ENCODE yields insights into the deeper genome

It has taken nearly a decade of hard work, but the first pages of an ‘Encyclopaedia Genomica’ have been published by an international consortium of researchers, revealing some surprising insights about the human genome.

The Encyclopedia of DNA Elements (ENCODE) was started in 2003, even before the first complete human genome had been published.

Already by that point, scientists had uncovered around 20,000 protein coding genes in the human genome. However, those coding regions accounted for only around one per cent of the three billion odd base pairs in the genome. The big questions was: what does the rest do?

ENCODE picked up where the Human Genome Project left off and sought to build a catalogue of all the functional DNA sequences, particularly those that lay outside the protein coding regions.

The project focused on one percent of the human genome, in the hope of developing the tools required to eventually catalogue the rest.

The first comprehensive results from ENCODE have been published in a number of journals today, including Nature, Science and Cell.

One of the most intriguing findings is that around 80 per cent of the genome serves some kind of biochemical function. This suggests that little, if any, of the so-called ‘junk DNA’ that resides between protein coding regions serves no function at all.

Instead, the researchers found the non-coding DNA played significant roles in regulating genes and transcribing proteins.

“The vast majority of the human genome does not code for proteins and, until now, did not seem to contain defined gene-regulatory elements,” Inês Barroso, from the Wellcome Trust Sanger Institute and the University of Cambridge, wrote in Nature.

“Why evolution would maintain large amounts of ‘useless’ DNA had remained a mystery, and seemed wasteful. It turns out, however, that there are good reasons to keep this DNA.

“Results from the ENCODE project show that most of these stretches of DNA harbour regions that bind proteins and RNA molecules, bringing these into positions from which they cooperate with each other to regulate the function and level of expression of protein-coding genes.”

The researchers found in the so-called ‘junk’ regions many ‘promoters,’ which sit just upstream of genes and appear to control gene expression, along with ‘enhancers,’ which regulate the expression of distant genes.

Many of the functional regions uncovered also appear to be related to diseases, suggesting that regulation and transcription may play a sizable role in disease rather than just genetic differences in protein coding regions.

The authors of one of the Nature papers stress that future genome-wide association studies should continue to explore the depths of the genome in the search for disease-causing variations, rather than sequencing just the exome containing protein coding genes.

The results of this massively collaborative project also shed light on some of the mysteries of human evolution, suggesting that at least some of the changes that occur over generations happen in non-coding regions of the genome.

The researchers stress that the ENCODE project is still in its early days, and there is a truly staggering mountain of data left to analyse, not to mention the remaining 99 per cent of the genome.

“Although the ENCODE catalogues represent a remarkable tour de force, they contain only an initial exploration of the depths of our genome, because many more cell types must yet be investigated,” wrote Barroso.

“Some of the remaining challenges for scientists searching for causal disease variants lie in: accessing data derived from cell types and tissues relevant to the disease under study; understanding how these functional units affect genes that may be distantly located; and the ability to generalize such results to the entire organism.”

The ENCODE Explorer can be found on the Nature website.