BASIC FACTS ABOUT MALARIA n Four Plasmodium species cause human malaria: P. falciparum (the most virulent), P. vivax, P. malariae, and P. ovale. Human malaria is transmitted by anopheline mosquitoes. n Malaria transmission occurs in more than 90 countries across the world. About 40% of the world´s population is at risk.

PREVALENCE n The worldwide prevalence of malaria ranges between million clinical cases each year. More than 90% of them are in sub-Saharan Africa, where over 1 million deaths due to malaria occur each year. n In the Americas, malaria transmission is mostly linked to activities such as road building, mining, and agricultural projects. One third of the population is at some risk of infection.

BIOLOGICAL ASPECTS n Malaria parasites undergo both sexual and asexual reproduction during their complex life cycle. There are two hosts: a vertebrate and a mosquito vector. n Malaria parasites are haploid during their development in vertebrate hosts, including humans. Sexual reproduction and meiosis take place in the vector.

CLINICAL ASPECTS n Severe complications of malaria in humans are virtually restricted to P. falciparum infections. In highly endemic areas, most infected people are symptom-less. Clinical symptoms of malaria include fever and chills, headache, repeated vomiting, generalized convulsions, and coma. Most patients are anemic. High- risk groups include pregnant women, under-five children, and non-immune travelers. Clinical symptoms of malaria include fever and chills, headache, repeated vomiting, generalized convulsions, and coma. Most patients are anemic. High- risk groups include pregnant women, under-five children, and non-immune travelers.

POPULATION GENETICS Population genetics studies the inheritance of genetic traits in natural populations. Population genetics studies the inheritance of genetic traits in natural populations. Population genetics provides insights into the spread of new alleles that make malaria parasites resistant to drugs, vaccines etc. Population genetics provides insights into the spread of new alleles that make malaria parasites resistant to drugs, vaccines etc.

ORIGIN OF NEW ALLELES n Alleles are alternative forms that exist, within a population, at a given locus. New alleles are mostly created by mutations, i.e., changes in nucleotide sequences, that are either synonymous or non- synonymous. New alleles are mostly created by mutations, i.e., changes in nucleotide sequences, that are either synonymous or non- synonymous.

ORIGIN OF NEW ALLELES n n Short repeat sequences commonly found in malarial antigens are particularly prone to mutations and mitotic recombination. n n Sexual recombination during meiosis also generates new alleles by exchanging blocks of sequences between homologous chromosomes.

POPULATION STRUCTURE n In clonal populations, separate genetic lineages, with little recombination between them, are maintained over generations. n In panmictic populations, recombination breaks down discrete genetic lineages by creating new combinations of alleles. An epidemic structure originates when a highly successful individual propagates rapidly in a population over a few generations. An epidemic structure originates when a highly successful individual propagates rapidly in a population over a few generations.

EXAMPLES OF POPULATION STRUCTURE

LINKAGE DISEQUILIBRIUM n Recombination disrupts the physical association between alleles at different loci. n If recombination rates are low, non- random associations between alleles at different loci are maintained, creating linkage disequilibrium. Linkage disequilibrium co-exists with high recombination rates when some particular associations between alleles are favored by selection. Linkage disequilibrium co-exists with high recombination rates when some particular associations between alleles are favored by selection.

PROBING THE POPULATION STRUCTURE OF Plasmodium falciparum n Worldwide P. falciparum populations differ in their recombination rates and population structure. n African populations are usually panmictic, with no apparent linkage disequilibrium. n Outside Africa, populations often are at linkage disequilibrium, due to either clonal reproduction or epidemic propagation of some lineages.

SELECTION OF NEW ALLELES n Mutant alleles may be selectively neutral, if mutation confers the same fitness to the parasite as the original allele, deleterious or advantageous. Highly advantageous alleles (for instance, drug-resistance alleles) are positively selected and rapidly spread in the population. Highly advantageous alleles (for instance, drug-resistance alleles) are positively selected and rapidly spread in the population.

VARIATION IN ANTIGENIC ALLELES n Despite the recent origin of P. falciparum, most antigens are highly polymorphic. n New antigenic alleles are created by both non-sexual (mitotic) and sexual (meiotic) mechanisms. n New alleles are positively selected if they facilitate immune evasion. The immune system acts as a diversifying force.

SOME TOPICS IN POPULATION GENETICS OF MALARIA PARASITES n How often new alleles encoding phenotypes such as increased virulence, drug resistance or immune evasion arise and spread in natural parasite populations? n How frequently sexual and non-sexual mechanisms create new alleles? How mutation, recombination and selection determine the evolution of P. falciparum genome? How mutation, recombination and selection determine the evolution of P. falciparum genome?