'Non-coding' DNA may organize brain cell connections.
Anyone who has ever put together self-assembly furniture knows that having the right parts is important, but what you do with them can make or break the project. The same seems to be true of the vast amounts of DNA in an organism's genome that used to be labelled as junk. Studies now indicate that this DNA may be responsible for the signals that were crucial for human evolution, directing the various components of our genome to work differently from the way they do in other organisms.
The findings seem to bolster a 30-year-old hypothesis that gene regulation — not the creation of new genes — has moulded the traits that make us unique.
The latest work looks for regions of the genome that have changed rapidly in human evolution, based on the theory that they are most likely to have shaped our differences from other animals. But instead of hunting for rapidly evolving DNA in genes, researchers are starting to look at non-coding DNA — stretches of DNA that don't encode proteins.
In a paper published in Science on 3 November, for example, a group led by Edward Rubin of the Lawrence Berkeley National Laboratory (LBNL) in Berkeley, California, reports the result of one hunt through the non-coding genome1. The team defined a group of 110,549 regions of non-coding DNA that are largely the same in humans and other mammals, reasoning that these regions must be important or they would have changed by randomly mutating over time. The researchers then narrowed the list to 992 regions that have changed markedly in humans compared with other mammals. Finally, they asked, if these pieces of DNA are regulators, what biological functions do they control?
They found that these stretches of non-coding DNA tend to lie near genes involved in brain-cell function — specifically, in building connections between brain cells. This suggests that the non-coding DNA pieces might orchestrate the wiring of our brains, says team member Shyam Prabhakar, a computational biologist also at LBNL. “This is really very striking,” he says. “It's the biggest signal we see in human evolution.”
“This is really very striking — It's the biggest signal we see in human evolution.”
Other genome analysts agree that the study is intriguing, but add a few notes of caution. First, the statistical significance of the link to the brain isn't as strong as some would like. Second, it's not clear whether the rapidly changing DNA is actually changing its function, or just accumulating insignificant mutations — in other words, were the changes caused by natural selection?
But the paper seems to agree with other recent analyses of non-coding DNA. The first, published by David Haussler's group at the University of California, Santa Cruz, used stricter data limits to define 202 rapidly evolving regions of DNA2. Many of these were non-coding, but the most dramatically evolving piece of DNA encodes an RNA molecule that is expressed in developing brain tissue3.
Another analysis, not yet published, from Manolis Dermitzakis's group at the Wellcome Trust Sanger Institute in Cambridge, UK, uses slightly different methods to trawl through non-coding DNA and finds 1,500 regions of interest. Some of those overlap with both Haussler's and Rubin's analyses, although Dermitzakis doesn't find the same association with brain function as does Rubin's group. But in unpublished work Gerton Lunter, a bioinformatician at the University of Oxford, UK, has found a link to the brain when he compares human and mouse non-coding DNA.
Altogether, Lunter says, the various results seem to be defining a set of key non-coding regions. “It all points in the same direction, so I think it's believable,” he says.
The challenge, of course, is to figure out how these DNA segments control our fate. On 5 November, Rubin's group published a method for identifying which pieces of non-coding DNA act to enhance the expression of nearby genes4. This is just one possible function of non-coding DNA; elsewhere, it might act as regulatory RNA, or do things researchers can't even guess at yet.
But that's what makes non-coding DNA so much fun, says Haussler. “Here we have a way of discovering new biology,” he says. “And looking at that biology is going to be so exciting.”
Prabhakar, S., Noonan, J. P., Pääbo, S. & Rubin, E. M. Science 314, 786 (2006).
Pollard, K. S. et al. PLoS Genet. doi:10.1371/journal.pgen.0020168; 2006).
Pollard, K. S. et al. Nature 443, 167–172 (2006).
Pennacchio, L. A. et al. Nature doi:10.1038/nature05295;doi:10.1038/nature05295 (2006).