Dissecting the Effects of Selective Pressures on the Genomes of Co-endemic Plasmodium vivax and Plasmodium falciparum in Cambodia Public Deposited

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  • March 20, 2019
Creator
  • Parobek, Christian
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Each year, the malaria parasites Plasmodium vivax and Plasmodium falciparum together infect hundreds of millions of people and cause hundreds of thousands of deaths. In Cambodia, these two parasites are co-endemic, transmitted by the same vectors, and cause disease in the same populations. Recently, pointed efforts have been made in western Cambodia to eliminate malaria. This selective pressure provides a natural experiment that enables direct comparison of P. vivax and P. falciparum populations. Here, we explore the genetic similarities and differences between co-endemic P. vivax and P. falciparum from Cambodia through three questions to be answered. First, we conducted a pilot study in which we deep sequenced two important antigens - pvmsp1 and pvcsp - from 48 P. vivax clinical isolates and explored the contrasting population genetics of these two antigens. We discovered that, in population genetic studies, marker choice has a profound effect on study outcomes, and that P. vivax and P. falciparum orthologs can host very different signatures of selection. Next, through whole-genome sequencing of 80 P. falciparum isolates, we found that population substructuring associates with artemisinin-combination therapy partner-drug in vitro IC50 and with clinical outcomes. This finding suggests that the P. falciparum population has in part responded to selective pressures with complex demographic changes. Finally, we whole-genome sequenced 70 sympatric P. vivax isolates. We found that, in spite of control efforts and in contrast to P. falciparum, the genetic diversity within the P. vivax population remains high and has been more rapidly expanding. We identified a minority of orthologous loci that have opposite signatures of selection in P. vivax and P. falciparum. Surprisingly, we found evidence of several strong and recent selective sweeps within the P. vivax population at transcriptional regulatory loci. This finding suggests that P. vivax may rely on a nuanced response to selective pressure, modulating transcript levels as a means to maintain population resilience.
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  • In Copyright
Advisor
  • Juliano, Jonathan
  • Bailey, Jeffrey
  • Meshnick, Steven R.
  • De Paris, Kristina
  • Sethupathy, Praveen
  • Jones, Corbin
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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