@article {767,
	title = {The origin of malignant malaria.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {106},
	year = {2009},
	month = {2009 Sep 1},
	pages = {14902-7},
	abstract = {Plasmodium falciparum, the causative agent of malignant malaria, is among the most severe human infectious diseases. The closest known relative of P. falciparum is a chimpanzee parasite, Plasmodium reichenowi, of which one single isolate was previously known. The co-speciation hypothesis suggests that both parasites evolved separately from a common ancestor over the last 5-7 million years, in parallel with the divergence of their hosts, the hominin and chimpanzee lineages. Genetic analysis of eight new isolates of P. reichenowi, from wild and wild-born captive chimpanzees in Cameroon and C{\^o}te d{\textquoteright}Ivoire, shows that P. reichenowi is a geographically widespread and genetically diverse chimpanzee parasite. The genetic lineage comprising the totality of global P. falciparum is fully included within the much broader genetic diversity of P. reichenowi. This finding is inconsistent with the co-speciation hypothesis. Phylogenetic analysis indicates that all extant P. falciparum populations originated from P. reichenowi, likely by a single host transfer, which may have occurred as early as 2-3 million years ago, or as recently as 10,000 years ago. The evolutionary history of this relationship may be explained by two critical genetic mutations. First, inactivation of the CMAH gene in the human lineage rendered human ancestors unable to generate the sialic acid Neu5Gc from its precursor Neu5Ac, and likely made humans resistant to P. reichenowi. More recently, mutations in the dominant invasion receptor EBA 175 in the P. falciparum lineage provided the parasite with preference for the overabundant Neu5Ac precursor, accounting for its extreme human pathogenicity.},
	keywords = {Amino Acid Sequence, Animals, Glycoproteins, Humans, Malaria, Molecular Sequence Data, Mutation, N-Acetylneuraminic Acid, Pan troglodytes, Phylogeny, Plasmodium, Plasmodium falciparum, Protozoan Infections, Animal, Protozoan Proteins, Sequence Alignment},
	issn = {1091-6490},
	doi = {10.1073/pnas.0907740106},
	author = {Rich, Stephen M and Leendertz, Fabian H and Xu, Guang and LeBreton, Matthew and Djoko, Cyrille F and Aminake, Makoah N and Takang, Eric E and Diffo, Joseph L D and Pike, Brian L and Rosenthal, Benjamin M and Formenty, Pierre and Boesch, Christophe and Ayala, Francisco J and Wolfe, Nathan D}
}
@article {777,
	title = {Sequence diversity and evolution of the malaria vaccine candidate merozoite surface protein-1 (MSP-1) of Plasmodium falciparum.},
	journal = {Gene},
	volume = {304},
	year = {2003},
	month = {2003 Jan 30},
	pages = {65-75},
	abstract = {The merozoite surface protein-1 (MSP-1) of the malaria parasite Plasmodium falciparum is a major blood-stage antigen containing highly polymorphic tripeptide repeats in the domain known as block 2 and several non-repetitive domains that are essentially dimorphic. We have analyzed sequence variation in block 2 repeats and in non-repetitive block 17, as well as other polymorphisms within the MSP-1 gene, in clinical isolates of P. falciparum. Repeat haplotypes were defined as unique combinations of repeat motifs within block 2, whereas block 17 haplotypes were defined as unique combinations of single nucleotide replacements in this domain. A new block 17 haplotype, E-TNG-L, was found in one isolate from Vietnam. MSP-1 alleles, defined as unique combinations of haplotypes in blocks 2 and 17 and other polymorphisms within the molecule, were characterized in 60 isolates from hypoendemic Brazil and 37 isolates from mesoendemic Vietnam. Extensive diversity has been created in block 2 and elsewhere in the molecule, while maintaining significant linkage disequilibrium between polymorphisms across the non-telomeric MSP-1 locus separated by a map distance of more than 4 kb, suggesting that low meiotic recombination rates occur in both parasite populations. These results indicate a role for non-homologous recombination, such as strand-slippage mispairing during mitosis and gene conversion, in creating variation in a malarial antigen under strong diversifying selection.},
	keywords = {Alleles, Animals, Brazil, DNA, Protozoan, Evolution, Molecular, Genetic Variation, Haplotypes, Linkage Disequilibrium, Malaria Vaccines, Merozoite Surface Protein 1, Molecular Sequence Data, Plasmodium falciparum, Polymorphism, Single Nucleotide, Recombination, Genetic, Sequence Analysis, DNA, Tanzania, Thailand, Vietnam},
	issn = {0378-1119},
	author = {Ferreira, Marcelo U and Ribeiro, Weber L and Tonon, Angela P and Kawamoto, Fumihiko and Rich, Stephen M}
}
@article {784,
	title = {Genetic variation and the recent worldwide expansion of Plasmodium falciparum.},
	journal = {Gene},
	volume = {261},
	year = {2000},
	month = {2000 Dec 30},
	pages = {161-70},
	abstract = {Plasmodium falciparum, the agent of human malignant malaria, diverged from Plasmodium reichenowi, the chimpanzee parasite, about the time the human and chimpanzee lineages diverged from each other. The absence of synonymous nucleotide variation at ten loci indicates that the world populations of P. falciparum derive most recently from one single strain, or {\textquoteright}cenancestor,{\textquoteright} which lived a few thousand years ago. Antigenic genes of P. falciparum (such as Csp, Msp-1, and Msp-2) exhibit numerous polymorphisms that have been estimated to be millions of years old. We have discovered in these antigenic genes short repetitive sequences that distort the alignment of alleles and account for the apparent old age of the polymorphisms. The processes of intragenic recombination that generate the repeats occur at rates about 10(-3) to 10(-2), several orders of magnitude greater than the typical mutational process of nucleotide substitutions. We conclude that the antigenic polymorphisms of P. falciparum are consistent with a recent expansion of the world populations of the parasite from a cenancestor that lived in tropical Africa a few thousand years ago.},
	keywords = {Animals, Antigens, Protozoan, Base Sequence, Genetic Variation, Merozoite Surface Protein 1, Molecular Sequence Data, Phylogeny, Plasmodium, Plasmodium falciparum, Polymorphism, Genetic, Protozoan Proteins, Repetitive Sequences, Nucleic Acid, RNA, Ribosomal, Sequence Homology, Nucleic Acid, Species Specificity},
	issn = {0378-1119},
	author = {Ayala, F J and Rich, S M}
}
@article {786,
	title = {The origin of antigenic diversity in Plasmodium falciparum.},
	journal = {Parasitol Today},
	volume = {16},
	year = {2000},
	month = {2000 Sep},
	pages = {390-6},
	abstract = {Most studies of genetic variability of Plasmodium falciparum have focused on protein antigens and the genes that encode them. The consensus is that populations exhibit high levels of genetic polymorphism, most notably the genes encoding surface proteins of the merozoite (Msp1, Msp2) and the sporozoite (Csp). The age and derivation of this variation is a subject that warrants further careful consideration, as discussed here by Stephen Rich, Marcelo Ferreira and Francisco Ayala.},
	keywords = {Amino Acid Sequence, Animals, Antigens, Protozoan, Base Sequence, Genes, Protozoan, Genetic Variation, Merozoite Surface Protein 1, Molecular Sequence Data, Plasmodium falciparum, Protozoan Proteins, Sequence Homology},
	issn = {0169-4758},
	author = {Rich, S M and Ferreira, M U and Ayala, F J}
}
@article {788,
	title = {Population structure and recent evolution of Plasmodium falciparum.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {97},
	year = {2000},
	month = {2000 Jun 20},
	pages = {6994-7001},
	abstract = {Plasmodium falciparum is the agent of malignant malaria, one of mankind{\textquoteright}s most severe maladies. The parasite exhibits antigenic polymorphisms that have been postulated to be ancient. We have proposed that the extant world populations of P. falciparum have derived from one single parasite, a cenancestor, within the last 5, 000-50,000 years. This inference derives from the virtual or complete absence of synonymous nucleotide polymorphisms at genes not involved in immune or drug responses. Seeking to conciliate this claim with extensive antigenic polymorphism, we first note that allele substitutions or polymorphisms can arise very rapidly, even in a single generation, in large populations subject to strong natural selection. Second, new alleles can arise not only by single-nucleotide mutations, but also by duplication/deletion of short simple-repeat DNA sequences, a process several orders of magnitude faster than single-nucleotide mutation. We analyze three antigenic genes known to be extremely polymorphic: Csp, Msp-1, and Msp-2. We identify regions consisting of tandem or proximally repetitive short DNA sequences, including some previously unnoticed. We conclude that the antigenic polymorphisms are consistent with the recent origin of the world populations of P. falciparum inferred from the analysis of nonantigenic genes.},
	keywords = {Amino Acid Sequence, Animals, Base Sequence, Biological Evolution, Genes, Protozoan, Genetics, Population, Molecular Sequence Data, Plasmodium falciparum},
	issn = {0027-8424},
	author = {Rich, S M and Ayala, F J}
}
@article {790,
	title = {Evolution of Plasmodium and the recent origin of the world populations of Plasmodium falciparum.},
	journal = {Parassitologia},
	volume = {41},
	year = {1999},
	month = {1999 Sep},
	pages = {55-68},
	abstract = {We have investigated the evolution of Plasmodium parasites by analyzing DNA sequences of several genes. We reach the following conclusions: (1) The four human parasites, P. falciparum, P. malariae, P. ovale, and P. vivax are very remotely related to each other, so that their evolutionary divergence predates the origin of the hominids; several of these parasites became associated with the human lineage by lateral transfer from other hosts. (2) P. falciparum diverged from P. reichenowi about 8 million years ago, consistently with the time of divergence of the human lineage from the apes; a parsimonious inference is that falciparum has been associated with humans since the origin of the hominids. (3) P. malariae is genetically indistinguishable from P. brasilianum, a parasite of New World monkeys; and, similarly. (4) P. vivax is genetically indistinguishable from the New World monkey parasite P. simium. We infer in each of these two cases a very recent lateral transfer between the human and monkey hosts, and explore alternative hypotheses about the direction of the transfer. We have also investigated the population structure of P. falciparum by analyzing 10 genes and conclude that the extant world populations of this parasite have evolved from a single strain within the last several thousand years. The extensive polymorphisms observed in the highly repetitive central region of the Csp gene, as well as the apparently very divergent two classes of alleles at the Msa-1 gene, are consistent with this conclusion.},
	keywords = {Amino Acid Sequence, Animals, Base Sequence, DNA, Protozoan, Evolution, Molecular, Hominidae, Humans, Merozoite Surface Protein 1, Molecular Sequence Data, Plasmodium, Plasmodium falciparum, Polymorphism, Genetic, Sequence Alignment},
	issn = {0048-2951},
	author = {Ayala, F J and Escalante, A A and Rich, S M}
}
@article {793,
	title = {Malaria{\textquoteright}s Eve: evidence of a recent population bottleneck throughout the world populations of Plasmodium falciparum.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {95},
	year = {1998},
	month = {1998 Apr 14},
	pages = {4425-30},
	abstract = {We have analyzed DNA sequences from world-wide geographic strains of Plasmodium falciparum and found a complete absence of synonymous DNA polymorphism at 10 gene loci. We hypothesize that all extant world populations of the parasite have recently derived (within several thousand years) from a single ancestral strain. The upper limit of the 95\% confidence interval for the time when this most recent common ancestor lived is between 24,500 and 57,500 years ago (depending on different estimates of the nucleotide substitution rate); the actual time is likely to be much more recent. The recent origin of the P. falciparum populations could have resulted from either a demographic sweep (P. falciparum has only recently spread throughout the world from a small geographically confined population) or a selective sweep (one strain favored by natural selection has recently replaced all others). The selective sweep hypothesis requires that populations of P. falciparum be effectively clonal, despite the obligate sexual stage of the parasite life cycle. A demographic sweep that started several thousand years ago is consistent with worldwide climatic changes ensuing the last glaciation, increased anthropophilia of the mosquito vectors, and the spread of agriculture. P. falciparum may have rapidly spread from its African tropical origins to the tropical and subtropical regions of the world only within the last 6,000 years. The recent origin of the world-wide P. falciparum populations may account for its virulence, as the most malignant of human malarial parasites.},
	keywords = {Africa, Animals, Asia, Climate, Demography, DNA, Protozoan, Evolution, Molecular, Genes, Protozoan, Humans, Life Cycle Stages, Malaria, Malaria, Falciparum, Netherlands, Phylogeny, Plasmodium, Plasmodium falciparum, Polymorphism, Genetic, South America, Tetrahydrofolate Dehydrogenase, Time},
	issn = {0027-8424},
	author = {Rich, S M and Licht, M C and Hudson, R R and Ayala, F J}
}
@article {792,
	title = {The recent origin of allelic variation in antigenic determinants of Plasmodium falciparum.},
	journal = {Genetics},
	volume = {150},
	year = {1998},
	month = {1998 Sep},
	pages = {515-7},
	keywords = {Alleles, Animals, Epitopes, Genetic Variation, Merozoite Surface Protein 1, Plasmodium falciparum, Protozoan Proteins},
	issn = {0016-6731},
	author = {Rich, S M and Ayala, F J}
}
@article {794,
	title = {Plasmodium falciparum antigenic diversity: evidence of clonal population structure.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {94},
	year = {1997},
	month = {1997 Nov 25},
	pages = {13040-5},
	abstract = {Plasmodium falciparum, the agent of malignant malaria, is one of mankind{\textquoteright}s most severe scourges. Efforts to develop preventive vaccines or remedial drugs are handicapped by the parasite{\textquoteright}s rapid evolution of drug resistance and protective antigens. We examine 25 DNA sequences of the gene coding for the highly polymorphic antigenic circumsporozoite protein. We observe total absence of silent nucleotide variation in the two nonrepeated regions of the gene. We propose that this absence reflects a recent origin (within several thousand years) of the world populations of P. falciparum from a single individual; the amino acid polymorphisms observed in these nonrepeat regions would result from strong natural selection. Analysis of these polymorphisms indicates that: (i) the incidence of recombination events does not increase with nucleotide distance; (ii) the strength of linkage disequilibrium between nucleotides is also independent of distance; and (iii) haplotypes in the two nonrepeat regions are correlated with one another, but not with the central repeat region they span. We propose two hypotheses: (i) variation in the highly polymorphic central repeat region arises by mitotic intragenic recombination, and (ii) the population structure of P. falciparum is clonal--a state of affairs that persists in spite of the necessary stage of physiological sexuality that the parasite must sustain in the mosquito vector to complete its life cycle.},
	keywords = {Amino Acid Sequence, Animals, Antigens, Protozoan, Molecular Sequence Data, Phylogeny, Plasmodium falciparum, Polymorphism, Genetic, Protozoan Proteins, Recombination, Genetic, Sequence Homology, Amino Acid},
	issn = {0027-8424},
	author = {Rich, S M and Hudson, R R and Ayala, F J}
}
