期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：39
DOI：10.1073/pnas.2204233119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
One core goal of genetics is to systematically understand the mapping between the DNA sequence of an organism (genotype) and its measurable characteristics (phenotype). Understanding this mapping is often challenging because of interactions between mutations, where the result of combining several different mutations can be very different than the sum of their individual effects. Here we provide a statistical framework for modeling complex genetic interactions of this type. The key idea is to ask how fast the effects of mutations change when introducing the same mutation in increasingly distant genetic backgrounds. We then propose a model for phenotypic prediction that takes into account this tendency for the effects of mutations to be more similar in nearby genetic backgrounds.
Contemporary high-throughput mutagenesis experiments are providing an increasingly detailed view of the complex patterns of genetic interaction that occur between multiple mutations within a single protein or regulatory element. By simultaneously measuring the effects of thousands of combinations of mutations, these experiments have revealed that the genotype–phenotype relationship typically reflects not only genetic interactions between pairs of sites but also higher-order interactions among larger numbers of sites. However, modeling and understanding these higher-order interactions remains challenging. Here we present a method for reconstructing sequence-to-function mappings from partially observed data that can accommodate all orders of genetic interaction. The main idea is to make predictions for unobserved genotypes that match the type and extent of epistasis found in the observed data. This information on the type and extent of epistasis can be extracted by considering how phenotypic correlations change as a function of mutational distance, which is equivalent to estimating the fraction of phenotypic variance due to each order of genetic interaction (additive, pairwise, three-way, etc.). Using these estimated variance components, we then define an empirical Bayes prior that in expectation matches the observed pattern of epistasis and reconstruct the genotype–phenotype mapping by conducting Gaussian process regression under this prior. To demonstrate the power of this approach, we present an application to the antibody-binding domain GB1 and also provide a detailed exploration of a dataset consisting of high-throughput measurements for the splicing efficiency of human pre-mRNA
5
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splice sites, for which we also validate our model predictions via additional low-throughput experiments.
关键词：engenotype–phenotype mapGaussian processesgenetic interactionsplicingprotein G
