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PreprintCited by 11Genomics and Rare DiseasesCancer Genomics and DiagnosticsProtein Structure and Dynamics

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SPRI: Structure-Based Pathogenicity Relationship Identifier for Predicting Effects of Single Missense Variants and Discovery of Higher-Order Cancer Susceptibility Clusters of Mutations

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Wang, Boshen, Lei, Xue, Tian, Wei, Perez-Rathke, Alan, Tseng, Yan-Yuan, Liang, Jie·2022·Briefings in Bioinformatics
DOI 10.1101/2022.09.27.508720PMC PMC10359089

Preprint — published as 10.1093/bib/bbad206 · Paper page

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Abstract

We report the Structure-based Pathogenicity Relationship Identifier (SPRI), a novel computational tool for accurate evaluation of pathological effects of missense single mutations and prediction of higher-order spatially organized units of mutational clusters. SPRI can effectively extract properties determining pathogenicity encoded in protein structures, and can identify deleterious missense mutations of germ line origin associated with Mendelian diseases, as well as mutations of somatic origin associated with cancer drivers. It compares favorably to other methods in predicting deleterious mutations. Furthermore, SPRI can discover spatially organized pathogenic higher-order spatial clusters (patHOS) of deleterious mutations, including those of low recurrence, and can be used for discovery of candidate cancer driver genes and driver mutations. We further demonstrate that SPRI can take advantage of AlphaFold2 predicted structures and can be deployed for saturation mutation analysis of the whole human proteome.

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Metadata

Authors
Wang, B., Lei, X., Tian, W., Perez-Rathke, A., Tseng, Y.-Y., & Liang, J.
Affiliations
  • University of Illinois Chicago (US)
  • Wayne State University (US)
Corresponding author
  • Tseng, Yan-Yuan
  • Liang, Jie
ORCID
Venue
Briefings in Bioinformatics
Publisher
openRxiv
Published
2022-09-28
Volume
24
Issue
4
ISSN
1467-5463 (ISSN-L)
DOI
10.1101/2022.09.27.508720
PMC
PMC10359089
OpenAlex
W4381124915
Cited by
11
References
1
Citations by year
2026: 2 · 2025: 6 · 2024: 3
FWCI
1.83
Type
journal article
Language
en
Open access
Locations
  • Briefings in Bioinformatics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (R35GM127084)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
deleterious mutation prediction, protein structure, cancer driver genes, driver mutations, monogenic disorders, germline mutations, somatic mutations, AlphaFold2, saturation mutagenesis, human proteome
MeSH terms
Humans, Mutation, Neoplasms, Virulence, Computational Biology, Mutation, Missense

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