What can we learn from fitness landscapes?

Hartl, Daniel L.

doi:10.1016/j.mib.2014.08.001

Cited by 58 publications

(51 citation statements)

References 47 publications

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“…falciparum parasites [67]. Furthermore, PfCRT mutations can be deleterious to parasite growth [16,42], a measurable phenotype that serves as a proxy for fitness and reflects parasite functional requirements [68]. To evaluate the contributions of Cam734-unique PfCRT mutations to parasite growth, we used previously established co-culture methods to derive relative growth estimates [16,69].…”

Section: Resultsmentioning

confidence: 99%

Evolution of Fitness Cost-Neutral Mutant PfCRT Conferring P. falciparum 4-Aminoquinoline Drug Resistance Is Accompanied by Altered Parasite Metabolism and Digestive Vacuole Physiology

et al. 2016

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Southeast Asia is an epicenter of multidrug-resistant Plasmodium falciparum strains. Selective pressures on the subcontinent have recurrently produced several allelic variants of parasite drug resistance genes, including the P. falciparum chloroquine resistance transporter (pfcrt). Despite significant reductions in the deployment of the 4-aminoquinoline drug chloroquine (CQ), which selected for the mutant pfcrt alleles that halted CQ efficacy decades ago, the parasite pfcrt locus is continuously evolving. This is highlighted by the presence of a highly mutated allele, Cam734 pfcrt, which has acquired the singular ability to confer parasite CQ resistance without an associated fitness cost. Here, we used pfcrt-specific zinc-finger nucleases to genetically dissect this allele in the pathogenic setting of asexual blood-stage infection. Comparative analysis of drug resistance and growth profiles of recombinant parasites that express Cam734 or variants thereof, Dd2 (the most common Southeast Asian variant), or wild-type pfcrt, revealed previously unknown roles for PfCRT mutations in modulating parasite susceptibility to multiple antimalarial agents. These results were generated in the GC03 strain, used in multiple earlier pfcrt studies, and might differ in natural isolates harboring this allele. Results presented herein show that Cam734-mediated CQ resistance is dependent on the rare A144F mutation that has not been observed beyond Southeast Asia, and reveal distinct impacts of this and other Cam734-specific mutations on CQ resistance and parasite growth rates. Biochemical assays revealed a broad impact of mutant PfCRT isoforms on parasite metabolism, including nucleoside triphosphate levels, hemoglobin catabolism and disposition of heme, as well as digestive vacuole volume and pH. Results from our study provide new insights into the complex molecular basis and physiological impact of PfCRT-mediated antimalarial drug resistance, and inform ongoing efforts to characterize novel pfcrt alleles that can undermine the efficacy of first-line antimalarial drug regimens.

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Section: Resultsmentioning

confidence: 99%

Evolution of Fitness Cost-Neutral Mutant PfCRT Conferring P. falciparum 4-Aminoquinoline Drug Resistance Is Accompanied by Altered Parasite Metabolism and Digestive Vacuole Physiology

et al. 2016

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“…This observation of two alternative residues in position V L Y50 raised the possibility of deleterious negative epistatic interactions454647 between these residues and other mutations and suggested a another possible driving force behind selection of either histidine or serine in this position. This bifurcation in the evolutionary history of the final variants48 would be indicative of a rugged fitness landscape4950.…”

Section: Resultsmentioning

confidence: 99%

A Shorter Route to Antibody Binders via Quantitative in vitro Bead-Display Screening and Consensus Analysis

Mankowska

Gatti‐Lafranconi

Chodorge³

et al. 2016

Sci Rep

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Affinity panning of large libraries is a powerful tool to identify protein binders. However, panning rounds are followed by the tedious re-screening of the clones obtained to evaluate binders precisely. In a first application of Bead Surface Display (BeSD) we show successful in vitro affinity selections based on flow cytometric analysis that allows fine quantitative discrimination between binders. Subsequent consensus analysis of the resulting sequences enables identification of clones that bind tighter than those arising directly from the experimental selection output. This is demonstrated by evolution of an anti-Fas receptor single-chain variable fragment (scFv) that was improved 98-fold vs the parental clone. Four rounds of quantitative screening by fluorescence-activated cell sorting of an error-prone library based on fine discrimination between binders in BeSD were followed by analysis of 200 full-length output sequences that suggested a new consensus design with a Kd ∼140 pM. This approach shortens the time and effort to obtain high affinity reagents and its cell-free nature transcends limitations inherent in previous in vivo display systems.

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“…Given this, we predict that the taxa that compose the gut microbiota might be similarly We found that higher-order interactions were present, and that taxa interacted both antagonistically (Hartl, 2014…”

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confidence: 90%

Deconstructingtaxa x taxa x environmentinteractions in the microbiota: A theoretical examination

Yitbarek

Guittar

Knutie

et al. 2019

Preprint

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13 1. The animal gut is a complex ecosystem containing many interacting species. A major 14 objective of microbiota research is to identity the scale at which gut taxa shape hosts. 15However, most studies focus solely on pairwise interactions and ignore higher-order 16interactions involving three or more component taxa. Higher-order interactions 17 represent non-additive effects that cannot be predicted from first-order or pairwise 18interactions. 192. Possible reasons as to why studies of higher higher-order interactions have been 20 scarce is that many host-associated systems are experimentally intractable, gut 21 microbiota are prohibitively species rich, and the influence of any given taxon on 22hosts is often context-dependent. Furthermore, quantifying emergent effects that 23 represent higher-order interactions that are not simply the result of lower-order 24 interactions, present a combinatorial challenge for which there are few well-25 developed statistical approaches in host-microbiota studies. 263. In this perspective, our goal is to quantify the existence of emerging higher-order 27 effects and characterize their prevalence in the microbiota. To do so, we adapt a 28 method from evolutionary genetics used to quantify epistatic effects between 29 mutations and use it to quantify the effects of higher-order microbial interactions on 30 host infection risk. 31 4. We illustrate this approach by applying it to an in silico dataset generated to resemble 32 a population of hosts with gut-associated microbial communities. We assign each host 33 a pathogen load, and then determine how emergent interactions between gut taxa 34 influence this host trait. 35 5. We find that the effect of higher-order interactions generally increases in magnitude 36with the number of species in the gut community. Based on the average magnitude of 37 interaction for each order, we find that 9 th order interactions have the largest non-38 linear effect on determining host infection risk. 39 6. Our approach illustrates how incorporating the effects of higher-order interactions 40 among gut microbiota can be essential for understanding their effects on host 41 infection risk. We conclude that insofar as higher-order interactions between taxa may 42 profoundly shape important organismal phenotypes (such as susceptibility to 43 infection), that they deserve greater attention in microbiome studies. 44 1 45 46 Introduction 47 Animal guts contain complex microbial communities whose structure and function 48 depend upon the interactions among microbes and the host. Gut microbiota serve as 49 key actors in host health, impacting development, metabolism, and pathogen 50 susceptibility (Brugman et al., 2018). The development of microbe-free (also known as 51 germ-free) model hosts has made it possible to experimentally study how the 52 microbiota influences host susceptibility to infection (Goodman et al., 2011; Ridaura et 53 al., 2013). However, most studies rely on correlations between the relative abundances 54 of individual bacterial taxa an...

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What can we learn from fitness landscapes?

Cited by 58 publications

References 47 publications

Evolution of Fitness Cost-Neutral Mutant PfCRT Conferring P. falciparum 4-Aminoquinoline Drug Resistance Is Accompanied by Altered Parasite Metabolism and Digestive Vacuole Physiology

Evolution of Fitness Cost-Neutral Mutant PfCRT Conferring P. falciparum 4-Aminoquinoline Drug Resistance Is Accompanied by Altered Parasite Metabolism and Digestive Vacuole Physiology

A Shorter Route to Antibody Binders via Quantitative in vitro Bead-Display Screening and Consensus Analysis

Deconstructingtaxa x taxa x environmentinteractions in the microbiota: A theoretical examination

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