绝大多数遗传疾病（如精神分裂症或乳腺癌）对不同的人具有不同的作用。携带相同的突变，一个人会致病，而另一个人不会，即便比较基因组相同的2个同卵双胞胎，情况也是如此。但是，为什么相同突变在不同个体中会有不同的影响？
图片显示：相同突变如何差异性影响线虫个体
自20世纪以来，科研人员研究了遗传变异和环境（消费习惯和生活方式等）对疾病形成的影响，而本论文作者之一Alejandro Burga称：“遗传和环境的差异不能充分解释疾病形成，近10年来，我们一直研究细菌等简单微生物，并发现即便没有遗传和环境的差异，基因表达在个体间差别也很大，不会产生2个完全相同的细胞，有时这种差异起源于随机过程。研究结果表明，这种突变类型可对动物表型产生重要作用，对它的检测能有助于准确预测疾病等异常表型的概率。”
科研人员利用蛔虫这一模式生物开展实验。微小的蛔虫凭借其简单性成为生物学领域研究最广泛的生物体之一，也是第一个基因组测通的动物。近来，3个不同的诺贝尔奖颁给了关于线虫的研究。
由于遗传组成和环境不足于确定突变能否影响个体，研究人员开发出一种方法用于检测体内基因表达的微小差异。Ben Lehner补充道：“挑战不只是开发出一种能定量个体间微小差异的方法，而且要能预测与特定突变相关的基因。在蛔虫和人的细胞中，基因能协调一致共同执行功能。一些基因非常‘慷慨’，帮助数百个其它基因执行多个不同过程，而另一些基因仅帮助其它基因执行特定功能。预测个体疾病的关键是检测这2种基因的表达差异。”
这项研究表明，即便完全了解对特定疾病起重要作用的所用基因，我们还不能单纯从基因组序列中预测个体疾病。然而，为了开发出个性化和预测性医疗，研究人员有必要考虑个体中基因表达或关闭的差异程度。
Predicting mutation outcome from early stochastic variation in genetic interaction partners
Alejandro Burga, M. Olivia Casanueva & Ben Lehner
Many mutations, including those that cause disease, only have a detrimental effect in a subset of individuals. The reasons for this are usually unknown, but may include additional genetic variation and environmental risk factors. However, phenotypic discordance remains even in the absence of genetic variation, for example between monozygotic twins, and incomplete penetrance of mutations is frequent in isogenic model organisms in homogeneous environments. Here we propose a model for incomplete penetrance based on genetic interaction networks. Using Caenorhabditis elegans as a model system, we identify two compensation mechanisms that vary among individuals and influence mutation outcome. First, feedback induction of an ancestral gene duplicate differs across individuals, with high expression masking the effects of a mutation. This supports the hypothesis that redundancy is maintained in genomes to buffer stochastic developmental failure. Second, during normal embryonic development we find that there is substantial variation in the induction of molecular chaperones such as Hsp90 (DAF-21). Chaperones act as promiscuous buffers of genetic variation, and embryos with stronger induction of Hsp90 are less likely to be affected by an inherited mutation. Simultaneously quantifying the variation in these two independent responses allows the phenotypic outcome of a mutation to be more accurately predicted in individuals. Our model and methodology provide a framework for dissecting the causes of incomplete penetrance. Further, the results establish that inter-individual variation in both specific and more general buffering systems combine to determine the outcome inherited mutations in each individual.
文献链接：https://www.nature.com/nature/journal/v480/n7376/full/nature10665.html
