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MS/MS in silico subtraction-based proteomic profiling as an approach to facilitate disease gene discovery: application to lens development and cataract

  • Sandeep Aryal
  • Deepti Anand
  • Francisco G. Hernandez
  • Bailey A. T. Weatherbee
  • Hongzhan Huang
  • Ashok P. Reddy
  • Phillip A. Wilmarth
  • Larry L. David
  • Salil A. LachkeEmail author
Original Investigation

Abstract

While the bioinformatics resource-tool iSyTE (integrated Systems Tool for Eye gene discovery) effectively identifies human cataract-associated genes, it is currently based on just transcriptome data, and thus, it is necessary to include protein-level information to gain greater confidence in gene prioritization. Here, we expand iSyTE through development of a novel proteome-based resource on the lens and demonstrate its utility in cataract gene discovery. We applied high-throughput tandem mass spectrometry (MS/MS) to generate a global protein expression profile of mouse lens at embryonic day (E)14.5, which identified 2371 lens-expressed proteins. A major challenge of high-throughput expression profiling is identification of high-priority candidates among the thousands of expressed proteins. To address this problem, we generated new MS/MS proteome data on mouse whole embryonic body (WB). WB proteome was then used as a reference dataset for performing “in silico WB-subtraction” comparative analysis with the lens proteome, which effectively identified 422 proteins with lens-enriched expression at ≥ 2.5 average spectral counts, ≥ 2.0 fold enrichment (FDR < 0.01) cut-off. These top 20% candidates represent a rich pool of high-priority proteins in the lens including known human cataract-linked genes and many new potential regulators of lens development and homeostasis. This rich information is made publicly accessible through iSyTE (https://research.bioinformatics.udel.edu/iSyTE/), which enables user-friendly visualization of promising candidates, thus making iSyTE a comprehensive tool for cataract gene discovery.

Notes

Acknowledgements

The authors thank Drs. Melinda Duncan and Velia Fowler for helpful discussions. This work was supported by National Institutes of Health/National Eye Institute [R01 EY021505 to S.L.]. Support from the University of Delaware Core Imaging Facility and Proteomics and Mass Spectrometry Facility was made possible through the Institutional Development Award (IDeA) from the National Institutes of Health/National Institute of General Medical Sciences INBRE Program Grant [Grant Number P20 GM103446]. Acquisition of the confocal microscope used in this study was funded by the National Institutes of Health/National Center for Research Resources Grant [S10 RR027273]. Mass spectrometric analysis was performed by the OHSU Proteomics Shared Resource with partial support from NIH core Grants P30 EY010572 and P30 CA069533 and shared instrument Grant S10OD-012246. S.A. was supported by a Fight for Sight Summer Student Fellowship and Sigma Xi award.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sandeep Aryal
    • 1
  • Deepti Anand
    • 1
  • Francisco G. Hernandez
    • 1
  • Bailey A. T. Weatherbee
    • 1
  • Hongzhan Huang
    • 2
  • Ashok P. Reddy
    • 3
  • Phillip A. Wilmarth
    • 3
  • Larry L. David
    • 3
    • 4
  • Salil A. Lachke
    • 1
    • 2
    Email author
  1. 1.Department of Biological SciencesUniversity of DelawareNewarkUSA
  2. 2.Center for Bioinformatics and Computational BiologyUniversity of DelawareNewarkUSA
  3. 3.Proteomics Shared ResourceOregon Health and Science UniversityPortlandUSA
  4. 4.Department of Chemical Physiology and BiochemistryOregon Health and Science UniversityPortlandUSA

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