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Proc Natl Acad Sci U S A. Feb 8, 2005; 102(6): 1980–1985.
Published online Jan 31, 2005. doi:  10.1073/pnas.0409652102
PMCID: PMC548581
Evolution

A monkey's tale: The origin of Plasmodium vivax as a human malaria parasite

Abstract

The high prevalence of Duffy negativity (lack of the Duffy blood group antigen) among human populations in sub-Saharan Africa has been used to argue that Plasmodium vivax originated on that continent. Here, we investigate the phylogenetic relationships among 10 species of Plasmodium that infect primates by using three genes, two nuclear (β-tubulin and cell division cycle 2) and a gene from the plastid genome (the elongation factor Tu). We find compelling evidence that P. vivax is derived from a species that inhabited macaques in Southeast Asia. Specifically, those phylogenies that include P. vivax as an ancient lineage from which all of the macaque parasites could originate are significantly less likely to explain the data. We estimate the time to the most recent common ancestor at four neutral gene loci from Asian and South American isolates (a minimum sample of seven isolates per locus). Our analysis estimates that the extant populations of P. vivax originated between 45,680 and 81,607 years ago. The phylogeny and the estimated time frame for the origination of current P. vivax populations are consistent with an “out of Asia” origin for P. vivax as hominoid parasite. The current debate regarding how the Duffy negative trait became fixed in Africa needs to be revisited, taking into account not only human genetic data but also the genetic diversity observed in the extant P. vivax populations and the phylogeny of the genus Plasmodium.

Keywords: Duffy, genetic diversity, host–switch

Almost 60 years ago, Haldane (1) proposed that human malaria might act as a selective force on human populations. Until recently, tests of this hypothesis were hampered by a limited amount of data and the lack of objective methods of phylogenetic reconstruction.

Initial phylogenetic investigations using molecular approaches have focused primarily on the origin of Plasmodium falciparum, the agent of malignant tertian malaria, and its relationship to other human and animal malaria parasite species (28). Two major conclusions were drawn from these studies. First, each of the four Plasmodium species parasitic to humans arose independently as human pathogens and, second, Plasmodium reichenowi, a parasite of the chimpanzee, is the species that shares the most recent common ancestor with P. falciparum (3, 6, 8). These findings have led to vigorous debate about the origin and age of the extant populations of P. falciparum (914). Until now, there has been limited information about the origin of P. vivax, the major and most prevalent human malaria parasite outside of sub-Saharan Africa.

Recent discussions on the origin of P. vivax have been driven for the most part by the analysis of indirect evidence without strong phylogenetic data. One of the earliest hypotheses placed the origin of P. vivax in Southeast Asia, together with other Plasmodium species parasitic in nonhuman primates (15). The argument was supported by the abundance of simian malaria parasite species in this region and the observation that several of the macaque parasites shared morphological and biological characteristics with P. vivax (1517). However, this “out of Asia” hypothesis has not been generally accepted in recent years. Particularly, arguments based merely on species abundance to identify “centers of origin” are questionable because they do not consider the rapid radiation of species in limited areas (6) or habitat changes that may affect the distribution and abundance of species. In contraposition, the high prevalence of Duffy negativity (lack of the Duffy blood group antigen or FY*O) among human populations in sub-Saharan Africa has been used to support an African origin for P. vivax (1618).

The Duffy blood group (FY) is a transmembrane glycoprotein that is also a chemokine receptor (19, 20). It has three blood types; two, FY*A and FY*B, correspond to functional protein, whereas the third, FY*O, fails to express a product on the red blood cell surface because of a promoter mutation. The Duffy antigen/chemokine receptor (also referred as DARC) is also an erythrocyte receptor targeted by P. vivax as its gateway to invading the red blood cell. Thus, Duffy negative (FY*O) homozygotes do not express the FY*A or FY*B proteins and are completely protected against P. vivax infection (17, 19, 20). The specificity of the Duffy–vivax interaction suggests that P. vivax could have been in contact with the African human population, allowing that selection imposed by the parasite to drive FY*O to fixation (17); thus, it is possible that P. vivax originated out of Africa, carried by any of the hominoid lineages that had their origin there, including modern humans. However, given that P. vivax does not exhibit high levels of virulence in terms of mortality rates, it is not likely to be such a strong selective factor (18). This hypothesis leaves open the possibility that the FY*O in Africa could have been fixed by another process (selection due to another pathogen or chance) and then became a barrier against a subsequent introduction of P. vivax (18).

An earlier phylogenetic study using the mitochondrial cytochrome b gene provided the first molecular suggestions about the origin of P. vivax. The estimated gene phylogeny indicated the following: (i) Asian primate malarias, including P. vivax, were apparently part of a recent species radiation (6); and (ii) there was a more ancient African origin for the lineage leading to the extant primate malarial species found in Southeast Asia (6). Specifically, parasites from Africa such as Plasmodium gonderi were placed at the base of the phylogeny as sister taxa of a monophyletic group that includes all existing Southeast Asian nonhuman primate parasites together with the human parasite, P. vivax (6). This phylogenetic information coincides with the origin and radiation of the various primate groups that are malaria hosts in Southeast Asia (21). This phylogenetic study also made less parsimonious that P. vivax could originate from a platyrrhine monkey parasite in South America such as Plasmodium simium. Indeed, P. simium is identical to several isolates of P. vivax (22) and most likely originated because of a human-to-primate host switch (6).

It is expected that the lineage from which primate malarias radiated in Southeast Asia should appear ancestral (basal) in the phylogeny (17). However, the data from the cytochrome b gene was not able to elucidate the finer evolutionary relationships existing among the primate malaria parasites in Southeast Asia. Thus, the estimated phylogeny was compatible with the introduction of malaria parasites into the region from Africa by any primate lineage, among them early hominoids such as Homo erectus or more recently by Homo sapiens. Because of this lack of resolution in the phylogenetic tree, we further studied the phylogenetic relationships among 10 Plasmodium species in primates (including P. vivax) by using three new genes, two nuclear and a gene from the plastid genome.

Our data are not compatible with an early African HomoP. vivax association. Furthermore, this investigation supports the notion that P. vivax originated from a primate malaria parasite in Southeast Asia, most likely a species infecting macaques.

Materials and Methods

Table 1 shows the species included in this study with some of their biologic characteristics and geographic distributions; additional information is available in refs. 23 and 24. Phylogenetic analysis was based on two nuclear genes, β-tubulin and cell division cycle 2 (CDC-2); and one plastid gene, the elongation factor Tu (TufA). The genes were amplified by PCR using the following pairs of primers: AL1508, GAA AA(A/G) GA(A/G) GA(T/C) (G/C)AA GG(A/C) AT(T/C) CC(A/G) TCA AC with AL1509, CC(A/G) AA(A/G) TCI GC(A/G) ATT TTT AAT TCI CC for CDC-2; AL1499, GGI CA(A/G) TG(T/C) GGI AA(T/C) CA(A/G) AT(T/A) GGT GCI AA(A/G) TT(T/C) TGG GA, with AL1500, (C/T)TC IGT (A/G)AA (C/T)TC CAT (T/C)TC (G/A)TC CAT for β-tubulin; and AL1447, GGI CAT GTA GAT CAT GGI AAA ACT AC, with AL1448, AT(A/T) AT(A/T) CCT GCT CCT AT(A/T) for TuFA. “I” codes for inosine. The amplification conditions for β-tubulin were as follows: first, 1 min at 94°C, followed by 30 cycles with 0.5 min of denaturation at 94°C, annealing at 45°C for 0.5 min, and elongation at 72°C for 1.5 min. After 30 cycles, a final elongation step at 72°C for 3.0 min was carried out. In the cases of CDC-2 and TufA, the amplification conditions were, first, 4 min at 94°C, followed by 30 cycles with 0.5 min of denaturation at 94°C, annealing at 45°C for 0.5 min, and elongation at 72°C for 1.0 min. After 30 cycles, a final elongation step at 72°C for 3.0 min was carried out. The amplified products were purified, cloned, and sequenced. Both strands were sequenced from at least two clones from two independent PCRs. The sequences were obtained by using the automated sequencer 3100 Genetic Analyzer (Applied Biosystems).

Table 1.
Plasmodium species with their host, geographic range, and two life history traits: periodicity and their capacity for relapse

Sequence alignment was performed manually; gaps were not considered in the analysis. We performed phylogenetic analyses by using maximum likelihood (ML) methods based on an initial tree calculated by the neighbor-joining algorithm. The phylogenies were estimated with paup (Version 4.0 beta10) (25) and paml (Version 3.13; ref. 26). The best substitution model was selected by likelihood ratio tests as implemented in model test (Version 3.06; ref. 27) for each gene by using the initial neighbor-joining trees. In addition, the most inclusive model was implemented in paml combining the information of the three genes to obtain a final ML phylogeny (28). Supporting values for the nodes of the ML phylogenies were obtained through a Monte Carlo Markov chain model as implemented in mr. bayes (29).

We tested the expected phylogenies under the following two principal alternative scenarios for the origin of P. vivax: (i) a hominoid origin (as proposed in ref. 17) and (ii) a macaque origin (Fig. 1). Under the hominoid scenario, P. vivax should be a basal lineage in the phylogeny relative to the other species parasitic of primates in Southeast Asia (Fig. 1A). The alternative tree shown in Fig. 1B represents the macaque scenario (as estimated in this study). Existing data suggest that gibbon and orangutan parasites are derived from macaque parasites (this study and N. Wolfe, A.A.E., and A.A.L., unpublished data). Alternative phylogenies were compared by using the Shimodaira–Hasegawa test (30), which allows for multiple comparisons.

Fig. 1.
Hypothetical tree topologies under the Homo (as proposed by ref. 17) (A) and the Macaca (as proposed in this study) (B) scenarios for the origin of P. vivax.

Once the best phylogeny was selected, the time to the most recent common ancestor (TMRCA) for P. vivax alleles was estimated for four gene loci from which no evidence for positive natural selection was found (31): β-tubulin (eight isolates from Colombia, Honduras, and Venezuela; two isolates from India, Thailand, Vietnam, and Sumatra); CDC-2 (seven sequences: six isolates from the same areas as β-tubulin but India and the sequence AF136377 from the GenBank database), dihydrofolate reductase (DHFR; 11 isolates as reported by ref. 32 including French Guyana, Surinam, Burma, Cambodia, Indonesia, Madagascar, and Comoros Islands); and Pvs25 (10 isolates from Colombia, Honduras, Venezuela, Nicaragua, Brazil, Indonesia, North Korea, Mauritania, and Papua New Guinea). The sampling covers the distribution of P. vivax including alleles from New World and Old World isolates (22). We followed a similar approach to that used by Hughes and Verra (11) and estimated R, the substitution rate per site per year, from time (t) by using the equation t = D/2R, where D is the average genetic distance among genes, and t was assumed under the scenarios described below. We first estimated the mutation rate for each homologous locus by using the divergence among macaque parasites. The assumption made here is that the mutation rates among macaque parasites are valid independent estimates of the mutation rate within P. vivax. We used the divergence among Plasmodium fragile, Plasmodium knowlesi, Plasmodium cynomolgi, and Plasmodium inui to estimate the mutation rates. These species were selected based on the estimated phylogeny to capture the maximum divergence among the malaria parasite lineages that are found in at least two major groups of macaque species. Although no evidence suggesting departure from neutrality was found within the P. vivax sample or between the species (26, 31), the rate of evolution among the Plasmodium species could be affected by several factors, such as differences in generation time or in their effective population sizes. Thus, we tested the assumption of constant rate of evolution as follows: complete phylogenies with all of the species but P. gonderi were analyzed for in the cases of CDC-2 and β-tubulin exons through the comparison of their likelihood estimated by dnaml (no molecular clock) and dnamlk (molecular clock) algorithms of the phylip package (33) without observing significant differences. In the cases of DHFR and Pvs25, relative ratio tests between P. cynomolgi and P. inui by using P. knowlesi as outgroup were performed, and the molecular clock was not rejected. In such cases, only the P. cynomolgiP. inui divergence was used. The time frame used was 1.4–2.5 million years (Myr) assuming that these parasite lineages diverged after the radiation within the major Macaca species groups (silenus, fascicularis, and sinica) on which P. cynomolgi and P. inui are found (23, 24). We did not assume cospeciation of the parasites with their hosts given that host switches appear to be common (see Table 1). We assumed only that the parasite radiation took place together with the radiation and/or population expansions of the major macaque lineages because we expected that a diverse and abundant fauna of hosts is a requirement for the differentiation of malarial parasites in sympatry. These time frames are supported by (i) fossil and molecular phylogenetic studies on macaques suggesting these time frames as the periods when the group became diverse and abundant (21, 34), and (ii) there was a high correlation between the distributions of the genus Homo and Macaca during this time frame (21). All of the sequences reported in this study are deposited in the GenBank database with accession nos. AY639953-AY640007.

Results

The phylogeny estimated by ML combining the three genes is depicted in Fig. 2. The model that fit the data best was the general time reverse model (35) with a gamma correction for heterogeneity among sites (genetic distances are provided in Table 4, which is published as supporting information on the PNAS web site). The same phylogeny was obtained by using ML or Bayesian methods. Additional phylogenetic analyses by using maximum parsimony led to similar results. The phylogenies derived from the analysis of individual genes were also consistent. The African primate parasite P. gonderi was used for rooting the phylogeny, given that previous studies have shown that Southeast Asia simian parasites originated in Africa (6). P. vivax shares a recent common ancestor with two clades, one that includes P. cynomolgi, P. fieldi, and P. simiovale (hereafter referred to as the P. cynomolgi lineage), and the clade of P. inui and the gibbon parasite P. hylobati (hereafter referred to as the P. inui lineage). We did not find any significant difference in the likelihood among topologies considering permutations of these two nonhuman primate parasite lineages and P. vivax by the Shimodaira–Hasegawa test as implemented in the program consel (30). This group of species (P. vivax plus P. cynomolgi and P. inui lineages) consistently appears as a sister lineage of the clade that includes P. knowlesi and P. coatneyi (hereafter referred to as the P. knowlesi lineage). All together, these simian malaria species appear as a monophyletic group, whereas P. fragile is consistently placed as the most basal macaque parasite in the phylogeny (Fig. 1).

Fig. 2.
ML phylogenetic tree based on the nuclear genes β-tubulin and CDC-2 and the plastid gene TuFA. Supporting values for the nodes of the tree were obtained through a Monte Carlo Markov chain model as implemented in mr. bayes (24).

We tested two scenarios for the origin of P. vivax: the hominoid origin (as proposed by ref. 17) and the macaca origin (estimated in this study). The two phylogenies expected under these scenarios (depicted in Fig. 1) were compared. The phylogenies were statistically different in their goodness of fit to the available data with the “macaque origin” being more likely (likelihood of –16865.31 vs. –16933.35 for 10 species). Furthermore, any phylogeny that placed simian parasites as derived from P. vivax fitted the data less well; thus, P. vivax appeared as a species derived from a Macaca lineage.

We also investigated the most recent common ancestor of the extant populations of P. vivax by using four genes, from which information from several isolates was available (Table 2). There was no evidence of departure from neutrality on any of these genes (Table 2), and the assumption of a molecular clock was tested among the primate species as described previously. Isolates from Asia and the Americas were included in this sample. DHFR sequences are described in ref. 31. CDC-2, β-tubulin, and Pvs25 are reported in this study. We estimated the average divergence time among the P. vivax alleles sampled in this investigation by including one allele per locality, considering the broad distribution of P. vivax. As explained before, we estimated R, the mutation rate, from t = D/2R. We used the mutation rates estimated from the divergence among the simian parasites as previously described. The mutation rates obtained can be found in Table 3 and are comparable with those estimated for other eukaryotes (36, 37). We also estimated the mutation rates for all loci considering P. vivax as part of this radiation process, and they were comparable with the values obtained among macaque parasite species. However, in preferring to avoid the risk of a circular argument, we excluded P. vivax from the mutation rate estimations whenever possible. An average TMRCA for the divergence of the P. vivax alleles was estimated by weighting the average. The TMRCA obtained is between 45,680 and 81,607 years ago (Table 3). However, the times estimated ranged from 17,114 to 74,123 under the 1.4-Myr scenario and between 30,507 and 132,445 under the 2.5-Myr scenario. This time frame includes the accepted estimates for the introduction of H. sapiens in Southeast Asia (38); however, other hominoids were present such as H. erectus (21).

Table 2.
Basic estimates for CDC-2, β-tubulin, DHFR, and Pvs25 alleles used for estimating time to the MRCA of P. vivax
Table 3.
TMRCA among P. vivax isolates estimated by t = D/2R

Discussion

The primary result of our analysis is that P. vivax shares a recent common ancestor with the three major macaque parasite lineages (P. cynomolgi, P. inui, and P. knowlesi). This observation corroborates the fact that biologic traits have limited value for assessing phylogenetic relationships among Plasmodium species (6). However, a phylogeny is still indispensable for understanding their evolution. In the specific case of periodicity, for example, quotidian and quartan parasites (P. knowlesi and P. inui, respectively) are derived from tertian parasites such as P. fragile. In contrast, the origin of the capacity of relapse in P. vivax and related parasites could be a single event under the scenario of P. vivax and P. cynomolgi being sister taxa.

The phylogeny estimated in this study provides insights on the origin of P. vivax as a Homo parasite. Specifically, the out-of-Africa scenario for the origin of P. vivax is a less parsimonious hypothesis to explain the data presented in this investigation.

Two observations make the scenario of Homo-facilitated introduction of primate malaria into Southeast Asia unlikely. First, P. vivax should appear as a sister taxa of all Southeast Asian primate parasites (Fig. 1 A), which should form a monophyletic group (17). The phylogeny reported in this investigation is not consistent with this prediction because P. vivax appears as a species derived from a Macaca lineage of simian parasites. Furthermore, the data support the P. vivax lineage originating after the divergence of some of the extant lineages of macaque parasites, notably after the divergence of P. fragile/P. knowlesi. Additionally, a scenario of an early African origin for P. vivax and a subsequent Homo introduction in Southeast Asia also implies there would be less diversity within the derived species (in this case, the species parasitic to macaques and other nonhuman primates) than in the ancestral one, P. vivax. Contrary to expectations, the diversity within some macaque species such as P. cynomolgi and P. inui is higher than within P. vivax, which shows low genetic diversity (39, 40). Two ad hoc assumptions need to be made to make the genetic data compatible with a host switch from Homo to Macaca, as follows: (i) There were several extinction and recolonization events that we cannot document with the extant species; thus, the P. vivax lineage that survives today is only a derived one, whereas all of the others became extinct; and (ii) there was a recent bottleneck in this remaining P. vivax lineage so that its population size became smaller than P. cynomolgi and P. inui in macaques.

Based on our results, the most parsimonious hypothesis is that the lineage leading to the origin of P. vivax as a human pathogen was introduced into Homo in Asia by a species of Plasmodium parasitic to macaques (Fig. 1B). A host switch from Macaca sp. to Homo is readily possible and has been demonstrated by natural infections in modern humans with P. knowlesi under circumstances of natural transmission in mainland Malaysia and Borneo (41, 42). In addition, it has been postulated that P. simiovale may be found in humans, although the data available is from a single gene (43, 44). Host switches appear to be common phenomena in malaria parasites as demonstrated in avian and other primate malaria parasites (23, 44, 45). These findings are also congruent with phylogenetic studies of cestodes (Taenia) (46), hookworms (Oesophagostomum), and pinworms (Enterobius) (47) indicating secondary acquisitions of parasites by humans when they colonized Southeast Asia.

It is important to emphasize that the genera Homo and Macaca represent the two most successful primate expansions, and their geographical distributions overlapped, especially, during the late Pliocene and middle Pleistocene (0.7–2.5 Myr) (21), making possible the exchange of parasites in any direction.

It is worth noting that our proposal of a macaque origin for P. vivax is not based on the number of Plasmodium species parasitic to primates in Southeast Asia (16, 17) but on the fact that Plasmodium sp. parasitic to macaques are basal in the phylogeny that includes P. vivax. Under this scenario, the relatively low genetic diversity in P. vivax (40, 48) is the natural consequence of the colonization of hominoids by a macaque parasite lineage that later became P. vivax. A cautionary note is necessary at this point: a broader sample of P. vivax isolates is needed, particularly isolates from Africa, where 10% of the malaria cases reported are P. vivax infections (49). This broader sample, together with more extensive molecular data, will allow elucidating the history of the extant populations of P. vivax. This investigation simply aims to underlay the inconsistency of the molecular data with an out-of-Africa origin of P. vivax.

A potential limitation in our analysis is the lack of a sample of P. schwetzi, a chimpanzee parasite that some authors consider closer to P. vivax but others described as a P. ovale-like parasite (23). No material of this parasite is available; thus, no data could be derived that challenges the evidence provided in this study. In addition, it is worth noting that the estimated time frames are consistent with both H. sapiens and H. erectus (21, 50). The role played by the dynamic of the hominoids in Southeast Asia could be very important in the evolution of P. vivax; however, we have no elements that allow us to speculate about the topic.

An Asian origin from a nonhuman primate raises questions about the hypothesis for fixation of the Duffy negativity in sub-Saharan Africa as the result of an ancient presence of P. vivax on that continent. We could speculate that the fixation of Duffy negativity was driven by selection from other P. vivax-like parasites because Asian malaria parasites, as a monophyletic group, derived from Plasmodium parasitic in primates in Africa as evidenced by P. gonderi and other malaria parasite species (6). However, the genetic signature of directional selection around FY*O is still controversial, and there is no evidence of a long effect of positive selection in the gene encoding the Duffy blood group when several primates are studied (51). Current investigations show some evidence for a selective sweep leading to the fixation of FY*O in Africa; however, the pattern is still unclear (5254). Indeed, FY*O fixation could have happened after the onset of agriculture, when human population sizes increased and selection due to malaria could operate (54), a scenario that is still compatible with an Asian origin of P. vivax. Finally, but no less important, the fixation of Duffy negativity could be the outcome of other historic or selective processes. Given the available data about the Duffy blood group and this phylogenetic analysis, it appears that by using the high prevalence of FY*O as evidence that P. vivax originated in Africa simply shows the inability of separating “current utility from reasons for origin” (55); that is, the fact that a trait is an adaptation today does not imply that it originated by natural selection. Our conclusion of an Asian origin is consistent with results from analyses of complete mitochondrial genomes (J. Mu, D. Joy, and X. Su, personal communication).

In summary, this investigation points to P. vivax being derived from ancestral macaque parasites when hominoids colonized Southeast Asia. Our results do not support that P. vivax was a Homo parasite before the expansion of the hominoids populations out of Africa. Thus the assumption that the high prevalence of Duffy negative is a consequence of a long H. sapiensP. vivax association in Africa needs to be revisited.

Supplementary Material

Supporting Table:

Acknowledgments

We thank J. W. Barnwell, D. Brooks, A. McCollum, C. Todd, V. Udhayakumar, D. Walliker, and two anonymous reviewers for valuable comments that improved the manuscript. A.A.E. is supported by National Institutes of Health Grant GM60740. O.E.C. is supported by a fellowship from Fondo Nacional de Ciencia, Tecnología e Innovación-Venezuela. Computer support is provided by Fondo Nacional de Ciencia, Tecnología e Innovación Grant G97000634 to Centro Nacional de Cálculo Científico Universidad de Los Andes.

Notes

Author contributions: A.A.E. and A.A.L. designed research; D.E.F., A.C.P., and E.D. performed research; W.E.C. contributed new reagents/analytic tools; A.A.E. and O.E.C. analyzed data; A.A.L. provided overall support in Atlanta; A.A.E. provided overall support in Venezuela; and A.A.E. wrote the paper.

Abbreviations: DHFR, dihydrofolate reductase; FY, Duffy blood group; ML, maximum likelihood; Myr, million years; TMRCA, time to the most recent common ancestor.

Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AY639953–AY640007).

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