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The origin of malaria: mixed messages from genetic diversity

Key Points

  • The past 35 years have seen an upsurge in the prevalence of malaria, caused by a number of mutually reinforcing factors, including the spread of drug-resistant Plasmodium falciparum parasites and insecticide-resistant mosquitoes, increased population density, global warming and poverty in affected countries.

  • There is evidence to indicate that a similar rapid expansion of the P. falciparum population took place about 10,000 years ago. Understanding the population history of P. falciparum is important for determining the most effective ways to combat the present malaria epidemic, as the level of genetic diversity present in the parasite genome has important implications for the evolution of parasite resistance to drugs.

  • Studies of the levels of synonymous polymorphism in P. falciparum protein-coding sequences generally support an expansion of the parasite population 10,000 years ago. However, differences in the sets of genes analysed, and errors in some sequence database entries, have led to discrepancies in the conclusions that have been drawn from these studies.

  • Analysis of non-coding parasite sequences should provide a more accurate picture of levels of genetic variation, as they are subject to a lower levels of selective constraints than are coding sequences. However, high levels of mutation in microsatellite sequences have led to difficulties in interpreting the results of such studies, as have discrepancies in the results obtained for different genomic regions, which are likely to result from the effects of recombination.

  • Mitochondrial DNA has been used to clarify the results obtained using other methods, as it is not subject to recombination. Analysis of the P. falciparum mitochondrial genome generally supports the theory that the parasite population expanded rapidly 10,000 years ago.

  • Altogether, these studies indicate that the level of genetic variation is much lower in P. falciparum than in many other microorganisms. This has important implications for strategies to combat malaria, as it suggests that the parasite is likely to require new mutations to occur in order to develop resistance to drugs, a theory that is borne out by the fact that resistance to chloroquine has been slow to evolve.

Abstract

Over the past 35 years, the incidence of malaria has increased 2–3-fold. At present, it affects 300–500 million people and causes about 1 million deaths, primarily in Africa. The continuing upsurge has come from a coincidence of drug-resistant parasites, insecticide-resistant mosquitoes, global climate change and continuing poverty and political instability. An analogous rapid increase in malaria might have taken place about 10,000 years ago. Patterns of genetic variation in mitochondrial DNA support this model, but variation in nuclear genes gives an ambiguous message. Resolving these discrepancies has implications for the evolution of drug resistance and vaccine evasion.

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Figure 1: Distribution of malaria, and the increase in its incidence in recent years.
Figure 2: Origin and spread of chloroquine resistance.

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Acknowledgements

By rights this piece should have many coauthors — the collaborators whose continuing support and advice have made it possible. I am very grateful to these many colleagues and collaborators, chiefly among them D. Wirth, K. Day, E. Lozovsky and S. Volkman. I am also grateful for the contributions of K. M. Nielsen, S. A. Sawyer, E. Winzeler, A. Barry, K. Amodu, T. Bedford, E. Lyons, M. Zilversmit, M. Choi and M. White, and for the support of the National Institutes of Health, the Ellison Medical Foundation and the Burroughs-Wellcome Fund.

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DATABASES

Entrez

GenBank

Plasmodium falciparum

FURTHER INFORMATION

Daniel L. Hartl's laboratory

Malaria Foundation International

Roll Back Malaria

The Plasmodium genome resource

What is malaria?

WHO/TDR malaria database

Glossary

VIRULENCE

A measure of the harm that an infectious disease inflicts on infected individuals, estimated variously as the case-fatality rate, the reduction in expected lifespan or the lethal dose of the infectious agent.

CASE-FATALITY RATE

The number of deaths due to a disease expressed as a percentage of total cases.

SEVERE MALARIA

Cases of malaria that are marked by one or more of the following symptoms: coma, convulsions, a severe drop in blood pressure, difficulty in breathing, jaundice, blood in the urine, extreme weakness or prostration, kidney impairment, severe anaemia or hypoglycaemia.

MICROSATELLITE POLYMORPHISM

A polymorphism in a population that results in a difference in the number of tandem repeats of a short (1–8 bp) DNA sequence.

REPLICATION SLIPPAGE

Aberrant replication across regions of DNA that contain short, tandemly repeated sequences that results in an increase or decrease in the number of repeats present in the daughter molecules.

NONSYNONYMOUS POLYMORPHISM

A single-nucleotide polymorphism in a coding region that results in an amino-acid replacement.

SYNONYMOUS POLYMORPHISM

A single-nucleotide polymorphism in a coding region that does not result in an amino-acid replacement.

CODON-USAGE BIAS

Nonrandom usage of synonymous codons, which specify the same amino acid in a polypeptide chain.

ALLOTYPES

Products of one or more alleles that result in inherited variants of a particular molecule, usually a protein.

GENE CONVERSION

A process in which the sequence of nucleotides in a gene or allele is changed by DNA-repair mechanisms, using the nucleotide sequence of a related gene or allele as the template for repair.

COALESCENT

The convergence, going backwards in time, of two or more gene lineages onto a single common ancestor.

MAXIMUM LIKELIHOOD

A method of statistical estimation that stipulates an underlying model of a process and that estimates any parameter as the value that maximizes the probability of the observed data given the correctness of the model.

SELECTIVE CONSTRAINT

A restriction on the level or type of polymorphism that is likely to be found in a population owing to deleterious effects of the polymorphism on the ability of their carriers to survive and reproduce.

SINGLE-NUCLEOTIDE POLYMORPHISM

(SNP). A position in a genomic DNA sequence in which the particular nucleotide pair that is present can differ from one individual (or chromosome) to the next; it normally refers to genetic variation that is common in the population, and excludes rare mutational variants.

MISMATCH REPAIR

A process of DNA repair in which a mispaired region of a DNA duplex is excised and replaced by resynthesis using the remaining strand as a template.

SELECTIVE SWEEP

The rapid increase in the frequency of a new favourable mutation to displace, or nearly displace, other alleles of the gene.

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Hartl, D. The origin of malaria: mixed messages from genetic diversity. Nat Rev Microbiol 2, 15–22 (2004). https://doi.org/10.1038/nrmicro795

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