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StabilitySort: assessment of protein stability changes on a genome-wide scale to prioritise potentially pathogenic genetic variation

Aaron Chuah, Sean Li, Andrea Do, Matt A Field, T. Daniel Andrews
doi: https://doi.org/10.1101/2021.11.28.470298
Aaron Chuah
1Genome Informatics Laboratory, Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
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Sean Li
1Genome Informatics Laboratory, Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
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Andrea Do
1Genome Informatics Laboratory, Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
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Matt A Field
2Australian Institute of Tropical Health and Medicine and Centre for Tropical Bioinformatics, James Cook University, Cairns, Queensland, Australia
3Immunogenomics Lab, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
4Menzies School of Health Research, Darwin, NT, Australia
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T. Daniel Andrews
1Genome Informatics Laboratory, Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
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  • For correspondence: Dan.Andrews@anu.edu.au
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Abstract

Summary Missense mutations that change protein stability are strongly associated with human inherited genetic disease. With the recent availability of predicted structures for all human proteins generated using the AlphaFold2 prediction model, genome-wide assessment of the stability effects of genetic variation can, for the first time, be easily performed. This facilitates the interrogation of personal genetic variation for potentially pathogenic effects through the application of stability metrics. Here, we present a novel algorithm to prioritise variants predicted to strongly destabilise essential proteins, available as both a standalone software package and a web-based tool. We demonstrate the utility of this tool by showing that at values of the Stability Sort Z-score above 1.6, pathogenic, protein-destabilising variants from ClinVar are detected at a 58% enrichment, over and above the destabilising (but presumably non-pathogenic) variation already present in the HapMap NA12878 genome.

Availability and Implementation StabilitySort is available as both a web service (http://130.56.244.113/StabilitySort/) and can be deployed as a standalone system (https://gitlab.com/baaron/StabilitySort).

Contact Dan.Andrews{at}anu.edu.au

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • http://130.56.244.113/StabilitySort

  • https://gitlab.com/baaron/StabilitySort

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 02, 2021.
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StabilitySort: assessment of protein stability changes on a genome-wide scale to prioritise potentially pathogenic genetic variation
Aaron Chuah, Sean Li, Andrea Do, Matt A Field, T. Daniel Andrews
bioRxiv 2021.11.28.470298; doi: https://doi.org/10.1101/2021.11.28.470298
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StabilitySort: assessment of protein stability changes on a genome-wide scale to prioritise potentially pathogenic genetic variation
Aaron Chuah, Sean Li, Andrea Do, Matt A Field, T. Daniel Andrews
bioRxiv 2021.11.28.470298; doi: https://doi.org/10.1101/2021.11.28.470298

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