Functional dissection of the impact of genetic variants one interaction at-a-time

This doctoral research work delves into the intricate world of protein-protein
interactions (PPIs), positioning them as the fundamental conductors of cellular
function. By wielding the tools of forward and reverse edgetics, we systematically
functionalize genetic variants observed in the human population and dissect a yeast
chromatin remodeling complex one interaction at-a-time, respectively, delivering a
deep understanding of biological processes with a granularity that surpasses
traditional genetic methods. The manuscript consists of three core chapters,
complemented by eight appendices.
The inaugural chapter, published as a review article in the International Journal of
Molecular Sciences, positions this work in the context of interactomics. It
comprehensively examines the utility of the baker’s yeast Saccharomyces cerevisiae
as a test tube for studying PPIs and their role in human disease development.
The second chapter tackles a critical challenge in human genetics: the
functionalization of the often uncharacterized "variome", or the vast spectrum of
genetic variations. We present a multidimensional framework for the systematic
characterization of variants associated with Mendelian diseases, aiming to unravel
their impact on cellular processes.
The final chapter focuses on the dissection of the yeast Rpd3L histone deacetylase
complex, a chromatin remodeling protein complex, with the aim to identify its
vulnerabilities. In this section, we leverage systematic protein fragmentation and
mutational scanning to pinpoint critically weak regions or residues within the
complex.
By combining the original research presented in the core chapters, this doctoral
work adopts an edgetic approach to the study of cellular function and seeks to deliver
systematic frameworks for the mapping and dissection of protein-protein interactions.
In addition, eight appendices showcase my significant contributions to collaborative
research projects that have resulted in original research articles either published in
peer-reviewed journals or as preprints.