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Abstract:
One of the main conditions for multicellularity is the limitation of long-term evolutionary
success of the somatic cells within an organism. The somatic cells often
constitute the vast majority of a multicellular organism. However, by definition they
have no chance to give their genome to the next generation of the organism and
merely act as a container for the successful reproduction of the few germ line cells.
Since nutrients and space are limited within a multicellular organism, a careful coordination
of the somatic cells in the tissue, along with a limitation of proliferation and
strict control over cell function, is paramount for the evolutionary success of the organism.
However, due to somatic mutations this balance can be disturbed such that
somatic cells regain proliferative ability and outcompete other cells within the organism.
This somatic evolution can ultimately lead to cancer or cancer-like phenomena
with unlimited growth of specific clones, which can be lethal for the multicellular
organism.
In this work I will present four different mathematical models showcasing processes
of somatic evolution. Both main ingredients of evolution — variation and selection
— will be shown in different examples in systems of different scales.
Firstly, on the molecular level, the basis for evolutionary processes of cells is the
long term storage of genetic information and the process of how this information
is converted into functional proteins. Slight changes in this process can have major
consequences for the affected cells, also and especially for somatic cells embedded into
multicellular organisms. Here, I will present a model for the translation of RNA into
functional protein which takes circularization of RNA into account. This reveals a
potential mechanisms for a fitness effect of synonymous mutations, that is mutations
that do not alter the protein produced.
Secondly, on a larger scale, the strict coordination of often billions of somatic cells
requires sophisticated tissue structures. These tissue structures can have a strong
impact on the somatic evolution of cells within the tissue. Since mutations mainly
arise on cell divisions, replicative age of cells in these structures is tightly controlled
and mutation accumulation is highly irregular across different cell types. I will show
how a measurable replicative age distribution might provide insight into specific tissue
dynamics of a hierarchically structured tissue such as blood.
Thirdly, tissue structure also has a strong impact on selection of previously emerged
mutants, as mutations can have varying fitness effects in different cell types. In this
i
work I will examine this for the example of chronic myeloid leukemia, a malignancy
which is caused by a known somatic mutation for which nowadays specific targeted
treatment is available.
Finally, evolution, and specifically evolution of somatic cells, has to be seen within
the environment and the ecological niche of the evolving cells, since successful traits
always depend on the momentary environment. In the context of cancer this environment
is often set by the treatment of the disease which shapes the growth and
extinction of cancer cells, which I will explore in more detail in this work.
Overall, the models presented in this work demonstrate mechanisms for observable
patterns in biological systems in the context of somatic evolution. This also shows
how experimental observations or data from clinical studies can be combined with
insights from theoretical models for a deeper understanding of somatic evolution on
the molecular scale, intercellular scale, or to support the treatment of cancer.
