Formal computational framework for the study of molecular evolution

Abstract

Over the past 10 years, multiple executable modelling formalisms for molecular biology have been developed in order to address the growing need for a system-level understanding of complex biological phenomena. An important class of these formalisms are biology-inspired process algebras, which offer-among other desirable properties - an almost complete separation of model specification (syntax) from model dynamics (semantics). In this thesis, the similarity between this separation and the genotype-phenotype duality in evolutionary biology is exploited to develop a process-algebraic approach to the study of evolution of biochemical systems. The main technical contribution of this thesis is the continuous π-calculus (cπ), a novel process algebra based on the classical π-calculus of Milner et. al. Its two defining characteristics are: continuous, compositional, computationally inexpensive semantics, and a exible interaction structure of processes (molecules). Both these features are conductive to evolutionary analysis of biochemical systems by, respectively, enabling many variants of a given model to be evaluated, and facilitating in silico evolution of new functional connections. A further major contribution is a collection of variation operators, syntactic model transformation schemes corresponding to common evolutionary events. When applied to a cπ model of a biochemical system, variation operators produce its evolutionary neighbours, yielding insights into the local fitness landscape and neutral neighbourhood. Two well-known biochemical systems are modelled in this dissertation to validate the developed theory. One is the KaiABC circadian clock in the cyanobacterium S. elongatus, the other is a mitogen-activated protein kinase cascade. In each case we study the system itself as well as its predicted evolutionary variants. Simpler examples, particularly that of a generic enzymatic reaction, are used throughout the thesis to illustrate important concepts as they are introduced.