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From Chemoproteomic-Detected Amino Acids to Genomic Coordinates: Insights into Precise Multi-omic Data Integration

Maria F. Palafox, Valerie A. Arboleda, View ORCID ProfileKeriann M. Backus
doi: https://doi.org/10.1101/2020.07.03.186007
Maria F. Palafox
1Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
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Valerie A. Arboleda
1Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
2Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
5Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA
7Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, 90095, USA
8Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, 90095, USA
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  • For correspondence: varboleda@mednet.ucla.edu kbackus@mednet.ucla.edu
Keriann M. Backus
3Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
4Department of Chemistry and Biochemistry, College of Arts and Sciences, UCLA, Los Angeles, CA, 90095, USA
5Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA
6DOE Institute for Genomics and Proteomics, UCLA, Los Angeles, CA, 90095, USA
7Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, 90095, USA
8Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, 90095, USA
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  • ORCID record for Keriann M. Backus
  • For correspondence: varboleda@mednet.ucla.edu kbackus@mednet.ucla.edu
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ABSTRACT

The integration of proteomic, transcriptomic, and genetic-variant annotation data will improve our understanding genotype-phenotype associations. Due, in part, to challenges associated with accurate inter-database mapping, such multi-omic studies have not extended to chemoproteomics, a method that measure the intrinsic reactivity and potential ‘druggability’ of nucleophilic amino acid side chains. Here, we evaluated two mapping approaches to match chemoproteomic-detected cysteine and lysine residues with their genetic coordinates. Our analysis reveals that databases update cycles and reliance on stable identifiers can lead to pervasive misidentification of labeled residues. Enabled by this examination of mapping strategies, we then integrated our chemoproteomic data with in silico generated predictions of genetic variant pathogenicity, which revealed that codons of highly reactive cysteines are enriched for genetic variants that are predicted to be more deleterious. Our study provides a roadmap for more precise inter-database comparisons and points to untapped opportunities to improve the predictive power of pathogenicity scores and to advance prioritization of putative druggable sites through integration of predictions of pathogenicity with chemoproteomic datasets.

  • Abbreviations

    (UniProtKB-SP)
    UniProt Knowledge Base-Swiss-Prot,
    (ENSP)
    External Reference (xref), Ensembl Protein,
    (ENSG)
    Ensembl Transcript (ENST), Ensembl Gene,
    (UKB)
    UniProt Knowledge Base,
    (CADD)
    Combined Annotation Dependent Depletion,
    (CpDAA)
    Chemoproteomic Detected Amino Acids,
    (CCDS)
    Consensus Coding Sequence,
    (DANN)
    Deleterious Annotation of genetic variants using Neural Networks,
    (FATHMM-MKL)
    Functional Analysis through Hidden Markov Models,
    (SNV)
    Protein Data Bank (PDB), single nucleotide variant,
    (dbNSFP)
    Database for Non Synonymous Functional predictions.
  • Copyright 
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    Posted July 04, 2020.
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    From Chemoproteomic-Detected Amino Acids to Genomic Coordinates: Insights into Precise Multi-omic Data Integration
    Maria F. Palafox, Valerie A. Arboleda, Keriann M. Backus
    bioRxiv 2020.07.03.186007; doi: https://doi.org/10.1101/2020.07.03.186007
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    From Chemoproteomic-Detected Amino Acids to Genomic Coordinates: Insights into Precise Multi-omic Data Integration
    Maria F. Palafox, Valerie A. Arboleda, Keriann M. Backus
    bioRxiv 2020.07.03.186007; doi: https://doi.org/10.1101/2020.07.03.186007

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