Biology subjects

Rockett, K. A.

Publications and source records attributed to Rockett, K. A..

6 recordsLinked to original sources

bioRxiv2024

Large-scale genotyping and meta-analysis of PIEZO1 short tandem repeat alleles suggest a modest association with malaria susceptibility

PIEZO1 forms a mechanosensitive ion channel involved in regulating calcium levels in red blood cells. E756del, a deletion allele within a short tandem repeat (STR) in PIEZO1, is common in many African populations and has been proposed to be associated with protection from malarial disease, but epidemiological evidence has been inconsistent. Here, we use Illumina sequencing of amplicons covering the PIEZO1 STR to genotype 5,558 severe malaria cases and 8,174 population controls from The Gambia, Kenya, and Malawi. We estimate a modest effect for E756del and meta-analysis with two published studies, for a total of 8,224 cases and 10,103 controls, reveals a consistent protective effect (OR=0.93, 95% CI 0.88-0.99). By comprehensively genotyping the STR, we identify additional, less common alleles, with two (Q745del and E756ins) showing consistent, but also modest, risk effects across studies. Although allele frequency differentiation between African and non-African populations could be consistent with a selective effect, we show that it is not exceptional compared with STR variants genome wide. Thus, our results support a protective effect of E756del against risk of malaria but with a much smaller effect size than initially reported.

genetics↗

bioRxiv2023

A fourth locus in the Plasmodium falciparum genome associated with sickle haemoglobin

BackgroundHeterozygosity for sickle haemoglobin (HbS) confers protection against severe malaria caused by the parasite Plasmodium falciparum. Recent work has suggested that this protective effect can depend on the parasite genotype: P. falciparum sickle-associated (Pfsa) variants were found disproportionately in individuals with severe malaria carrying HbS alleles in The Gambia and Kenya. Interactions between the P. falciparum genome and HbS have not previously been investigated in mild malaria cases or in Ghana. MethodsWe performed a genome-wide association analysis of P. falciparum against human {beta}-globin genotypes in a sample of 1,368 people with mild malaria in northern Ghana. ResultsWe replicated the previously identified associations with HbS at two parasite loci (Pfsa1 and Pfsa3). Pfsa2 was absent from this population. A candidate newly identified locus within the serine/ threonine kinase FIKK4.2, which we putatively term Pfsa4, was also associated with HbS; this finding replicated in a published sample from Mali. The Pfsa1-4 mutations vary widely in frequencies across Africa, are absent or very low frequency in Asia, and are highly correlated with each-other across multiple populations. We found no strong associations with haemoglobin C. ConclusionsThis study replicates previously reported sickle-associated loci in the P. falciparum genome and has produced new evidence of a potential association with sickle haemoglobin at a fourth parasite locus. Further research is needed to validate the tentative fourth locus. These findings add new complexity to the emerging picture of association between human and co-evolving malaria parasite genomes, suggesting new avenues for functional exploration.

microbiology↗

bioRxiv2021

The protective effect of sickle cell haemoglobin against severe malaria depends on parasite genotype

Host genetic factors can confer resistance against malaria, raising the question of whether this has led to evolutionary adaptation of parasite populations. In this study we investigated the correlation between host and parasite genetic variation in 4,171 Gambian and Kenya children ascertained with severe malaria due to Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and variation in three regions of the parasite genome, including nonsynonymous variants in the acyl-CoA synthetase family member PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The HbS-associated parasite alleles are in strong linkage disequilibrium and have frequencies which covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome, and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations.

genetics↗

bioRxiv2019

Genome variation and population structure among 1,142 mosquitoes of the African malaria vector species Anopheles gambiae and Anopheles coluzzii

Mosquito control remains a central pillar of efforts to reduce malaria burden in sub-Saharan Africa. However, insecticide resistance is entrenched in malaria vector populations, and countries with high malaria burden face a daunting challenge to sustain malaria control with a limited set of surveillance and intervention tools. Here we report on the second phase of a project to build an open resource of high quality data on genome variation among natural populations of the major African malaria vector species Anopheles gambiae and Anopheles coluzzii. We analysed whole genomes of 1,142 individual mosquitoes sampled from the wild in 13 African countries, and a further 234 individuals comprising parents and progeny of 11 lab crosses. The data resource includes high confidence single nucleotide polymorphism (SNP) calls at 57 million variable sites, genome-wide copy number variation (CNV) calls, and haplotypes phased at biallelic SNPs. We used these data to analyse genetic population structure, and characterise genetic diversity within and between populations. We also illustrate the utility of these data by investigating species differences in isolation by distance, genetic variation within proposed gene drive target sequences, and patterns of resistance to pyrethroid insecticides. This data resource provides a foundation for developing new operational systems for molecular surveillance, and for accelerating research and development of new vector control tools.

genomics↗

bioRxiv2019

A high throughput multi-locus insecticide resistance marker panel for tracking resistance emergence and spread in Anopheles gambiae

The spread of resistance to insecticides in the mosquito vectors of diseases such as malaria and dengue poses a threat to the effectiveness of control programmes, which rely largely on insecticide-based interventions. Monitoring the resistance status of mosquito populations is therefore essential, but obtaining direct phenotypic measurements of resistance is laborious and error-prone. In contrast, high-throughput genotyping offers the prospect of quick and repeatable estimates of resistance, while also allowing the genotypic markers of resistance to be tracked and studied. We developed a panel of 28 known or putative markers of resistance in the major malaria vector Anopheles gambiae, which we use to test the association of these markers with resistance and to study their geographic distribution. We screened resistance-phenotyped An. gambiae from populations from a wide swathe of Sub-Saharan Africa (Burkina Faso, Ghana, Democratic Republic of Congo (DRC) and Kenya), and found evidence of resistance association for four mutations, including a novel mutation in the detoxification gene Gste2 (Gste2-119V). We also identified a gene duplication in Gste2 which combines a resistance-associated mutant form of the gene with its wild-type counterpart, potentially alleviating the costs of resistance. Finally, we describe the distribution of the multiple evolutionary origins of kdr resistance, finding unprecedented levels of diversity in the DRC. This panel represents the first step towards developing a quantitative predictive genotypic model of insecticide resistance that can be used to screen An. gambiae populations and predict resistance status.

evolutionary biology↗

bioRxiv2016

A structural variant encoding hybrid glycophorins is associated with resistance to severe malaria

Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. Here we analyse whole genome sequence data from worldwide human populations, including 765 new genomes from across sub-Saharan Africa, and identify a diverse array of large copy number variants affecting the host invasion receptor genes GYPA and GYPB. We find that a nearby reported association with severe malaria is explained by a complex structural variant that involves the loss of GYPB and gain of two hybrid genes, each with a GYPB extracellular domain and GYPA intracellular domain. This variant reduces the risk of severe malaria by 40% and has recently risen in frequency in parts of Kenya. We show that the structural variant encodes the Dantu blood group antigen, and therefore a serologically distinct red cell phenotype. These findings demonstrate that structural variation of red blood cell invasion receptors is associated with natural resistance to P. falciparum malaria.

genomics↗