Modes of Selection in Tumors as Reflected by Two Mathematical Models and Site Frequency Spectra

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dc.citation.articleNumber889438en_US
dc.citation.journalTitleFrontiers in Ecology and Evolutionen_US
dc.citation.volumeNumber10en_US
dc.contributor.authorKurpas, Monika K.en_US
dc.contributor.authorKimmel, Mareken_US
dc.date.accessioned2022-09-08T14:40:03Zen_US
dc.date.available2022-09-08T14:40:03Zen_US
dc.date.issued2022en_US
dc.description.abstractThe tug-of-war model was developed in a series of papers of McFarland and co-authors to account for existence of mutually counteracting rare advantageous driver mutations and more frequent slightly deleterious passenger mutations in cancer. In its original version, it was a state-dependent branching process. Because of its formulation, the tug-of-war model is of importance for tackling the problem as to whether evolution of cancerous tumors is “Darwinian” or “non-Darwinian.” We define two Time-Continuous Markov Chain versions of the model, including identical mutation processes but adopting different drift and selection components. In Model A, drift and selection process preserves expected fitness whereas in Model B it leads to non-decreasing expected fitness. We investigate these properties using mathematical analysis and extensive simulations, which detect the effect of the so-called drift barrier in Model B but not in Model A. These effects are reflected in different structure of clone genealogies in the two models. Our work is related to the past theoretical work in the field of evolutionary genetics, concerning the interplay among mutation, drift and selection, in absence of recombination (asexual reproduction), where epistasis plays a major role. Finally, we use the statistics of mutation frequencies known as the Site Frequency Spectra (SFS), to compare the variant frequencies in DNA of sequenced HER2+ breast cancers, to those based on Model A and B simulations. The tumor-based SFS are better reproduced by Model A, pointing out a possible selection pattern of HER2+ tumor evolution. To put our models in context, we carried out an exploratory study of how publicly accessible data from breast, prostate, skin and ovarian cancers fit a range of models found in the literature.en_US
dc.identifier.citationKurpas, Monika K. and Kimmel, Marek. "Modes of Selection in Tumors as Reflected by Two Mathematical Models and Site Frequency Spectra." <i>Frontiers in Ecology and Evolution,</i> 10, (2022) Frontiers Media S.A.: https://doi.org/10.3389/fevo.2022.889438.en_US
dc.identifier.digitalfevo-10-889438en_US
dc.identifier.doihttps://doi.org/10.3389/fevo.2022.889438en_US
dc.identifier.urihttps://hdl.handle.net/1911/113194en_US
dc.language.isoengen_US
dc.publisherFrontiers Media S.A.en_US
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleModes of Selection in Tumors as Reflected by Two Mathematical Models and Site Frequency Spectraen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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