CRISPR-based homing gene drives can be designed to disrupt essential genes whilst biasing their own inheritance, leading to suppression of mosquito populations in the laboratory. This class of gene drives relies on CRISPR-Cas9 cleavage of a target sequence and copying ('homing') therein of the gene drive element from the homologous chromosome. However, target site mutations that are resistant to cleavage yet maintain the function of the essential gene are expected to be strongly selected for. Targeting functionally constrained regions where mutations are not easily tolerated should lower the probability of resistance. Evolutionary conservation at the sequence level is often a reliable indicator of functional constraint, though the actual level of underlying constraint between one conserved sequence and another can vary widely. Here we generated a novel adult lethal gene drive (ALGD) in the malaria vector Anopheles gambiae, targeting an ultra-conserved target site in a haplosufficient essential gene (AGAP029113) required during mosquito development, which fulfils many of the criteria for the target of a population suppression gene drive. We then designed a selection regime to experimentally assess the likelihood of generation and subsequent selection of gene drive resistant mutations at its target site. We simulated, in a caged population, a scenario where the gene drive was approaching fixation, where selection for resistance is expected to be strongest. Continuous sampling of the target locus revealed that a single, restorative, in-frame nucleotide substitution was selected. Our findings show that ultra-conservation alone need not be predictive of a site that is refractory to target site resistance. Our strategy to evaluate resistance in vivo could help to validate candidate gene drive targets for their resilience to resistance and help to improve predictions of the invasion dynamics of gene drives in field populations.
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http://dx.doi.org/10.1371/journal.pgen.1009740 | DOI Listing |
Sci Rep
December 2024
Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh.
Protein phosphatases (PPs) are a class of enzymes that play a critical role in cellular regulation by catalyzing the removal of phosphate groups from proteins. This dephosphorylation process is essential for controlling and modulating various cellular functions, including signal transduction, cell cycle progression, metabolic regulation, and stress responses. This study focuses on the comprehensive genomic identification, evolutionary analysis, and transcript profiling of the PP2C gene family within Solanum lycopersicum, an economically significant crop with substantial agricultural and nutritional importance.
View Article and Find Full Text PDFMol Cell Endocrinol
December 2024
Amsterdam Institute for Life and Environment (A-Life), Vrije Universiteit Amsterdam (VU), De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
Adequate levels of thyroid hormones (THs) in the fetal brain are vital for early neurodevelopment. Most of TH in fetal brain is derived from circulating thyroxine (T4), which gets locally converted into the biologically active triiodothyronine (T3) by deiodinase enzymes. One of the major routes of TH into the brain is through the blood-cerebrospinal fluid barrier (BCSFB).
View Article and Find Full Text PDFBiochem Biophys Res Commun
December 2024
Department of Systems Biology, Yonsei University, Seoul, 03722, Republic of Korea. Electronic address:
The root epidermis of Arabidopsis (Arabidopsis thaliana) consists of two distinct cell types: hair (H) cells and non-hair (N) cells, whose patterning is regulated by a network of genes. Among these, the WEREWOLF (WER) gene, encoding an R2R3 MYB transcription factor, acts as a master regulator by promoting the expression of key downstream genes, such as GLABRA2 and CAPRICE. However, the mechanisms controlling WER expression have remained largely unexplored.
View Article and Find Full Text PDFNat Commun
December 2024
Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
The rate and pattern of mutagenesis in cancer genomes is significantly influenced by DNA accessibility and active biological processes. Here we show that efficient sites of replication initiation drive and modulate specific mutational processes in cancer. Sites of replication initiation impede nucleotide excision repair in melanoma and are off-targets for activation-induced deaminase (AICDA) activity in lymphomas.
View Article and Find Full Text PDFNat Commun
December 2024
Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA.
Modern maize (Zea mays ssp. mays) was domesticated from Teosinte parviglumis (Zea mays ssp. parviglumis), with subsequent introgressions from Teosinte mexicana (Zea mays ssp.
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