Fine-tuning protein language models to understand the functional impact of missense variants.
Details
Serval ID
serval:BIB_226EA46C949F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Fine-tuning protein language models to understand the functional impact of missense variants.
Journal
Computational and structural biotechnology journal
ISSN
2001-0370 (Print)
ISSN-L
2001-0370
Publication state
Published
Issued date
2025
Peer-reviewed
Oui
Volume
27
Pages
2199-2207
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
Abstract
Elucidating the functional effects of missense variants is crucial yet challenging. To investigate their impact, we fine-tuned protein language models, including ESM2 and ProtT5, to classify 20 protein features at amino acid resolution. In addition, we trained a fully connected neural network classifier on frozen embeddings and compared its performance to fine-tuning in order to quantify the added value of task-specific adaptation. We then used the fine-tuned models to: 1) identify protein features enriched in either pathogenic or benign missense variants, and 2) compare the predicted feature profiles of proteins with reference and alternate alleles to understand how missense variants affect protein functionality. We show that our models can be used to reclassify variants of uncertain significance and provide mechanistic insights into the functional consequences of missense mutations.
Keywords
Fine-tuning, Mechanistic interpretation, Missense variant, Protein language models, Token classification
Pubmed
Web of science
Open Access
Yes
Create date
23/06/2025 13:58
Last modification date
24/06/2025 7:13