦点を予め泳動レーンに一致させておく
ことにより、その一体化構造体をゲル電気泳動板に密着
させることで、光学系の調整を必要としない構造とな
る。According to the present invention, the excitation / reception optical system is integrated, and the focus of the optical system is matched with the migration lane in advance so that the integrated structure is brought into close contact with the gel electrophoresis plate. The structure does not require adjustment of the optical system.
【００１７】また、泳動レーン毎に励起・受光光学系を
１個設けているので、光学系の走査機能を排除できる。Since one excitation / light receiving optical system is provided for each migration lane, the scanning function of the optical system can be eliminated.
【００１８】[0018]
【実施例】本発明の実施例を図面に基づいて説明する。
図１は、本発明にかかる装置の全体概略図で、１はゲル
電気泳動板を示す。これは、例えば厚さ５ｍｍのパイレ
ックスガラス板１ａ、１ａ´間に６％ポリアクリルアミ
ドゲル１ｂを０．３５ｍｍの厚さに挟んで形成される。Embodiments of the present invention will be described with reference to the drawings.
FIG. 1 is an overall schematic view of an apparatus according to the present invention, and 1 shows a gel electrophoresis plate. This is formed, for example, by sandwiching a 6% polyacrylamide gel 1b between Pyrex glass plates 1a and 1a 'having a thickness of 5 mm to a thickness of 0.35 mm.
【００１９】２は、ゲル電気泳動板に形成された凹状の
ウェルで、凹部に蛍光ラベルしたＤＮＡ断片が注入され
る。従って、このウェル２の凹部をゲル電気泳動板２の
長さ方向に延長したのが泳動レーンとなる。なお、ウェ
ルの幅は典型的には５ｍｍ〜１０ｍｍの範囲にある。Numeral 2 is a concave well formed on the gel electrophoresis plate, into which the fluorescently labeled DNA fragment is injected. Accordingly, the migration lane is formed by extending the recess of the well 2 in the length direction of the gel electrophoresis plate 2. The width of the well is typically in the range of 5 mm to 10 mm.
【００２０】ゲル電気泳動板１の両端は緩衝液槽３、４
に挿入され、この緩衝液槽３、４に一対の電極（図示せ
ず）を入れて高電圧電源（図示せず）と接続する。高電
圧の印加によりウェル２に注入されたＤＮＡ断片は図の
矢印方向に泳動する。なお、緩衝液槽３、４に入れる緩
衝液としては、例えば、リン酸緩衝液を用いる。Both ends of the gel electrophoresis plate 1 are buffer tanks 3 and 4.
And a pair of electrodes (not shown) are placed in the buffer tanks 3 and 4 and connected to a high voltage power source (not shown). The DNA fragment injected into the well 2 by applying a high voltage migrates in the direction of the arrow in the figure. As the buffer solution to be placed in the buffer solution tanks 3 and 4, for example, a phosphate buffer solution is used.
【００２１】ゲル電気泳動板１の裏面には、泳動中にゲ
ル電気泳動板を水冷する水冷装置５が設置されており、
この水冷装置５は、例えば、平板に溝を切り、そこに水
が流せるようになっている。なお、水の導入出口は図示
省略してある。On the back surface of the gel electrophoresis plate 1, a water cooling device 5 for cooling the gel electrophoresis plate with water during electrophoresis is installed.
The water cooling device 5 has, for example, a flat plate having a groove formed therein so that water can flow therethrough. The water inlet / outlet is omitted in the figure.
【００２２】ゲル電気泳動板１での泳動方向（図の矢印
方向）には、マウント部材６が嵌め込まれており、この
マウント部材６にセンサヘッド７が複数個設置される。
センサヘッド７の間隔は、ウェルの幅に対応し、各泳動
レーンに１個設置されることになる。A mount member 6 is fitted in the migration direction of the gel electrophoresis plate 1 (the direction of the arrow in the figure), and a plurality of sensor heads 7 are installed on this mount member 6.
The interval between the sensor heads 7 corresponds to the width of the well, and one sensor head 7 is installed in each migration lane.
【００２３】ここで、センサヘッド７の内部構造とゲル
電気泳動板１の関係を図２に示す。センサヘッド７は、
光源であるＬＥＤ７１と検出器であるアバランシェ・フ
ォトダイオード（ＡＰＤ）７２を筒７０内に固定してい
る。ＬＥＤ７１から発せられる光は干渉フィルタ７７を
通り、不必要波長がカットされた後、集光レンズ７３で
集光しゲル１ｂに照射される。集光レンズ７３の焦点は
ゲル１ｂに合致されているのは勿論のことである。蛍光
ラベルしたＤＮＡ断片から発せられる蛍光は、接眼レン
ズ７４で集光し平行光にした後、干渉フィルタ及び色フ
ィルタ７５、集光レンズ７６を通り、ＡＰＤ７２に入射
されるようになっている。The relationship between the internal structure of the sensor head 7 and the gel electrophoresis plate 1 is shown in FIG. The sensor head 7 is
An LED 71 which is a light source and an avalanche photodiode (APD) 72 which is a detector are fixed in a cylinder 70. The light emitted from the LED 71 passes through the interference filter 77, and after unnecessary wavelengths are cut off, the light is condensed by the condenser lens 73 and applied to the gel 1b. Needless to say, the focus of the condenser lens 73 is aligned with the gel 1b. The fluorescence emitted from the fluorescently labeled DNA fragment is condensed by the eyepiece lens 74 to be parallel light, and then passes through the interference filter and color filter 75 and the condenser lens 76 to enter the APD 72.
【００２４】なお、使用するＬＥＤの種類・波長等は、
蛍光ラベルの種類により適宜選択される。例えば、蛍光
ラベルとしてテキサスレッドを用いる場合は５９０ｎｍ
を中心とする光を発するＬＥＤを用い、干渉フィルタ７
７で６１０ｎｍより長波長の光をカットする。また、前
記の蛍光ラベルの場合、蛍光ラベルより発せられる蛍光
は中心波長６１５ｎｍのものとなり、フィルタ７５で６
１０ｎｍ以下の波長をカットして、ＡＰＤ７２に入るよ
うにする。The types and wavelengths of the LEDs used are as follows:
It is appropriately selected depending on the type of fluorescent label. For example, when using Texas Red as the fluorescent label, it is 590 nm.
Using an LED that emits light centered on
In step 7, light having a wavelength longer than 610 nm is cut. Further, in the case of the above-mentioned fluorescent label, the fluorescence emitted from the fluorescent label has a central wavelength of 615 nm, and the
A wavelength of 10 nm or less is cut so that it enters the APD 72.
【００２５】センサヘッド７からの信号はＣＰＵ（図示
せず）に導かれ、そこで信号処理されて塩基配列が決定
される。The signal from the sensor head 7 is guided to a CPU (not shown), where it is subjected to signal processing to determine the base sequence.
【００２６】なお、センサヘッドの構造は図２のものに
は限定されず、図３〜図５のものでも良い。図３は、図
２のものとは接眼レンズが異なり、半球状の接眼レンズ
７８を用いている。これにより、接眼レンズ７８は蛍光
の集光レンズとしての機能だけでなく、ＬＥＤ７１の集
光レンズを兼ねることにもなり、部品点数を少なく出来
るとともに、等方的に発せられる蛍光に対し、立体角を
広く集光できることになり、光学系が明るくなる。The structure of the sensor head is not limited to that shown in FIG. 2 and may be one shown in FIGS. 3 is different from that of FIG. 2 in that a hemispherical eyepiece lens 78 is used. As a result, the eyepiece lens 78 not only functions as a condenser lens for fluorescent light, but also serves as a condenser lens for the LED 71, so that the number of parts can be reduced and the solid angle with respect to the fluorescence emitted isotropically. Can be widely condensed, and the optical system becomes bright.
【００２７】図４は、センサヘッド７の設置面と反対側
に反射板（Ａｌ反射鏡）７９を配置しており、これによ
り、ゲル電気泳動板を通過した光（入射光、蛍光の両
方）を再度利用できることになり、光利用効率を高める
ことができる。In FIG. 4, a reflector (Al reflector) 79 is arranged on the side opposite to the surface on which the sensor head 7 is installed, whereby light (both incident light and fluorescence) that has passed through the gel electrophoresis plate is arranged. Can be reused, and light utilization efficiency can be improved.
【００２８】図５は、図４の変形で、ガラス板１ａ´の
ゲル側にＡｌ８０を蒸着しておくことにより、図４と同
様の効果をもたらしている。FIG. 5 is a modification of FIG. 4, in which Al 80 is vapor-deposited on the gel side of the glass plate 1 a ′, and the same effect as in FIG. 4 is brought about.
【００２９】なお、図３〜図５中、図２と同じものには
同じ番号が付されている。3 to 5, the same parts as those in FIG. 2 are designated by the same reference numerals.
【００３０】[0030]
【発明の効果】本発明によれば、泳動レーン毎に励起・
受光光学系を１個設けているので、光学系の走査機能を
排除できる。According to the present invention, excitation / excitation for each migration lane
Since one light receiving optical system is provided, the scanning function of the optical system can be eliminated.
【００３１】また、励起・受光光学系を一体化し、その
光学系焦点を予め泳動レーンに一致させてゲル電気泳動
板に密着させているので、光学系の調整を必要としな
い。Further, since the excitation / light receiving optical system is integrated and the focus of the optical system is preliminarily aligned with the migration lane and brought into close contact with the gel electrophoresis plate, there is no need to adjust the optical system.
【図１】本発明の装置の全体概略を示す図である。FIG. 1 is a diagram showing an overall outline of an apparatus of the present invention.
【図２】本発明のセンサヘッドを示す図である。FIG. 2 is a diagram showing a sensor head of the present invention.
【図３】本発明のセンサヘッドの他の実施例図である。FIG. 3 is a diagram showing another embodiment of the sensor head of the present invention.
【図４】本発明のセンサヘッドの他の実施例図である。FIG. 4 is a diagram showing another embodiment of the sensor head of the present invention.
【図５】本発明のセンサヘッドの他の実施例図である。FIG. 5 is a diagram showing another embodiment of the sensor head of the present invention.
【図６】従来装置の概略図である。FIG. 6 is a schematic view of a conventional device.
【図７】従来装置の欠点を示す図である。FIG. 7 is a diagram showing a drawback of the conventional device.
１：ゲル電気泳動板 ３、４：緩衝液槽 ７：センサヘッド ７１：ＬＥＤ ７２：ＡＰＤ 1: Gel electrophoresis plate 3, 4: Buffer solution tank 7: Sensor head 71: LED 72: APD
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|---|---|---|---|
| JP5270514AJPH07120392A (en) | 1993-10-28 | 1993-10-28 | Nucleotide sequencer |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5270514AJPH07120392A (en) | 1993-10-28 | 1993-10-28 | Nucleotide sequencer |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6327393ADivisionJPH07174701A (en) | 1994-12-28 | 1994-12-28 | Nucleotide sequencer |
| Publication Number | Publication Date |
|---|---|
| JPH07120392Atrue JPH07120392A (en) | 1995-05-12 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5270514APendingJPH07120392A (en) | 1993-10-28 | 1993-10-28 | Nucleotide sequencer |
| Country | Link |
|---|---|
| JP (1) | JPH07120392A (en) |
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