Mike is very busy being an awesome scientist. So, I have the duty of reacting to the latest “ENCODE takedown” published by Graur et al in Genome Biology and Evolution: “On the immortality of television sets: ‘function’ in the human genome according to the evolution-free gospel of ENCODE”. The title kind of tells you that the ENCODE consortium has a snowball’s chance in Hell of coming out of this one looking good – not that the paper was written by unbiased critics.
ENCODE made a big mistake when they equated “biochemical activity in some assay” with “biological function”. Similarly, Graur et al make a big mistake in equating conservation with function. The fact that less than 10% of the human genome shows evidence of purifying selection (selection that keeps a DNA sequence the same) is not definitive proof that 80% of the genome is not functional, without having to throw out evolutionary theory. While ENCODE’s 80% functional sequence number is ridiculous, genome sequences can have biological function with no conservation for a variety of reasons. Ones that leap to mind include, but are not limited to: function with fitness effects that fall below the threshold for efficient selection in humans, novel functional variation, or the fact that function and conservation are not binary characters, but exist on a spectrum – to name a few.
In essence, there is plenty of gray area between their definitions of “causal role” function and “selected effect” function. “Selected effect” is indeed a conservative way to assign “function”. It is so conservative that it can easily label sequences with physiological consequences (not necessarily fitness consequences) as non-functional. This is the inverse extreme of ENCODE, which makes the error of applying the “causal role” function definition so liberally that their conclusions could only be treated seriously thanks to the combined gravitas of the ENCODE consortium members.
In the body of the paper, Graur et al are actually relatively balanced about these points and address most of the issues I raised in the two prior paragraphs. They are correct about many of the mistakes made in the ENCODE analysis regarding the amount of the genome that is “functional”. You might not notice their good points due to the hostile presentation. If you already agree with the authors, you might enjoy the spilt bile, but you already agree and hardly need to be educated on the failings of ENCODE’s initial analysis, now do you?
This paper is less a reflection of the mistakes made by the ENCODE project and more about the deep rifts in the research community, especially amongst genomics researchers. Emphasis on big projects (eg, human genome, ENCODE, brain mapping) or big prizes to already established researchers, leaves small, independent researchers pursuing creative questions feeling left out in the cold. Frankly, in genomics, you cannot compete with the resources these consortia and genome sequence centers can bring to bear on a project
I also think that, while the fields of marketing and public relations are overly reliant on pseudoscience, Graur et al are misrepresenting those fields by implying that the ENCODE media blitz was designed using their best practices.
The ENCODE results were predicted by one of its authors to necessitate the rewriting of textbooks. We agree, many textbooks dealing with marketing, mass-media hype, and public relations may well have to be rewritten.
Indeed, the biting critique of ENCODE’s failures of presentation is a bit ironic given Graur et al’s counterproductive rhetoric.