Biology subjects

Derenyi, I.

Publications and source records attributed to Derenyi, I..

6 recordsLinked to original sources

bioRxiv2021

Simultaneous estimation of per cell division mutation rate and turnover rate from bulk tumour sequence data

Tumors often harbor orders of magnitude more mutations than healthy tissues. The increased number of mutations may be due to an elevated mutation rate or frequent cell death and correspondingly rapid cell turnover, or a combination of the two. It is difficult to disentangle these two mechanisms based on widely available bulk sequencing data, where sequences from individual cells are intermixed and, thus, the cell lineage tree of the tumor cannot be resolved. Here we present a method that can simultaneously estimate the cell turnover rate and the rate of mutations from bulk sequencing data. Our method works by simulating tumor growth and finding the parameters with which the observed data can be reproduced with maximum likelihood. Applying this method to a real tumor sample, we find that both the mutation rate and the frequency of death may be high. Author SummaryTumors frequently harbor an elevated number of mutations, compared to healthy tissue. These extra mutations may be generated either by an increased mutation rate or the presence of cell death resulting in increased cellular turnover and additional cell divisions for tumor growth. Separating the effects of these two factors is a nontrivial problem. Here we present a method which can simultaneously estimate cell turnover rate and genomic mutation rate from bulk sequencing data. Our method is based on the estimation of the parameters of a generative model of tumor growth and mutations. Applying our method to a human hepatocellular carcinoma sample reveals an elevated per cell division mutation rate and high cell turnover.

bioinformatics↗

bioRxiv2021

How plants minimize somatic evolution

A remarkable property of plants is their ability to accumulate mutations at a very slow pace despite their potentially long lifespans, during which they continually form buds, each with the potential to become a new branch. Because replication errors in cell division represent an unavoidable source of mutations, minimizing mutation accumulation requires the minimization of cell divisions. Here we show that there exists a well defined theoretical minimum for the branching cost, defined as the number of cell divisions necessary for the creation of each branch. Most importantly, we also show that this theoretical minimum can be closely approached by a simple pattern of cell divisions in the meristematic tissue of apical buds during the generation of novel buds. Both the optimal pattern of cell divisions and the associated branching cost are consistent with recent experimental data, suggesting that plant evolution has led to the discovery of this mechanism.

evolutionary biology↗

bioRxiv2020

Trade-off between reducing mutational load and increasing commitment to differentiation determines tissue organization

Species-specific differences control cancer risk across orders of magnitude variation in body size and lifespan, e.g., by varying the copy numbers of tumor suppressor genes. It is unclear, however, how different tissues within an organism can control somatic evolution despite being subject to markedly different constraints, but sharing the same genome. Hierarchical differentiation, characteristic of self-renewing tissues, can restrain somatic evolution both by limiting divisional load, thereby reducing mutation accumulation, and by increasing cells commitment to differentiation, which can "wash out" mutants. Here, we explore the organization of hierarchical tissues that have evolved to limit their lifetime incidence of cancer. Estimating the likelihood of cancer in the presence of mutations that enhance self-proliferation, we demonstrate that a trade-off exists between mutation accumulation and the strength of washing out. Our results explain differences in the organization of widely different hierarchical tissues, such as colon and blood.

evolutionary biology↗

bioRxiv2020

Cancer Risk and the Somatic Cell Lineage Tree

All the cells of a multicellular organism are the product of cell divisions that trace out a single binary tree, the so-called cell lineage tree. Because cell divisions are accompanied by replication errors, the shape of the cell lineage tree is one of the key determinants of how somatic evolution, which can potentially lead to cancer, proceeds. Cancer initiation usually requires the accumulation of a certain number of driver mutations. By mapping the accumulation of driver mutations into a graph theoretical problem, we show that in leading order of the mutation rate the probability of collecting a given number of driver mutations depends only on the distribution of the lineage lengths (irrespective of any other details of the cell lineage tree), and we derive a simple analytical formula for this probability. Our results are crucial in understanding how natural selection can shape the cell lineage trees of multicellular organisms in order to reduce their lifetime risk of cancer. In particular, our results highlight the significance of the longest cell lineages. Our analytical formula also provides a tool to quantify cancer susceptibility in theoretical models of tissue development and maintenance, as well as for empirical data on cell linage trees. Significance StatementA series of cell divisions starting from a single cell produce and maintain tissues of multicellular organisms. Somatic evolution, including the development of cancer, takes place along the cell lineage tree traced out by these cell divisions. A fundamental question in cancer research is how the lifetime risk of cancer depends on the properties of an arbitrary cell lineage tree. Here we show that for small mutation rates (which is the case in reality) the distribution of the lineage lengths alone determines cancer risk, and that this risk can be described by a simple analytical formula. Our results have far-reaching implications not only for cancer research, but also for evolutionary biology in general.

evolutionary biology↗

bioRxiv2019

A compartment size-dependent selective threshold limits mutation accumulation in hierarchical tissues

Cancer is a genetic disease fueled by somatic evolution. Hierarchical tissue organization can slow somatic evolution by two qualitatively different mechanisms: by cell differentiation along the hierarchy "washing out" harmful mutations (Nowak et al. 2003, Werner et al. 2013) and by limiting the number of cell divisions required to maintain a tissue (Derenyi and Szoll[o] si 2017). Here we explore the effects of compartment size on somatic evolution in hierarchical tissues by considering cell number regulation that acts on cell division rates such that the number of cells in the tissue has the tendency to return to its desired homeostatic value. Introducing mutants with a proliferative advantage we demonstrate the existence of a third fundamental mechanism by which hierarchically organized tissues are able to slow down somatic evolution. We show that tissue size regulation leads to the emergence of a threshold proliferative advantage, below which mutants cannot persist. We find that the most significant determinant of the threshold selective advantage is compartment size, with the threshold being higher the smaller the compartment. Our results demonstrate that in sufficiently small compartments even mutations that confer substantial proliferative advantage cannot persist, but are expelled from the tissue by differentiation along the hierarchy. The resulting selective barrier can significantly slow down somatic evolution and reduce the risk of cancer by limiting the accumulation of mutations that increase the proliferation of cells. O_TEXTBOXSignificance StatementRenewed tissues of multicellular organism accumulate mutations that lead to ageing and cancer. To mitigate these effects self-renewing tissues produce cells along differentiation hierarchies, which have been shown to suppress somatic evolution both by limiting the number of cell divisions, and thus reducing mutational load, and by differentiation "washing out" mutations. Our analytical results reveal the existence of a third mechanism: a compartment size dependent threshold in proliferative advantage, below which mutations cannot persist, but are rapidly expelled from the tissue by differentiation. In sufficiently small compartments the resulting selective barrier can greatly slow down somatic evolution and reduce the risk of cancer by preventing the accumulation of mutations even if even they confer substantial proliferative advantage. C_TEXTBOX

evolutionary biology↗

bioRxiv2017

Hierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations

How can tissues generate large numbers of cells, yet keep the divisional load (the number of divisions along cell lineages) low in order to curtail the accumulation of somatic mutations and reduce the risk of cancer? To answer the question we consider a general model of hierarchically organized self-renewing tissues and show that the lifetime divisional load of such a tissue is independent of the details of the cell differentiation processes, and depends only on two structural and two dynamical parameters. Our results demonstrate that a strict analytical relationship exists between two seemingly disparate characteristics of self-renewing tissues: divisional load and tissue organization. Most remarkably, we find that a sufficient number of progressively slower dividing cell types can be almost as efficient in minimizing the divisional load, as non-renewing tissues. We argue that one of the main functions of tissue-specific stem cells and differentiation hierarchies is the prevention of cancer.

cancer biology↗