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表观遗传学的神奇世界

发布: 2019-10-24 1,248阅读 306评论

“表观遗传”使获得性遗传再次引起科学家的兴奋，它已成为生命科学界最热门领域之一。以DNA为载体的中心法则仍是传递遗传信息的主要方式；而表观遗传可作为它重要的有益补充，而非你死我活的针锋相对。

瘾君子吸毒之后生出的婴儿，长大后也有步父母后尘的可能；甚至不经意的一些习惯，比如吸烟，喝酒，熬夜，嗜吃甜食都会影响后代……

这听起来有些可怕。

经典遗传学家斩钉截铁的“不”字会给你些许安慰。传统知识告诉我们，后天的行为方式不会在短时间内遗传，需要漫长世代的自我选择；而所谓的“获得性遗传”，更是一度被当做反例“批判”。进化论泰斗达尔文曾经希望他的物种演化理论能让即使十岁的孩子也看得懂，然而大自然不会给人类这样的机会。人类发现，自身获得的知识越多，越不得不感叹生命的精妙和复杂。近来，一门被称作“表观遗传”的学科引起科学家极大的兴奋。它已成为生命科学界最热门的领域之一。

7岁的奥利维亚和伊莎贝拉来自英国，她们是一对同卵双胞胎，拥有近乎完全一致的遗传信息。不过，两个女孩的命运却迥然相异。2005年6月，1岁的奥利维亚忽然高烧不退。血液化验的结果让大家大吃一惊：奥利维亚患上了急性白血病。因为是同卵双胞胎，医生连忙对伊莎贝拉也进行了检查，结果让人松了一口气：一切正常。在医生们的帮助下，小奥利维亚最终恢复健康，但医学专家们却遇到了一个困惑多年的难题：既然是同卵双胞胎，为何奥利维亚不断生病，而伊莎贝拉却非常健康呢？

随着研究越来越深入，困扰医生的答案也将渐渐浮出水面。这些经典遗传学无法解释的现象，表观遗传学有望部分揭示。2009年，西班牙和美国的科学家在全基因组水平分析了一对同卵双胞胎的基因组：他们一方正常，一方患有红斑狼疮。研究人员发现，虽为同卵双胞胎，但双方个体对遗传信息的“表观修饰”存在大量差异——DNA甲基化水平不同。

事实上，很多例子证明了“表观修饰”的存在。

同样是2009年，来自拉什大学医学中心和塔夫茨大学医学院的科学家对一些小鼠的遗传基因进行人为突变，使其智力出现缺陷。当这些小鼠被置于丰富环境中进行刺激、并频繁与各物体接触两周后，它们原有的记忆力缺陷得到了恢复。数月后，小鼠们受孕。虽然它们的后代也出现了和母亲同样的基因缺陷，但没有接触复杂丰富的环境并受刺激的新生小鼠丝毫没有记忆力缺陷的迹象。在这篇发表在《神经科学》的文章中，拉里·费格博士谈到，发生在小鼠身上、把对环境的感应遗传下去的现象，在理论上被称为“表观遗传学”。

表观遗传学（epigenetics）是指不涉及DNA?序列改变的基因或者蛋白表达的变化，?并可以在发育和细胞增殖过程中稳定传递的遗传学分支学科。表观遗传的现象很多，已知的有DNA甲基化(DNA methylation)，基因组印记(genomic impriting)，母体效应(maternal effects)，基因沉默(gene silencing)，核仁显性，休眠转座子激活和RNA编辑(RNA editing)等，国际上表观遗传学已经构成了系统遗传学研究的一个重要方面。

表观遗传学是与遗传学(genetic)相对应的概念。遗传学是指基于基因序列改变所 致基因表达水平变化，如基因突变、基因杂合丢失和微卫星不稳定等;而表观遗传学 则是指基于非基因序列改变所致基因表达水平变化，如DNA甲基化和染色质构象变 化等。比较通俗的讲表观遗传学是研究在没有细胞核DNA序列改变的情况时，基因功能的可逆的、可遗传的改变。也指生物发育过程中包含的程序的研究。在这两种情况下，研究的对象都包括在DNA序列中未包含的基因调控信息如何传递到(细胞或生物体的)下一代这个问题。在西方文字中epigenetics即指在DNA包含的遗传信息以外附加的(希腊文前缀epi-)。

也就是说，人类不仅有作为遗传物质的基因组信息，还有一套管理、调控、修饰基因组的密码指令系统。不同的个体，指令系统也不同。另外，这套密码指令还能在特定环境下发生改变。更神奇的是，改变后的指令很可能会遗传下去。然而，这套系统是如何发生改变并遗传，在相当长一段时间内并不为人知。

神奇的开关

事情慢慢有了转机。科学家们发现了一种甲基分子（-CH3），它就像一个帽子：带上它，基因关闭；摘掉它，基因表达——被分别称为甲基化和去甲基化。这些数以百万计的甲基有些直接附着在DNA上面，有些则附着在某些和DNA纠结在一起的组蛋白上。当机体不希望某些基因信息被读取时，基因的“启动子”DNA就被戴上很多甲基帽，使得基因无法从那里读取，启动功能。因此，即使携带遗传信息完全一样的两个个体，由于表达修饰上的差异，也可能会表现出完全不同的性状。

2001年，科学家们做了这样一个实验。研究者采用遗传背景完全相同的小鼠作为实验对象,来观察其皮毛的颜色。结果发现，小鼠们皮毛的颜色各种各样，从黄色到各种杂合色都有。让人意外的是，皮毛颜色的不同竟取决于它们从母鼠中继承的“agouti基因”甲基化程度高低。

2003年，美国杜克大学教授兰迪·朱特尔和罗伯特·沃特兰博士终于掀开了DNA甲基化的神秘面纱。人们此前认为，在形成精子和胚胎前的植入阶段，细胞中的DNA甲基化几乎会完全重新洗牌，也就是说“基因修饰”没有遗传下去的可能。近些年来，越来越多的研究证明，某些甲基化是可以遗传的。

2007年，日本科学家在小鼠中发现，一种称为stella的蛋白质能够有效保护卵子中某些基因的甲基化修饰，并传给下一代。研究人员还得出结论，基因的甲基化或者去甲基化，和环境的改变息息相关。也就是说，虽然遗传信息没有改变，但环境的改变、丰富的经历、甚至不良的习惯，都有可能遗传给后代。

然而，这些对基因的表观修饰是通过怎样的方式进行，它们又是靠怎样的机制遗传下去的呢？这一切曾经是个谜。不过近年来，科学家们已经获得了一些信息。

2011年6月，马萨诸塞大学医学院的科学家们发现，当果蝇处于胁迫条件下，它们会因适应环境而发生改变：原本紧密结合在“异染色质” DNA缠绕区的一种转录因子被释放出来，这些缠绕区域得以解开并进行复制。

表观遗传并非只是DNA甲基化这么简单。科学家们发现，对基因组的表观遗传修饰还包括组蛋白（可供DNA缠绕）的修饰、染色质的重塑、微小RNA的调节等诸多内容。

上帝的礼物

1939年,生物学家Waddington率先创造了“表观遗传学”这一术语；1942年，他认为生物体从基因到基因表型之间存在一种控制，这种控制机制就是“表观遗传学”。科普作家戴维·申克在作品《我们都是天才，是什么误导了我们》中写到，“人‘先天与后天之争’，因为表观遗传而显得苍白无力。表观遗传学可能是自发现基因后另一项最重要的发现。”甚至有人戏称，这是上帝送给人类的礼物。之所以称为礼物，是因为在肿瘤生成和治疗、干细胞分化等诸多领域，表观遗传学扮演了重要角色。

有研究人员发现，一部分DNA甲基化在肿瘤形成的早期发生了变化。并且，它不但对肿瘤早期转化起作用，甚至也能影响肿瘤的转移。2004年，美国食品及药品管理局首次批准了一种DNA甲基化抑制剂的新药——氮杂胞苷，用于治疗骨髓增生异常综合征。该药能通过去甲基化作用，提高“正面”基因的主导地位。据药品开发商Celgene公司介绍，重症病人服用氮杂胞苷后，寿命能延长约两年；而采用传统疗法的患者，存活期只有15个月。

正因如此，不少技术人员对利用表观遗传学开发药物表现出极大兴趣。例如，目前尚无好方法治疗药物成瘾。科学家发现，成瘾药物会导致脑区的基因调控水平的改变。即使戒药后，这些基因表达的变化仍可存月余，甚至导致病人终生心理成瘾。而表观遗传让饱受困扰的病人看到了曙光。正因为这份礼物非常厚重，所以关于它的研究持续升温，进行得如火如荼。孙方霖认为，类似人类重大疾病、干细胞、体细胞重编程、衰老、神经科学研究等科学问题，其分子机制都离不开表观遗传调控。而基因组学的科学家们，正尝试着找出某一特定群体之间表观遗传的差异，更好地诠释生命奥秘。

拉马克主义归来？

19世纪初，法国人拉马克提出了“获得性性状”可以遗传的假说，该假说被称为“拉马克主义”。比达尔文大84岁的拉马克，认为进化有可能在较短世代间发生：受环境选择，生物努力向优等方面进化，而达尔文却认为优胜劣汰是自然界的长久主题，进化存在于相当漫长的时间内。

一只长颈鹿可以很好地诠释他们之间的分歧：拉马克认为，长颈鹿的祖先生活在缺乏青草的环境里，不得不经常努力地伸长脖子去吃树上的叶子，由于经常使用，颈和前肢逐渐变得越来越长，并且这些“获得的性状”能够遗传给后代；达尔文则认为，在某些个体偶然产生变异、脖子变长后，由于更适应自然，经过逐代积累，“长脖子”占据优势，完成缓慢进化。

在孟德尔经典遗传学——中心法则被确立为正统地位后，拉马克主义更是彻底被当时的人们所抛弃。然而，表观遗传学的发现，却对经典遗传学构成极大挑战，使人们不得不重新审视拉马克主义。这是因为，表观遗传在某些方面表现出了“获得性遗传”。首先，可以从后天环境中“获得”性状；其次，这种性状可以“遗传”给后代。

那么，拉马克主义是否成功归来了？事实可远没有这么简单。毕竟，表观遗传还未被证明在任何外界压力下都会产生性状改变，不能够像DNA遗传那样，“一是一，二是二”，另外，一些缺失的环节仍然有待发现。例如有实验表明，表观遗传的印记在没有环境压力的数代之后，可能会渐渐丢失。

事实上，以DNA为载体的中心法则仍是传递遗传信息的主要方式；而表观遗传可作为它重要的有益补充，而非你死我活的针锋相对。无论如何，获得性遗传现象的发现，足够令人深省。当人类获知生命奥妙的半径越大，基因调控这个大圆周长也就越长，圆面积也就越大。要知道，生命机制可远比人类预期要复杂得多。科学，就是在构建——推翻——再构建中曲折前行。我们需要保持对自然的足够敬畏，或许哪怕一丁点儿的傲慢就将让我们与真理失之交臂。即使拉马克主义不能归来，也到该为他正名的时候了。

上述对“表观遗传学”这神奇的历史发展介绍后，相信童鞋们对此有浓厚的兴趣，而它未来的走向又如何，是否有更精彩纷呈的篇章！待我们一起去编写和发现！

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