The truth about ENCODE

A few months ago I highlighted a paper by Casane et al. (2015) where they said ...

In September 2012, a batch of more than 30 articles presenting the results of the ENCODE (Encyclopaedia of DNA Elements) project was released. Many of these articles appeared in Nature and Science, the two most prestigious interdisciplinary scientific journals. Since that time, hundreds of other articles dedicated to the further analyses of the Encode data have been published. The time of hundreds of scientists and hundreds of millions of dollars were not invested in vain since this project had led to an apparent paradigm shift: contrary to the classical view, 80% of the human genome is not junk DNA, but is functional. This hypothesis has been criticized by evolutionary biologists, sometimes eagerly, and detailed refutations have been published in specialized journals with impact factors far below those that published the main contribution of the Encode project to our understanding of genome architecture. In 2014, the Encode consortium released a new batch of articles that neither suggested that 80% of the genome is functional nor commented on the disappearance of their 2012 scientific breakthrough. Unfortunately, by that time many biologists had accepted the idea that 80% of the genome is functional, or at least, that this idea is a valid alternative to the long held evolutionary genetic view that it is not. In order to understand the dynamics of the genome, it is necessary to re-examine the basics of evolutionary genetics because, not only are they well established, they also will allow us to avoid the pitfall of a panglossian interpretation of Encode. Actually, the architecture of the genome and its dynamics are the product of trade-offs between various evolutionary forces, and many structural features are not related to functional properties. In other words, evolution does not produce the best of all worlds, not even the best of all possible worlds, but only one possible world.

How did we get to this stage where the most publicized result of papers published by leading scientists in the best journals turns out to be wrong, but hardly anyone knows it?

Back in September 2012, the ENCODE Consortium was preparing to publish dozens of papers on their analysis of the human genome. Most of the results were quite boring but that doesn't mean they were useless. The leaders of the Consortium must have been worried that science journalists would not give them the publicity they craved so they came up with a strategy and a publicity campaign to promote their work.

Their leader was Ewan Birney, a scientist with valuable skills as a herder of cats but little experience in evolutionary biology and the history of the junk DNA debate.

The ENCODE Consortium decided to add up all the transcription factor binding sites—spurious or not—and all the chromatin makers—whether or not they meant anything—and all the transcripts—even if they were junk. With a little judicious juggling of numbers they came up with the following summary of their results (Birney et al., 2012) ..

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

See What did the ENCODE Consortium say in 2012? for more details on what the ENCODE Consortium leaders said, and did, when their papers came out.

The bottom line is that these leaders knew exactly what they were doing and why. By saying they have assigned biochemical functions for 80% of the genome they knew that this would be the headline. They knew that journalists and publicists would interpret this to mean the end of junk DNA. Most of ENCODE leaders actually believed it.

That's exactly what happened ... aided and abetted by the ENCODE Consortium, the journals Nature and Science, and gullible science journalists all over the world. (Ryan Gregory has published a list of articles that appeared in the popular press: The ENCODE media hype machine..)

Almost immediately the knowledgeable scientists and science writers tried to expose this publicity campaign hype. The first criticisms appeared on various science blogs and this was followed by a series of papers in the published scientific literature. Ed Yong, an experienced science journalist, interviewed Ewan Birney and blogged about ENCODE on the first day. Yong reported the standard publicity hype that most of our genome is functional and this interpretation is confirmed by Ewan Birney and other senior scientists. Two days later, Ed Yong started adding updates to his blog posting after reading the blogs of many scientists including some who were well-recognized experts on genomes and evolution [ENCODE: the rough guide to the human genome].

Within a few days of publishing their results the ENCODE Consortium was coming under intense criticism from all sides. A few journalists, like John Timmer, recongized right away what the problem was ...

Yet the third sentence of the lead ENCODE paper contains an eye-catching figure that ended up being reported widely: "These data enabled us to assign biochemical functions for 80 percent of the genome." Unfortunately, the significance of that statement hinged on a much less widely reported item: the definition of "biochemical function" used by the authors.

This was more than a matter of semantics. Many press reports that resulted painted an entirely fictitious history of biology's past, along with a misleading picture of its present. As a result, the public that relied on those press reports now has a completely mistaken view of our current state of knowledge (this happens to be the exact opposite of what journalism is intended to accomplish). But you can't entirely blame the press in this case. They were egged on by the journals and university press offices that promoted the work—and, in some cases, the scientists themselves.

[Most of what you read was wrong: how press releases rewrote scientific history]

Nature may have begun to realize that it made a mistake in promoting the idea that most of our genome was functional. Two days after the papers appeared, Brendan Maher, a Feature Editor for Nature, tried to get the journal off the hook but only succeeded in making matters worse [see Brendan Maher Writes About the ENCODE/Junk DNA Publicity Fiasco].

Meanwhile, two private for-profit companies, illumina and Nature, team up to promote the ENCODE results. They even hire Tim Minchin to narrate it. This is what hype looks like ...


Soon articles began to appear in the scientific literature challenging the ENCODE Consortium's interpretation of function and explaining the difference between an effect—such as the binding of a transcription factor to a random piece of DNA—and a true biological function.

Eddy, S.R. (2012) The C-value paradox, junk DNA and ENCODE. Current Biology, 22:R898. [doi: 10.1016/j.cub.2012.10.002]

Niu, D. K., and Jiang, L. (2012) Can ENCODE tell us how much junk DNA we carry in our genome?. Biochemical and biophysical research communications 430:1340-1343. [doi: 10.1016/j.bbrc.2012.12.074]

Doolittle, W.F. (2013) Is junk DNA bunk? A critique of ENCODE. Proc. Natl. Acad. Sci. (USA) published online March 11, 2013. [PubMed] [doi: 10.1073/pnas.1221376110]

Graur, D., Zheng, Y., Price, N., Azevedo, R. B., Zufall, R. A., and Elhaik, E. (2013) On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE. Genome Biology and Evolution published online: February 20, 2013 [doi: 10.1093/gbe/evt028

Eddy, S.R. (2013) The ENCODE project: missteps overshadowing a success. Current Biology, 23:R259-R261. [10.1016/j.cub.2013.03.023]

Hurst, L.D. (2013) Open questions: A logic (or lack thereof) of genome organization. BMC biology, 11:58. [doi:10.1186/1741-7007-11-58]

Morange, M. (2014) Genome as a Multipurpose Structure Built by Evolution. Perspectives in biology and medicine, 57:162-171. [doi: 10.1353/pbm.2014.000]

Palazzo, A.F., and Gregory, T.R. (2014) The Case for Junk DNA. PLoS Genetics, 10:e1004351. [doi: 10.1371/journal.pgen.1004351]

By March 2013—six months after publication of the ENCODE papers—some editors at Nature decided that they had better say something else [see Anonymous Nature Editors Respond to ENCODE Criticism]. Here's the closest thing to an apology that they have ever written ....

The debate over ENCODE’s definition of function retreads some old battles, dating back perhaps to geneticist Susumu Ohno’s coinage of the term junk DNA in the 1970s. The phrase has had a polarizing effect on the life-sciences community ever since, despite several revisions of its meaning. Indeed, many news reports and press releases describing ENCODE’s work claimed that by showing that most of the genome was ‘functional’, the project had killed the concept of junk DNA. This claim annoyed both those who thought it a premature obituary and those who considered it old news.

There is a valuable and genuine debate here. To define what, if anything, the billions of non-protein-coding base pairs in the human genome do, and how they affect cellular and system-level processes, remains an important, open and debatable question. Ironically, it is a question that the language of the current debate may detract from. As Ewan Birney, co-director of the ENCODE project, noted on his blog: “Hindsight is a cruel and wonderful thing, and probably we could have achieved the same thing without generating this unneeded, confusing discussion on what we meant and how we said it”.

Oops! The importance of junk DNA is still an "important, open and debatable question" in spite of what the video sponsored by Nature might imply.

(To this day, neither Nature nor Science have actually apologized for misleading the public about the ENCODE results. [see Science still doesn't get it ])

The ENCODE Consortium leaders responded in April 2014—eighteen months after their original papers were published.

Kellis, M., Wold, B., Snyder, M.P., Bernstein, B.E., Kundaje, A., Marinov, G.K., Ward, L.D., Birney, E., Crawford, G. E., and Dekker, J. (2014) Defining functional DNA elements in the human genome. Proc. Natl. Acad. Sci. (USA) 111:6131-6138. [doi: 10.1073/pnas.1318948111]

In that paper they acknowledge that there are multiple meanings of the word function and their choice of "biochemical" function may not have been the best choice ....

However, biochemical signatures are often a consequence of function, rather than causal. They are also not always deterministic evidence of function, but can occur stochastically.

This is exactly what many scientists have been telling them. Apparently they did not know this in September 2012.

They also include in their paper a section on "Case for Abundant Junk DNA." It summarizes the evidence for junk DNA, evidence that the ENCODE Consortium did not acknowledge in 2012 and certainly didn't refute.

In answer to the question, "What Fraction of the Human Genome Is Functional?" they now conclude that ENCODE hasn't answered that question and more work is needed. They now claim that the real value of ENCODE is to provide "high-resolution, highly-reproducible maps of DNA segments with biochemical signatures associate with diverse molecular functions."

We believe that this public resource is far more important than any interim estimate of the fraction of the human genome that is functional.

There you have it, straight from the horse's mouth. The ENCODE Consortium now believes that you should NOT interpret their results to mean that 80% of the genome is functional and therefore not junk DNA. There is good evidence for abundant junk DNA and the issue is still debatable.

I hope everyone pays attention and stops referring to the promotional hype saying that ENCODE has refuted junk DNA. That's not what the ENCODE Consortium leaders now say about their results.

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Casane, D., Fumey, J., et Laurenti, P. (2015) L’apophénie d’ENCODE ou Pangloss examine le génome humain. Med. Sci. (Paris) 31: 680-686. [doi: 10.1051/medsci/20153106023]