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：1
DOI：10.1073/pnas.2109649118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The properties of proteins and other biological molecules are encoded in large part in the sequence of amino acids or nucleotides that defines them. Increasingly, researchers estimate functions that map sequences to a particular property using machine learning and related statistical approaches. However, an important question remains unanswered: How many experimental measurements are needed in order to accurately learn these “fitness” functions? We leverage perspectives from the fields of biophysics, evolutionary biology, and signal processing to develop a theoretical framework that enables us to make progress on answering this question. We demonstrate that this framework can be used to make useful calculations on real-world data and suggest how these calculations may be used to guide experiments.
Fitness functions map biological sequences to a scalar property of interest. Accurate estimation of these functions yields biological insight and sets the foundation for model-based sequence design. However, the fitness datasets available to learn these functions are typically small relative to the large combinatorial space of sequences; characterizing how much data are needed for accurate estimation remains an open problem. There is a growing body of evidence demonstrating that empirical fitness functions display substantial sparsity when represented in terms of epistatic interactions. Moreover, the theory of Compressed Sensing provides scaling laws for the number of samples required to exactly recover a sparse function. Motivated by these results, we develop a framework to study the sparsity of fitness functions sampled from a generalization of the NK model, a widely used random field model of fitness functions. In particular, we present results that allow us to test the effect of the Generalized NK (GNK) model’s interpretable parameters—sequence length, alphabet size, and assumed interactions between sequence positions—on the sparsity of fitness functions sampled from the model and, consequently, the number of measurements required to exactly recover these functions. We validate our framework by demonstrating that GNK models with parameters set according to structural considerations can be used to accurately approximate the number of samples required to recover two empirical protein fitness functions and an RNA fitness function. In addition, we show that these GNK models identify important higher-order epistatic interactions in the empirical fitness functions using only structural information.
