Site-saturation mutagenesis of 500 human protein domains

Nature, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Abstract Missense variants that change the amino acid sequences of proteins cause one-third human genetic diseases 1 . Tens millions missense exist in current population, and vast majority these have unknown functional consequences. Here we present a large-scale experimental analysis across many different proteins. Using DNA synthesis cellular selection experiments quantify effect more than 500,000 on abundance 500 protein domains. This dataset reveals 60% pathogenic reduce stability. The contribution stability to fitness varies is particularly important recessive disorders. We combine measurements with language models annotate sites Mutational effects are largely conserved homologous domains, enabling accurate prediction entire families using energy models. Our data demonstrate feasibility assaying at scale provides large consistent reference for clinical variant interpretation training benchmarking computational methods.

Язык: Английский

Why is it so hard to rewrite a genome?

Nature, Год журнала: 2025, Номер 638(8051), С. 848 - 850

Опубликована: Фев. 18, 2025

Язык: Английский