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Out of curiosity, I got this question whether knocking out (deletion) of a gene on one side and knocking down (RNAi) of the same gene on the other side will affect the cell in a similar manner or not.

If not why? If yes, is it applied to every gene?

Knock out of a gene will correspond to no expression (gene deletion) in the cell, which can be appropriate to confirm the functional specificity, to observe processes which are affected in its absence and some other processes which are compensating the absence of the gene.

Knockdown of a gene will result in expression defect by decreasing the level of the transcript (mRNA silencing).

Now, the points which I am wondering upon are:

  1. no mRNA presence and silenced mRNA will create two different environments for the cell to deal with or not.
  2. whether the whole amount of transcript should be targeted to have the same phenotype as of gene knockout.
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  • $\begingroup$ As I understand KD, it is a significant reduction of gene expression (the gene is "down"), while KO (in a homozygote/haploid organism) results in no expression of the gene (it is "out"). $\endgroup$ – abukaj Apr 16 '18 at 10:07
  • $\begingroup$ @abukaj This sounds like a good start for an answer. Why don't you write one? $\endgroup$ – Arsak Apr 16 '18 at 10:08
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This is a fascinating set of questions. The only one I can comment on is: is KD qualitatively similar to KO?

My answer is: sometimes yes, in general no. To understand why, I like to think of a hypothetical plot of "phenotype of interest" on the y axis, and "expression of gene" on the x axis. You can imagine that this plot could be monotonic, i.e. that the phenotype continuously increases or decreases as expression increases. Or it is also possible that this plot could have one or more minima or maxima in it. One example of KD giving dissimilar results from KO is for essential genes. If they are knocked out, they of course kill the organism. However, there may be some levels of essential gene knockdown for which the phenotype is actually increased relative to wild-type!

I will selfishly share one of my articles where I observed something like this. We found that ADH1 knockdown improves butanol tolerance in yeast, but that ADH1 knockout was highly detrimental to butanol tolerance. http://dx.doi.org/10.1007/s10295-015-1713-7

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Naively you would expect that they should have about the same effect, but in reality a lot of things can happen. Gene knockout can induce compensating upregulation of other genes and RNAi can have off-target effects. See e.g. this paper "Genetic compensation induced by deleterious mutations but not gene knockdowns" https://www.nature.com/articles/nature14580

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As I understand KD, it is a significant reduction of gene expression (the gene is "down"), while KO (in a homozygote/haploid organism) results in no expression of the gene (it is "out").

Quoting Wikipedia:

Since RNAi may not totally abolish expression of the gene, this technique is sometimes referred as a "knockdown", to distinguish it from "knockout" procedures in which expression of a gene is entirely eliminated.

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