Utilizing protein structure graph embeddings to predict the pathogenicity of missense variants

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Background Genetic variants can impact the structure of the corresponding protein, which can have detrimental effects on protein function. While the effect of protein truncating variants is often easier to evaluate, most genetic variants are missense variants. These variants are mostly single nucleotide variants which result in the exchange of a single amino acid. The effect on protein function of these variants can be challenging to deduce. To aid the interpretation of missense variants a variety of bioinformatic algorithms have been developed, yet current algorithms rarely directly use the protein structure as a feature to consider. Results We developed a machine learning workflow that utilizes the protein-language-model ESMFold to predict the protein structure of missense variants, which is subsequently embedded using graph autoencoders. The generated embeddings are used in a classifier model which predicts pathogenicity. We provide evidence that the generated graph embeddings improve classification accuracy of a XGBoost pathogenicity predictor, which should lead to a wide applicability for human genetic diseases. Additionally, we explored different levels of abstraction of the graph embeddings and their influence on the classifier. Finally, we compare the utility of graph embeddings from different protein-folding models.

Authors 5

1. Martin Danner Aachen 1. Institute for human genetics and genomic medicine Medical Faculty Institute for Human Genetics and Genomic Medicine

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   1. Institute for human genetics and genomic medicine, Medical Faculty, Uniklinik RWTH Aachen, Pauwelsstrasse 30, Aachen, 52074, North-Rhine-Westphalia, Germany. 2. scieneers GmbH, Kantstrasse 1a, Karlsruhe, 76137, Baden-Wuerttemberg, Germany.;

   . Institute for human genetics and genomic medicine, Medical Faculty, Uniklinik RWTH Aachen, Pauwelsstrasse 30, Aachen, 52074, North-Rhine-Westphalia, Germany. 2. scieneers GmbH, Kantstrasse a, Karlsruhe, 7637, Baden-Wuerttemberg, Germany

2. Matthias Begemann Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for human genetics and genomic medicine, Medical Faculty, Uniklinik RWTH Aachen, Pauwelsstrasse 30, Aachen, 52074, North-Rhine-Westphalia, Germany

   Institute for human genetics and genomic medicine, Medical Faculty, Uniklinik RWTH Aachen, Pauwelsstrasse 30, Aachen, 5074, North-Rhine-Westphalia, Germany

3. Miriam Elbracht Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for human genetics and genomic medicine, Medical Faculty, Uniklinik RWTH Aachen, Pauwelsstrasse 30, Aachen, 52074, North-Rhine-Westphalia, Germany

   Institute for human genetics and genomic medicine, Medical Faculty, Uniklinik RWTH Aachen, Pauwelsstrasse 30, Aachen, 5074, North-Rhine-Westphalia, Germany

4. Ingo Kurth Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for human genetics and genomic medicine, Medical Faculty, Uniklinik RWTH Aachen, Pauwelsstrasse 30, Aachen, 52074, North-Rhine-Westphalia, Germany

   Institute for human genetics and genomic medicine, Medical Faculty, Uniklinik RWTH Aachen, Pauwelsstrasse 30, Aachen, 5074, North-Rhine-Westphalia, Germany

5. Jeremias Krause corresponding Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for human genetics and genomic medicine, Medical Faculty, Uniklinik RWTH Aachen, Pauwelsstrasse 30, Aachen, 52074, North-Rhine-Westphalia, Germany

   Institute for human genetics and genomic medicine, Medical Faculty, Uniklinik RWTH Aachen, Pauwelsstrasse 30, Aachen, 5074, North-Rhine-Westphalia, Germany