A landscape of population-specific variation effects on ligand binding site in the healthy population

Sun, Mo

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A landscape of population-specific variation effects on ligand binding site in the healthy population

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There has been of considerable interest in understanding how the genetic mutations could rewire the macromolecular interaction network mediated by proteins. Protein-ligand interactions, as one of the macromolecular interactions, can be associated with mutations at the ligand-binding sites (LBSs) to influencing protein structure stability, binding affinity with small molecules, hormone regulation, and drug resistance in people. Recent studies have shown that ligand binding residues have a significantly higher mutation rate than other parts of the protein in 16 types of cancers. Our study focuses on LBSs mutation in healthy populations and makes the most comprehensive human LBSs mutation map to date. By integrating BioLip and gnomAD data, we created a comprehensive LBSs-associated mutation map in eight populations and to help exploring the relationship between the variation profiles of different populations and the ligand-binding region corresponding to different types of ligands. Specifically, each LBSs was annotated and grouped into different categories based on the molecular structure and function similarity of the corresponding ligand, which allows looking for common ligand mutation patterns. In our work, we hypothesized that LBSs of proteins are enriched with the population-specific mutations, which means that the frequencies of these mutations are not evenly distributed in every population. Furthermore, we test if the specific categories of LBSs are not equally susceptible to variation across different healthy groups. We observed distinct mutation across different groups of ligands. As a case study, we determined 20 variants in 14 pharmacological genes from PharmGKB ( https://www.pharmgkb.org/) VIPs to study the deleterious, neutral, and beneficial effect on the LBSs of nicotine, phenytoin, and other drugs. Meanwhile, further study is needed to determine whether all the genetic variants in our map would damage the normal interaction and what the specific mechanism about on how they would damage

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