Combinatorial biological complexity : a study of amino acid side chains and alternative splicing
Both, laymen and experts have always been intrigued by nature’s vast complexity and variety. Often, these phenomena arise from combination of parts, as for example, cell types of the human body, or the diverse proteins of a cell. In this thesis I investigate three instances of combinatorial complexity: combinations of aliphatic amino acid side chains, alternative mRNA splicing in fungi, and mutually exclusively spliced exons in human and mouse. In the first part the number of aliphatic amino acid side chains is studied. Structural combinations yield a vast theoretical number, yet we find that only a fraction of them is realized in nature. Reasons especially with respect to restrictions by the genetic code are discussed. Moreover, strategies for the need for increased diversity are examined. In the second part, the extent of alternative splicing (AS) in fungi is investigated. A genome-wide, comparative multi-species study is conducted. I find that AS is common in fungi, but with lower frequency compared to plants and animals. AS is more common in more complex fungi, and is over-represented in pathogens. It is hypothesized that AS contributes to multi-cellular complexity in fungi. In the third part, mutually exclusive exons (MXEs) of mouse and human are detected and characterized. Rather unexpected patterns arose: the majority of MXEs originate from non-adjacent exons and frequently appear in clusters. Known regulatory mechanisms of MXE splicing are unsuitable for these MXEs, and thus, new mechanisms have to be sought. Summarizing it is hypothesized that complexity from combinations constitutes a universal principle in biology. However, there seems to be a need to restrict the combinatorial potential. This is highlighted by the interdependence of MXEs and the low number of realized amino acids in the genetic code. Combinatorial complexity and its restriction are discussed with respect to other biological systems to further substantiate the hypotheses.