Date of Award
Dr. David Zuzga
Enteric pathogens employ numerous strategies to breach the intestinal epithelial barrier. One critical target of these pathogens is the host cell cytoskeleton. Pathogens may induce cytoskeletal remodeling to disrupt tight junctions and increase the permeability of the epithelium to gain access to underlying tissue. Alternatively, the cytoskeletal machinery may be directly co-opted to facilitate the attachment, invasion, or intracellular motility of these pathogens. The vasodilator-stimulated phosphoprotein (VASP) is a processive actin polymerase that induces membrane remodeling through the polymerization of actin cytoskeletal filaments. Interestingly, VASP is regulated by a variety of pathogens to induce cytoskeletal remodeling in host cells. If VASP is indeed a conversed target of pathogens, it is plausible that evolutionary pressure on host cells would select for genetic variants of VASP to inhibit the ability of pathogens to co-opt VASP function. To investigate this possibility, we determined the minor allele (MAF) frequency of all single nucleotide polymorphisms (SNPS) in VASP across 26 global populations. A heatmap was constructed to represent the minor allele frequency of >400 SNPs and revealed increased minor allele frequency in Sub-Saharan African populations, that exhibit disproportionally high burdens of infectious disease compared with global populations. Next, linkage disequilibrium (LD) analysis was conducted on SNPS with increased MAF in Sub-Saharan African populations and likely to impact VASP function. SNPs found to be in linkage disequilibrium were then employed to reconstruct VASP haplotypes
Phun, Melinda; Rosenn, Blake; Glenn, Danny; Rupasinghe, Dhanushi; Church, James; Zuzga, David; Fan, Shaohua; and Tishkoff, Sarah, "Association of VASP Polymorphisms and Infectious Disease Burden in Global Populations and Identification of Candidate Resistance Haplotypes in Sub-Saharan Africa" (2018). HON499 projects. 18.