2013年抹香鲸爆炸:进化，就现在

       在进化学说中有一个信条，那就是生物基因的微小改变将会传递给后代。通常来说，我们认为这一过程发生在DNA序列中：后代继承了微小而随机的基因突变结果。诚然，许多被继承的特征都存在于基因当中，比如水果的颜色、花朵的形状、身材的大小或者蜗牛壳的漩涡方向等，但它们并不是完全按照孟德尔遗传法则进行的。就如同孟德尔曾为山柳菊而困扰一样，转座因子、额外基因和单性生殖可以被用来解释一些反常现象，而最近的焦点则是外遗传修饰。

Frank Johannes at the University of Groningen in The Netherlands has been trying to understand the intricacies of epigenetic inheritance—specifically, how methylation of DNA bases can contribute to the inheritance of particular characteristics in Arabidopsis. “People are beginning to speculate,” he says. “ ‘ Wait a minute. What’s going on in nature? Does this contribute significantly to adaptation?’ ”

       荷兰格罗宁根大学的Frank Johannes正试图解析复杂的表观遗传现象，具体而言，是DNA碱基的甲基化在拟南芥植株某些特征的遗传中起到了怎样的作用。他说：“人们会禁不住开始猜测。自然界究竟发生了什么？这一点在适应自然的过程中起到了重要作用吗？”

But it’s hard to tell in most natural populations whether inheritance is due to DNA sequence variation or epigenetic changes. “We cannot delineate these two causes very well,” Johannes says. So with his collaborator, Fabrice Roux at the University of Science and Technology in Lille, France, he has been studying a large population of Arabidopsis plants with disrupted methylation patterns. The plants were derived from two Arabidopsis parents with essentially identical genomes, but with one having a mutated DDM1 DNA methylation gene. DDM1 is required for normal methylation—the conversion of cytosine, in cytosine-guanine pairs in the DNA, into 5-methylcytosine—and its mutation reduces genomic methylation by 70 percent.

       但在自然界大多数种群中，很难判断遗传是否源于DNA序列改变或者表观基因变异。Frank Johannes说：“我们还无法很好地描述这两种起因。”在法国里尔的科技大学，Fabrice Roux 及其拍档对处于中断甲基化模式下的拟南芥植株进行了大量的研究。这些植株源自两棵基因几乎相同的拟南芥，但其中一棵含有突变的DDM1甲基化DNA。甲基化需要DDM1，在甲基化过程中，DNA胞嘧啶-鸟嘌呤碱基对中的胞嘧啶发生转化，进而变成5-甲基胞嘧啶，而DDM1的突变可使基因甲基化的比例下降70%。

A team headed by Vincent Colot, now at the école Normale Supérieure in Paris, backcrossed the first generation offspring and selected progeny that were homozygous for the wild type DDM1 gene; in other words, with fully functional methylation machinery. They propagated the plants through a further six rounds of inbreeding, creating “epigenetic recombinant inbred lines” (epiRILs), which carried a mosaic of the parental epigenome. When Roux grew them in a common garden in northern France to subject the almost 6,000 plants to “realistic” ecological selection, they found that the epiRILs yielded plants with distinctly different phenotypes despite being effectively genetically identical.

       在巴黎高等师范学院，以 Vincent Colot为首的研究团队逆代杂交了第一代后代，并挑选出与野生DDM1基因可以纯合的后代；也就是说，它们拥有完整功能的甲基化特性。他们对这些植株进行了6个月的同系繁殖，创造出了携带有母体表观基因组的“额外基因重组体自交系”（epiRILs）。Roux把它们种植在法国北部的一个普通花园里，让这近6000棵植株经受“真实的”生态选择，结果这些 基因相同的epiRILs植株的后代却拥有完全不同的表型。　　

The segregation and heritability of these traits—which included flowering time and plant height—mirrored those found in naturally divergent Arabidopsis populations, in which phenotypic variation represents adaptations to different environmental conditions. But natural populations have had thousands of years to generate these variations: the epiRILs managed to do it in just eight generations. Andrew Hudson at the University of Edinburgh says there is a clear implication that “DNA methylation and epigenetic changes are important in evolution.”

       这些特征的隔离与可遗传性，包括花期和植株高度，与自然分化的拟南芥种群保持了一致，而自然生长的拟南芥其表型变异则代表着对不同环境条件的适应。自然物种经过了数千年才产生这些变异，而epiRILs仅仅过了8代就完成了。爱丁堡大学的Andrew Hudson表示，这明显意味着“DNA甲基化和表观基因变异在进化中是非常重要的”。

Johannes explains that there are at least two processes that can influence the epigenome: point mutations in genes that control methylation such as DDM1 that create an additional layer of variation; and environmental impacts that can influence the methylation state, which can then be inherited. New variations of plants, perhaps better adapted to a change in environment, could therefore arise much more quickly than previously thought. Research in this area is “still correlative but nevertheless very interesting,” Hudson says.

       Johannes解释称，至少存在2个可以影响表观基因组的过程：基因中控制甲基化的部分，例如DDM1，发生点突变，产生了额外的一层变异；环境因素影响了甲基化状态，并被遗传下去。也许是更好地适应了环境的变化，植株进一步的变异可能因此会以更快的速度涌现。Hudson说，该领域的研究“仍然相互关联但却十分有趣”。

But epigenetic changes are not typically as stable as changes in DNA sequence. Some stretches of DNA do remain unmethylated for at least ten generations, Johannes says, but other sequences revert to their “wild type” methylation state due to random fluctuations, or reversion brought about by small RNAs that try to correct the defects. It may be that epigenetic changes could be reinforced by mutations in the DNA, making them stable and heritable in the conventional way. Indeed, some of the sequences affected by the DDM1 mutation are likely to be associated with the mobilization of transposable elements, which would result in immediate—and heritable—DNA sequence changes.

       但表观基因组的变异并不如DNA序列的改变那么稳定。Johannes称，DNA的一些片段在至少10代之内都不会发生甲基化，但其它序列却由于随机的波动恢复到“野生品种”的甲基化状态，或者由于一些很小的RNA试图修正错误而恢复到原来的状态。也许表观基因变异会因DNA突变而得到强化，且由此变得稳定并以常规方式遗传下去。一些受到DDM1突变影响的序列的确有可能与转座因子的活动有关联，而这将导致直接且可遗传的DNA序列变化。

Another complication arises because some traits, particularly those associated with seed production, don’t seem to dabble in epigenetic inheritance. Johannes speculates that there might be an “obscure epigenetic editing process going on” that repairs disadvantageous epigenetic states for crucial genes. “You can imagine,” he says, that there’s “some sort of rescue mechanism,” particularly for gene networks that control a process as important as seed production.

       在研究过程中还出现了另外一个复杂的问题，一些生物特征，尤其是那些与育种有关的特征，似乎与表观基因遗传并不相关。Johannes推测也许存在一个“不明显的表观基因改写过程”，这为关键基因修复了有缺点的表观基因状态。他说，“可以想象一下”，在控制育种等重要过程的基因网络中存在“某种修复机制”。

In collaboration with Colot, Johannes hopes to answer such questions by performing genome-wide measurements to establish exactly which genetic elements in the genome are affected by epigenetic perturbation. He already has measurements of genome-wide methylation from more than a hundred individual plants, and is performing what he thinks is the first genome-wide epigenetic linkage study—the epigenetic equivalent of genome-wide association studies of human disease. In parallel, he wants to mathematically model the epigenetic effects and incorporate them into population genetics models, to understand dynamic inheritance patterns that cannot be explained by purely Mendelian genetics.

       在与Colot,的合作中，Johannes希望能通过全基因组测量的方法找出究竟哪些基因片段受到了表观基因扰动的影响，并进而回答前面提到的问题。 他如今已经完成了对100多种植物的全基因组甲基化测量，并开始着手于他认为的首次全基因组表观基因连接研究，该研究与人类疾病的全基因组关联研究在表观基因方面具有同等价值。同时，他还想建立表观基因效应的数学模型，并将其与种群遗传学模型进行结合，用以理解孟德尔遗传学所无法解释的动态遗传方式。

Correction (10/04/2011): The original version of this article incorrectly stated that Fabrice Roux created the epiRILs used to demonstrate the effects of methylation on the phenotypic variation that can arise in just 8 generations within a population of Arabidopsis plants grown in the same environment. In fact, a team led by Vincent Colot created the plants, and the story has been corrected to reflect this. The Scientist regrets the error.

更正（10/04/2011）：该文章的原始版本错误地认为Fabrice Roux创造了epiRILs，而事实上应该归功于Vincent Colot的团队。《科学家》杂志已经勘误并致歉。