This month there has been a bit of a dust-up over the question of how much of our genome is functional. ENCODE results say 80% – or do they? Is it 20%? Or more like 8%?
Did ENCODE scientists play fast and loose with the definition of function, or is genome function legitimately defined as those activities the consortium measured? Is functional DNA something that has an effect on phenotype? (Does that include damaging gain-of-function mutations?) Is functional DNA only that DNA present in your genome because of natural selection? (Then what about hitchhiker alleles?) Is a novel mutation existing in only a single individual functional if that mutation is ultimately destined to become fixed in the population by natural selection?
We have to face the fact that, like much else in biology, boundaries between categories are fluid. It makes no sense to try to cleanly divide the genome into functional and non-functional elements. Even what seems like an obvious boundary line, the boundary between protein-coding and non-coding DNA is blurry: many coding regions have cis-regulatory sites with a non-coding, functional role. To divide the genome into categories of coding- and non-coding function, or function and non-function, may satisfy our insatiable desire to classify for our own cognitive comfort, but from the perspective of the cell there is no such distinction.
Let’s take an example that I see crop up with some regularity. Some biologists propose that we can (at least in principle) determine how much of the genome is functional by seeing how much DNA we can delete without adverse effects. Biologists who, like me, believe that most of the genome is there for non-functional reasons, may argue that we can delete most of the genome without consequence. In fact, Nature has done something like that experiment in the puffer fish, which has essentially the same genes and cellular functions we have, but has a genome 13% the size of ours. So we conclude that, at most, 13% of our genome is functional.
But not everyone agrees. Biologists who like to think that probably all of our genome is functional propose the same genome deletion experiment and say, ‘surely if you delete big chunks of DNA that look like pointless filler, you’ll see an effect on the cell. Therefore, that filler DNA is actually functional.’
My response to that idea is to invoke Donald Rumsfeld, who might say that your species evolves with the genome you have, not the genome you might want or wish to have at a later time. That is, whatever bits of our genome we want to call functional are embedded within a very specific genomic context, and function produced by natural selection emerged within, and certainly depends on, that context.
This is why computer analogies of our genome are bad. Our genome isn’t a giant control panel packed with million of switches, blinking lights, buzzers, gauges, and chrome-plated knobs. Our genome is like Darwin’s tangled bank, an ecosystem filled with elements that have their own agenda in mind. Function is a fluid thing. Regulatory sites wink into and out of existence. Transposable elements pick up transcription factor binding sites, giving themselves an advantage, but they spread those sites around, occasionally leaving something that, with a tweak, turns out to be useful. Function emerges from, and disappears back into the seething genomic jungle.
This is what biology looks like, and the failed media coverage of the genome this past month was so damaging because we lost a chance to tell people about biology.