Biology subjects

Kwiatkowski, D. P.

Publications and source records attributed to Kwiatkowski, D. P..

3 recordsLinked to original sources

bioRxiv2018

Whole genome sequencing reveals high complexity of copy number variation at insecticide resistance loci in malaria mosquitoes

BackgroundPolymorphisms in the copy number of a genetic region can influence gene expression, coding sequence and zygosity, making them powerful actors in the evolutionary process. Copy number variants (CNVs) are however understudied, being more difficult to detect than single nucleotide polymorphisms. We take advantage of the intense selective pressures on the major malaria vector Anopheles gambiae, caused by the widespread use of insecticides for malaria control, to investigate the role of CNVs in the evolution of insecticide resistance.\n\nResultsUsing the whole-genome sequencing data from 1142 samples in the An. gambiae 1000 genomes project, we identified 1557 independent increases in copy number, encompassing a total of 267 genes, which were enriched for gene families linked to metabolic insecticide resistance. The five major candidate genes for metabolic resistance were all found in at least one CNV, and were often the target of multiple independent CNVs, reaching as many as 16 CNVs in Cyp9k1. These CNVs have furthermore been spreading due to positive selection, indicated by high local CNV frequencies and extended haplotype homozygosity.\n\nConclusionsOur results demonstrate the importance of CNVs in the response to selection, with CNVs being closely associated with genes involved in the evolution of resistance to insecticides, highlighting the urgent need to identify their relative contributions to resistance and to track their spread as the application of insecticide in malaria endemic countries intensifies. Our detailed descriptions of CNVs found across the species range provides the tools to do so.

evolutionary biology↗

bioRxiv2017

Origins of the current outbreak of multidrug resistant malaria in Southeast Asia: a retrospective genetic study

BackgroundAntimalarial failure is rapidly spreading across parts of Southeast Asia where dihydroartemisinin-piperaquine (DHA-PPQ) is used as first line treatment. The first published reports came from western Cambodia in 2013. Here we analyse genetic changes in the Plasmodium falciparum population of western Cambodia in the six years prior to that.\n\nMethodsWe analysed genome sequence data on 1492 P. falciparum samples from Southeast Asia, including 464 collected in western Cambodia between 2007 and 2013. Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13 artemisinin resistance locus and the plasmepsin 2-3 piperaquine resistance locus.\n\nFindingsWe identified over 30 independent origins of artemisinin resistance, of which the O_SCPCAPKELC_SCPCAP1 lineage accounted for 91% of DHA-PPQ-resistant parasites. In 2008, O_SCPCAPKELC_SCPCAP1 combined with O_SCPCAPPLAC_SCPCAP1, the major lineage associated with piperaquine resistance. By 2012, the O_SCPCAPKELC_SCPCAP1/O_SCPCAPPLAC_SCPCAP1 co-lineage had reached over 60% frequency in western Cambodia and had spread to northern Cambodia.\n\nInterpretationThe O_SCPCAPKELC_SCPCAP1/O_SCPCAPPLAC_SCPCAP1 co-lineage emerged in the same year that DHA-PPQ became the first line antimalarial drug in western Cambodia and spread aggressively thereafter, displacing other artemisinin-resistant parasite lineages. These findings have significant implications for management of the global health risk associated with the current outbreak.\n\nFundingWellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and Intramural Research Program of the US National Institute of Allergy and Infectious Diseases, National Institutes of Health.

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↗