Arresting Evolution

Bull, James J.; Barrick, Jeffrey E.

doi:10.1016/j.tig.2017.09.008

Cited by 36 publications

(30 citation statements)

References 65 publications

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“…As is well known, cancer cells can escape controls on cell division and programmed cell death through “fast” evolution . Therefore, inhibiting the evolution of cancer cells will be an efficient way to combat cancer.…”

Section: Evolutionary Features Of Drug Targetsmentioning

confidence: 99%

“…Therefore, inhibiting the evolution of cancer cells will be an efficient way to combat cancer. Recently, Bull and Barrick proposed that some genome engineering‐based strategies can stop or slow the cancer cell evolution through changing their evolution pathways, resulting in reducing their fitness and cancer progression . Therefore, the key genes involved in “fast” evolution of cancer cells could be useful targets in cancer treatment.…”

Section: Evolutionary Features Of Drug Targetsmentioning

confidence: 99%

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Evolutionary and genetic features of drug targets

Yuan

Wang

Chu

et al. 2018

Medicinal Research Reviews

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In the modern drug discovery pipeline, identification of novel drug targets is a critical step. Despite rapid progress in developing biomedical techniques, it is still a great challenge to find promising new targets from the ample space of human genes. This fact is partially responsible for the situation of "more investments, fewer drugs" in the pharmaceutical industry. A series of recent researches revealed that successfully targeted genes share some common evolutionary and genetic features, which means that the knowledge accumulated in modern evolutionary biology and genetics is very helpful to identify potential drug targets and to find new drugs as well. In this article, we comprehensively summarize the links between human drug targets and genetic diseases and their evolutionary origins, with an attempt to introduce these novel concepts and their medical implications to the biomedical community.

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Section: Evolutionary Features Of Drug Targetsmentioning

confidence: 99%

Section: Evolutionary Features Of Drug Targetsmentioning

confidence: 99%

Evolutionary and genetic features of drug targets

Yuan

Wang

Chu

et al. 2018

Medicinal Research Reviews

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“…Rational genetic engineering poses many design constraints, that are dealt with approaches stemming from electrical engineering. However, evolution brings a particular set of challenges [5,13].…”

Section: Introductionmentioning

confidence: 99%

“…If a synthetic gene of interest overlaps with an essential gene, many of the loss-offunction mutations will also affect this essential gene and be evolutionary dead-ends (figure 1b). This led us [15] and others [5] to suggest that gene overlaps could be engineered and used as a method for preventing gene loss in synthetically engineered organisms.…”

Section: Introductionmentioning

confidence: 99%

Engineering gene overlaps to sustain genetic constructs in vivo

Decrulle

Frénoy²,

Meiller-Legrand³

et al. 2019

Preprint

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Evolution is often an obstacle to the engineering of stable biological systems due to the selection of mutations inactivating costly gene circuits. Gene overlaps induce important constraints on sequences and their evolution. We show that these constraints can be harnessed to increase the stability of synthetic circuits by purging loss-of-function mutations. We combine computational and synthetic biology approaches to rationally design an overlapping reading frame expressing an essential gene within an existing gene to protect. Our algorithm succeeded in creating overlapping reading frames in 80% of E. coli genes. Experimentally, scoring mutations in both genes of such overlapping construct, we found that a significant fraction of mutations impacting the gene to protect have a deleterious effect on the essential gene. Such an overlap thus protects a costly gene from removal by natural selection by associating the benefit of this removal with a larger or even lethal cost. In our synthetic constructs, the overlap converts many of the possible mutants into evolutionary dead-ends, effectively changing the fitness landscape and reducing the evolutionary potential of the system.

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“…Several strategies are already available to deal with this issue (2,3): One possibility is to engineer redundant genetic circuits that can withstand mutations without loss-offunction (4). Another solution is to design DNA sequences that are less prone to mutation-acquisition, mainly by relying on experimental observations and computational designs (5,6).…”

Section: Introductionmentioning

confidence: 99%

CRISPR-interference based modulation of mobile genetic elements in bacteria

Nyerges

Bálint

Cseklye

et al. 2018

Preprint

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Spontaneous mutagenesis of synthetic genetic constructs by mobile genetic elements frequently results in the rapid loss of advantageous functions. Previous efforts to minimize such mutations required the exceedingly time-consuming manipulation of bacterial chromosomes and the complete removal of insertional sequences (ISes). To this aim, we developed a single plasmid-based system (pCRIS) that applies CRISPRinterference to inhibit the transposition of bacterial ISes. pCRIS expresses multiple guide RNAs to direct inactivated Cas9 (dCas9) to simultaneously silence IS1, IS3, IS5, and IS150 at up to 38 chromosomal loci in Escherichia coli, in vivo. As a result, the transposition rate of all four targeted ISes dropped to negligible levels at both chromosomal and episomal targets, increasing the half-life of exogenous protein expression. Most notably, pCRIS, while requiring only a single plasmid delivery performed within a single day, provided a reduction of IS-mobility comparable to that seen in genome-scale chromosome engineering projects. Global transcriptomics analysis revealed nevertheless only minute alterations in the expression of untargeted genes. Finally, the transposition-silencing effect of pCRIS was easily transferable across multiple E. coli strains. The plasticity and robustness of our IS-silencing system make it a promising tool to stabilize bacterial genomes for synthetic biology and industrial biotechnology applications.

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Arresting Evolution

Cited by 36 publications

References 65 publications

Evolutionary and genetic features of drug targets

Evolutionary and genetic features of drug targets

Engineering gene overlaps to sustain genetic constructs in vivo

CRISPR-interference based modulation of mobile genetic elements in bacteria

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