Discovering genotype-phenotype relationships with machine learning and the Visual Physiology Opsin Database (VPOD)

Abstract

Background: Predicting phenotypes from genetic variation is foundational for fields as diverse as bioengineering and global change biology, highlighting the importance of efficient methods to predict gene functions. Linking genetic changes to phenotypic changes has been a goal of decades of experimental work, especially for some model gene families including light-sensitive opsin proteins. Opsins can be expressed in vitro to measure light absorption parameters, including λmax - the wavelength of maximum absorbance - which strongly affects organismal phenotypes like color vision. Despite extensive research on opsins, the data remain dispersed, uncompiled, and often challenging to access, thereby precluding systematic and comprehensive analyses of the intricate relationships between genotype and phenotype. Results: Here, we report a newly compiled database of all heterologously expressed opsin genes with λ max phenotypes called the Visual Physiology Opsin Database ( VPOD ). VPOD_1.0 contains 864 unique opsin genotypes and corresponding λ max phenotypes collected across all animals from 73 separate publications. We use VPOD data and deepBreaks to show regression-based machine learning (ML) models often reliably predict λ max , account for non-additive effects of mutations on function, and identify functionally critical amino acid sites. Conclusion: The ability to reliably predict functions from gene sequences alone using ML will allow robust exploration of molecular-evolutionary patterns governing phenotype, will inform functional and evolutionary connections to an organism’s ecological niche, and may be used more broadly for de-novo protein design. Together, our database, phenotype predictions, and model comparisons lay the groundwork for future research applicable to families of genes with quantifiable and comparable phenotypes. Key Points: We introduce the Visual Physiology Opsin Database (VPOD_1.0), which includes 864 unique animal opsin genotypes and corresponding λ max phenotypes from 73 separate publications. We demonstrate that regression-based ML models can reliably predict λmax from gene sequence alone, predict non-additive effects of mutations on function, and identify functionally critical amino acid sites. We provide an approach that lays the groundwork for future robust exploration of molecular-evolutionary patterns governing phenotype, with potential broader applications to any family of genes with quantifiable and comparable phenotypes.