决定氨基酸的密码子通常不止一个，三联体密码子中第三个核苷酸的置换往往并不影响蛋白质在该处的氨基酸组成，因此研究人员认为最终得到的蛋白质结构和功能也不会产生变化，这样的突变被称为“沉默突变”。
但是现在，这一细胞生物学理论却有可能被颠覆。美国食物和药品管理局的Chava Kimchi-Sarfaty和他的同事日前在《科学》杂志在线报告说，这种沉默突变并不“沉默”，在某种情况下可以决定蛋白质的最终表现。
沉默突变不影响氨基酸顺序可能是因为蛋白质是由三个核苷酸编码的，每个核苷酸都负责在蛋白质链上加一个特定的氨基酸。突变的核苷酸也可能依然添加上同样的氨基酸。因此氨基酸组成和蛋白质结构也被认为不会变化。
然而，每隔一段时间，就会有一些数据不符合这个假设，比如一种叫做多药物排斥-1(MDR-1)的基因。该基因已经被发现在人类癌细胞中频繁地发生特殊的沉默突变。MDR-1编码的蛋白P-gp可以把化学疗法的药物排出癌细胞，从而使药物失效。对为什么叫做C3435T的沉默突变比对癌细胞存活没有作用的突变发生得更频繁，研究人员感到好奇。
Kimchi-Sarfaty的小组得到了以下几个版本的细胞系：正常MDR-1基因细胞系，携带C3435T 突变的MDR-1基因细胞系，携带常伴随C3435T出现的两个突变(一个是沉默突变，另外一个是非沉默突变，但对蛋白的功能没有影响)的MDR-1基因细胞系，和一些同时携带两种或三种突变的MDR-1细胞系。
研究结果显示，各种突变单独看来似乎都不受影响：每个版本的基因变量编码的P-gp蛋白都能精确地把药物排出细胞。但是携带了C3435T突变和另外一两种突变的MDR-1基因的细胞可以更好地使癌细胞摆脱药物，从而使细胞活得更久。然而如果突变的P-gp拥有和正常的P-gp相同的氨基酸顺序的话，怎么会发生这种情况呢？
令研究人员吃惊的是，一项生化测试显示，突变的P-gp的三维结构略有不同。Kimchi-Sarfaty表示，沉默突变也许发生在细胞不常使用的三联体核苷酸上，这些三联体核苷酸可以减缓细胞的蛋白质制造机制。类似Silly String牌喷彩摩丝以不同速度喷射出去的设计，氨基酸链三维结构的折叠也是由速度决定的，较慢的折叠可以导致蛋白质最终形式的改变。细胞可能可以弥补一次沉默突变，但对那些多重的极少使用的三联体密码子则不行。
波特兰俄勒冈健康和科学大学的细胞生物学家William Skach表示，这是一个极具争议的结论，沉默突变可能有这样的效果是“一个全新的概念”。他预言，更多的研究人员将会开始研究沉默突变。
英文原文：
Noise.
The normal gene for P-gp (left) and a triple mutant (right) make the same amount of protein in the cell. But the protein's structure and function are altered.
Credit: C. Kimchi-Sarfaty et al.
The Sound of a Silent Mutation
Another dogma in cell biology seems about to be toppled: If a mutation in a gene doesn't change the basic sequence of building blocks, then it has no effect. Chava Kimchi-Sarfaty of the U.S. Food and Drug Administration in Bethesda, Maryland, and colleagues report online this week in Science that such "silent mutations" can, under certain circumstances, determine how well a final protein performs--an "extremely provocative" result, says cell biologist William Skach of Oregon Health & Science University in Portland.
Silent mutations occur when the change of a single DNA nucleotide within a protein-coding portion of a gene does not affect the sequence of amino acids that make up the gene's protein. That's possible because proteins are encoded by "triplets" of nucleotides, each responsible for adding a particular amino acid to the protein chain. A change in one nucleotide, however, doesn't always change the triplet's meaning; the mutated triplet may still add the same amino acid. And when the amino acids of a protein stay the same, researchers believed, so do its structure and function.
But every once in a while, data crop up that don't make sense; for example, a gene called multidrug resistance-1 (MDR-1) has been found to frequently have a particular silent mutation in human cancer cells. MDR-1 produces P-gp, a protein that pumps chemotherapy drugs out of cancer cells, thus making the drugs useless. Researchers wondered why the silent mutation, called C3435T, showed up much more frequently than expected for a change that doesn't have an effect on the cancer cells' survival.
Kimchi-Sarfaty's team made cell lines that had either the normal MDR-1 gene, a version with the C3435T mutation, versions with either of two other mutations known to occur sometimes along with C3435T (one of them silent as well, the other nonsilent but without an effect on protein function), and versions with various combinations of two or three of the mutations.
They found that the mutations individually appeared to have no effect: The P-gp proteins encoded by each gene variant were just as proficient at pumping drugs out of cells. But cells with the MDR-1 gene containing the C3435T mutation plus one or two of the other two mutations did a much better job of ridding cancer cells of the drugs, allowing the cells to live another day.
How is this possible if the variant P-gp has the same string of amino acids as the normal one? To the researchers' surprise, a biochemical test suggested that the mutant P-gp has a slightly different three-dimensional shape. Perhaps, Kimchi-Sarfaty says, the silent mutations reside in nucleotide triplets that cells don't use very often, which could slow down the cell's proteinmaking machinery. Like designs made with Silly String spraying out at different velocities, the folding of an amino acid chain into a 3D structure is somewhat speed-dependent, and slower production could cause the protein to take an altered final form. The cell might be able to compensate for one silent mutation but not for multiple rarely used triplets.
The idea that silent mutations might have such effects is "an entirely new concept," Skach says. His prediction: More researchers will start listening to what silent mutations have to say.
