Combinatorial Genetics Reveals a Scaling Law for the Effects of Mutations on Splicing
Combinatorial Genetics Reveals a Scaling Law for the Effects of Mutations on Splicing
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DOI：
10.1016/j.cell.2018.12.010
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发表时间：
2019-01-24
期刊：
影响因子：
64.5
通讯作者：
Lehner, Ben
中科院分区：
文献类型：
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作者：
Baeza-Centurion, Pablo;Minana, Belen;Lehner, Ben
尽管有丰富的分子知识，但用于准确预测生物现象的定量定律仍然很少。前体mRNA选择性剪接是人类疾病中基因表达经常受到干扰的重要调控步骤。为了了解突变在进化过程中的综合效应，我们量化了在选择性剪接的人类外显子出现期间积累的外显子突变的所有可能组合的效应。这揭示了突变效应随着外显子的包含水平非单调地缩放，每个突变在可预测的中间包含水平具有最大效应。这种缩放在全基因组范围内观察到剪接的顺式和反式扰动，包括天然和疾病相关的变体。数学建模表明，选择性剪接位点之间的竞争足以导致基因型-表型图谱中的这种非线性。将全局标度律与相邻突变之间的特定成对相互作用相结合，可以准确预测涉及>10个突变的复杂基因型变化的影响。
Despite a wealth of molecular knowledge, quantitative laws for accurate prediction of biological phenomena remain rare. Alternative pre-mRNA splicing is an important regulated step in gene expression frequently perturbed in human disease. To understand the combined effects of mutations during evolution, we quantified the effects of all possible combinations of exonic mutations accumulated during the emergence of an alternatively spliced human exon. This revealed that mutation effects scale non-monotonically with the inclusion level of an exon, with each mutation having maximum effect at a predictable intermediate inclusion level. This scaling is observed genome-wide for cis and trans perturbations of splicing, including for natural and disease-associated variants. Mathematical modeling suggests that competition between alternative splice sites is sufficient to cause this non-linearity in the genotype-phenotype map. Combining the global scaling law with specific pairwise interactions between neighboringmutations allows accurate prediction of the effects of complex genotype changes involving >10 mutations.