doi:10.1016/j.virol.2004.08.014 
Copyright © 2004 Elsevier Inc. All rights reserved.
Molecular clock-like evolution of human immunodeficiency virus type 1
Yi Liua, 
, 
, David C. Nicklea, Daniel Shrinera, Mark A. Jensena, Gerald H. Learn, Jr.a, John E. Mittlera and James I. Mullinsa, b, c
aDepartment of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, United States
bDepartment of Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States
cDepartment of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States
Received 19 April 2004;
revised 22 June 2004;
accepted 16 August 2004.
Available online 18 September 2004.
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Abstract
The molecular clock hypothesis states that the rate of nucleotide substitution per generation is constant across lineages. If generation times were equal across lineages, samples obtained at the same calendar time would have experienced the same number of generations since their common ancestor. However, if sequences are not derived from contemporaneous samples, differences in the number of generations may be misinterpreted as variation in substitution rates and hence may lead to false rejection of the molecular clock hypothesis. A recent study has called into doubt the validity of clock-like evolution for HIV-1, using molecular sequences derived from noncontemporaneous samples. However, after separating their within-individual data according to sampling time, we found that what appeared to be nonclock-like behavior could be attributed, in most cases, to noncontemporaneous sampling, with contributions also likely to derive from recombination. Natural selection alone did not appear to obscure the clock-like evolution of HIV-1.
Keywords: Molecular clock; HIV-1; Natural selection; Recombination
Fig. 1. Idealized tree structures under the null and alternative hypotheses for LRT of a molecular clock. “v” indicates branch lengths. (A) Under the null hypothesis with the constraint of a molecular clock, the substitution rate is constant across lineages. All contemporaneously sampled sequences in the tree have the same distance from the tip to the root. In the rooted case of n = 3 sequences, v1 = v2 and v1 + v3 = v4, such that there are n − 1 = 2 free branch length parameters. (B) Under the alternative hypothesis without the constraint of a molecular clock, the rate is heterogeneous across lineages. In the unrooted case of n = 3 sequences, there are 2n − 3 = 3 free branch length parameters.
Fig. 2. The probability of an individual of the current generation becoming the parent of a particular offspring of the next generation. (A) Under neutrality, the probability, pneu, is (1/N). (B) Under natural selection, the probabilities for an adv (advantageous genotype; open circle ), padv, and for a dis (disadvantageous genotype; filled circle), pdis, are given. The circles on the top row represent parents and those on the bottom represent offspring. wadv and wdis are fitness values for adv and dis, respectively. N is the total population size, Nadv is the population size of adv, and Ndis is the population size of dis.
Table 1.
Results of the LRT and the parametric bootstrap test of the molecular clock hypothesisa
a All data are from Posada and Crandall's within-individual data sets (
Posada and Crandall, 2001). The -lnL
1 and -lnL
0 values for the combined 1985 and 1990 samples are taken from their Table 6, and the
P values by LRT were calculated from the log likelihood values they reported.
Table 2.
Results of the LRT and the parametric bootstrap test for the gag genea
a Regions identified by PLATO as potentially having experienced recombination or natural selection were excluded from the
gag gene of Posada and Crandall's within-individual data sets (
Posada and Crandall, 2001).
Table 3.
Results of simulations of different types of selection
a s:selection coefficient.
b False-positive rejection rate by LRT.
c P values of Kolmogorov–Smirnov tests of the probability distributions of −2 log Λ between simulations of selection and the neutral distribution.
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