Jun Fan

Publications (3)16.37 Total impact

• Source

  Available from: Eric Arts

  Article: Identifying the important HIV-1 recombination breakpoints.

  John Archer, John W Pinney, Jun Fan, Etienne Simon-Loriere, Eric J Arts, Matteo Negroni, David L Robertson
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  ABSTRACT: Recombinant HIV-1 genomes contribute significantly to the diversity of variants within the HIV/AIDS pandemic. It is assumed that some of these mosaic genomes may have novel properties that have led to their prevalence, particularly in the case of the circulating recombinant forms (CRFs). In regions of the HIV-1 genome where recombination has a tendency to convey a selective advantage to the virus, we predict that the distribution of breakpoints--the identifiable boundaries that delimit the mosaic structure--will deviate from the underlying null distribution. To test this hypothesis, we generate a probabilistic model of HIV-1 copy-choice recombination and compare the predicted breakpoint distribution to the distribution from the HIV/AIDS pandemic. Across much of the HIV-1 genome, we find that the observed frequencies of inter-subtype recombination are predicted accurately by our model. This observation strongly indicates that in these regions a probabilistic model, dependent on local sequence identity, is sufficient to explain breakpoint locations. In regions where there is a significant over- (either side of the env gene) or under- (short regions within gag, pol, and most of env) representation of breakpoints, we infer natural selection to be influencing the recombination pattern. The paucity of recombination breakpoints within most of the envelope gene indicates that recombinants generated in this region are less likely to be successful. The breakpoints at a higher frequency than predicted by our model are approximately at either side of env, indicating increased selection for these recombinants as a consequence of this region, or at least part of it, having a tendency to be recombined as an entire unit. Our findings thus provide the first clear indication of the existence of a specific portion of the genome that deviates from a probabilistic null model for recombination. This suggests that, despite the wide diversity of recombinant forms seen in the viral population, only a minority of recombination events appear to be of significance to the evolution of HIV-1.
  PLoS Computational Biology 10/2008; 4(9):e1000178. · 5.22 Impact Factor
• Article: The distribution of HIV-1 recombination breakpoints.

  Jun Fan, Matteo Negroni, David L Robertson
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  ABSTRACT: We find that recombination breakpoints are non-randomly distributed across the genomes of HIV-1 intersubtype recombinants. In particular we find two recombination prone regions, "hot spots", located approximately either side of the envelope gene. To investigate this, we test whether there is a correlation between the distribution of the recombinant breakpoints with (1) genetic similarity, (2) predicted locations of secondary RNA structure, (3) regions identified as recombinant hot spots from experimental studies and (4) the predicted locations of positively selected sites. No detectable relationship with RNA secondary structure was found. A weak relationship with genetic similarity exists but it does not account for the recombination hot spots. The comparison with the published experimental studies indicated that the identified recombination hot spots differ in their locations, indicating that selection is having an impact on HIV-1 recombinant structures in infected individuals. We observe an association between recombination prone regions and strong positive selection across the envelope gene in support of this hypothesis.
  Infection Genetics and Evolution 01/2008; 7(6):717-23. · 3.13 Impact Factor
• Source

  Available from: Eric Arts

  Article: Sequence determinants of breakpoint location during HIV-1 intersubtype recombination.

  Heather A Baird, Román Galetto, Yong Gao, Etienne Simon-Loriere, Measho Abreha, John Archer, Jun Fan, David L Robertson, Eric J Arts, Matteo Negroni
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  ABSTRACT: Retroviral recombination results from strand switching, during reverse transcription, between the two copies of genomic RNA present in the virus. We analysed recombination in part of the envelope gene, between HIV-1 subtype A and D strains. After a single infection cycle, breakpoints clustered in regions corresponding to the constant portions of Env. With some exceptions, a similar distribution was observed after multiple infection cycles, and among recombinant sequences in the HIV Sequence Database. We compared the experimental data with computer simulations made using a program that only allows recombination to occur whenever an identical base is present in the aligned parental RNAs. Experimental recombination was more frequent than expected on the basis of simulated recombination when, in a region spanning 40 nt from the 5' border of a breakpoint, no more than two discordant bases between the parental RNAs were present. When these requirements were not fulfilled, breakpoints were distributed randomly along the RNA, closer to the distribution predicted by computer simulation. A significant preference for recombination was also observed for regions containing homopolymeric stretches. These results define, for the first time, local sequence determinants for recombination between divergent HIV-1 isolates.
  Nucleic Acids Research 02/2006; 34(18):5203-16. · 8.03 Impact Factor