* Center for Reproduction of Endangered Species, Zoological Society of San Diego, San Diego, California
Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
Laboratory of Molecular Genetics, Yunnan University, Kunming, Yunnan, China
Correspondence: E-mail: oryder{at}ucsd.edu.
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Abstract |
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Key Words: CCR5 evolution primates
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Introduction |
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According to the strictly neutral theory, the amount of variation within species is expected to be correlated with the rate of divergence between species for different genes (Maynard Smith 1970). Comparison of intra- and interspecific variation serves as a valuable test to examine if mutations follow the neutral model. This approach has been applied broadly, disclosing adaptive (McDonald and Kreitman 1991; Eanes, Kirchner, and Yoon 1993; Karotam, Boyce, and Oakeshott 1995; King 1998; Fay, Wyckoff, and Wu 2001, 2002) or disadvantageous (Ballard and Kreitman 1994; Nachman, Boyer, and Aquadro 1994; Templeton 1996) molecular evolution. However, most of these studies only compared two or three closely related species, and many of them were for Drosophila species or focused on mitochondrial DNA sequences, or both.
In a previous report, we studied sequence evolution of the CCR5 gene among primates. Only one sequence from each species was obtained, and intraspecific variation in primates was not evaluated (Zhang, Ryder, and Zhang 1999). To provide a broader perspective on CCR5 evolution in primates, additional non-human primate CCR5 sequences have been obtained and compared with those available in the expanding collections of GenBank. The CCR5 protein acts not only as a chemokine receptor but also as a major co-receptor for human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection (Alkhatib et al. 1996; Dragic et al. 1996). Separate CCR5 domains are associated with its multiple functions (Atchison et al. 1996; Doranz et al. 1997; Edinger et al. 1997; Wu et al. 1997). Consequently, we have also tested the neutral theory at different CCR5 domains to evaluate evolutionary aspects of virus-host interactions.
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Materials and Methods |
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When two or more sequences were available from one species, we analyzed the intraspecific variation and hypothesized a possible ancestral CCR5 sequence according to parsimony principles, with the help of MacClade (Maddison and Maddison 1992) and using other closely related species' sequences as outgroups. Indels and nonsense substitutions were found in some sequences, but these sites were excluded from intra- and interspecific variation comparisons. We focused the analyses on two substitution groups: synonymous substitutions (SS) and strict nonsynonymous substitutions (NS) (see below). Genetic diversity at the nucleotide level (Pi value, the average number of nucleotide differences per site between two sequences) within species was estimated by using the Arlequin software package (Schneider et al. 1997). There were five primate lineages studied here: hominoids, colobines, cercopithecines, platyrrhines (New World monkeys), and lemurs. Therefore, we also estimated the CCR5 genetic distance (uncorrected P value) within and between each lineage by using PAUP*4.0 (Sinauer Associates).
The neutral theory predicts that the ratio of synonymous (silent) and nonsynonymous (replacement) nucleotide substitutions will be the same for intraspecific polymorphisms and interspecific fixed substitutions. Based on this rationale, McDonald and Kreitman (1991) formulated a test to examine if mutations follow the neutral model by using a 2 x 2 contingency table to compare the numbers of NS and SS substitutions within and between species. Unlike most tests of the neutral theory, this test does not require that populations have reached equilibrium. By using the McDonald-Kreitman test (G-test with William's correction), we evaluated CCR5 mutations to see if they followed the neutral theory during the course of evolution of higher primates. In this analysis, only species with two or more available sequences were included. Because we do not know exactly if the sequences of Ateles sp. and Saguinus sp. represent one species or different species, they were excluded from this analysis. The lemur data were also excluded from this analysis because of the very early divergence time between lemurs and other primate lineages. Because some sequences are not complete at the N-terminus and the C-terminus, we only used 1,017 bp of the CCR5 gene for comparisons (nucleotide site 221038, counting from the start codon ATG), which encodes 339 amino acids (amino acid site 8346). We used the phylogeny-based analysis for evaluating interspecific variation (Zhang, Rosenberg, and Nei 1998). We first constructed CCR5 gene trees by using different methods (parsimony, distance, maximum likelihood, and Bayesian), using software packages: PAUP (Sinauer Associates), PHYLIP (Felsenstein 1989), MEGA2 (Kumar et al. 2001), or MrBayes (Huelsenbeck and Ronquist 2001). We assumed that one tree constructed by the Neighbor-Joining (NJ) distance method with a gamma-justified Kimura-2-P model (Kimura 1980) represented the actual primate phylogeny. We used both the distance-based Bayesian method (Zhang and Nei 1997; Zhang, Rosenberg, and Nei 1998) and parsimony principles to infer the ancestral CCR5 sequences at all interior nodes of the tree and then counted the numbers of NS and SS on each branch of the tree. For intraspecific variation, we used both the (NJ) distance method and the parsimony method to construct haplotype trees for each species and then counted the numbers of NS and SS on each branch of the trees. The NS and SS substitutions were then pooled from each species.
McDonald and Kreitman (1991) limited the tree category dimension of the contingency test to "fixed" versus "polymorphic." Castelloe and Templeton (1994) evaluated rooting intraspecific gene trees and suggested that a refinement consisting of splitting the intraspecific "polymorphic" class into "tip" class and "interior" class would be meaningful: a tip haplotype is connected to only one other haplotype in the tree, and an interior haplotype is connected to two or more other haplotypes in the tree and thus represents an interior node in a topological sense. Templeton (1996) used this categorization for testing the neutrality of the mitochondrial cytochrome oxidase II gene in hominoid primates. We also followed this categorization with the CCR5 data and tested different mutational categories with the contingency method: intraspecific tip class versus intraspecific interior class and intraspecific interior class versus interspecific fixed mutations. Because of the limited numbers of interior mutations, these comparisons were studied only at the whole-gene level.
The functional importance of different CCR5 domains may affect selection of mutations in these domains: more functionally crucial domains are expected to be less likely to accumulate nonsynonymous mutations. Thus we also explored the distribution patterns of intra- and interspecific variation for different CCR5 functional domains. The CCR5 functional domains were classified as the N-terminus (N-t, corresponding to nucleotide sites 2293; sites 121 were eliminated from our analysis), the seven transmembrane domains combined (TM, including nucleotide sites 94168, 202264, 307372, 433501, 592654, 706771, and 838906), the three intercellular domains combined (I, nucleotide sites 169201, 373432, and 655705), each of the three extracellular domains: E1 (265306), E2 (502591), and E3 (772837), and the C-terminus (C-t, 907-1038; nucleotide sites 10391056 were eliminated from our analysis). As the number of observed nucleotide substitutions on each domain is correlated with the domain length, we evaluated the relative number of substitutions (substitutions/domain length). The McDonald-Kreitman test was also performed to explore if mutations at different domains follow the neutral model.
Adaptive evolution among CCR5 amino acids was tested by using PAML (Yang 1997). Based on contingency test results on different CCR5 domains, we partitioned CCR5 amino acids into two classes: (N-t, E1, E2, E3, C-t) and (TM, I). Six models were used here: M0, M1, M2, M3, M7, and M8; and their specifications are explained in Yang and Swanson (2002).
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Results |
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From the deduced ancestral sequences of each species exhibiting polymorphism, CCR5 gene trees were constructed by different methods and with different models. All the trees have similar topologies, and their differences lie within the interpretation of the relationships within genera. A tree constructed by the Neighbor-Joining distance method (see fig. 1) was used here, whose topology conformed well to the generally accepted phylogenetic families and subfamilies of primate phylogeny (e.g., Goodman et al. 1998). We found that different analysis methods generated the same conclusions, so we have listed only results based on node sequences deduced by the distance-based Bayesian method (Zhang and Nei 1997; Zhang et al. 1997). This method provided highly reliable inference of interior node sequences, with probabilities over 96%. The numbers of interspecific NS and SS occurring on each branch are listed in figure 1. In contrast, at the intraspecific level, the parsimony method was more conservative than the NJ method at inferring relationships between haplotypes. Both methods counted the same numbers of NS and SS for most species, and differences of final pooling results between the two methods were small (total NS/SS = 178/121 for the NJ method and 181/124 for the parsimony method). As both methods provided essentially the same results, only results based on the NJ method are presented in figure 1. Detailed haplotype trees with NS and SS information for each species are available from the authors on request. We performed the McDonald-Kreitman test for intra- and interspecific NS and SS comparison in different primate lineages. The proportion of NS to SS at the intraspecific level is always higher than the proportion at the interspecific level, and the differences are statistically significant (fig. 1).
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Discussion |
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Unobserved multiple hits on some classes of mutations could affect the accuracy of branch lengths, and thus could have an impact on the contingency test (Maynard Smith 1994; Templeton 1996). For example, Maynard Smith (1994) pointed out that synonymous substitutions tend to be transitions, and nonsynonymous substitutions are more often transversions. When the genetic distance between species is large, there is a bias toward undercounting the number of transitions, and thus the number of SS. This effect is not important if the between-species differences are not close to saturation (Templeton 1996). However, considering our CCR5 data, even if the number of SS between species were undercounted, a correction would only increase the significance of the outcome. It is unlikely, however, that substitutions within nuclear genes such as CCR5 have reached saturation. We constructed a worse-case scenario by presuming that the NJ method estimated the number of intraspecific NS accurately while the parsimony method estimated the number of intraspecific SS accurately; thus the proportion of NS to SS at the intraspecific level was reduced from 178/121 to 178/124, and the McDonald-Kreitman test still suggested a highly significant deviation from neutrality (G = 19.37, P = 0.00001).
One assumption for the contingency test is that sequences have been sampled at random with respect to different categories of variation. Because most of our sequences were from GenBank, it is hard to estimate their randomness. However, we may tend to "randomize" samples by nesting our analysis on those species with five or more available sequences. The nested analysis results were shown in figure 3 and the result was essentially the same.
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By splitting the intraspecific "polymorphic" class into "tip" class and "interior" class, it showed that for an intraspecific haplotype tree, interior haplotypes strongly tend to be older than tip haplotypes, and that interior haplotypes also tend to be more frequent in the gene pool than tip haplotypes (Castelloe and Templeton 1994; Templeton 1996). Because the mutations that are ultimately fixed derive preferentially from the old, common class (interior) and not the young, rare class (tip) under neutrality, polymorphic mutations on interior branches may well have evolutionary properties more akin to fixed interspecific mutations than to polymorphic tip branches (Templeton 1996). Our results did support this hypothesis: the contingency test did not detect differences between intraspecific interior mutation patterns and interspecific fixed mutation patterns. Still, there was a significant difference between the intraspecific tip class and the interior class, suggesting deviation from neutrality (table 2). This finding conforms with Fu and Li's results (1993), who demonstrated that deviations from neutrality can be detected with intraspecific data by discriminating between "external" (tip) versus "internal" (interior) mutations.
Selection at Different CCR5 Domains
The CCR5 protein acts not only as a chemokine receptor but also as a major co-receptor for viruses such as HIV and SIV (Alkhatib et al. 1996; Dragic et al. 1996). Some studies revealed that interactions between CCR5 and HIV/SIV are conformationally complex and involve multiple CCR5 domains; the amino terminal domain and extracellular loop are two critical domains for CCR5 co-receptor function (Atchison et al. 1996; Doranz et al. 1997; Edinger et al. 1997). However, the pattern for chemokine binding is relatively simple, as only the second extracellular loop (E2) seems to be involved (Wu et al. 1997). The carboxyl terminus (C-t) of CCR5 correlates with receptor phosphorylation (Oppermann et al. 1999). Thus different CCR5 domains are associated with different CCR5 functions, and it would be informative to investigate how selection acted on these different domains.
Interestingly, our results showed that CCR5 transmembrane domains and intercellular domains have experienced strong selective constraints. Although we do not know why selective constraints acted on intercellular domains, the anchor function of transmembrane domains for CCR5 expression on the cell surface might be a reasonable explanation for selective constraints on transmembrane domains. Strikingly, for the other CCR5 domains that are more closely correlated with and important for its chemokine receptor and virus co-receptor functions, there was no obvious evidence to show deviation from neutrality. There is conjecture that some amino acids on these functional domains may have experienced positive selection, contradicting the effects of purifying selection if there were any. We tested different models but found that only amino acid residue 15Y on the N-terminus had the sign of positive selection. When this codon was excluded, the results remained the same. These results therefore imply that selective constraints did not act strongly on these domains, or that the CCR5 chemokine receptor function in vivo is not very important, an observation that would be consistent with the finding that deficient CCR5 proteins do not show obvious detrimental effects in humans (O'Brien and Dean 1997). One possible explanation is that the CCR5 chemokine receptor function is at least partially redundant and can be compensated for by other chemokine receptors (Baggiolini, Dewald, and Moser 1997).
CCR5 Polymorphisms and Genetic Diversity
We compared different non-human primate CCR5 sequences to human ones and found that they share high similarity at both the nucleotide and the protein level. Computer simulation of some primate CCR5 sequences has revealed high structural similarity (Yang et al. 2000). These results together imply that different primate CCR5 proteins, at least for closely related species, perform the same or similar functions in vivo. In vitro experiments have revealed that HIV can use a non-human primate CCR5 as a co-receptor, and SIV can also use the human CCR5 as a co-receptor (Chen et al. 1997; Marcon et al. 1997; Pretet et al. 1997), findings consistent with the hypothesis that HIV originated as a result of cross-species transmission of SIV from African apes or monkeys to humans. Evidence has been reported to suggest that HIV-2 originated from sooty mangabey SIVs and that HIV-1 originated from chimpanzee SIVs (Gao et al. 1992, 1999).
Many CCR5 polymorphisms have been found in humans, one of which, 32-deletion, has been identified to be highly resistant to HIV infection (Dean et al. 1996; Liu et al. 1996). Some other polymorphisms may potentially change the efficiency of CCR5 as an HIV/SIV co-receptor, such as M303, which is a single-nucleotide polymorphism (T
A at nucleotide site 303, T303A) and causes premature translation termination (Carrington et al. 1997; Quillent et al. 1998). Our sequence comparison results showed that notable CCR5 polymorphisms also exist in non-human primates. One fragment deletion allele,
24-deletion, has been found in mangabey species (Cercocebus torquatus), resulting in a mutant protein that is not expressed at the cell surface and thus does not function as a viral co-receptor (Palacios et al. 1998). Single-nucleotide polymorphisms causing premature translation termination were also found in one rhesus monkey (Macaca mulatta, AF161958, G569A) and one marmoset (Callithrix jacchus, AF161942, C304T). These polymorphisms might also change the efficiency of CCR5 as a HIV/SIV co-receptor and be useful mutant animal models for a HIV/SIV and CCR5 interaction study.
In an earlier study we found that the CCR5 gene evolved faster in rodents than in primates (Zhang, Ryder, and Zhang 1999). Consistent with that finding, the present study showed that the CCR5 genetic diversity in rodents is higher than that in primates (table 1). Differences of the efficiency of the DNA repair system, generation time, and/or metabolic rate have been used to explain rate variation among different lineages (Wu and Li 1985; Li 1997).
Comparison of intra- and interspecific variation is a powerful test to study mutation models. However, so far most studies involving this test compared only very closely related species; a possible reason for this is that there usually were limited sequences available from divergent species, constraining broader comparisons. Because CCR5 acts as an important co-receptor for HIV/SIV infection (Alkhatib et al. 1996; Dragic et al. 1996) and because HIV originated from SIV (Gao et al. 1992, 1999), researchers have had a great interest in identifying genetic variation between different primate CCR5s that modulate pathogenesis. Although there is no evidence showing that CCR5 variation between nonhuman primate species has an effect on different HIV/SIV pathogenetic mechanisms (e.g., Muller-Trutwin et al. 1999), such an interest has generated so many CCR5 sequences of divergent species that we had the opportunity to compare intra- and interspecific variation across a broad range of primate species.
This study focused on the CCR5 coding sequences themselves. Evidence for selection at this locus could also arise as a result of linked sequences, such as promoters (Bamshad et al. 2002). As comparative genomic studies advance, progress can be anticipated as additional evaluations of co-evolution of pathogens and the host proteins upon which they depend provide new insights into the selective focus that affects genome sequences and their variation.
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Acknowledgements |
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Footnotes |
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Keith Crandall, Associate Editor
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