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Intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction

The phenotypic efficacy of somatic copy number alterations (SCNAs) stems from their incidence per base pair of the genome, which is orders of magnitudes greater than that of point mutations. One mitotic event stands out in its potential to significantly change a cell’s SCNA burden–a chromosome misse...

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Detalles Bibliográficos
Autores principales: Kimmel, Gregory J., Beck, Richard J., Yu, Xiaoqing, Veith, Thomas, Bakhoum, Samuel, Altrock, Philipp M., Andor, Noemi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917311/
https://www.ncbi.nlm.nih.gov/pubmed/36689467
http://dx.doi.org/10.1371/journal.pcbi.1010815
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author Kimmel, Gregory J.
Beck, Richard J.
Yu, Xiaoqing
Veith, Thomas
Bakhoum, Samuel
Altrock, Philipp M.
Andor, Noemi
author_facet Kimmel, Gregory J.
Beck, Richard J.
Yu, Xiaoqing
Veith, Thomas
Bakhoum, Samuel
Altrock, Philipp M.
Andor, Noemi
author_sort Kimmel, Gregory J.
collection PubMed
description The phenotypic efficacy of somatic copy number alterations (SCNAs) stems from their incidence per base pair of the genome, which is orders of magnitudes greater than that of point mutations. One mitotic event stands out in its potential to significantly change a cell’s SCNA burden–a chromosome missegregation. A stochastic model of chromosome mis-segregations has been previously developed to describe the evolution of SCNAs of a single chromosome type. Building upon this work, we derive a general deterministic framework for modeling missegregations of multiple chromosome types. The framework offers flexibility to model intra-tumor heterogeneity in the SCNAs of all chromosomes, as well as in missegregation- and turnover rates. The model can be used to test how selection acts upon coexisting karyotypes over hundreds of generations. We use the model to calculate missegregation-induced population extinction (MIE) curves, that separate viable from non-viable populations as a function of their turnover- and missegregation rates. Turnover- and missegregation rates estimated from scRNA-seq data are then compared to theoretical predictions. We find convergence of theoretical and empirical results in both the location of MIE curves and the necessary conditions for MIE. When a dependency of missegregation rate on karyotype is introduced, karyotypes associated with low missegregation rates act as a stabilizing refuge, rendering MIE impossible unless turnover rates are exceedingly high. Intra-tumor heterogeneity, including heterogeneity in missegregation rates, increases as tumors progress, rendering MIE unlikely.
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spelling pubmed-99173112023-02-11 Intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction Kimmel, Gregory J. Beck, Richard J. Yu, Xiaoqing Veith, Thomas Bakhoum, Samuel Altrock, Philipp M. Andor, Noemi PLoS Comput Biol Research Article The phenotypic efficacy of somatic copy number alterations (SCNAs) stems from their incidence per base pair of the genome, which is orders of magnitudes greater than that of point mutations. One mitotic event stands out in its potential to significantly change a cell’s SCNA burden–a chromosome missegregation. A stochastic model of chromosome mis-segregations has been previously developed to describe the evolution of SCNAs of a single chromosome type. Building upon this work, we derive a general deterministic framework for modeling missegregations of multiple chromosome types. The framework offers flexibility to model intra-tumor heterogeneity in the SCNAs of all chromosomes, as well as in missegregation- and turnover rates. The model can be used to test how selection acts upon coexisting karyotypes over hundreds of generations. We use the model to calculate missegregation-induced population extinction (MIE) curves, that separate viable from non-viable populations as a function of their turnover- and missegregation rates. Turnover- and missegregation rates estimated from scRNA-seq data are then compared to theoretical predictions. We find convergence of theoretical and empirical results in both the location of MIE curves and the necessary conditions for MIE. When a dependency of missegregation rate on karyotype is introduced, karyotypes associated with low missegregation rates act as a stabilizing refuge, rendering MIE impossible unless turnover rates are exceedingly high. Intra-tumor heterogeneity, including heterogeneity in missegregation rates, increases as tumors progress, rendering MIE unlikely. Public Library of Science 2023-01-23 /pmc/articles/PMC9917311/ /pubmed/36689467 http://dx.doi.org/10.1371/journal.pcbi.1010815 Text en © 2023 Kimmel et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kimmel, Gregory J.
Beck, Richard J.
Yu, Xiaoqing
Veith, Thomas
Bakhoum, Samuel
Altrock, Philipp M.
Andor, Noemi
Intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction
title Intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction
title_full Intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction
title_fullStr Intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction
title_full_unstemmed Intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction
title_short Intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction
title_sort intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917311/
https://www.ncbi.nlm.nih.gov/pubmed/36689467
http://dx.doi.org/10.1371/journal.pcbi.1010815
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