Identifying the important HIV-1 recombination breakpoints.
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.
Archer
John
J
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Pinney
John W
JW
Fan
Jun
J
Simon-Loriere
Etienne
E
Arts
Eric J
EJ
Negroni
Matteo
M
Robertson
David L
DL
D019295:Computational Biology; D019143:Evolution, Molecular; D015752:Genes, env; D014644:Genetic Variation; D016679:Genome, Viral; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D015233:Models, Statistical; D012367:RNA, Viral / Q000235:genetics; D011995:Recombination, Genetic
D012367:RNA, Viral
J Mol Evol. 1995 Mar;40(3):249-59
7723052
J Mol Evol. 2003 Aug;57(2):212-21
14562964
J Virol. 2006 Oct;80(19):9519-29
16973556
Mol Biol Evol. 2007 Dec;24(12):2787-801
17921487
Nature. 2001 Apr 26;410(6832):1047-8
11323659
J Exp Med. 2008 Aug 4;205(8):1789-96
18625749
J Biol Chem. 1993 May 5;268(13):9793-802
7683663
Science. 1996 Apr 26;272(5261):537-42
8614801
AIDS. 2007 Aug 20;21(13):1693-700
17690566
Nature. 1995 Jan 12;373(6510):123-6
7816094
J Biol Chem. 2004 Aug 27;279(35):36625-32
15218022
Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6900-3
7688465
J Virol. 2006 Mar;80(5):2472-82
16474154
Mol Biol Evol. 2006 Sep;23(9):1724-30
16774976
J Virol. 2007 Jul;81(14):7620-8
17494080
J Virol. 2004 Feb;78(4):1962-70
14747561
PLoS Genet. 2005 Oct;1(4):e51
16244707
Infect Genet Evol. 2007 Dec;7(6):717-23
17851137
PLoS Pathog. 2007 Nov;3(11):e181
18052529
Annu Rev Genet. 2001;35:275-302
11700285
Science. 2000 Apr 7;288(5463):55-6
10766634
Nucleic Acids Res. 2006;34(18):5203-16
17003055
J Virol. 2000 Feb;74(3):1234-40
10627533
Nature. 1995 Jan 12;373(6510):117-22
7529365
AIDS. 2004 Jan 23;18(2):153-9
15075531
J Virol. 2005 Sep;79(18):11693-704
16140747
Infect Genet Evol. 2007 Jul;7(4):476-83
17369105
Nature. 2003 Mar 20;422(6929):307-12
12646921
J Virol. 2007 May;81(9):4492-500
17314156
Science. 2004 Nov 26;306(5701):1547-50
15567861
Nat Rev Genet. 2004 Jan;5(1):52-61
14708016
J Biol Chem. 2003 May 2;278(18):15973-82
12595540
Infect Genet Evol. 2005 Jan;5(1):85-95
15567142
J Virol. 1994 Apr;68(4):2409-14
7511170
PLoS Comput Biol. 2007 Jan 19;3(1):e11
17238283
PLoS Pathog. 2007 Nov;3(11):e177
18020705
Curr Infect Dis Rep. 2005 Nov;7(6):480-8
16225787