Comparative evolutionary pharmacogenomics of human prostaglandin-endoperoxide synthase paralogs identifies population-structured coding variation and protein-contextual candidates in N-terminal leader-sequence and catalytic-channel regions
- 1Department of Microbiology and Parasitology, Faculty of Medicine, St. Francis University College of Health and Allied Sciences (SFUCHAS), Ifakara, Tanzania
Abstract
Human PTGS1 and PTGS2 encode cyclooxygenase paralogs that regulate prostaglandin biosynthesis and are major targets of nonsteroidal anti-inflammatory drugs (NSAIDs). Interpreting population-differentiated PTGS variation requires integration of allele-frequency structure with transcript consequence, protein topology, splice-prediction evidence and structural context. This study integrated allele-resolved population differentiation, transcript-aware consequence annotation, splice-prediction boundary checks, protein-domain mapping, direct leader-sequence property calculations and controlled structural analyses. Candidate classes distinguished high-FST synonymous contextual markers, N-terminal PTGS1 leader-sequence missense variants, splice-region candidates and PTGS2 p.Val511Ala. Web-based SpliceAI/Pangolin evaluation of seven splice-relevant or comparator variants provided limited support for splice alteration. A retrospective comparison of 31 missense candidates showed that Val511Ala was not the most differentiated missense variant overall, but ranked first by allele frequency, allele-frequency range and maximum pairwise FST within four channel-context candidates; FST was used only to describe population differentiation. Canonical Val511 mapped to 5KIR Val525, a second-shell position adjacent to the rofecoxib-contact network. Controlled docking-score, contact and direct-frame pose analyses detected no systematic variant-associated shift under the tested conditions. PTGS1 p.Trp8Arg and p.Pro17Leu produced distinct directly calculated changes in net-charge proxy, hydrophobic-residue count, mean Kyte-Doolittle hydropathy, aromatic-residue count and proline count across the 23-residue leader sequence and descriptive H-region. No signal-peptide predictor output was used, and effects on SRP recognition, ER targeting, translocation, cleavage, membrane insertion, maturation, abundance, localization, enzyme activity or drug response were not demonstrated. These results support a calibrated prioritisation framework in which population differentiation identifies structured variation, while transcript consequence, protein context and reproducible quantitative analyses define experimentally testable candidates.
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BibTeX
@article{maghembe2026comparative,
title = {{Comparative evolutionary pharmacogenomics of human prostaglandin-endoperoxide synthase paralogs identifies population-structured coding variation and protein-contextual candidates in N-terminal leader-sequence and catalytic-channel regions}},
author = {Reuben S. Maghembe},
journal = {PLOS One},
year = {2026},
month = sep,
doi = {10.1371/journal.pone.0358222},
url = {https://doi.org/10.1371/journal.pone.0358222},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Comparative evolutionary pharmacogenomics of human prostaglandin-endoperoxide synthase paralogs identifies population-structured coding variation and protein-contextual candidates in N-terminal leader-sequence and catalytic-channel regions
AU - Reuben S. Maghembe
PY - 2026
DA - 2026/09/25
JO - PLOS One
DO - 10.1371/journal.pone.0358222
UR - https://doi.org/10.1371/journal.pone.0358222
AB - Human PTGS1 and PTGS2 encode cyclooxygenase paralogs that regulate prostaglandin biosynthesis and are major targets of nonsteroidal anti-inflammatory drugs (NSAIDs). Interpreting population-differentiated PTGS variation requires integration of allele-frequency structure with transcript consequence, protein topology, splice-prediction evidence and structural context. This study integrated allele-resolved population differentiation, transcript-aware consequence annotation, splice-prediction boundary checks, protein-domain mapping, direct leader-sequence property calculations and controlled structural analyses. Candidate classes distinguished high-FST synonymous contextual markers, N-terminal PTGS1 leader-sequence missense variants, splice-region candidates and PTGS2 p.Val511Ala. Web-based SpliceAI/Pangolin evaluation of seven splice-relevant or comparator variants provided limited support for splice alteration. A retrospective comparison of 31 missense candidates showed that Val511Ala was not the most differentiated missense variant overall, but ranked first by allele frequency, allele-frequency range and maximum pairwise FST within four channel-context candidates; FST was used only to describe population differentiation. Canonical Val511 mapped to 5KIR Val525, a second-shell position adjacent to the rofecoxib-contact network. Controlled docking-score, contact and direct-frame pose analyses detected no systematic variant-associated shift under the tested conditions. PTGS1 p.Trp8Arg and p.Pro17Leu produced distinct directly calculated changes in net-charge proxy, hydrophobic-residue count, mean Kyte-Doolittle hydropathy, aromatic-residue count and proline count across the 23-residue leader sequence and descriptive H-region. No signal-peptide predictor output was used, and effects on SRP recognition, ER targeting, translocation, cleavage, membrane insertion, maturation, abundance, localization, enzyme activity or drug response were not demonstrated. These results support a calibrated prioritisation framework in which population differentiation identifies structured variation, while transcript consequence, protein context and reproducible quantitative analyses define experimentally testable candidates.
SN - 1932-6203
ER -