1. Evolutionary Biology
  2. Microbiology and Infectious Disease

Common host variation drives malaria parasite fitness in healthy human red cells

  1. Emily R Ebel
  2. Frans A Kuypers
  3. Carrie Lin
  4. Dmitri A Petrov  Is a corresponding author
  5. Elizabeth S Egan  Is a corresponding author
  1. Stanford University, United States
  2. Children's Hospital Oakland Research Institute, United States
  3. Stanford University School of Medicine, United States
https://doi.org/10.7554/eLife.69808
Share this article
Cite this article
  1. Emily R Ebel
  2. Frans A Kuypers
  3. Carrie Lin
  4. Dmitri A Petrov
  5. Elizabeth S Egan
(2021)
Common host variation drives malaria parasite fitness in healthy human red cells
eLife 10:e69808.
https://doi.org/10.7554/eLife.69808
  2. Download BibTeX
  3. Download .RIS

Abstract

The replication of Plasmodium falciparum parasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. Deleterious alleles like hemoglobin S are well-known to confer strong resistance to malaria, but the effects of common RBC variation are largely undetermined. Here we collected fresh blood samples from 121 healthy donors, most with African ancestry, and performed exome sequencing, detailed RBC phenotyping, and parasite fitness assays. Over one third of healthy donors unknowingly carried alleles for G6PD deficiency or hemoglobinopathies, which were associated with characteristic RBC phenotypes. Among non-carriers alone, variation in RBC hydration, membrane deformability, and volume was strongly associated with P. falciparum growth rate. Common genetic variants in PIEZO1, SPTA1/SPTB, and several P. falciparum invasion receptors were also associated with parasite growth rate. Interestingly, we observed little or negative evidence for divergent selection on non-pathogenic RBC variation between Africans and Europeans. These findings suggest a model in which globally widespread variation in a moderate number of genes and phenotypes modulates P. falciparum fitness in RBCs.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 4, and 5 and other raw data and normalization scripts are available at https://github.com/emily-ebel/RBC

The following data sets were generated

Article and author information

Author details

  1. Emily R Ebel

    Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3244-4250

  2. Frans A Kuypers

    Children's Hospital Oakland Research Institute, Oakland, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Carrie Lin

    Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Dmitri A Petrov

    Department of Biology, Stanford University, Stanford, United States
    For correspondence
    dpetrov@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3664-9130

  5. Elizabeth S Egan

    Stanford University School of Medicine, Stanford, United States
    For correspondence
    eegan@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2112-7700

Funding

Stanford Maternal and Child Health Research Institute (N/A)

  • Elizabeth S Egan

Stanford University School of Medicine Office of Faculty Development and Diversity (N/A)

  • Elizabeth S Egan

Stanford Center for Computational, Evolutionary, and Human Genomics (N/A)

  • Emily R Ebel

National Institute of General Medical Sciences (5R35GM118165-05)

  • Dmitri A Petrov

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Written informed consent and consent to publish was obtained from each subject and/or their parent as part of a protocol approved by the Stanford University Institutional Review Board (#40479).

Copyright

© 2021, Ebel et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,295
    views
  • 247
    downloads
  • 19
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Emily R Ebel
  2. Frans A Kuypers
  3. Carrie Lin
  4. Dmitri A Petrov
  5. Elizabeth S Egan
(2021)
Common host variation drives malaria parasite fitness in healthy human red cells
eLife 10:e69808.
https://doi.org/10.7554/eLife.69808

Share this article

https://doi.org/10.7554/eLife.69808

Categories and tags

Research organisms

Further reading

    1. Evolutionary Biology

    The population genetics of convergent adaptation in maize and teosinte is not locally restricted

    Silas Tittes, Anne Lorant ... Jeffrey Ross-Ibarra
    Research Article

    What is the genetic architecture of local adaptation and what is the geographic scale over which it operates? We investigated patterns of local and convergent adaptation in five sympatric population pairs of traditionally cultivated maize and its wild relative teosinte (Zea mays subsp. parviglumis). We found that signatures of local adaptation based on the inference of adaptive fixations and selective sweeps are frequently exclusive to individual populations, more so in teosinte compared to maize. However, for both maize and teosinte, selective sweeps are also frequently shared by several populations, and often between subspecies. We were further able to infer that selective sweeps were shared among populations most often via migration, though sharing via standing variation was also common. Our analyses suggest that teosinte has been a continued source of beneficial alleles for maize, even after domestication, and that maize populations have facilitated adaptation in teosinte by moving beneficial alleles across the landscape. Taken together, our results suggest local adaptation in maize and teosinte has an intermediate geographic scale, one that is larger than individual populations but smaller than the species range.

    1. Evolutionary Biology
    2. Neuroscience

    Vision: The inner workings of a miniature eye

    Gregor Belušič
    Insight

    The first complete 3D reconstruction of the compound eye of a minute wasp species sheds light on the nuts and bolts of size reduction.

    1. Evolutionary Biology
    2. Genetics and Genomics

    Template switching during DNA replication is a prevalent source of adaptive gene amplification

    Julie N Chuong, Nadav Ben Nun ... David Gresham
    Research Article

    Copy number variants (CNVs) are an important source of genetic variation underlying rapid adaptation and genome evolution. Whereas point mutation rates vary with genomic location and local DNA features, the role of genome architecture in the formation and evolutionary dynamics of CNVs is poorly understood. Previously, we found the GAP1 gene in Saccharomyces cerevisiae undergoes frequent amplification and selection in glutamine-limitation. The gene is flanked by two long terminal repeats (LTRs) and proximate to an origin of DNA replication (autonomously replicating sequence, ARS), which likely promote rapid GAP1 CNV formation. To test the role of these genomic elements on CNV-mediated adaptive evolution, we evolved engineered strains lacking either the adjacent LTRs, ARS, or all elements in glutamine-limited chemostats. Using a CNV reporter system and neural network simulation-based inference (nnSBI) we quantified the formation rate and fitness effect of CNVs for each strain. Removal of local DNA elements significantly impacts the fitness effect of GAP1 CNVs and the rate of adaptation. In 177 CNV lineages, across all four strains, between 26% and 80% of all GAP1 CNVs are mediated by Origin Dependent Inverted Repeat Amplification (ODIRA) which results from template switching between the leading and lagging strand during DNA synthesis. In the absence of the local ARS, distal ones mediate CNV formation via ODIRA. In the absence of local LTRs, homologous recombination can mediate gene amplification following de novo retrotransposon events. Our study reveals that template switching during DNA replication is a prevalent source of adaptive CNVs.