Overlapping genes pose an evolutionary dilemma as one DNA sequence evolves under the selection pressures of multiple proteins. Here, we perform systematic statistical and mutational analyses of the overlapping HIV-1 genes tat and rev and engineer exhaustive libraries of non-overlapped viruses to perform deep mutational scanning of each gene independently. We find a "segregated" organization in which overlapped sites encode functional residues of one gene or the other, but never both. Furthermore, this organization eliminates unfit genotypes, providing a fitness advantage to the population. Our comprehensive analysis reveals the extraordinary manner in which HIV minimizes the constraint of overlapping genes and repurposes that constraint to its own advantage. Thus, overlaps are not just consequences of evolutionary constraints, but rather can provide population fitness advantages.
Submitter: Marie Ary
Submission Date: June 28, 2018, 1:09 p.m.
|Number of data points||4444|
|Proteins||Protein Tat (HIV-1 HXB2) ; Protein Rev ; Protein Tat (HIV-1 NL4-3)|
|Assays/Quantities/Protocols||Experimental Assay: Tat Sel Coeff Mean ; Experimental Assay: Rev Sel Coeff Mean ; Experimental Assay: Rev Relative Activity (induction of intracellular p24 levels ) ; Experimental Assay: Tat Relative Activity (induction of firefly luciferase) ; Derived Quantity: SD of Rev Relative Activity (induction of intracellular p24 levels ) ; Derived Quantity: SD of Tat Relative Activity (induction of firefly luciferase)|
|Libraries||Tat DMS: Exp. fitness (mean selection coeff) of every residue of Tat in non-overlapped tat in nef viruses (Table S1) ; Rev DMS: Exp. fitness (mean selection coeff) of every residue of Rev in non-overlapped rev in nef viruses (Table S1) ; Tat Ala scan relative activities (Fig 2A) ; Rev Ala scan relative activities|