MUTATIONAL SCANNING

Description

We use massive-scale experimentation and mathematical modeling to understand and predict how the biophysical properties of the molecules of life are encoded in their sequences. These fundamental encoding functions underlie all of biology with implications for our understanding of genetic diseases, evolutionary adaptation, and biomolecular engineering.

To approach these problems, we use deep mutational scanning (DMS), a powerful experimental technique that allows us to systematically measure the functional effects of thousands of genetic variants in a single experiment. By combining high-throughput mutagenesis with functional selection assays and deep sequencing readouts, we create comprehensive maps of how sequence changes affect the functions and biophysical properties of biomolecules. We then use these rich, well-calibrated datasets to train predictive models to generalize beyond the proteins that we have measured.

Strategy to solve the fundamental encoding functions of biology

We specialize in developing and applying DMS approaches to understand the effects of mutations on human proteins in the context of genetic diseases. Mutations can disrupt protein function through different molecular mechanisms including destabilization, loss of activity or protein-protein interactions, aggregation, or gain of function – often occurring in the same gene. To move towards true personalized medicine for genetic diseases, a complete predictive understanding of mutation effects in proteins is required: only this will allow us to develop treatments effective for every specific mutation present in every individual patient. To move in this direction, we are using DMS to generate mechanistic maps of mutation effects across the human proteome.

Mutation effects on stability in four different human genetic disease protein domains

Personal

Last Publications

1. Site-saturation mutagenesis of 500 human protein domains. A Beltran, X Jiang, Y Shen, B Lehner (2025). Nature, 637, 885–894
2. Deep indel mutagenesis reveals the impact of amino acid insertions and deletions on protein stability and function. M Topolska, A Beltran, B Lehner (2025). Nature communications, 16, 2617.
3. The allosteric landscape of the Src kinase. A Beltran, AJ Faure, B Lehner (2024). bioRxiv, 2024.04. 26.591297.
4. The genetic architecture of protein stability. AJ Faure, A Martí-Aranda, C Hidalgo-Carcedo, A Beltran, JM Schmiedel, B Lehner (2024). Nature, 634, 995–1003
5. Revolutionizing large-scale DNA synthesis with a microchip-based massive in parallel synthesis system. X Zhang, X Jiang, Y Wang, Q Chen, R Zhang, H Jiang, H Zhang, A Beltran, et al. (2024). bioRxiv, 2024.10. 30.619547.