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Science Reports on Approach to Detect Multiple RNA Biomarkers, Studies of Bacteriophages' Z Genomes

A diagnostic platform that can detect multiple RNA biomarkers in a single test using noncanonical CRISPR RNAs (crRNAs) is described in Science this week. In the report, a team led by scientists from the Helmholtz-Center for Infection Research finds that crRNAs, which are used in CRISPR-Cas9 systems to target foreign genetic material for degradation, can be derived from cellular RNAs not associated with viral defense in type II CRISPR systems. Based on this, the investigators engineered crRNAs that link the presence of an RNA of interest to DNA targeting with different Cas9 orthologs, forming the basis for their multiplexable diagnostic platform. They demonstrate the platform by detecting RNAs from multiple viruses in a single test, as well as distinguishing SARS-CoV-2 from one of its variants with single-base resolution in patient samples.

Three studies appearing in Science this week provide new details about the Z-genome of bacteriophages. Genomic DNA is composed of four standard nucleotides, each with a different nucleobase — adenine (A), thymine (T), cytosine (C), and guanine (G) — that is conserved across all domains of life. However, around 40 years ago, the DNA virus cyanophage S-2L was discovered with all instances of A substituted with 2-aminoadenine (Z) throughout its genome. In two of the papers, independent teams from Tianjin University and Institut Pasteur characterize the proteins involved in the biosynthesis of Z, while in the third paper a group led by investigators from Université Paris-Saclay identify a Z-specific polymerase that is responsible for assembling Z-substituted DNA from available nucleotides. In an accompanying perspective, a pair of Yale University researchers discuss the implications of the findings and how they may help drive new innovations in materials and biotechnology.