Genomics 2 Proteins portal: A resource and discovery tool for linking genetic screening outputs to protein sequences and structures

Abstract

Recent advances in AI-based methods have revolutionized the field of structural biology. Concomitantly, high-throughput sequencing and functional genomics technologies have enabled the detection and generation of variants at an unprecedented scale. However, efficient tools and resources are needed to link these two disparate data types – to “map” variants onto protein structures, to better understand how the variation causes disease and thereby design therapeutics. Here we present the Genomics 2 Proteins Portal (G2P; g2p.broadinstitute.org/): a human proteome-wide resource that maps 19,996,443 genetic variants onto 42,413 protein sequences and 77,923 structures, with a comprehensive set of structural and functional features. Additionally, the G2P portal generalizes the capability of linking genomics to proteins beyond databases by allowing users to interactively upload protein residue-wise annotations (variants, scores, etc.) as well as the protein structure to establish the connection. The portal serves as an easy-to-use discovery tool for researchers and scientists to hypothesize the structure-function relationship between natural or synthetic variations and their molecular phenotype.

ema-tool: a Python Library for the Comparative Analysis of Embeddings from Biomedical Foundation Models

“…By comparing the embedding representations of all 880 HCN1 missense variants to a set of protein features collected from UniProt (25) and the Genomics 2 Proteins Portal (26), we find that embeddings of the subset of variants that are located in disordered regions of the protein (397 variants) are clustered in the embedding space of ESM-1b, but not that of ESM-2, when visually inspecting the first two principle components of each embedding space (see Figure 2 B). Interestingly, 100% of the 397 variants located in the disordered regions are putatively benign population variants from the gnomAD database.…”