Malaria: looking for selection signatures in the human PKLR gene region

Abstract

Summary The genetic component of susceptibility to malaria is both complex and multigenic and the better‐known protective polymorphisms are those involving erythrocyte‐specific structural proteins and enzymes. In vivo and in vitro data have suggested that pyruvate kinase deficiency, which causes a nonspherocytic haemolytic anaemia, could be protective against malaria severity in humans, but this hypothesis remains to be tested. In the present study, we conducted a combined analysis of Short Tandem Repeats (STRs) and Single Nucleotide Polymorphisms (SNPs) in the pyruvate kinase‐encoding gene (PKLR) and adjacent regions (chromosome 1q21) to look for malaria selective signatures in two sub‐Saharan African populations from Angola and Mozambique, in several groups with different malaria infection outcome. A European population from Portugal, including a control and a pyruvate kinase‐deficient group, was used for comparison. Data from STR and SNP loci spread along the PKLR gene region showed a considerably higher differentiation between African and Portuguese populations than that usually found for neutral markers. In addition, a wider region showing strong linkage disequilibrium was found in an uncomplicated malaria group, and a haplotype was found to be associated with this clinical group. Altogether, this data suggests that malaria selective pressure is acting in this genomic region.

Genetic diversity in human erythrocyte pyruvate kinase

“…Our data is almost certainly an underestimate as the sequencing technology failed to accurately read through two highly repetitive AT-rich regions of the gene. 7 The majority of SNPs were in non-coding regions, though seven synonymous coding SNPs (A36A, Q57Q, L61L, R194R, L236L, L301L and R569R) and seven non-synonymous mutations were detected ( Figure 2). Many SNPs (21/59) were limited to a single heterozygote individual.…”

Triosephosphate isomerase gene promoter variation: -5G/A and -8G/A polymorphisms in clinical malaria groups in two African populations

“…The 124 individuals from Angola belong to the following malaria outcome groups: 44 SM, 43 UM and 37 AI (Machado et al, 2010). Same criteria were used to group the 263 isolates from Mozambique: 93 SM, 150 UM and 20 AI (Marques et al, 2005;Machado et al, 2010Machado et al, , 2012.…”

“…Peripheral whole blood samples were collected from unrelated individuals (mainly children under or equal to 15 years-old; only 7 adults with more or equal than 16 years-old in the asymptomatic group from Maputo, Mozambique) from two malaria endemic sub-Saharan African areas, Angola (N = 124 from Luanda, Machado et al, 2010) and Mozambique (N = 250 from Maputo, Machado et al, 2010Machado et al, , 2012 and N = 13 from Manhiça district, Marques et al, 2005).…”

“…Same criteria were used to group the 263 isolates from Mozambique: 93 SM, 150 UM and 20 AI (Marques et al, 2005;Machado et al, 2010Machado et al, , 2012.…”

“…Humphries et al (1999a) reported that -5G and associated haplotypes were found to be in linkage disequilibrium (LD) with an intragenic polymorphism at nucleotide 2262 in intron 5 (Arya et al, 1997), which could be indicative of a common ancestral origin. Schneider et al (1998) suggests that the high incidence of these TPI1 promoter polymorphisms in African-origin populations, associated to a reduced enzyme activity, may have resulted from some selective advantage for survival similarly to glucose-6-phosphate dehydrogenase (G6PD) deficient variants (Luzzatto, 2006) and pyruvate kinase (PK) deficient variants (Machado et al, 2010(Machado et al, , 2012 and hemoglobin polymorphisms (HbS) (Fleming et al, 1979). These are reminiscent examples of genetic diversity in African populations associated to protection of human host against malaria infection and resulting from the selective pressure that malaria has imposed to human populations.…”