title: Inferred relatedness and heritability in malaria parasites.
abstract: Malaria parasites vary in phenotypic traits of biomedical or biological interest such as growth rate, virulence, sex ratio and drug resistance, and there is considerable interest in identifying the genes that underlie this variation. An important first step is to determine trait heritability (H(2)). We evaluate two approaches to measuring H(2) in natural parasite populations using relatedness inferred from genetic marker data. We collected single-clone Plasmodium falciparum infections from 185 patients from the Thailand-Burma border, monitored parasite clearance following treatment with artemisinin combination therapy (ACT), measured resistance to six antimalarial drugs and genotyped parasites using 335 microsatellites. We found strong relatedness structure. There were 27 groups of two to eight clonally identical (CI) parasites, and 74 per cent of parasites showed significant relatedness to one or more other parasites. Initially, we used matrices of allele sharing and variance components (VC) methods to estimate H(2). Inhibitory concentrations (IC(50)) for six drugs showed significant H(2) (0.24 to 0.79, p = 0.06 to 2.85 x 10(-9)), demonstrating that this study design has adequate power. However, a phenotype of current interest--parasite clearance following ACT--showed no detectable heritability (H(2) = 0-0.09, ns) in this population. The existence of CI parasites allows the use of a simple ANOVA approach for quantifying H(2), analogous to that used in human twin studies. This gave similar results to the VC method and requires considerably less genotyping information. We conclude (i) that H(2) can be effectively measured in malaria parasite populations using minimal genotype data, allowing rational design of genome-wide association studies; and (ii) while drug response (IC(50)) shows significant H(2), parasite clearance following ACT was not heritable in the population studied.
authors.affiliation: Southwest Foundation for Biomedical Research, San Antonio, TX, USA. tanderso@sfbrgenetics.org
authors.forename: Tim J C
authors.initials: TJ
authors.lastname: Anderson
authors.forename: Jeff T
authors.initials: JT
authors.lastname: Williams
authors.forename: Shalini
authors.initials: S
authors.lastname: Nair
authors.forename: Daniel
authors.initials: D
authors.lastname: Sudimack
authors.forename: Marion
authors.initials: M
authors.lastname: Barends
authors.forename: Anchalee
authors.initials: A
authors.lastname: Jaidee
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
authors.forename: François
authors.initials: F
authors.lastname: Nosten
mesh_terms: D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use; D004351:Drug Resistance; D014644:Genetic Variation; D006801:Humans; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D010641:Phenotype; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin
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