Nature介绍预测基因突变结果的新方法

　　

生物通报道：来自西班牙庞培法布拉大学的研究人员发表了一篇题为“Predicting mutation outcome from early stochastic variation in genetic interaction partners”的小短文，介绍了他们建立的一种可以直接预测发育中的动物的突变后果的方法，这种方法可以预测每个动物个体的成年表现型，相关成果公布在Nature杂志上。

许多基因突变，包括引起疾病的突变，都只会产生个体亚集的一个不利影响，其中的原因未知，但有研究表明这可能与额外的遗传变异，和环境风险因素有关。然而目前的基因决定论也存在局限性，比如说双胞胎的相同基因损伤却会产生不相同的后果，或者实验室中的突变，即便是在同质化环境中，在同基因的动物中也会产生不同的影响。

为了能更清楚的了解基因突变带来的影响，在这篇文章中，研究人员建立了一个基于遗传相互作用网络，可以直接预测发育中的动物的突变后果的模型方法。他们利用线虫作为模式系统，采用了一种非侵入性的、基于荧光的方法来监测线虫胚胎发育过程中的基因表达，并回顾性地将各个胚胎中的分子噪音与各自成年个体中的表现型进行了比较。

这样研究人员就识别出了两个调控性补偿机制：一个出现在密切相关的基因中；另一个涉及伴护分子等普遍性调控因子。根据这些补偿的强度，可以预测每个动物个体的成年表现型。这一模型和方法学为分析不完全外显（incomplete penetrance）成因提供了一个框架，而且也分析内部遗传突变与外部环境影响提供了新方法。

除此之外，近期的研究表明平均每个人的体内基因组都出现了大约60处各种突变。人类基因组由23对染色体组成。这项研究发现携带父亲染色体的精子和携带母亲染色体的卵子的基因成分都出现了突变，从而在孩子的基因组构成中出现了在父母基因组中都不曾出现的新基因。这项研究也使之前有关这种基因变异究竟源自父方还是母方的争议变得模糊起来，因为这意味着这样的争论是没有意义的，这种变异因人而异，或来自父方，或来自母方。

延伸阅读：《Nature Genetics》揭示人群间新突变产生速度和模式的差异

（生物通：万纹）

原文摘要：

Predicting mutation outcome from early stochastic variation in genetic interaction partners

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 factors1. However, phenotypic discordance remains even in the absence of genetic variation, for example between monozygotic twins2, and incomplete penetrance of mutations is frequent in isogenic model organisms in homogeneous environments3, 4. Here we propose a model for incomplete penetrance based on genetic interaction networks5, 6. 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 failure7. 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 variation8, 9, 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.