A promising "word processor" to modify genomes

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An American team has developed a macromolecule potentially capable of better targeting genetic diseases while reducing accidental alterations.

By Hervé Morin Posted yesterday at 17:00

Time to Reading 3 min.

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Representation of the double helix DNA.
Representation of the double helix DNA. AFP

Genetics continues to refine its genome editing tools, an expression that refers to the ability to inactivate, replace, or repair genes by modifying the sequence of "letters" – the A, T bases , C and G – which carry the information contained in the DNA. The revolution represented by Crispr-Cas9, a system discovered in 2012 making it possible to carry out these operations in an easy and inexpensive way, suggested that total gene control had occurred.

In fact, the technique is still very imperfect: DNA breakage and the repair mechanisms on which it is based may be unclear and cause undesirable effects, such as insertions and loss of genetic material at the targeted site, or off-target changes. And it does not work in all cell types. In total, very few of the more than 75,000 known genetic mutations involved in diseases can in practice be corrected.

New tool

An article published in Nature, Monday, October 21, presents a technique potentially capable of repairing 89% of these deleterious genetic variants. A team led by David Liu (Broad Institute, Cambridge, Massachusetts) describes a new tool, called "Premium editing"premium meaning "first", "principal" or "excellent", but also "initiate a reaction". The team of David Liu had already proposed in 2016 base editors, able to induce point mutations – transitions replacing C by T or G by A, and vice versa – without breaking the two strands constituting the double helix of DNA. But they were unable to perform all twelve possible permutations, such as converting a T-A base pair to A-T, an operation that would be required to correct one of the most common causes of sickle cell disease.

The premium editor developed by Liu and his postdoctoral fellow Andrew Anzalone overcomes these limitations and does more. The researchers combined an enzyme, Cas9, with a second enzyme called "reverse transcriptase". The resulting molecular machine, when coupled to a guide made of RNA (a molecule complementary to the targeted DNA), can both look for a specific site on the DNA and make the new genetic information that will take over. place of the target sequence. And all without breaking the two strands of the DNA molecule, which greatly reduces the risk of faulty repair.

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