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Sloan Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000879","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Simons Center for Quantitative Biology at CSHL"},{"DOI":"10.13039\/100013428","name":"College of Liberal Arts and Sciences at the University of Florida","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013428","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Quantitative models of sequence-function relationships are ubiquitous in computational biology, e.g., for modeling the DNA binding of transcription factors or the fitness landscapes of proteins. Interpreting these models, however, is complicated by the fact that the values of model parameters can often be changed without affecting model predictions. Before the values of model parameters can be meaningfully interpreted, one must remove these degrees of freedom (called \u201cgauge freedoms\u201d in physics) by imposing additional constraints (a process called \u201cfixing the gauge\u201d). However, strategies for fixing the gauge of sequence-function relationships have received little attention. Here we derive an analytically tractable family of gauges for a large class of sequence-function relationships. These gauges are derived in the context of models with all-order interactions, but an important subset of these gauges can be applied to diverse types of models, including additive models, pairwise-interaction models, and models with higher-order interactions. Many commonly used gauges are special cases of gauges within this family. We demonstrate the utility of this family of gauges by showing how different choices of gauge can be used both to explore complex activity landscapes and to reveal simplified models that are approximately correct within localized regions of sequence space. The results provide practical gauge-fixing strategies and demonstrate the utility of gauge-fixing for model exploration and interpretation.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012818","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T13:44:22Z","timestamp":1742478262000},"page":"e1012818","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Gauge fixing for sequence-function relationships"],"prefix":"10.1371","volume":"21","author":[{"given":"Anna","family":"Posfai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juannan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"McCandlish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1897-3778","authenticated-orcid":true,"given":"Justin B.","family":"Kinney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,3,20]]},"reference":[{"key":"pcbi.1012818.ref001","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1146\/annurev-genom-083118-014845","article-title":"Massively parallel assays and quantitative sequence-function relationships","volume":"20","author":"JB Kinney","year":"2019","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"pcbi.1012818.ref002","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/BF00216965","article-title":"Fourier and Taylor series on fitness landscapes","volume":"65","author":"ED Weinberger","year":"1991","journal-title":"Biol Cybern"},{"key":"pcbi.1012818.ref003","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF01165154","article-title":"Landscapes and their correlation functions","volume":"20","author":"PF Stadler","year":"1996","journal-title":"J Math Chem"},{"issue":"6","key":"pcbi.1012818.ref004","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.gde.2013.10.007","article-title":"Should evolutionary geneticists worry about higher-order epistasis?","volume":"23","author":"DM Weinreich","year":"2013","journal-title":"Curr Opin Genet Dev"},{"issue":"6","key":"pcbi.1012818.ref005","doi-asserted-by":"crossref","first-page":"e1004771","DOI":"10.1371\/journal.pcbi.1004771","article-title":"The context-dependence of mutations: a linkage of formalisms","volume":"12","author":"FJ Poelwijk","year":"2016","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1012818.ref006","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.jtbi.2016.01.037","article-title":"Measuring epistasis in fitness landscapes: the correlation of fitness effects of mutations","volume":"396","author":"L Ferretti","year":"2016","journal-title":"J Theor Biol"},{"issue":"49","key":"pcbi.1012818.ref007","doi-asserted-by":"crossref","first-page":"14085","DOI":"10.1073\/pnas.1612676113","article-title":"On the (un)predictability of a large intragenic fitness landscape","volume":"113","author":"C Bank","year":"2016","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pcbi.1012818.ref008","doi-asserted-by":"crossref","first-page":"4213","DOI":"10.1038\/s41467-019-12130-8","article-title":"Learning the pattern of epistasis linking genotype and phenotype in a protein","volume":"10","author":"FJ Poelwijk","year":"2019","journal-title":"Nat Commun"},{"issue":"1","key":"pcbi.1012818.ref009","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13059-022-02661-7","article-title":"MAVE-NN: learning genotype-phenotype maps from multiplex assays of variant effect","volume":"23","author":"A Tareen","year":"2022","journal-title":"Genome Biol"},{"key":"pcbi.1012818.ref010","doi-asserted-by":"crossref","first-page":"e2109649118","DOI":"10.1073\/pnas.2109649118","article-title":"On the sparsity of fitness functions and implications for learning","volume":"119","author":"D Brookes","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"pcbi.1012818.ref011","doi-asserted-by":"crossref","first-page":"e1012132","DOI":"10.1371\/journal.pcbi.1012132","article-title":"An extension of the Walsh-Hadamard transform to calculate and model epistasis in genetic landscapes of arbitrary shape and complexity","volume":"20","author":"AJ Faure","year":"2024","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1012818.ref012","doi-asserted-by":"crossref","unstructured":"Metzger BPH, Park Y, Starr TN, Thornton JW. 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