I expect that we will be seeing several harsh critiques of ENCODE’s extraordinary claims about function in the human genome and the equally incredible mega-hype associated with the project. I know of at least one more that is forthcoming from a heavy-hitter in the field, but as a snarky smackdown, it will be very tough to beat the recent paper by Dan Graur and colleagues published in Genome Biology and Evolution. The paper is open-access, so go ahead and read it yourself here. Meantime, enjoy the following zingers:
ENCODE adopted a strong version of the causal role definition of function, according to which a functional element is a discrete genome segment that produces a protein or an RNA or displays a reproducible biochemical signature (for example, protein binding).
Oddly, ENCODE not only uses the wrong concept of functionality, it uses it wrongly and inconsistently.
…the ENCODE authors singled out transcription as a function, as if the passage of RNA polymerase through a DNA sequence is in some way more meaningful than other functions. But, what about DNA polymerase and DNA replication? Why make a big fuss about 74.7% of the genome that is transcribed, and yet ignore the fact that 100% of the genome takes part in a strikingly “reproducible biochemical signature”—it replicates!
Ward and Kellis (2012) confirmed that ~5% of the genome is interspecifically conserved, and by using intraspecific variation, found evidence of lineage-specific constraint suggesting that an additional 4% of the human genome is under selection (i.e., functional), bringing the total fraction of the genome that is certain to be functional to approximately 9%. The journal Science used this value to proclaim “No More Junk DNA” Hurtley 2012), thus, in effect rounding up 9% to 100%.
ENCODE chose to bias its results by excessively favoring sensitivity over specificity. In fact, they could have saved millions of dollars and many thousands of research hours by ignoring selectivity altogether, and proclaiming a priori that 100% of the genome is functional. Not one functional element would have been missed by using this procedure.
Interestingly, ENCODE, which is otherwise quite miserly in spelling out the exact function of its “functional” elements, provides putative functions for each of its 12 histone modifications. For example, according to ENCODE, the putative function of the H4K20me1 modification is “preference for 5’ end of genes.” This is akin to asserting that the function of the White House is to occupy the lot of land at the 1600 block of Pennsylvania Avenue in Washington, D.C.
In a miraculous feat of “next generation” science, the ENCODE authors were able to determine the frequencies of nonexistent derived alleles.
… a surprisingly large number of scientists have had their knickers in a twist over “junk DNA” ever since the term was coined by Susumu Ohno (1972).
In dissecting common objections to “junk DNA,” we identified several misconceptions, chief among them (1) a lack of knowledge of the original and correct sense of the term, (2) the belief that evolution can always get rid of nonfunctional DNA, and (3) the belief that “future potential” constitutes “a function.”
We urge biologists not be afraid of junk DNA. The only people that should be afraid are those claiming that natural processes are insufficient to explain life and that evolutionary theory should be supplemented or supplanted by an intelligent designer (e.g., Dembski
1998; Wells 2004). ENCODE’s take-home message that everything has a function implies purpose, and purpose is the only thing that evolution cannot provide. Needless to say, in light of our investigation of the ENCODE publication, it is safe to state that the news concerning the death of “junk DNA” have been greatly exaggerated.
ENCODE’s biggest scientific sin was not being satisfied with its role as data provider; it assumed the small-science role of interpreter of the data, thereby performing a kind of textual hermeneutics on a 3.5-billion-long DNA text. Unfortunately, ENCODE disregarded the rules of scientific interpretation and adopted a position common to many types of theological hermeneutics, whereby every letter in a text is assumed a priori to have a meaning.
So, what have we learned from the efforts of 442 researchers consuming 288 million dollars? According to Eric Lander, a Human Genome Project luminary, ENCODE is the “Google Maps of the human genome” (Durbin et al. 2010). We beg to differ, ENCODE is considerably worse than even Apple Maps.
We conclude that the ENCODE Consortium has, so far, failed to provide a compelling reason to abandon the prevailing understanding among evolutionary biologists according to which most of the human genome is devoid of function. The ENCODE results were
predicted by one of its lead authors to necessitate the rewriting of textbooks (Pennisi 2012). We agree, many textbooks dealing with marketing, mass-media hype, and public relations may well have to be rewritten.
UPDATE: Listen to a discussion of this topic by Dan Graur and Michael Eisen