Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance
Abstract Background Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the kelch13 gene have been implicated in this resistance. We u...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2017-04-01
|
| Series: | Genome Biology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13059-017-1204-4 |
| _version_ | 1819055907879780352 |
|---|---|
| author | Gustavo C. Cerqueira Ian H. Cheeseman Steve F. Schaffner Shalini Nair Marina McDew-White Aung Pyae Phyo Elizabeth A. Ashley Alexandre Melnikov Peter Rogov Bruce W. Birren François Nosten Timothy J. C. Anderson Daniel E. Neafsey |
| author_facet | Gustavo C. Cerqueira Ian H. Cheeseman Steve F. Schaffner Shalini Nair Marina McDew-White Aung Pyae Phyo Elizabeth A. Ashley Alexandre Melnikov Peter Rogov Bruce W. Birren François Nosten Timothy J. C. Anderson Daniel E. Neafsey |
| author_sort | Gustavo C. Cerqueira |
| collection | DOAJ |
| description | Abstract Background Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the kelch13 gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001–2014). Results We evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After Kelch13-C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance. Conclusions This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations. |
| first_indexed | 2024-12-21T13:14:59Z |
| format | Article |
| id | doaj.art-827f2a0a516745d098ef8cbb6210961b |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-12-21T13:14:59Z |
| publishDate | 2017-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-827f2a0a516745d098ef8cbb6210961b2022-12-21T19:02:46ZengBMCGenome Biology1474-760X2017-04-0118111310.1186/s13059-017-1204-4Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistanceGustavo C. Cerqueira0Ian H. Cheeseman1Steve F. Schaffner2Shalini Nair3Marina McDew-White4Aung Pyae Phyo5Elizabeth A. Ashley6Alexandre Melnikov7Peter Rogov8Bruce W. Birren9François Nosten10Timothy J. C. Anderson11Daniel E. Neafsey12Broad Institute of MIT and HarvardTexas Biomedical Research InstituteBroad Institute of MIT and HarvardTexas Biomedical Research InstituteTexas Biomedical Research InstituteShoklo Malaria Research Unit, Mahidol UniversityShoklo Malaria Research Unit, Mahidol UniversityBroad Institute of MIT and HarvardBroad Institute of MIT and HarvardBroad Institute of MIT and HarvardShoklo Malaria Research Unit, Mahidol UniversityTexas Biomedical Research InstituteBroad Institute of MIT and HarvardAbstract Background Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the kelch13 gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001–2014). Results We evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After Kelch13-C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance. Conclusions This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations.http://link.springer.com/article/10.1186/s13059-017-1204-4MalariaDrug resistanceGenomicsSurveillanceEpistasis |
| spellingShingle | Gustavo C. Cerqueira Ian H. Cheeseman Steve F. Schaffner Shalini Nair Marina McDew-White Aung Pyae Phyo Elizabeth A. Ashley Alexandre Melnikov Peter Rogov Bruce W. Birren François Nosten Timothy J. C. Anderson Daniel E. Neafsey Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance Genome Biology Malaria Drug resistance Genomics Surveillance Epistasis |
| title | Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance |
| title_full | Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance |
| title_fullStr | Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance |
| title_full_unstemmed | Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance |
| title_short | Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance |
| title_sort | longitudinal genomic surveillance of plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance |
| topic | Malaria Drug resistance Genomics Surveillance Epistasis |
| url | http://link.springer.com/article/10.1186/s13059-017-1204-4 |
| work_keys_str_mv | AT gustavoccerqueira longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT ianhcheeseman longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT stevefschaffner longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT shalininair longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT marinamcdewwhite longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT aungpyaephyo longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT elizabethaashley longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT alexandremelnikov longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT peterrogov longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT brucewbirren longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT francoisnosten longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT timothyjcanderson longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance AT danieleneafsey longitudinalgenomicsurveillanceofplasmodiumfalciparummalariaparasitesrevealscomplexgenomicarchitectureofemergingartemisininresistance |