从1977年第一代DNA测序技术（桑格法），发展至今将近四十年时间，测序技术已取得了相当大的发展。虽然就当前形势看来，第二代短读长测序技术在全球测序市场上仍然占有着绝对的优势位置，但第三测序技术也在逐步成熟之中。测序技术的每一次变革，都对基因组研究，疾病研究，药物研发等领域产生巨大的推动作用。小编在本文就简单介绍一下DNA测序的发展流程和初代桑格测序的原理。在下期的文章中，小编会再聊聊第二代和第三代测序技术。
测序技术发展史
自从确定了DNA是遗传物质以后，人类就没有停止过对DNA的探索。继上世纪五十年代确定DNA双螺旋结构后，二十世纪七十年代，桑格（Sanger）和考尔森（Coulson）开创了双脱氧链终止法用于DNA测序。值得注意的是，桑格法的发明其实是早于PCR技术的（图1）。
图1：DNA测序技术发展历史。图中显灰色的部分为初代桑格法测序技术的发展成就。粉色条框为第二代测序技术的成就。橙色部分则是第三代测序的成就。
由于测序技术的迅速发展，测序成本逐年降低，也导致各种大型商业化的测序中心的成立。如图2，世界上主流测序平台的分布图。值得骄傲的是，中国的测序业的发展并不逊色于欧洲各国，美国还是聚集了世界上最多的测序中心。
图2：测序平台在世界各地的分布情况。数字代表测序中心的数量。该地区超过百个测序中心，定位圆圈则会显示为红色。数据来源：http://omicsmaps.com/ 想知道你家附近有没有基因测序中心，到这个地图里查查就知道咯~~
初代桑格法
桑格法的核心原理非常简单，由于ddNTP的3’都不含羟基（-OH），其在DNA的合成过程中不能形成磷酸二酯键，因此可以用来中断DNA合成反应。在4个DNA合成反应体系中分别加入一定比例带有放射性同位素标记的ddNTP（分为：ddATP, ddCTP, ddGTP和ddTTP），通过凝胶电泳和放射自显影后可以根据电泳带的位置确定待测分子的DNA序列，如图3和图4。
图3:ddNTP比正常的dNTP还要少一个氧原子，会终止DNA链的合成。
图4:桑格法原理。
由于dNTP中混入了一定比例的某一特定的ddNTP，而且有四种不同的dNTP。那么分成四组反应，如图4（c）。分别加入ddTTP、ddCTP、ddATP和ddGTP的反应会间歇性地停止，合成出不同长度的DNA单链。电泳的结果则能告诉我们生成的DNA链的长短，进而判断每个位点的碱基是什么。
以上就是测序技术的简单发展史和初代桑格法。下期文章会带来二代和三代测序技术的内容，敬请期待。欢迎小伙伴们来信讨论！
图片来自网络，文字部分由BioEngX原创。
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你确定标记核素的是ddNTP?
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