Gauge fixing for sequence-function relationships

Posfai, Anna, Zhou, Juannan, McCandlish, David M, Kinney, Justin B (March 2025) Gauge fixing for sequence-function relationships. PLoS Computational Biology, 21 (3). e1012818. ISSN 1553-734X (Public Dataset)

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Abstract

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 "gauge freedoms" in physics) by imposing additional constraints (a process called "fixing the gauge"). 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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > computational biology > algorithms bioinformatics > computational biology bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:	Posfai, Anna Zhou, Juannan McCandlish, David Kinney, Justin B.
Communities:	CSHL labs > Kinney lab CSHL labs > McCandlish lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	20 March 2025
Date Deposited:	24 Mar 2025 12:09
Last Modified:	24 Mar 2025 12:09
Related URLs:	Publisher
Dataset ID:	https://github.com/jbkinney/24_posfai1 https://doi.org/10.5281/zenodo.14811498
URI:	https://repository.cshl.edu/id/eprint/41828

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