Ed Yong Updates His Post on the ENCODE Papers

For decades we've known that less than 2% of the human genome consists of exons and that protein encoding genes represent more than 20% of the genome. (Introns account for the difference between exons and genes.) [What's in Your Genome?]. There are about 20,500 protein-encoding genes in our genome and about 4,000 genes that encode functional RNAs for a total of about 25,000 genes [Humans Have Only 20,500 Protein-Encoding Genes]. That's a little less than the number predicted by knowledgeable scientists over four decades ago [False History and the Number of Genes]. The definition of "gene" is somewhat open-ended but, at the very least, a gene has to have a function [Must a Gene Have a Function?].

We've known about all kinds of noncoding DNA that's functional, including origins of replication, centromeres, genes for functional RNAs, telomeres, and regulatory DNA. Together these functional parts of the genome make up almost 10% of the total. (Most of the DNA giving rise to introns is junk in the sense that it is not serving any function.) The idea that all noncoding DNA is junk is a myth propagated by scientists (and journalists) who don't know their history.

We've known about the genetic load argument since 1968 and we've known about the C-Value "Paradox" and it's consequences since the early 1970's. We've known about pseudogenes and we've known that almost 50% of our genome is littered with dead transposons and bits of transposons. We've known that about 3% of our genome consists of highly repetitive DNA that is not transcribed or expressed in any way. Most of this DNA is functional and a lot of it is not included in the sequenced human genome [How Much of Our Genome Is Sequenced?]. All of this evidence indicates that most of our genome is junk. This conclusion is consistent with what we know about evolution and it's consistent with what we know about genome sizes and the C-Value "Paradox." It also helps us understand why there's no correlation between genome size and complexity.

Many science writers published articles on the new ENCODE papers when the embargo was raised last week. One of them was Ed Yong who blogs at Not Exactly Rocket Science. Ed Yong is one of the best science journalists in the world. He was taking on a very difficult job and, in my opinion, he didn't get it right. In light of the ENCODE/junk DNA fiasco that erupted following those publications, Ed has updated his blog post: ENCODE: the rough guide to the human genome.

Here's the slightly modified version of the text in the main body of the article. This was the part that upset me because it seemed to ignore all the evidence for junk DNA.

For years, we’ve known that only 1.5 percent of the genome actually contains instructions for making proteins, the molecular workhorses of our cells. But ENCODE has shown that the rest of the genome – the non-coding majority – is still rife with “functional elements”. That is, it’s doing something.

It contains docking sites where proteins can stick and switch genes on or off. Or it is read and ‘transcribed’ into molecules of RNA. Or it controls whether nearby genes are transcribed (promoters; more than 70,000 of these). Or it influences the activity of other genes, sometimes across great distances (enhancers; more than 400,000 of these). Or it affects how DNA is folded and packaged. Something.

According to ENCODE’s analysis, 80 percent of the genome has a “biochemical function”. More on exactly what this means later, but the key point is: It’s not “junk”. Scientists have long recognised that some non-coding DNA has a function, and more and more solid examples have come to light [edited for clarity - Ed]. But, many maintained that much of these sequences were, indeed, junk. ENCODE says otherwise. “Almost every nucleotide is associated with a function of some sort or another, and we now know where they are, what binds to them, what their associations are, and more,” says Tom Gingeras, one of the study’s many senior scientists.

And what’s in the remaining 20 percent? Possibly not junk either, according to Ewan Birney, the project’s Lead Analysis Coordinator and self-described “cat-herder-in-chief”. He explains that ENCODE only (!) looked at 147 types of cells, and the human body has a few thousand. A given part of the genome might control a gene in one cell type, but not others. If every cell is included, functions may emerge for the phantom proportion. “It’s likely that 80 percent will go to 100 percent,” says Birney. “We don’t really have any large chunks of redundant DNA. This metaphor of junk isn’t that useful.”

Ed Yong has now added several updates to his post in order to point to critics of the claims made by the leadership of the ENCODE Consortium. For example,

[Update 07/09 23:00] Birney was right about the scepticism. Gregory says, “80 percent is the figure only if your definition is so loose as to be all but meaningless.” Larry Moran from the University of Toronto adds, “Functional” simply means a little bit of DNA that’s been identified in an assay of some sort or another. That’s a remarkably silly definition of function and if you’re using it to discount junk DNA it’s downright disingenuous.”

This is the main criticism of ENCODE thus far, repeated across many blogs and touched on in the opening section of this post. There are other concerns. For example, White notes that many DNA-binding proteins recognise short sequences that crop up all over the genome just by chance. The upshot is that you’d expect many of the elements that ENCODE identified if you just wrote out a random string of As, Gs, Cs, and Ts. “I’ve spent the summer testing a lot of random DNA,” he tweeted. “It’s not hard to make it do something biochemically interesting.”

Gregory asks why, if ENCODE is right and our genome is full of functional elements, does an onion have around five times as much non-coding DNA as we do? Or why pufferfishes can get by with just a tenth as much? Birney says the onion test is silly. While many genomes have a tight grip upon their repetitive jumping DNA, many plants seem to have relaxed that control. Consequently, their genomes have bloated in size (bolstered by the occasional mass doubling). “It’s almost as if the genome throws in the towel and goes: Oh sod it, just replicate everywhere.” Conversely, the pufferfish has maintained an incredibly tight rein upon its jumping sequences. “Its genome management is pretty much perfect,” says Birney. Hence: the smaller genome.

But Gregory thinks that these answers are a dodge. “I would still like Birney to answer the question. How is it that humans “need” 100% of their non-coding DNA, but a pufferfish does fine with 1/10 as much [and] a salamander has at least 4 times as much?” [I think Birney is writing a post on this, so expect more updates as they happen, and this post to balloon to onion proportions].

These criticisms only hint at the much larger problem; namely, the fact that Birney (and most science journalists) ignored years of evidence supporting junk DNA. They also ignored many papers in the scientific literature than challenge the conclusions of the ENCODE pilot project in 2007 and challenge many other papers claiming that transcription and DNA binding were evidence of function.

There's nothing fundamentally new new in the ENCODE results that we didn't know before. What's new is the spin that flies in the face of evidence.

The most interesting update comment is ...

Update (07/09/12 11:00): The ENCODE reactions have come thick and fast, and Brendan Maher has written the best summary of them. I’m not going to duplicate his sterling efforts. Head over to Nature’s blog for more.

We're going to take a look at that paper in my next post.

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[Image Credit: The human karyotype is from the Ensembl website.]