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Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure: implications for variant effect prediction

Lukas Gerasimavicius, Benjamin J Livesey, View ORCID ProfileJoseph A. Marsh
doi: https://doi.org/10.1101/2021.10.23.465554
Lukas Gerasimavicius
MRC Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK
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Benjamin J Livesey
MRC Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK
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Joseph A. Marsh
MRC Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK
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  • ORCID record for Joseph A. Marsh
  • For correspondence: joseph.marsh@ed.ac.uk
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Abstract

Most known pathogenic mutations occur in protein-coding regions of DNA and change the way proteins are made. Taking protein structure into account has therefore provided great insight into the molecular mechanisms underlying human genetic disease. While there has been much focus on how mutations can disrupt protein structure and thus cause a loss of function (LOF), alternative mechanisms, specifically dominant-negative (DN) and gain-of-function (GOF) effects, are less understood. Here, we have investigated the protein-level effects of pathogenic missense mutations associated with different molecular mechanisms. We observe striking differences between recessive vs dominant, and LOF vs non-LOF mutations, with dominant, non-LOF disease mutations having much milder effects on protein structure, and DN mutations being highly enriched at protein interfaces. We also find that nearly all computational variant effect predictors underperform on non-LOF mutations, even those based solely on sequence conservation. However, we do find that non-LOF mutations could potentially be identified by their tendency to cluster in space. Overall, our work suggests that many pathogenic mutations that act via DN and GOF mutations are likely being missed by current variant prioritisation strategies, but that there is considerable scope to improve computational predictions through consideration of molecular disease mechanisms.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://doi.org/10.7488/ds/3153

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 24, 2021.
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Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure: implications for variant effect prediction
Lukas Gerasimavicius, Benjamin J Livesey, Joseph A. Marsh
bioRxiv 2021.10.23.465554; doi: https://doi.org/10.1101/2021.10.23.465554
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Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure: implications for variant effect prediction
Lukas Gerasimavicius, Benjamin J Livesey, Joseph A. Marsh
bioRxiv 2021.10.23.465554; doi: https://doi.org/10.1101/2021.10.23.465554

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