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Harnessing Advances in Genomics and Molecular Genetics to Inform Understanding of P. vivax Epidemiology, Evolution, and Drug Resistance.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Harnessing Advances in Genomics and Molecular Genetics to Inform Understanding of P. vivax Epidemiology, Evolution, and Drug Resistance./
作者:	Buyon, Lucas Evan.
面頁冊數:	1 online resource (194 pages)
附註:	Source: Dissertations Abstracts International, Volume: 83-12, Section: B.
Contained By:	Dissertations Abstracts International83-12B.
標題:	Parasitology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29066610click for full text (PQDT)
ISBN:	9798819379813

Harnessing Advances in Genomics and Molecular Genetics to Inform Understanding of P. vivax Epidemiology, Evolution, and Drug Resistance.
Buyon, Lucas Evan.

Harnessing Advances in Genomics and Molecular Genetics to Inform Understanding of P. vivax Epidemiology, Evolution, and Drug Resistance. - 1 online resource (194 pages)

Source: Dissertations Abstracts International, Volume: 83-12, Section: B.

Thesis (Ph.D.)--Harvard University, 2022.

Includes bibliographical references

Plasmodium vivax and Plasmodium falciparum are two parasites that cause most malaria cases worldwide. P. vivax is chronically understudied compared to P. falciparum, and significant aspects of its biology remain a mystery. This dearth of understanding stems from the lack of an in vitro culture system for P. vivax and the difficulty in generating high-quality sequencing data from patient samples because of low parasitemia. However, novel techniques, including selective whole genome amplification, which allows the sequencing of P. vivax samples directly from the blood, and the development of culture systems of closely related parasites P. knowlesi and P. cynomolgi, have enabled large scale population genomic studies and molecular genetic experiments to study P. vivax epidemiology and biology. In this dissertation, I use these new scientific tools to explore P. vivax transmission dynamics in and assess risk case importation in Panama, use comparative population genomics to identify candidate P. vivax drug resistance loci, and validate a P. vivax gene, pvmdr1, for a functional role regarding drug resistance. In Chapter One, I summarize advances in P. vivax genomics, the state of molecular surveillance for P. vivax, and what is known about the molecular basis of P. vivax drug resistance. In Chapter Two, I showcase work using selective whole genome amplification and sequencing to understand P. vivax population structure in a low transmission setting and the risk of P. vivax case importation in Panama. I find that there is a single highly related lineage of P. vivax parasites in Panama that has persisted for over a decade. I also uncover several likely imported cases and discuss possible future uses of molecular surveillance for identifying case importation. In Chapter Three, I discuss the use of comparative selection scans to identify and prioritize candidate P. vivax drug resistance loci for experimental characterization. P. knowlesi has only recently been understood as a human infection but is not thought to have human to human transmission. Therefore, P. knowlesi has only recently been exposed to anti-malarial drugs, and its genome should not exhibit signs of selection due to pressure from these drugs. I hypothesized that genes with a signal of selection only in P. vivax populations (and not in P. knowlesi populations) and from regions with co-infection in P. falciparum and known drug resistance are likely candidate drug resistance causing loci. I compared signals of evolution in both P. vivax and P. knowlesi to identify a set of candidate drug resistance loci in P. vivax to prioritize for in vitro characterization with regards to drug resistance. In Chapter Four, I discuss my work interrogating a set of globally representative pvmdr1 alleles for their role in mediating P. vivax drug resistance. I conducted a population genomic analysis of variation in this gene and identified 10 SNPs with minor allele frequencies greater than 5%, which exist as 23 unique haplotypes in natural populations. I took advantage of the recent development of a continuous culture system for the closely related parasite P. knowlesi and used CRISPR/Cas9 to construct transgenic P. knowlesi lines expressing these 23 pvmdr1 haplotypes. I also mapped on known pfmdr1 drug resistance polymorphisms on pvmdr1 and constructed lines that contained these mutations. Finally, I constructed an overexpression plasmid containing pvmdr1 to test the effect of copy number variation to mediate drug resistance. I then assayed all transgenic pvmdr1 lines and the P. knowlesi YH1 line, to identify changes in their susceptibility, if any, to an array of antimalarial compounds. I found that pvmdr1 mutations confer reduced susceptibility to mefloquine, lumefantrine, dihydroartemisinin, and halofantrine. I also discuss implications of these findings for P. vivax treatment, control, and molecular surveillance. In Chapter Five, I explore the implications of this thesis on future molecular surveillance of P. vivax and on exploring its biology in the future.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798819379813Subjects--Topical Terms:

635062
Parasitology.
Subjects--Index Terms:

DrugIndex Terms--Genre/Form:

542853
Electronic books.

Harnessing Advances in Genomics and Molecular Genetics to Inform Understanding of P. vivax Epidemiology, Evolution, and Drug Resistance.
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520 $a Plasmodium vivax and Plasmodium falciparum are two parasites that cause most malaria cases worldwide. P. vivax is chronically understudied compared to P. falciparum, and significant aspects of its biology remain a mystery. This dearth of understanding stems from the lack of an in vitro culture system for P. vivax and the difficulty in generating high-quality sequencing data from patient samples because of low parasitemia. However, novel techniques, including selective whole genome amplification, which allows the sequencing of P. vivax samples directly from the blood, and the development of culture systems of closely related parasites P. knowlesi and P. cynomolgi, have enabled large scale population genomic studies and molecular genetic experiments to study P. vivax epidemiology and biology. In this dissertation, I use these new scientific tools to explore P. vivax transmission dynamics in and assess risk case importation in Panama, use comparative population genomics to identify candidate P. vivax drug resistance loci, and validate a P. vivax gene, pvmdr1, for a functional role regarding drug resistance. In Chapter One, I summarize advances in P. vivax genomics, the state of molecular surveillance for P. vivax, and what is known about the molecular basis of P. vivax drug resistance. In Chapter Two, I showcase work using selective whole genome amplification and sequencing to understand P. vivax population structure in a low transmission setting and the risk of P. vivax case importation in Panama. I find that there is a single highly related lineage of P. vivax parasites in Panama that has persisted for over a decade. I also uncover several likely imported cases and discuss possible future uses of molecular surveillance for identifying case importation. In Chapter Three, I discuss the use of comparative selection scans to identify and prioritize candidate P. vivax drug resistance loci for experimental characterization. P. knowlesi has only recently been understood as a human infection but is not thought to have human to human transmission. Therefore, P. knowlesi has only recently been exposed to anti-malarial drugs, and its genome should not exhibit signs of selection due to pressure from these drugs. I hypothesized that genes with a signal of selection only in P. vivax populations (and not in P. knowlesi populations) and from regions with co-infection in P. falciparum and known drug resistance are likely candidate drug resistance causing loci. I compared signals of evolution in both P. vivax and P. knowlesi to identify a set of candidate drug resistance loci in P. vivax to prioritize for in vitro characterization with regards to drug resistance. In Chapter Four, I discuss my work interrogating a set of globally representative pvmdr1 alleles for their role in mediating P. vivax drug resistance. I conducted a population genomic analysis of variation in this gene and identified 10 SNPs with minor allele frequencies greater than 5%, which exist as 23 unique haplotypes in natural populations. I took advantage of the recent development of a continuous culture system for the closely related parasite P. knowlesi and used CRISPR/Cas9 to construct transgenic P. knowlesi lines expressing these 23 pvmdr1 haplotypes. I also mapped on known pfmdr1 drug resistance polymorphisms on pvmdr1 and constructed lines that contained these mutations. Finally, I constructed an overexpression plasmid containing pvmdr1 to test the effect of copy number variation to mediate drug resistance. I then assayed all transgenic pvmdr1 lines and the P. knowlesi YH1 line, to identify changes in their susceptibility, if any, to an array of antimalarial compounds. I found that pvmdr1 mutations confer reduced susceptibility to mefloquine, lumefantrine, dihydroartemisinin, and halofantrine. I also discuss implications of these findings for P. vivax treatment, control, and molecular surveillance. In Chapter Five, I explore the implications of this thesis on future molecular surveillance of P. vivax and on exploring its biology in the future.
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