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  1. Article ; Online: SUNi mutagenesis: Scalable and uniform nicking for efficient generation of variant libraries.

    Mighell, Taylor L / Toledano, Ignasi / Lehner, Ben

    PloS one

    2023  Volume 18, Issue 7, Page(s) e0288158

    Abstract: Multiplexed assays of variant effects (MAVEs) have made possible the functional assessment of all possible mutations to genes and regulatory sequences. A core pillar of the approach is generation of variant libraries, but current methods are either ... ...

    Abstract Multiplexed assays of variant effects (MAVEs) have made possible the functional assessment of all possible mutations to genes and regulatory sequences. A core pillar of the approach is generation of variant libraries, but current methods are either difficult to scale or not uniform enough to enable MAVEs at the scale of gene families or beyond. We present an improved method called Scalable and Uniform Nicking (SUNi) mutagenesis that combines massive scalability with high uniformity to enable cost-effective MAVEs of gene families and eventually genomes.
    MeSH term(s) Mutagenesis ; Mutation ; Genome
    Language English
    Publishing date 2023-07-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0288158
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The energetic and allosteric landscape for KRAS inhibition.

    Weng, Chenchun / Faure, Andre J / Escobedo, Albert / Lehner, Ben

    Nature

    2023  Volume 626, Issue 7999, Page(s) 643–652

    Abstract: Thousands of proteins have been validated genetically as therapeutic targets for human ... ...

    Abstract Thousands of proteins have been validated genetically as therapeutic targets for human diseases
    MeSH term(s) Humans ; Allosteric Regulation/drug effects ; Allosteric Regulation/genetics ; Allosteric Site/drug effects ; Allosteric Site/genetics ; Mutation ; Protein Binding ; Protein Folding ; Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors ; Proto-Oncogene Proteins p21(ras)/chemistry ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Reproducibility of Results ; Substrate Specificity/drug effects ; Substrate Specificity/genetics ; Thermodynamics
    Chemical Substances KRAS protein, human ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
    Language English
    Publishing date 2023-12-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-023-06954-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  3. Article ; Online: Dominance vs epistasis: the biophysical origins and plasticity of genetic interactions within and between alleles.

    Xie, Xuan / Sun, Xia / Wang, Yuheng / Lehner, Ben / Li, Xianghua

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 5551

    Abstract: An important challenge in genetics, evolution and biotechnology is to understand and predict how mutations combine to alter phenotypes, including molecular activities, fitness and disease. In diploids, mutations in a gene can combine on the same ... ...

    Abstract An important challenge in genetics, evolution and biotechnology is to understand and predict how mutations combine to alter phenotypes, including molecular activities, fitness and disease. In diploids, mutations in a gene can combine on the same chromosome or on different chromosomes as a "heteroallelic combination". However, a direct comparison of the extent, sign, and stability of the genetic interactions between variants within and between alleles is lacking. Here we use thermodynamic models of protein folding and ligand-binding to show that interactions between mutations within and between alleles are expected in even very simple biophysical systems. Protein folding alone generates within-allele interactions and a single molecular interaction is sufficient to cause between-allele interactions and dominance. These interactions change differently, quantitatively and qualitatively as a system becomes more complex. Altering the concentration of a ligand can, for example, switch alleles from dominant to recessive. Our results show that intra-molecular epistasis and dominance should be widely expected in even the simplest biological systems but also reinforce the view that they are plastic system properties and so a formidable challenge to predict. Accurate prediction of both intra-molecular epistasis and dominance will require either detailed mechanistic understanding and experimental parameterization or brute-force measurement and learning.
    MeSH term(s) Alleles ; Epistasis, Genetic ; Ligands ; Protein Folding ; Biophysics
    Chemical Substances Ligands
    Language English
    Publishing date 2023-09-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-41188-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation.

    Seuma, Mireia / Lehner, Ben / Bolognesi, Benedetta

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 7084

    Abstract: Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms. To date, MAVEs have focussed on a single mutation type-amino acid (AA) substitutions-despite the diversity of coding variants that cause ... ...

    Abstract Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms. To date, MAVEs have focussed on a single mutation type-amino acid (AA) substitutions-despite the diversity of coding variants that cause disease. Here we use Deep Indel Mutagenesis (DIM) to generate a comprehensive atlas of diverse variant effects for a disease protein, the amyloid beta (Aβ) peptide that aggregates in Alzheimer's disease (AD) and is mutated in familial AD (fAD). The atlas identifies known fAD mutations and reveals that many variants beyond substitutions accelerate Aβ aggregation and are likely to be pathogenic. Truncations, substitutions, insertions, single- and internal multi-AA deletions differ in their propensity to enhance or impair aggregation, but likely pathogenic variants from all classes are highly enriched in the polar N-terminal region of Aβ. This comparative atlas highlights the importance of including diverse mutation types in MAVEs and provides important mechanistic insights into amyloid nucleation.
    MeSH term(s) Humans ; Alzheimer Disease/metabolism ; Amyloid/genetics ; Amyloid/metabolism ; Amyloid beta-Peptides/metabolism ; Mutation, Missense
    Chemical Substances Amyloid ; Amyloid beta-Peptides
    Language English
    Publishing date 2022-11-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-34742-3
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  5. Article: Vitellogenins - Yolk Gene Function and Regulation in

    Perez, Marcos Francisco / Lehner, Ben

    Frontiers in physiology

    2019  Volume 10, Page(s) 1067

    Abstract: Vitellogenins are a family of yolk proteins that are by far the most abundant among oviparous animals. In the model ... ...

    Abstract Vitellogenins are a family of yolk proteins that are by far the most abundant among oviparous animals. In the model nematode
    Language English
    Publishing date 2019-08-21
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2019.01067
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  6. Article ; Online: Biophysical ambiguities prevent accurate genetic prediction.

    Li, Xianghua / Lehner, Ben

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 4923

    Abstract: A goal of biology is to predict how mutations combine to alter phenotypes, fitness and disease. It is often assumed that mutations combine additively or with interactions that can be predicted. Here, we show using simulations that, even for the simple ... ...

    Abstract A goal of biology is to predict how mutations combine to alter phenotypes, fitness and disease. It is often assumed that mutations combine additively or with interactions that can be predicted. Here, we show using simulations that, even for the simple example of the lambda phage transcription factor CI repressing a gene, this assumption is incorrect and that perfect measurements of the effects of mutations on a trait and mechanistic understanding can be insufficient to predict what happens when two mutations are combined. This apparent paradox arises because mutations can have different biophysical effects to cause the same change in a phenotype and the outcome in a double mutant depends upon what these hidden biophysical changes actually are. Pleiotropy and non-monotonic functions further confound prediction of how mutations interact. Accurate prediction of phenotypes and disease will sometimes not be possible unless these biophysical ambiguities can be resolved using additional measurements.
    MeSH term(s) Bacteriophage lambda/genetics ; Biophysical Phenomena/genetics ; Gene Expression Regulation, Viral ; Genetic Association Studies/methods ; Models, Genetic ; Mutation ; Phenotype ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Thermodynamics ; Viral Regulatory and Accessory Proteins/genetics ; Viral Regulatory and Accessory Proteins/metabolism
    Chemical Substances Repressor Proteins ; Viral Regulatory and Accessory Proteins ; phage repressor proteins
    Language English
    Publishing date 2020-10-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-18694-0
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  7. Article ; Online: Author Correction: The impact of rare germline variants on human somatic mutation processes.

    Vali-Pour, Mischan / Park, Solip / Espinosa-Carrasco, Jose / Ortiz-Martínez, Daniel / Lehner, Ben / Supek, Fran

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 5448

    Language English
    Publishing date 2023-09-06
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-41324-4
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  8. Article ; Online: Biophysical ambiguities prevent accurate genetic prediction

    Xianghua Li / Ben Lehner

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 11

    Abstract: In quantitative genetics, it is widely assumed that mutations combine additively or epistasis can be predicted with statistical or mechanistic models. Here, the authors use the phage lambda repressor model to show how biophysical ambiguity and non- ... ...

    Abstract In quantitative genetics, it is widely assumed that mutations combine additively or epistasis can be predicted with statistical or mechanistic models. Here, the authors use the phage lambda repressor model to show how biophysical ambiguity and non-monotonic functions confound phenotypic prediction.
    Keywords Science ; Q
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Biophysical ambiguities prevent accurate genetic prediction

    Xianghua Li / Ben Lehner

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 11

    Abstract: In quantitative genetics, it is widely assumed that mutations combine additively or epistasis can be predicted with statistical or mechanistic models. Here, the authors use the phage lambda repressor model to show how biophysical ambiguity and non- ... ...

    Abstract In quantitative genetics, it is widely assumed that mutations combine additively or epistasis can be predicted with statistical or mechanistic models. Here, the authors use the phage lambda repressor model to show how biophysical ambiguity and non-monotonic functions confound phenotypic prediction.
    Keywords Science ; Q
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers.

    Park, Solip / Supek, Fran / Lehner, Ben

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 7051

    Abstract: The classic two-hit model posits that both alleles of a tumor suppressor gene (TSG) must be inactivated to cause cancer. In contrast, for some oncogenes and haploinsufficient TSGs, a single genetic alteration can suffice to increase tumor fitness. Here, ... ...

    Abstract The classic two-hit model posits that both alleles of a tumor suppressor gene (TSG) must be inactivated to cause cancer. In contrast, for some oncogenes and haploinsufficient TSGs, a single genetic alteration can suffice to increase tumor fitness. Here, by quantifying the interactions between mutations and copy number alterations (CNAs) across 10,000 tumors, we show that many cancer genes actually switch between acting as one-hit or two-hit drivers. Third order genetic interactions identify the causes of some of these switches in dominance and dosage sensitivity as mutations in other genes in the same biological pathway. The correct genetic model for a gene thus depends on the other mutations in a genome, with a second hit in the same gene or an alteration in a different gene in the same pathway sometimes representing alternative evolutionary paths to cancer.
    MeSH term(s) Alleles ; Carcinogenesis/genetics ; DNA Copy Number Variations ; Datasets as Topic ; Genes, Tumor Suppressor ; Haploinsufficiency ; Humans ; Models, Genetic ; Mutation ; Neoplasms/genetics ; Oncogenes
    Language English
    Publishing date 2021-12-03
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-27242-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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