Functional Segregation of Overlapping Genes in HIV.


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.

Submission Details


Submitter: Marie Ary

Submission Date: June 28, 2018, 1:09 p.m.

Version: 1

Publication Details
Fernandes JD;Faust TB;Strauli NB;Smith C;Crosby DC;Nakamura RL;Hernandez RD;Frankel AD,Cell (2016) Functional Segregation of Overlapping Genes in HIV. PMID:27984726
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)

Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1RPV 1995-05-04T00:00:00+0000 0 HIV-1 REV PROTEIN (RESIDUES 34-50)
3LPH 2010-02-05T00:00:00+0000 2.5 Crystal structure of the HIV-1 Rev dimer
4PMI 2014-05-21T00:00:00+0000 3.2 Crystal structure of Rev and Rev-response-element RNA complex
6HIP 2018-08-30T00:00:00+0000 1.2 Structure of SPF45 UHM bound to HIV-1 Rev ULM
7JYA 2020-08-30T00:00:00+0000 2.46 Crystal structure of E3 ligase in complex with peptide
2X7L 2010-03-01T00:00:00+0000 3.17 Implications of the HIV-1 Rev dimer structure at 3.2A resolution for multimeric binding to the Rev response element
3MI9 2010-04-09T00:00:00+0000 2.1 Crystal structure of HIV-1 Tat complexed with human P-TEFb
3MIA 2010-04-09T00:00:00+0000 3.0 Crystal structure of HIV-1 Tat complexed with ATP-bound human P-TEFb
4OR5 2014-02-10T00:00:00+0000 2.9 Crystal structure of HIV-1 Tat complexed with human P-TEFb and AFF4
5DHV 2015-08-31T00:00:00+0000 2.3 HIV-1 Rev NTD dimers with variable crossing angles

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Protein Tat (HIV-1 HXB2) P04608 TAT_HV1H2
98.0 Protein Tat (HIV-1 HXB2) P04612 TAT_HV1B5
94.1 Protein Tat (HIV-1 HXB2) P19552 TAT_HV1S3
99.1 Protein Rev P04618 REV_HV1H2
94.8 Protein Rev P04620 REV_HV1BR
94.0 Protein Rev P04325 REV_HV112
94.0 Protein Rev P04616 REV_HV1B1
93.1 Protein Rev P69718 REV_HV1H3
91.4 Protein Rev P05872 REV_HV1SC
92.2 Protein Rev P04623 REV_HV1A2
96.2 Protein Rev P05864 REV_HV1B8
94.2 Protein Tat (HIV-1 NL4-3) P05907 TAT_HV1C4