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One man’s junk: What non-coding DNA means for pharma

ENCODE has identified 400 regions of ‘junk’ or non-coding DNA that may have a bearing on disease states, and the implications for pharma and patients are huge

One mans junk... 

The announcement in September that hefty chunks of DNA, which have been dismissed for years as 'junk', are in fact crucial to the smooth operation of the human genome prompted hundreds of news articles – and no small amount of controversy.

The work revealed by the Encyclopaedia of DNA Elements (ENCODE) project is a phenomenal achievement, consigning to history the long-held view that more than 97 per cent of the genetic sequence in human cells, which occurs between the 3 per cent coding for our 20,000 genes, has no function.

The ENCODE team – comprising around 450 scientists from genetics labs around the world – now suggests that more than 80 per cent of the human genome sequence has some form of biochemical function, and a subpart of this of around 20 per cent is thought to be involved in regulating the genes themselves. 

Its work paints a picture of an active genome, in which proteins routinely turn genes on and off – or reduce and raise their level of activity – using sites that are sometimes at great distances from the genes themselves.

… more than 80 per cent of the human genome sequence has some form of biochemical function

The scientists mapped more than four million regulatory regions where proteins specifically interact with the DNA, revealing a “complex molecular choreography required for converting genetic information into living cells and organisms”, according to Eric Green, director of the National Human Genome Research Institute (NHGRI) in the US.

The ENCODE team carried out thousands of experiments on almost 150 different tissue types – racking up 300 years of computer time – to arrive at what is being described as a 'Google Maps' for the human genome. The work has also led to the publication of around 40 papers in recent weeks.

Profound implications for pharma
The implications for human genetics and indeed the pharmaceutical industry could be profound, as the ENCODE project could lead to a greater understanding of what goes wrong in diseases with some form of genetic basis.

For instance, the data provided by ENCODE has already led to the identification of around 400 regions of 'junk' or non-coding DNA that seem to have a bearing on disease states.

“We were surprised that disease-linked genetic variants are not in protein-coding regions,” says Mike Pazin, an ENCODE researcher working at the NHGRI. “We expect to find that many genetic changes causing a disorder are within regulatory regions, or switches, that affect how much protein is produced or when the protein is produced, rather than affecting the structure of the protein itself.”

The ENCODE data provides a tool to help researchers explore the function of non-coding sequences, but the concept of 'junk' DNA has actually been in decline in recent years. Scientists have been trying to explain why humans and chimpanzees are so different, for example, even though the coding portions of their DNA are almost identical. 

Studies have shown that pieces of DNA in non-coding regions known as transposable elements affect the extent to which genes are turned on or off, and that insertion or deletion of pieces of DNA in these regions is highly variable between humans and chimps.

That finding suggests that the morphological and behavioural differences between humans and chimpanzees are due mainly to differences in the regulation of genes, rather than differences in the genes themselves.

Ramifications on medical research
The concept of some portions of junk DNA having biochemical function was discussed at length when the ENCODE consortium published pilot studies in 2007, but the new detailed map reinforces and extends that idea, with huge ramifications on medical research.

Ewan Birney, senior scientist on the ENCODE project working at the European Bioinfomatics Institute near Cambridge in the UK, notes that the 15 terabytes of data generated in the ENCODE can be used to work out what causes one cell to look and behave differently from another. “ENCODE will help us determine what makes a liver cell different from a kidney cell,” says Birney, adding that this is “a first view of the complexity that generates a human being”.

Researchers can use the ENCODE data in a number of ways, according to Birney. For example the database can be interrogated to identify which specific cell types are associated with a disease.

Courting controversy
Given the emerging understanding that inter-genic DNA sequences have a role to play in regulating our genes, it is perhaps surprising that the publication of ENCODE sparked heated debate in the press and journal letters pages.

The sticking point has been the researchers' definition of 'functional' – a problem that has been acknowledged by the ENCODE team and is explained concisely on Birney's own blog.

While the 80 per cent figure was presented as a simple way to get the message across to the media, as noted here, researchers suggest that in fact only around 20 per cent of the genome is directly involved in regulation of DNA:protein interactions.

The ENCODE team has been accused of being too liberal with its definition, and failing to rein in science journalists fixated on the 80 per cent figure.

To some extent, this disparity has polarised the scientific community, loosely split between those who find it perfectly rational to accept that evolution – being inherently messy – has left humans with a redundant payload of DNA, and those who believe that in time functions will be ascribed to most of the genome.

ENCODE will help us determine what makes a liver cell different from a kidney cell

The latter camp notes that ENCODE focused on 147 cell types out of a few thousand encountered in the human body, and these may account for the 20 per cent of DNA with no obvious biochemical function.

Opponents point out that many of the functional elements have been classified as such because they transcribe RNA, but as yet the physiological role of these – if any – has yet to be determined. They argue that these could be relics of defunct genes or the ghost of viral infections from our evolutionary past.

“A simple Google search will reveal that the concept of junk DNA is still alive and well,” comments Larry Moran, a professor in the department of biochemistry at the University of Toronto in a blog slamming the way in which the findings were presented and reported.

“A search like that will also reveal the problems with interpreting the ENCODE result since we've had years of debate over the initial pilot study.”

Meanwhile, the debate has even been hijacked by supporters of creationism, who claim that the 80 per cent finding pokes holes in evolutionist arguments – put forward by the likes of Richard Dawkins – that redundant DNA peppered with evolutionary relics is evidence against the idea of an intelligent design.

Despite the wrangling, there's no doubt that ENCODE is a fantastically sophisticated piece of scientific work and will drive research for years into the future.

According to Tim Hubbard of the Sanger Institute in Cambridge – who heads the GENCODE Consortium which contributed to the project – the findings will change how we think of disease. 

GENCODE scientists provided a more detailed map of the protein-coding areas of the genome and also mapped more than 9,000 non-coding sequences that were transcribed to RNA.

“If the Human Genome Project was the baseline for genetics, ENCODE is the baseline for biology, and GENCODE are the parts that make the human biological machine work,” he added. 

“Our list is essential to all those who would fix the human machine.”

Phil Taylor
The Author

Phil Taylor is a freelance journalist specialising in the pharmaceutical industry

6th December 2012

From: Research



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