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Interpreting dN/dS under different selective regimes in cancer evolution

Andrés Pérez-Figueroa, View ORCID ProfileDavid Posada
doi: https://doi.org/10.1101/2021.11.30.470556
Andrés Pérez-Figueroa
1Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Portugal
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David Posada
2CINBIO, Universidade de Vigo, 36310 Vigo, Spain
3Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO
4Department of Biochemistry, Genetics, and Immunology, Universidade de Vigo, 36310 Vigo, Spain
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  • ORCID record for David Posada
  • For correspondence: dposada@uvigo.es
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Abstract

The standard relationship between the dN/dS statistic and the selection coefficient is contingent upon the computation of the rate of fixation of non-synonymous and synonymous mutations among divergent lineages (substitutions). In cancer genomics, however, dN/dS is typically calculated by including mutations that are still segregating in the cell population. The interpretation of dN/dS within sexual populations has been shown to be problematic. Here we used a simple model of somatic evolution to study the relationship between dN/dS and the selection coefficient in the presence of deleterious, neutral, and beneficial mutations in cancer. We found that dN/dS can be used to distinguish cancer genes under positive or negative selection, but it is not always informative about the magnitude of the selection coefficient. In particular, under the asexual scenario simulated, dN/dS is insensitive to negative selection strength. Furthermore, the relationship between dN/dS and the positive selection coefficient depends on the mutation detection threshold, and, in particular scenarios, it can become non-linear. Our results warn about the necessary caution when interpreting the results drawn from dN/dS estimates in cancer.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://github.com/anpefi/pNpS_sims

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-NC 4.0 International license.
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Posted December 01, 2021.
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Interpreting dN/dS under different selective regimes in cancer evolution
Andrés Pérez-Figueroa, David Posada
bioRxiv 2021.11.30.470556; doi: https://doi.org/10.1101/2021.11.30.470556
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Interpreting dN/dS under different selective regimes in cancer evolution
Andrés Pérez-Figueroa, David Posada
bioRxiv 2021.11.30.470556; doi: https://doi.org/10.1101/2021.11.30.470556

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