On the Diversity of Eukaryotic Transcription Factor Specificities

Transcription factor (TF) DNA-binding specificities (motifs) are often conserved between species, and many TFs have conserved functions over long evolutionary distances. As a consequence, changes in gene expression are largely attributed to evolution of cis-regulatory DNA sequences rather than changes to TF coding sequences. However, the number and diversity of TFs vary greatly between species, and there are numerous well-studied examples of TF diversification in DNA-binding and protein-interaction specificities. TF motif evolution has previously not been explored comprehensively, and its prevalence is largely unknown. In this thesis, I describe three studies that identify, measure, and predict the similarities between TFs and their motifs. I first describe an analysis of Caenorhabditis elegans TF specificities, and the discovery of novel motifs in expanded TF families. I then describe a novel method to better describe the similarity of two motifs. I conclude by estimating the degree of motif conservation between eukaryotic species at varying evolutionary distances using Similarity Regression (SR), which is an improved method to classify pairs of TFs as having similar or dissimilar motifs on the basis of their DNA-binding domain (DBD) sequences. Within major eukaryotic kingdoms (e.g. metazoans, plants, and fungi) it is typical that just over half of the TF motifs are conserved since the last common ancestor, indicating that diversification has occurred in multiple TF families. Even relatively small evolutionary distances (e.g. human to mouse) are associated with marked alterations in TF motifs, mainly in gene families with many duplications, like the C2H2 ZFs and Myb TFs. These studies indicate that TF motif evolution is prevalent, particularly in expanded TF families, and occurs in parallel with changes to cis-regulatory sequences.Ph.D