= Solution
\b[It is a useful depletion control, but not an automatically modification-free negative control.] A nominal knockout may retain functional products, and loss of one writer does not establish absence of every relevant <RNA> modification. Calling the sample completely negative requires independent validation of the molecular state being used as ground truth.
This distinction has direct experimental support: alternatively spliced functional <METTL3> products have been found in some nominal knockout lines.<Alternative splicing of METTL3 explains apparently METTL3-independent m6A modifications in mRNA by Hui Xian Poh and others>[Abstract and Results: residual functional METTL3 isoforms in purported knockout cells]{ref} That result identifies a possible failure mode; it does not prove that this particular sample has the same defect. A modification-free reference preparation and an independent chemical measurement would strengthen the interpretation.
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