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Demeter Márton

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Demeter Márton Csaba
The structure of hierarchical tissues that minimize somatic evolution

Aug 28 - szerda

13:30 – 15:30

II. Poszterszekció

P39

The structure of hierarchical tissues that minimize somatic evolution 

Demeter Márton Csaba¹, Derényi Imre² és Szöllősi Gergely³

^1,2,3 ELTE-MTA „Lendület” Evolúciós Genomika kutatócsoport

Self-renewing tissues of multicellular organisms produce cells using hierarhical differentaion. Such hierarhically organised tissues surpress somatic evolution and thus delay aging and the emergence of tumours at two levels of the evolutaionry process. At the level of selection, even mutations that provide a proliferative advantage can be "washed out" as a result of differntiaion [2], while at the level of mutation accumulation hierarhical organizagtion can limit the number of cell divisions, and as a result the mutaional burden of maintaining tissues [1].

Here we explore the structure of hierarchical tissues that minimize somatic evolution. We introduce a generic quantity, the self-renewal potential, which quantifies the ability of cells to avoid being "washed out" and determines their fitness at a hierarchical level. Using the self-renewal potential, which in healthy tissue is negative for non stem cells, the critical number of mutations, necessary for triggering neoplastic progression at a certain hierarchical level can be obtained. We are able to analytically estimate the probability of neoplastic progression in hierarhical tissues using the theory of birth death processes and the statistical characteristics of the cell-linage tree. We find that in general there is a trade off between mutation accumulation and the proliferative disadvantage of cells in the hierarchy leading to an evolutionary optimum in the probability of neoplastic progression.

In particular we find that in tissues with physiologically realistic parameters the division rate of stem cell is higher than the extremely low rates required to minimize mutation accumulation alone. The resulting optimum induced by selection is characterized by a relatively large number of stem cell divisions, with the consequence that the majority of the driver mutations can accumulate within stem cells.

Irodalom

[1] Hierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations, Imre Derenyi, Gergely J Szollosi Nature Communications volume 8, Article number: 14545 (2017) https://doi.org/10.1038/ncomms14545

[2] Nowak, Michor, Isawa, The linear process of somatic evolution. PNAS 2003

Szöllősi Gergely
Hierarchical tissues that minimize somatic evolution

Aug 28 - szerda

13:30 – 15:30

II. Poszterszekció

P42

Hierarchical tissues that minimize somatic evolution

Demeter Márton ² , Grajzel Dániel ² , Derényi Imre ¹ , Szöllősi Gergely ^1,2

¹ Biológiai Fizika Tanszék, ELTE

² MTA-ELTE “Lendület” Evolúciós Genomika Kcs.

Cancer development is a somatic evolutionary process where cells must divide and as a result mutations that can ultimately lead to neoplastic progression may accumulate. Hierarchically organized tissues can slow down somatic evolution by reducing the number of cell divisions along cell lineages thus limiting mutation accumulation [1] and by ”washing out” mutations even if they confer a proliferative advantage [2].

Here we explore the structure of hierarchical tissues that minimize somatic evolution. We derive the critical number of mutations, necessary for triggering neoplastic progression as a function of dynamical parameters of the hierarchy. Using this results we are able to analytically estimate the probability of neoplastic progression based on statistical characteristics of the cell-linage tree. We find a trade off between mutation accumulation and the proliferative disadvantage of cells in the hierarchy leading to an evolutionary optimum in the probability of neoplastic progression.

In particular we find that in tissues with physiologically realistic parameters the division rate of stem cells is higher than the extremely low rates required to minimize mutation accumulation [1]. The resulting optimum induced by selection is characterized by a relatively large number of stem cell divisions, with the consequence that the majority of the driver mutations can accumulate within stem cells.

References:

[1] Derenyi & Szollosi, Hierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations.

Nature Communications 2017

[2] Nowak, Michor, Isawa, The linear process of somatic evolution. PNAS 2003