Biology subjects

Rozhok, A.

Publications and source records attributed to Rozhok, A..

3 recordsLinked to original sources

bioRxiv2018

A somatic evolutionary model of the dynamics of aneuploid cells during hematopoietic reconstitution

Aneuploidy is associated with many cancers. Recent studies demonstrate that in thehematopoietic stem and progenitor cell (HSPC) compartment aneuploid cells havereduced fitness and are efficiently purged from the bone marrow. However, early phasesof hematopoietic reconstitution following bone marrow transplantation provide awindow of opportunity whereby aneuploid cells rise in frequency, only to decline to basallevels thereafter. Here we demonstrate by Monte Carlo modeling that two mechanismscould underlie this aneuploidy peak: rapid expansion of the engrafted HSPC populationand bone marrow microenvironment degradation caused by pre-transplantationradiation treatment. Both mechanisms reduce the strength of purifying selection actingin early post-transplantation bone marrow. We explore the contribution of other factorssuch as alterations in cell division rates that affect the strength of purifying selection, thebalance of drift and selection imposed by the HSPC population size, and the mutationselectionbalance dependent on the rate of aneuploidy generation per cell division. Wepropose a somatic evolutionary model for the dynamics of cells with aneuploidy or otherfitness-reducing mutations during hematopoietic reconstitution following bone marrowtransplantation.\n\nSignificanceBone marrow transplantations (BMT) following ablative irradiation pose a great health risk. Its been shown that additionally the bone microenvironment is conducive to elevated frequencies of aneuploid cells in mice during bone marrow reconstitution post-BMT. As aneuploidy is linked with many cancers, we explore the reasons of such aberrant cell frequency peaks by Monte Carlo modeling. We demonstrate that elevated rates of aneuploidy early post-BMT are likely to be caused by reduced purifying somatic selection resulting from the expansion of the reconstituting population and the damage to stem cell niches caused by ablative radiation

cell biology↗

bioRxiv2018

A generalized theory of somatic evolution

The modern Multi-Stage Model of Carcinogenesis (MMC) was developed in the 1950s through the 70s and postulated carcinogenesis as a process of rounds of Darwinian selection favoring progressively more malignant cell phenotypes. Through this period, almost nothing was known about driver mutations in cancers. Also, stem cells and cellular tissue organization were poorly characterized. The general multi-stage process was later confirmed by experimental studies, and cancer risk and incidence has been explained as primarily a function of mutation occurrence. However, the MMC has never been formally tested for its ability to account for current knowledge about cancer evolution. In particular, different numbers of cancer drivers required for different cancers and vast discrepancies in the organization of stem cell compartments for different tissues appear inconsistent with the very similar age distribution of the vast majority of cancers. In this regard, the initial theoretical idea underlying MMC is often over-interpreted with little connection to modern evidence, and a general theory of somatic evolution still does not exist. In this study, we applied Monte Carlo modeling and demonstrated the effect of various parameters, such as mutation rate, mutation effects and cell division, on the MMC performance. Our modeling demonstrates that the MMC requires considerable modification in order to describe cancer incidence. We elucidate the required conditions for how somatic cell selection should operate within the MMC in order to explain modern data on stem cell clonality and cancer, and propose a generalized theory of somatic evolution based on these results.

cancer biology↗

bioRxiv2017

On somatic constraints in the evolution of multicellularity

The evolution of multi-cellular animals has produced a conspicuous trend toward increased body size. This trend has introduced at least two novel problems: an elevated risk of somatic disorders, such as cancer, and declining evolvability due to reduced population size, lower reproduction rate and extended generation time. Low population size is widely recognized to explain the high mutation rates in animals by limiting the presumed universally negative selection acting on mutation rates. Here, we present evidence from stochastic modeling that the direction and strength of selection acting on mutation rates is highly dependent on the evolution of somatic maintenance, and thus longevity, which modulates the cost of somatic mutations. We argue that this mechanism may have been critical in facilitating animal evolution.

evolutionary biology↗