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  1. Article ; Online: Developing evolution-resistant drugs for COVID-19.

    Weinreich, Daniel M

    eLife

    2022  Volume 11

    Abstract: Analyzing how mutations affect the main protease of SARS-CoV-2 may help researchers develop drugs that are effective against current and future variants of the virus. ...

    Abstract Analyzing how mutations affect the main protease of SARS-CoV-2 may help researchers develop drugs that are effective against current and future variants of the virus.
    MeSH term(s) Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; Coronavirus 3C Proteases ; Cysteine Endopeptidases ; Humans ; Molecular Docking Simulation ; Protease Inhibitors ; SARS-CoV-2 ; Viral Nonstructural Proteins
    Chemical Substances Antiviral Agents ; Protease Inhibitors ; Viral Nonstructural Proteins ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Language English
    Publishing date 2022-07-26
    Publishing country England
    Document type Editorial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.81334
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  2. Article: Beyond the (geometric) mean: stochastic models undermine deterministic predictions of bet hedger evolution.

    Weissman, Maya Rochelle / Raynes, Yevgeniy / Weinreich, Daniel M

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Bet hedging is a ubiquitous strategy for risk reduction in the face of unpredictable environmental change where a lineage lowers its variance in fitness across environments at the expense of also lowering its arithmetic mean fitness. Classically, the ... ...

    Abstract Bet hedging is a ubiquitous strategy for risk reduction in the face of unpredictable environmental change where a lineage lowers its variance in fitness across environments at the expense of also lowering its arithmetic mean fitness. Classically, the benefit of bet hedging has been quantified using geometric mean fitness (GMF); bet hedging is expected to evolve if and only if it has a higher GMF than the wild-type. We build upon previous research on the effect of incorporating stochasticity in phenotypic distribution, environment, and reproduction to investigate the extent to which these sources of stochasticity will impact the evolution of real-world bet hedging traits. We utilize both individual-based simulations and Markov chain numerics to demonstrate that modeling stochasticity can alter the sign of selection for the bet hedger compared to deterministic predictions. We find that bet hedging can be deleterious at small population sizes and beneficial at larger population sizes. This non-monotonic dependence of the sign of selection on population size, known as sign inversion, exists across parameter space for both conservative and diversified bet hedgers. We apply our model to published data of bet hedging strategies to show that sign inversion exists for biologically relevant parameters in two study systems: Papaver dubium, an annual poppy with variable germination phenology, and Salmonella typhimurium, a pathogenic bacteria that exhibits antibiotic persistence. Taken together, our results suggest that GMF is not enough to predict when bet hedging is adaptive.
    Language English
    Publishing date 2024-01-11
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.07.11.548608
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  3. Article: Genomic clustering of fitness-affecting mutations favors the evolution of chromosomal instability.

    Raynes, Yevgeniy / Weinreich, Daniel M

    Evolutionary applications

    2018  Volume 12, Issue 2, Page(s) 301–313

    Abstract: Most solid cancers are characterized by chromosomal instability (CIN)-an elevated rate of large-scale chromosomal aberrations and ploidy changes. Chromosomal instability may arise through mutations in a range of genomic integrity loci and is commonly ... ...

    Abstract Most solid cancers are characterized by chromosomal instability (CIN)-an elevated rate of large-scale chromosomal aberrations and ploidy changes. Chromosomal instability may arise through mutations in a range of genomic integrity loci and is commonly associated with fast disease progression, poor prognosis, and multidrug resistance. However, the evolutionary forces promoting CIN-inducing alleles (hereafter, CIN mutators) during carcinogenesis remain poorly understood. Here, we develop a stochastic, individual-based model of indirect selection experienced by CIN mutators via genomic associations with fitness-affecting mutations. Because mutations associated with CIN affect large swaths of the genome and have the potential to simultaneously comprise many individual loci, we show that indirect selection on CIN mutators is critically influenced by genome organization. In particular, we find strong support for a key role played by the spatial clustering of loci with either beneficial or deleterious mutational effects. Genomic clustering of selected loci allows CIN mutators to generate favorable chromosomal changes that facilitate their rapid expansion within a neoplasm and, in turn, accelerate carcinogenesis. We then examine the distribution of oncogenic and tumor-suppressing loci in the human genome and find both to be potentially more clustered along the chromosome than expected, leading us to speculate that human genome may be susceptible to CIN hitchhiking. More quantitative data on fitness effects of individual mutations will be necessary, though, to assess the true levels of clustering in the human genome and the effectiveness of indirect selection for CIN. Finally, we use our model to examine how therapeutic strategies that increase the deleterious burden of genetically unstable cells by raising either the rate of CIN or the cost of deleterious mutations affect CIN evolution. We find that both can inhibit CIN hitchhiking and delay carcinogenesis in some circumstances, yet, in line with earlier work, we find the latter to be considerably more effective.
    Language English
    Publishing date 2018-10-11
    Publishing country England
    Document type Journal Article
    ZDB-ID 2405496-3
    ISSN 1752-4563 ; 1752-4571
    ISSN (online) 1752-4563
    ISSN 1752-4571
    DOI 10.1111/eva.12717
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  4. Article ; Online: Covalent docking and molecular dynamics simulations reveal the specificity-shifting mutations Ala237Arg and Ala237Lys in TEM beta-lactamase.

    Silva, Gabriel Monteiro da / Yang, Jordan / Leang, Bunlong / Huang, Jessie / Weinreich, Daniel M / Rubenstein, Brenda M

    PLoS computational biology

    2022  Volume 18, Issue 6, Page(s) e1009944

    Abstract: The rate of modern drug discovery using experimental screening methods still lags behind the rate at which pathogens mutate, underscoring the need for fast and accurate predictive simulations of protein evolution. Multidrug-resistant bacteria evade our ... ...

    Abstract The rate of modern drug discovery using experimental screening methods still lags behind the rate at which pathogens mutate, underscoring the need for fast and accurate predictive simulations of protein evolution. Multidrug-resistant bacteria evade our defenses by expressing a series of proteins, the most famous of which is the 29-kilodalton enzyme, TEM β-lactamase. Considering these challenges, we applied a covalent docking heuristic to measure the effects of all possible alanine 237 substitutions in TEM due to this codon's importance for catalysis and effects on the binding affinities of commercially-available β-lactam compounds. In addition to the usual mutations that reduce substrate binding due to steric hindrance, we identified two distinctive specificity-shifting TEM mutations, Ala237Arg and Ala237Lys, and their respective modes of action. Notably, we discovered and verified through minimum inhibitory concentration assays that, while these mutations and their bulkier side chains lead to steric clashes that curtail ampicillin binding, these same groups foster salt bridges with the negatively-charged side-chain of the cephalosporin cefixime, widely used in the clinic to treat multi-resistant bacterial infections. To measure the stability of these unexpected interactions, we used molecular dynamics simulations and found the binding modes to be stable despite the application of biasing forces. Finally, we found that both TEM mutants also bind strongly to other drugs containing negatively-charged R-groups, such as carumonam and ceftibuten. As with cefixime, this increased binding affinity stems from a salt bridge between the compounds' negative moieties and the positively-charged side chain of the arginine or lysine, suggesting a shared mechanism. In addition to reaffirming the power of using simulations as molecular microscopes, our results can guide the rational design of next-generation β-lactam antibiotics and bring the community closer to retaking the lead against the recurrent threat of multidrug-resistant pathogens.
    MeSH term(s) Anti-Bacterial Agents/metabolism ; Anti-Bacterial Agents/pharmacology ; Cefixime ; Molecular Dynamics Simulation ; Mutation ; beta-Lactamase Inhibitors/pharmacology ; beta-Lactamases/metabolism ; beta-Lactams
    Chemical Substances Anti-Bacterial Agents ; beta-Lactamase Inhibitors ; beta-Lactams ; Cefixime (97I1C92E55) ; beta-Lactamases (EC 3.5.2.6)
    Language English
    Publishing date 2022-06-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1009944
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  5. Article: Variability in fitness effects can preclude selection of the fittest.

    Graves, Christopher J / Weinreich, Daniel M

    Annual review of ecology, evolution, and systematics

    2017  Volume 48, Issue 1, Page(s) 399–417

    Abstract: Evolutionary biologists often predict the outcome of natural selection on an allele by measuring its effects on lifetime survival and reproduction of individual carriers. However, alleles affecting traits like sex, evolvability, and cooperation can cause ...

    Abstract Evolutionary biologists often predict the outcome of natural selection on an allele by measuring its effects on lifetime survival and reproduction of individual carriers. However, alleles affecting traits like sex, evolvability, and cooperation can cause fitness effects that depend heavily on differences in the environmental, social, and genetic context of individuals carrying the allele. This variability makes it difficult to summarize the evolutionary fate of an allele based solely on its effects on any one individual. Attempts to average over this variability can sometimes salvage the concept of fitness. In other cases evolutionary outcomes can only be predicted by considering the entire genealogy of an allele, thus limiting the utility of individual fitness altogether. We describe a number of intriguing new evolutionary phenomena that have emerged in studies that explicitly model long-term lineage dynamics and discuss implications for the evolution of infectious diseases.
    Language English
    Publishing date 2017-08-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2131661-2
    ISSN 1543-592X
    ISSN 1543-592X
    DOI 10.1146/annurev-ecolsys-110316-022722
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    In stock of ZB MED Bonn / Germany

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  6. Article ; Online: Migration promotes mutator alleles in subdivided populations.

    Raynes, Yevgeniy / Sniegowski, Paul D / Weinreich, Daniel M

    Evolution; international journal of organic evolution

    2019  Volume 73, Issue 3, Page(s) 600–608

    Abstract: Mutator alleles that elevate the genomic mutation rate may invade nonrecombining populations by hitchhiking with beneficial mutations. Mutators have been repeatedly observed to take over adapting laboratory populations and have been found at high ... ...

    Abstract Mutator alleles that elevate the genomic mutation rate may invade nonrecombining populations by hitchhiking with beneficial mutations. Mutators have been repeatedly observed to take over adapting laboratory populations and have been found at high frequencies in both microbial pathogen and cancer populations in nature. Recently, we have shown that mutators are only favored by selection in sufficiently large populations and transition to being disfavored as population size decreases. This population size-dependent sign inversion in selective effect suggests that population structure may also be an important determinant of mutation rate evolution. Although large populations may favor mutators, subdividing such populations into sufficiently small subpopulations (demes) might effectively inhibit them. On the other hand, migration between small demes that otherwise inhibit hitchhiking may promote mutator fixation in the whole metapopulation. Here, we use stochastic, agent-based simulations and evolution experiments with the yeast Saccharomyces cerevisiae to show that mutators can, indeed, be favored by selection in subdivided metapopulations composed of small demes connected by sufficient migration. In fact, we show that population structure plays a previously unsuspected role in promoting mutator success in subdivided metapopulations when migration is rare.
    MeSH term(s) Genome, Fungal/physiology ; Models, Genetic ; Mutation Rate ; Population Density ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/physiology ; Selection, Genetic
    Language English
    Publishing date 2019-01-16
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2036375-8
    ISSN 1558-5646 ; 0014-3820
    ISSN (online) 1558-5646
    ISSN 0014-3820
    DOI 10.1111/evo.13681
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  7. Article ; Online: High-throughput identification of genetic interactions in HIV-1.

    Weinreich, Daniel M

    Nature genetics

    2011  Volume 43, Issue 5, Page(s) 398–400

    MeSH term(s) Epistasis, Genetic ; Evolution, Molecular ; Genes, Viral ; HIV Infections/virology ; HIV-1/drug effects ; HIV-1/genetics ; HIV-1/isolation & purification ; HIV-1/physiology ; High-Throughput Screening Assays ; Humans ; Mutation ; Virus Replication/genetics
    Language English
    Publishing date 2011-04-26
    Publishing country United States
    Document type Comment ; News
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/ng.820
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3613: Show issues Location:
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  8. Article ; Online: Density fluctuations, homeostasis, and reproduction effects in bacteria.

    Nemati, Shahla / Singh, Abhyudai / Dhuey, Scott D / McDonald, Armando / Weinreich, Daniel M / Vasdekis, Andreas E

    Communications biology

    2022  Volume 5, Issue 1, Page(s) 397

    Abstract: Single-cells grow by increasing their biomass and size. Here, we report that while mass and size accumulation rates of single Escherichia coli cells are exponential, their density and, thus, the levels of macromolecular crowding fluctuate during growth. ... ...

    Abstract Single-cells grow by increasing their biomass and size. Here, we report that while mass and size accumulation rates of single Escherichia coli cells are exponential, their density and, thus, the levels of macromolecular crowding fluctuate during growth. As such, the average rates of mass and size accumulation of a single cell are generally not the same, but rather cells differentiate into increasing one rate with respect to the other. This differentiation yields a density homeostasis mechanism that we support mathematically. Further, we observe that density fluctuations can affect the reproduction rates of single cells, suggesting a link between the levels of macromolecular crowding with metabolism and overall population fitness. We detail our experimental approach and the "invisible" microfluidic arrays that enabled increased precision and throughput. Infections and natural communities start from a few cells, thus, emphasizing the significance of density-fluctuations when taking non-genetic variability into consideration.
    MeSH term(s) Escherichia coli/metabolism ; Homeostasis ; Macromolecular Substances/metabolism ; Reproduction
    Chemical Substances Macromolecular Substances
    Language English
    Publishing date 2022-04-28
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-022-03348-2
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  9. Article ; Online: Density fluctuations, homeostasis, and reproduction effects in bacteria

    Shahla Nemati / Abhyudai Singh / Scott D. Dhuey / Armando McDonald / Daniel M. Weinreich / Andreas. E. Vasdekis

    Communications Biology, Vol 5, Iss 1, Pp 1-

    2022  Volume 10

    Abstract: Quantitative imaging, invisible microfluidics, and mathematical models demonstrate how the density of single E. coli cells fluctuates during the cell cycle, unmasking key homeostasis and population fitness effects. ...

    Abstract Quantitative imaging, invisible microfluidics, and mathematical models demonstrate how the density of single E. coli cells fluctuates during the cell cycle, unmasking key homeostasis and population fitness effects.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Sign of selection on mutation rate modifiers depends on population size.

    Raynes, Yevgeniy / Wylie, C Scott / Sniegowski, Paul D / Weinreich, Daniel M

    Proceedings of the National Academy of Sciences of the United States of America

    2018  Volume 115, Issue 13, Page(s) 3422–3427

    Abstract: The influence of population size ( ...

    Abstract The influence of population size (
    MeSH term(s) Evolution, Molecular ; Genetic Drift ; Models, Genetic ; Mutation ; Mutation Rate ; Population Density ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics ; Selection, Genetic
    Chemical Substances Saccharomyces cerevisiae Proteins
    Language English
    Publishing date 2018-03-12
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1715996115
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
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