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Effect of cell cycle duration on somatic evolutionary dynamics.

ABSTRACT: Cellular checkpoints prevent damage and mutation accumulation in tissue cells. DNA repair is one mechanism that can be triggered by checkpoints and involves temporary cell cycle arrest and thus delayed reproduction. Repair-deficient cells avoid this delay, which has been argued to lead to a selective advantage in the presence of frequent damage. We investigate this hypothesis with stochastic modeling, using mathematical analysis and agent-based computations. We first model competition between two cell types: a cell population that enters temporary cell cycle arrest, corresponding to repair (referred to as arresting cells), and one that does not enter arrest (referred to as nonarresting cells). Although nonarresting cells are predicted to grow with a faster rate than arresting cells in isolation, this does not translate into a selective advantage in the model. Interestingly, the evolutionary properties of the nonarresting cells depend on the measure (or observable) of interest. When examining the average populations sizes in competition simulations, nonarresting and arresting cells display neutral dynamics. The fixation probability of nonarresting mutants, however, is lower than predicted for a neutral scenario, suggesting a selective disadvantage in this setting. For nonarresting cells to gain a selective advantage, additional mechanisms must be invoked in the model, such as small, repeated phases of tissue damage, each resulting in a brief period of regenerative growth. The same properties are observed in a more complex model where it is explicitly assumed that repair and temporary cell cycle arrest are dependent on the cell having sustained DNA damage, the rate of which can be varied. We conclude that repair-deficient cells are not automatically advantageous in the presence of frequent DNA damage and that mechanisms beyond avoidance of cell cycle delay must be invoked to explain their emergence.

SUBMITTER: Wodarz D

PROVIDER: S-EPMC5680637 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Effect of cell cycle duration on somatic evolutionary dynamics.

Wodarz Dominik D Goel Ajay A Komarova Natalia L NL

Evolutionary applications 20171012 10

Cellular checkpoints prevent damage and mutation accumulation in tissue cells. DNA repair is one mechanism that can be triggered by checkpoints and involves temporary cell cycle arrest and thus delayed reproduction. Repair-deficient cells avoid this delay, which has been argued to lead to a selective advantage in the presence of frequent damage. We investigate this hypothesis with stochastic modeling, using mathematical analysis and agent-based computations. We first model competition between tw ...[more]

PMID: 29151865

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Project description:Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder characterized by impaired apoptotic homeostasis. The clinical characteristics include lymphoproliferation, autoimmunity (mainly cytopenia), and an increased risk of lymphoma. A distinctive biological feature is accumulation (>2.5%) of an abnormal cell subset composed of TCRαβ+ CD4-CD8- T cells (DNTs). The most common genetic causes of ALPS are monoallelic pathogenic variants in the FAS gene followed by somatic FAS variants, mainly restricted to DNTs. Identification of somatic FAS variants has been typically addressed by Sanger sequencing in isolated DNTs. However, this approach can be costly and technically challenging, and may not be successful in patients with normal DNT counts receiving immunosuppressive treatment. In this study, we identified a novel somatic mutation in FAS (c.718_719insGTCG) by Sanger sequencing on purified CD3+ cells. We then followed the evolutionary dynamics of the variant along time with an NGS-based approach involving deep amplicon sequencing (DAS) at high coverage (20,000-30,000x). Over five years of clinical follow-up, we obtained six blood samples for molecular study from the pre-treatment (DNTs>7%) and treatment (DNTs<2%) periods. DAS enabled detection of the somatic variant in all samples, even the one obtained after five years of immunosuppressive treatment (DNTs: 0.89%). The variant allele frequency (VAF) range was 4%-5% in pre-treatment samples and <1.5% in treatment samples, and there was a strong positive correlation between DNT counts and VAF (Pearson's R: 0.98, p=0.0003). We then explored whether the same approach could be used in a discovery setting. In the last follow-up sample (DNT: 0.89%) we performed somatic variant calling on the FAS exon 9 DAS data from whole blood and purified CD3+ cells using VarScan 2. The c.718_719insGTCG variant was identified in both samples and showed the highest VAF (0.67% blood, 1.58% CD3+ cells) among >400 variants called. In summary, our study illustrates the evolutionary dynamics of a somatic FAS mutation before and during immunosuppressive treatment. The results show that pathogenic somatic FAS variants can be identified with the use of DAS in whole blood of ALPS patients regardless of their DNT counts.

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Effect of cell cycle duration on somatic evolutionary dynamics.

Publications

Effect of cell cycle duration on somatic evolutionary dynamics.

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