Intrinsic disorder and tandem repeats - match made in evolution : Computational studies of molecular evolution

Abstract: Proteins are both the building blocks and workers of the cell, carrying out most of the important functions. For a long time, their structure has been regarded as the primary factor for their function, but intrinsically disordered proteins demonstrate an alternative to this paradigm. Disordered proteins can temporarily assume different forms based on their interactions with other molecules and play critical roles in several biological processes, including cell signaling and regulation of gene expression.Tandem repeats are repeated patterns in genetic sequence. The role of tandem repeats in many protein structures is well documented today, but their role in disordered proteins is not entirely clear. This thesis aims to shed light on the mechanisms by which protein disorder and tandem repeats are linked.Only 2.5% of residues in all known protein sequences are characterized by the overlap of tandem repeats and protein disorder as described in Paper III, but many of these proteins have crucial functions and are linked to human diseases. Short tandem repeats emerge in this study as most frequently occurring in disordered regions. Genetic variation in disordered proteins accounts for length differences in eukaryotic genes (Paper I) and many orphan, recently evolved proteins, are disordered due to high GC content (Paper II). A medical application of this research is illustrated in the thesis with examples of variations in short tandem repeats (STRs) and their role in human diseases. Paper IV presents a comprehensive resource of human STR variation and Paper V illustrates how it can be used to identify specific STRs of interest, such as in the case of colorectal cancer where variations in certain STRs lead to altered gene expression patterns in tumors.