A genotype-phenotype-fitness map reveals local modularity and global pleiotropy of adaptation

Kinsler, Grant; Geiler-Samerotte, Kerry; Petrov, Dmitri A.

doi:10.1101/2020.06.25.172197

Cited by 6 publications

(7 citation statements)

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“…Some other conceivable RBC phenotypes, such as the dynamics of membrane modification during P. falciparum development, may only become evident in more detailed time course experiments. The true number of RBC phenotypes that impact P. falciparum may be effectively infinite (Kinsler, Geiler-Samerotte and Petrov, 2020), making it useful in practice that genetic variation is more predictive of parasite growth.…”

Section: Discussionmentioning

confidence: 99%

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

Ebel

Kuypers²,

Lin

et al. 2021

eLife

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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.

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Section: Discussionmentioning

confidence: 99%

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

Ebel

Kuypers²,

Lin

et al. 2021

eLife

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“…A broad genomic response, involving many loci (polygenic), could be termed “multidimensional,” whereas selection on a single locus might be termed “unidimensional” (Kinsler et al. 2020), regardless of the number of selection pressures to which they respond. On average, one might expect that multidimensional divergent selection elicits multidimensional genomic responses (Nosil et al.…”

Section: Multidimensionality and Extrinsic Isolationmentioning

confidence: 99%

Multidimensional divergent selection, local adaptation, and speciation

White

Butlin

2021

Evolution

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Divergent selection applied to one or more traits drives local adaptation and may lead to ecological speciation. Divergent selection on many traits might be termed “multidimensional” divergent selection. There is a commonly held view that multidimensional divergent selection is likely to promote local adaptation and speciation to a greater extent than unidimensional divergent selection. We disentangle the core concepts underlying dimensionality as a property of the environment, phenotypes, and genome. In particular, we identify a need to separate the overall strength of selection and the number of loci affected from dimensionality per se, and to distinguish divergence dimensionality from dimensionality of stabilizing selection. We then critically scrutinize this commonly held view that multidimensional selection promotes speciation, re‐examining the evidence base from theory, experiments, and nature. We conclude that the evidence base is currently weak and generally suffers from confounding of possible causal effects. Finally, we propose several mechanisms by which multidimensional divergent selection and related processes might influence divergence, both as a driver and as a barrier.

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“…Other conceivable RBC phenotypes, such as the dynamics of membrane modification during P. falciparum development, may only become evident in more detailed time course experiments. The true number of RBC phenotypes important to P. falciparum may be effectively infinite (Kinsler, Geiler-Samerotte and Petrov, 2020), making it very useful in practice that static genetic variation is so strongly predictive of parasite growth.…”

Section: Discussionmentioning

confidence: 99%

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

Ebel

Kuypers²,

Lin

et al. 2020

Preprint

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SUMMARYThe replication of Plasmodium falciparum malaria parasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. The influence of host erythrocyte variation on parasite replication is largely uncharted, aside from a handful of deleterious alleles like sickle cell. Here, we integrated analyses of exome sequencing, RBC phenotyping, and parasite fitness assays on blood donated by 122 individuals, most with African ancestry. In donors lacking alleles for hemoglobinopathies or G6PD deficiency, RBC phenotypes including size, deformability, and hydration status explained 21-38% of the variation in parasite growth rate. Furthermore, non-pathogenic polymorphisms in 14 RBC proteins including SPTA1, PIEZO1, and ATP2B4 explained 45-70% of parasite growth variation. Interestingly, we observed little evidence for divergent selection on this variation between Africans and Europeans. These findings suggest a model in which widespread, non-pathogenic variation in a moderate number of genes strongly modulates P. falciparum fitness in RBCs.

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A genotype-phenotype-fitness map reveals local modularity and global pleiotropy of adaptation

Cited by 6 publications

References 103 publications

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

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

Multidimensional divergent selection, local adaptation, and speciation

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

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