Genome editing: Covering all the bases
Nature
October 26, 2017
A new class of 'base editors' - programmable protein machines that rearrange the atoms of one DNA base to resemble a different base in the genome of living cells - now make it possible to individually replace all four bases of DNA selectively and efficiently, without causing any double-stranded DNA breaks. These new base editors, reported online this week in Nature, could potentially be used to correct single-base mutations that cause genetic diseases and to introduce disease-suppressing single-base mutations, raising hopes that they might contribute to our understanding of genetic disease and the search for new therapies.
The DNA double helix is made of four chemical bases or ‘letters’ - adenine (A), guanine (G), cytosine (C) and thymine (T) - arranged so that C pairs with G, and A with T. Last year, David Liu and colleagues described the development of a CRISPR-Cas9-related base editing method for targeting and modifying single letters of the genetic code. The system was welcomed because it was more efficient than previous methods at correcting single-base mutations and less prone to generating undesired DNA modifications without causing random deletions or insertions in the genome - a common outcome of methods, such as CRISPR-Cas9, that make double-stranded breaks in DNA. However, researchers were then only able to convert G-C base pairs to T-A base pairs. In the new study, Liu and co-authors describe a new class of adenine base editors (ABEs) that enable A-T base pairs to be converted to G-C base pairs.
About half of all known disease-related single-base-pair changes involve the conversion of a wild-type G-C base pair to a mutant A-T base pair, so the new system offers the chance to reverse many such mutations. The ABEs are shown to work on DNA in both bacterial and human cells. In human cells, they can introduce the desired genetic change at a wide range of target regions with an efficiency of around 50%, higher than that of other genome-editing methods, and with virtually no undesired by-products, such as random insertions, deletions or other mutations.
doi: 10.1038/nature24644
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