The status of oligonucleotides within the context of site-directed mutagenesis

COGEM has been requested by VROM to advise on the question whether an oligonucleotide is a recombinant nucleic acid. The answer to this question is important for deciding whether GMO legislation applies to plants developed with targeted mutagenesis.

‘Classical’ mutagenesis has been exempted from European GMO legislation. Classical mutagenesis employs chemical or radioactive mutagens to induce random deletions or reorganisations in the genome. Nowadays, it is also possible to create targeted mutations, using short nucleic acid molecules (oligonucleotides) with sequences that are nearidentical to the target sequence in the receiving genome. This type of site-directed mutagenesis is generally considered safer than classical mutagenesis because it causes fewer random mutations in the genome of the plant. However, it is uncertain if exemption from GMO legislation applies to site-directed mutagenesis. This depends on whether an oligonucleotide should be considered a recombinant nucleic acid or not.

COGEM points out that the question whether an oligonucleotide is a recombinant nucleic acid cannot be answered univocally. It depends on the context in which the oligonucleotide is used, and the order of its sequence. COGEM limits the scope for its considerations to those oligonucleotides that are used to establish mutations in genome sequences in a cell. COGEM is of the opinion that an oligonucleotide used for sitedirected mutagenesis should not be considered a recombinant nucleic acid.

COGEM notes that this request for advice underscores the fact that the framework and principles supporting the current European GMO legislation have been caught up by technological developments, putting the scientific basis of these regulations at stake.