The problem comes from the fact that ENCODE looked for chemically active parts in the DNA and called those parts "functional." Not all of that activity is necessarily important for human life, however. For example, ENCODE scientists looked for DNA regions that bind to proteins, because such binding is essential to opening, reading and bookmarking DNA. But a region can also bind proteins without affecting human health. The human genome is full of DNA picked up from viruses in our evolutionary past. Sequences that don't harm or help their hosts may still contain regions that bind to proteins or do other things without affecting cell function.
ENCODE inevitably ended up recording certain regions as active and functional that likely don't do anything important in the body. ENCODE's definition of functional does not have anything to do with why certain regions might be important or what exactly the regions are doing for human health, says John Stamatoyannopoulos, a genomics researcher at the University of Washington in Seattle and one of ENCODE's senior scientists.
Nevertheless, he and some other biologists think ENCODE’s 80 percent conclusion could offer a new view of the human genome. The fact that so much of the genome was biochemically active suggests that much more of the genome may be regulatory than previously believed, Stamatoyannopoulos says. Even some sequences that originally came from a virus or another parasite may have been co-opted to do something useful for the human body. "I just think that the sophistication of this regulatory network is just going to continue to increase and expand our minds," says Eric Schadt, a geneticist at the Icahn School of Medicine at Mount Sinai who was not involved in ENCODE. "I think we will see that the vast majority of the genome can play a role in that."
Active but not important
Critics emphasize that ENCODE was not designed to test how much of the nonprotein-coding genome is doing something important for human health. They say that without first performing experiments that show exactly how the newly discovered "functional" regions impact the body, it's irresponsible to say science has learned something new and revolutionary.
ENCODE's leaders have painted a picture of the human genome in which most of the parts are efficiently put to use, and that's not the right way to see it, critics say. "It's important to distinguish between: Is the human genome a perfect machine? The best of all possible genomes? Or is it a mess?" says Sean Eddy, a genomics researcher at the Howard Hughes Medical Institute's Janelia Farm Research Campus in Virginia who helped plan ENCODE. "What we know about genomes is far more compatible with its being a glorious mess."
By “mess,” Eddy is referring to conclusions from mathematical models of evolution, which suggest at least 85 to 90 percent of the genome must not be critical to human health, even if it is chemically active. Part of the reasoning is that so many random mutations arise over time, humans would have died off if most of the genome were so critical that mutating it would have a major effect on health. On the other hand, Stamatoyannopoulos and Schadt say that those models, some of which rely on simple equations that have been around since the 1960s, could have gotten their numbers wrong. That's possible, Eddy says, but scientists should develop better arguments against the models before discounting them.
Don't bet on a resolution anytime soon. After all, discerning what counts as essential and nonessential DNA for the human body is difficult. Any change to the genome, no matter how small, would likely make some difference to the overall organism—a kind of butterfly effect for DNA, Eddy says. Function lies on a continuum, and different scientists will likely define it differently for years to come.