Machine Learning Algorithm Measures Prime Editing Efficiency
Prime editing is a form of genome editing that employs a ‘search-and-replace’ technique. The approach used by Wellcome Sanger Institute employs primed editors that can action precise changes to both single bases and small stretches of sequence. This capability relies upon a nicking version of Cas9 that implements DNA single-strand breaks as opposed to double-strand breaks.
In a study published by Nature Biotechnology, researchers from the institute explained how they use a nicking Cas9 enzyme that has been joined to a reverse transcriptase domain in addition to the prime editing guide RNA, containing the target edit and the corresponding desired sequence.
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However, this is easier said than done. “The potential of prime editing to improve human health is vast, but first we need to understand the easiest, most efficient, and safest ways to make these edits,” Leopold Parts, the study's senior author, explained in an official press release statement.
During the study, investigators profiled insertion rates for numerous prime editing experiments. Over 3600 DNA sequences with varying lengths — ranging from a single up to 69 bases — were involved. There were targeted to four distinct locations within the genome in three separate human cell lines.
To interpret the data, researchers looked to machine learning to identify patterns determining insertion success. Such trends included length and the specific type of DNA repair involved. Following this, the algorithm then tested on newer data and was shown to accurately predict insertion success.
“Put simply, several different combinations of three DNA letters can encode for the same amino acid in a protein. That’s why there are hundreds of ways to edit a gene to achieve the same outcome at the protein level,” co-author Juliane Weller elaborated.
“By feeding these potential gene edits into a machine learning algorithm, we have created a model to rank them on how likely they are to work,” she continued. “We hope this will remove much of the trial and error involved in prime editing and speed up progress considerably.”
Next, researchers at the Wellcome Sanger Institute aim to create models for all known human genetic diseases. This step will ensure a better understanding of potential treatment options using prime editing. According to Parts, "It's all about understanding the rules of the game, which the data and tool resulting from this study will help us to do.”
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