articleNatureJan 8, 2025HYBRID OA

Site-saturation mutagenesis of 500 human protein domains

ABAntoni BeltranXJXiang’er JiangYSYue ShenBLBen Lehner

Centre for Genomic Regulation · BGI Group (China) · +4 more institutions

PubMed
Indexed incrossrefpubmed

Abstract

. Tens of millions of missense variants exist in the current human population, and the vast majority of these have unknown functional consequences. Here we present a large-scale experimental analysis of human missense variants across many different proteins. Using DNA synthesis and cellular selection experiments we quantify the effect of more than 500,000 variants on the abundance of more than 500 human protein domains. This dataset reveals that 60% of pathogenic missense variants reduce protein stability. The contribution of stability to protein fitness varies across proteins and diseases and is particularly important in recessive disorders. We combine stability measurements with protein language models to…

Citation impact

83
total citations
FWCI
114.10
Percentile
100%
References
95
Citations per year

Authors

4

Topics & keywords

Topics
Keywords
  • Missense mutation
  • Biology
  • Computational biology
  • Genetics
  • Saturated mutagenesis
  • Population
  • Phenotype
  • Protein superfamily
No related works found for this paper.

Funding