Thesis Defense: Maxim Wolf Title: Evolutionary and Structural Signatures of Protein-Coding Function: Understanding Synonymous Acceleration and Stop Codon Read-through in BRI3BP


Maxim Wolf
Kellis Lab, MIT, CSAIL
Evolutionary signatures are specific, common patterns in the way that DNA sequence has changed over time due to the process of evolution. In my thesis I observe these signatures to understand the sources of highly mutable coding regions in mammals and elucidate a new candidate function for a stop codon readthrough candidate gene, BRI3BP. First, I identify deviations from the normal evolutionary signatures in protein coding genes to recognize synonymous acceleration elements (SAEs): regions with unusually high rates of synonymous substitution. These SAEs are driven by an increased mutation rate, which persists in the human lineage, in otherwise evolutionarily constrained protein-coding regions. SAEs provide an important resource to better characterize protein-coding constraint in mammals and within humans. Second, I combine evolutionary signatures at the protein-coding and protein-folding level to characterize the functional implication of stop-codon readthrough in BRI3BP. I demonstrate that this readthrough region has conserved spaced hydrophobic residues that pattern match to the c-terminal helix forming a coiled-coil-like domain. Readthrough alters BRI3BP function from pro-growth to pro-apoptotic, similarly to another human stop-codon readthrough gene. This suggests that readthrough-triggered apoptosis may represent a general mechanism for limiting growth of cells with aberrant ribosomal termination.