title: Functional Segregation of Overlapping Genes in HIV.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA; Program in Pharmaceutical Sciences and Pharmacogenomics, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Fernandes
authors.affiliation: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA; Tetrad Program, Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Tyler B
authors.initials: TB
authors.lastname: Faust
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Nicolas B
authors.initials: NB
authors.lastname: Strauli
authors.affiliation: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Crosby
authors.affiliation: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nakamura
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Hernandez
authors.affiliation: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address: frankel@cgl.ucsf.edu.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Frankel
mesh_terms: D005075:Biological Evolution; D019277:Entropy; D056084:Genetic Fitness; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D016366:Open Reading Frames; D054321:rev Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D054321:rev Gene Products, Human Immunodeficiency Virus; C514860:rev protein, Human Immunodeficiency Virus-1; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: HIV; Rev; Tat; alanine scanning; deep mutational scanning; evolution; overlapping reading frames; overprinting; viral evolution; virus