ENCODE Nature Publicaiton Selected Media and Web Clippings 6

ENCODE Nature Publicaiton Selected Media and Web Clippings

6/13 to 6/18, 2007

BBC News “Genome Further Unraveled” Financial Times “Research Reveals Complexity in How Human Genes Interact The Guardian “Study Shines New Light on Genome” The Times “DNA Analysis Provides New Insight into the Roots of Our Illnesses” The Glasgow Herald “Genome ‘Junk’ May Be Key To How We Work” Business Weekly “’Parts List’ Could Reshape Genome Understanding” New Scientist “’Junk’ DNA Make Compulsive Reading” Nature “Genome Project Turn Up Evolutionary Surprises” The Economist “Really New Advances” ABC News “Landmark Genome Study Shows Complexity of Human ‘Code’” Bloomberg “’Junk’ Isn’t Junk” Boston Globe “DNA Study Challenges Basic Idea of Genetics” Boston Globe “Science: Miracles and Mysteries” CBS News “DNA Decoding Landmark” PBS Newshour “’Landmark’ Study Changes Long-Held DNA Beliefs” Reuters “Human Instruction Book Not So Simple;Studies” Washington Post “Human Genome Yields Up More Secrets” Washington Post “Intricate Toiling Found in Nooks of DNA…” Washington Post Graphic from article above” WebMD “Genetics Revolution Arrives” Scientific American “The 1 Percent Genome Solution” The Scientist “First Pages of Regulation ‘Encyclopedia’” Science “DNA Study Forces Rethink of What It Means to Be a Gene” Wired “Your Genome is Really, Really, REALLY Complicated” National Public Radio “Reading between the Genomes” Ars Technica “ENCODE Finds the Human Genome to Be an Active Place” Chemical and Eng. News “Finding Function in the Genome” GenomeWeb “Human Genome Not So Tidy After All, ENCODE Project Suggests” Toronto Star “DNA ‘Junk’ Appears to Have Uses” Agence France Presse “Landmark Study Prompts Rethink of Genetic Code” La Republlica “Svolta Nello Studio…” El Mundo “Un Nuevo ‘Manuel de Instrucciones’ del genoma…” Foha de Sao Paulo “A Biologie Acaba…” Frankfurter Neue Presse “Grammatik der Gene Viel Komplexer als Gedacht“ Belgium Cordis News “New Research Challenges Understanding of Human Genome” Xinhua News Agency Untitled

Human genome further unravelled

A close-up view of the human genome has revealed its innermost workings to be far more complex than first thought.

The study, which was carried out on just 1% of our DNA code, challenges the view that genes are the main players in driving our biochemistry.

Instead, it suggests genes, so called junk DNA and other elements, together weave an intricate control network.

The work, published in the journals Nature and Genome Research, is to be scaled up to the rest of the genome.

Views transformed

The Encyclopaedia of DNA Elements (Encode) study was a collaborative effort between 80 organisations from around the world.

It has been described as the next step on from the Human Genome Project, which provided the sequence for all of the DNA that makes up the human species' biochemical "book of life".

Ewan Birney, from the European Molecular Biology Laboratory's European Bioinformatics Institute, led Encode's analysis effort. He told the BBC: "The Human Genome Project gave us the letters of the genome, but not a great deal of understanding. The Encode project tries to understand the genome."

The researchers focussed on 1% of the human genome sequence, carrying out 80 different types of experiments that generated more than 600 million data points.

The surprising results, explained Tim Hubbard from the Wellcome Trust Sanger Institute, "transform our view of the genome fabric".

We are now seeing the majority of the rest of the genome is active to some extent Tim Hubbard, Sanger Institute

THE DNA MOLECULE

The double-stranded DNA molecule - wound in a helix - is held together by four chemical components called bases Adenine (A) bonds with thymine (T); cytosine(C) bonds with guanine (G) Groupings of these "letters" form the "code of life"; a code that is very nearly universal to all Earth's organisms Written in the DNA are genes which cells use as starting

Page 1 of 3BBC NEWS | Science/Nature | Human genome further unravelled

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Previously, genome activity was thought of in terms of the 22,000 genes that make proteins - the functional building blocks in our cells - along with patches of DNA that control, or regulate, the genes.

The other 97% or so of the genome was said to be made up of "junk" DNA - so called because it had no known biological function.

However, junk DNA may soon need a new moniker.

Dr Hubbard said: "We are now seeing the majority of the rest of the genome is active to some extent."

He explained that the study had found junk DNA was being transcribed, or copied, into RNA - an active molecule that relays information from DNA to the cellular machinery.

He added: "This is a remarkable finding, since most prior research suggested only a fraction of the genome was transcribed."

'Complex picture'

Dr Birney added that many of the RNA molecules were copying overlapping sequences of DNA.

He said: "The genome looks like it is far more of a network of RNA transcripts that are all collaborating together. Some go off and make proteins; [and] quite a few, although we know they are there, we really do not have a good understanding of what they do.

"This leads to a much more complex picture."

The researchers now hope to scale up their efforts to look at the other 99% of the genome.

By finding out more about its workings, scientists hope to have a better understanding of the mechanics of certain diseases.

Dr Birney said that in the future, they would hope to combine their findings with some of the larger studies that are currently investigating genes known to be associated with particular conditions.

He added: "As we understand these things better, we get better insight into disease, and when we get better insight into disease, we get better insight into diagnosis and the chances to create new drugs."

Story from BBC NEWS: http://news.bbc.co.uk/go/pr/fr/-/1/hi/sci/tech/6749213.stm

templates to make proteins; these sophisticated molecules build and maintain our bodies

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Research reveals complexity in how human genes interact By Clive Cookson in London Published: June 14 2007 03:00 | Last updated: June 14 2007 03:00

The first thorough examination of how the human genome works, published today, has overthrown the traditional view of our genetic blueprint as a collection of independent genes floating in an ocean of "junk DNA".

Instead, the 3bn chemical "letters" of the human genetic blueprint form an extremely complex network in which genes, regulatory elements and other DNA sequences interact in overlapping ways that are not yet understood.

The new view of the genome appears in 29 scientific papers published simultaneously in the journals Nature and Genome Research. It comes from a $42m (€31m, £23m) international project called the Encyclopedia of DNA elements (Encode) consortium, led by the US National Human Genome Research Institute with the Wellcome Trust and the European Bioinformatics Institute.

Francis Collins, NHGRI director, called the results"a landmark in molecular biology". He said: "This impressive effort has uncovered many exciting surprises and blazed the way for future efforts to explore the functional landscape of the entire human genome."

Conventional genes - stretches of DNA coding for proteins, the molecules that do almost all the biochemical work in living creatures - make up only 2 per cent of the human genome. Even with the separate control and regulatory regions of the genome that are responsible for switching conventional genes on and off, no more than 10 per cent of human DNA is made of such clear-cut functional elements. Until now, many biologists have regarded the majority of the genome as "junk DNA" carried from generation to generation but with no biological function.

The Encode project analysed in great depth a representative 1 per cent of the genome (30m letters of DNA). This showed that most human DNA is biologically active, rather than being pure junk DNA.

The purpose of all this transcribed genomic information remains unclear. Some of it represents a more sophisticated control system for conventional genes; the new work identifies many previously unknown regulatory regions and shows that control regions may be in quite different areas of the genome from the genes they affect. This could complicate efforts to treat diseases.

Other parts of the genome may represent a previously unsuspected evolutionary reserve - not doing much at the moment but potentially useful for the future.

Dr Collins provided an analogy: "It is like the clutter in the attic of your house, which you don't get rid of, in case you ever need it," he said.

"Most of the time, the genome is acting on the first and second floors but over evolutionary time [millions of years] theclutter in the attic may be useful."

Comparisons show that many of these regions are not shared with other species but are restricted to the human genome - a potential source of new variation.

Copyright The Financial Times Limited 2007

BUSINESS LIFE SCIENCE & ENVIRONMENT

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Study shines new light on genome

· Most intensive study ever of our genetic code · So-called junk DNA found to play highly active role

Ian Sample, science correspondent Thursday June 14, 2007

Guardian

Scientists have been forced to rethink how the human genome turns a single cell into a complex living being following the most intensive study of our genetic code ever undertaken.

The research reveals that genes make up only a tiny fraction of the role played by the 3bn letters that constitute the entirety of the human genome.

Large swaths of the genome, previously dismissed as "junk DNA" because it was thought to serve no practical purpose, have been found to be highly active inside the cells in our bodies. Other sequences of genetic code are thought to be "on standby", awaiting a time further down the evolutionary path when they will be beneficial to human beings.

The scientists claim the findings will have a dramatic impact on their ability to pinpoint how genetic defects trigger diseases. Instead of simply looking for mutations in individual genes, it is certain that defects in other parts of the genome will contribute to complex conditions, among them diabetes and coronary heart disease.

The results, published in Nature today, are the culmination of a $42m, five-year project called ENCODE (ENCyclopaedia Of DNA Elements) involving 80 different scientific teams in 11 countries.

The project set out to examine the human genome in unprecedented detail, to work out every different way in which the genetic building blocks, represented by the letters G, T, A and C, work within the body.

The scientists found that beyond genes lay a multitude of other jobs being done by sequences of DNA. Much of the genetic material is transcribed into molecules that relay information from the genome to the biological machinery of our cells.

"If you think of the letters that make up the human genome as the alphabet, then you can think of genes as the verbs. With this project we're identifying all of the other grammatical elements and the syntax of the language we need to read the genetic code completely," said Manolis Dermitzakis, a scientist on the ENCODE project at the Wellcome Trust Sanger Institute in Cambridge.

The findings highlighted how scientists had become so blinded by the importance of genes that the role of other parts of the genome had largely gone unappreciated, he said.

In the pilot study, the researchers focused on 1% of the human genome, or 3bn letters, which were chosen to represent the entire human genetic code. They aim to examine the rest of the genome over the next four years, streamlining the process to complete it for less than $100m.

By understanding how every letter of the human genome functions in the body, scientists believe they will be able to learn how complex diseases are caused by genetic glitches that build up throughout the genome.

EducationGuardian.co.uk © Guardian News and Media Limited 2007

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June 14, 2007

DNA analysis provides new insight into the roots of our illnesses

Mark Henderson, Science Editor

A new understanding of how DNA shapes our health and makes us human has emerged from the most exhaustive analysis yet of the workings of the human genome.

The first “parts list” of genetic elements that are biologically active in the body has revealed that DNA functions in a much more complex fashion than was once assumed, offering insights into the inherited roots of diseases such as diabetes and cancer.

The work of the Encode Consortium — the acronym stands for Encyclopedia of DNA Elements — also sheds important light on the genetic differences that separate humans from chimpanzees and other species.

While the human genome is made up of approximately three billion DNA “letters”, only about 3 per cent of these are known to contribute to 22,000 or so genes — DNA “sentences” containing instructions for making proteins that control the body’s chemical reactions. Most of the remaining 97 per cent has traditionally been thought of as “junk DNA”, which appeared to be an evolutionary relic that performed no tasks of significance.

The new research shows that much of this junk DNA is not redundant but is chemically active in ways that influence how genes are switched on and off.

Mutations in these regulatory genetic regions are thus likely to explain some of our varying susceptibility to disease — some have already been linked to type 2 diabetes and prostate and colon tumours.

While the bulk of our genes are shared with other organisms, much more of our junk DNA is peculiar to our species: 99 per cent of human and chimpanzee genes are identical compared with only 96 per cent of all DNA. As there is more variation in the junk, this could influence traits such as intelligence and language.

Ewan Birney, of the European Bioinformatics Institute, near Cambridge, who led the analysis, said: “Our data certainly agree with the idea that many of the differences between mammals lie in this junk DNA. We now have a much better idea of what most of our DNA might actually be doing. That is also going to help us to characterise what is going on in disease.”

Francis Collins, director of the US National Human Genome Research Institute, which funded the project, said: “This impressive effort has uncovered many exciting surprises and blazed the way for future efforts to explore the functional landscape of the entire human genome.”

The consortium, which pub-lishes its results today in Nature and Genome Research, set out to examine what every bit of DNA does by looking in detail at 30 million letters or base pairs — 1 per cent of the genome.

About 3 per cent of the DNA — the genes — was found to be transcribed into the signalling molecule RNA and then to make proteins. Another 6 per cent hitherto regarded as junk, however, was unexpectedly found to be written into RNA without producing proteins. It is this part of the genome that appears to play a critical regulatory role, controlling when genes are active or silent.

From The Times

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Some of this active DNA outside genes, however, appears to make RNA without affecting the functions of cells — it is chemically alive but neutral. While scientists do not yet know what proportion is neutral, or why, one theory is that it provides a stock of genetic material from which potentially useful mutations can arise to drive evolution.

“It may be a kind of warehouse for natural selection,” Dr Birney said. “Evolution seems to have kept this around for a reason, to somehow set itself up for the future. It is a bit like Pop Idol— if you throw the net widely, you can pick up talent when it appears.”

The Encode team is working to scale up the project to cover the entire human genome.

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Genome ‘junk’ may be key to how we work

The human genetic code is far more complex and dynamic than scientists had previously imagined, a study by experts from around the world has found.

It was previously assumed only certain stretches of DNA, the genes, had any important function. However, the study shows most of the genome, including parts dismissed as "junk", appears to be actively involved in relaying instructions to cells within the body.

Instead of a desert containing occasional oases, scientists now see the genome as an intricate tapestry of interwoven connections.

Dr Tim Hubbard, from the Wellcome Trust Sanger Institute in Hinxton, Cambridge-shire, who took part in the research, said: "The majority of the genome is copied, or transcribed, into RNA, the active molecule in our cells.

"This is a remarkable finding, since most prior research suggested only a fraction of the genome was transcribed."

Scientists had already learned areas of DNA outside the genes were involved in gene regulation but the new work identifies previously unknown control regions.

"The integrated approach has helped us to identify new regions of gene regulation and altered our view of how it occurs," said Dr Hubbard.

The ENCODE (ENCyclopaedia Of DNA Elements) project involved scientists from 80 centres and took five years.

Dr Manolis Dermitzakis, another member of the Sanger Centre team, said: "A major surprise was that many of the novel control regions are not shared with other species. We appear to have a reservoir of active elements that seem to provide no specific or direct benefit.

"Our suggestion is these elements can provide a source for new variation between species and within the human genome. This is our genomic seedcorn for the future."

12:11am Thursday 14th June 2007

By JAMES MORGAN reporter

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‘PARTS LIST’ COULD RESHAPE GENOME UNDERSTANDING

By Business Weekly, 14 June 2007

An exhaustive four-year international effort to build a ‘parts list’ of all biologically functional elements in one per cent of the human genome is promising to reshape our understanding of how the human genome functions, challenging the traditional view of a genetic blueprint as a tidy collection of independent genes.

Ewan Birney, head of genome annotation at EMBL-EBI Picture courtesy: EMBL photolab.

The repercussions of the findings could potentially affect views and processes in a wide range of

areas stretching from evolution to human disease.

The project, which will serve as a pilot to test the feasibility of a full-scale initiative to produce a

comprehensive catalogue of all components of the human genome crucial for biological function,

found that there exists a network in which genes, regulatory elements and other types of DNA

sequences interact in complex, overlapping ways.

Led by the European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI) in

Hinxton, Cambridge, the ENCyclopedia Of DNA Elements – ENCODE – drew on expertise from 35

groups from 80 organisations around the world.

Major findings include the discovery that the majority of human DNA is transcribed into RNA and

that these transcripts extensively overlap, challenging the long-standing view that the human

genome consists of a small set of discrete genes, along with a vast amount of ‘junk’ DNA that is not

biologically active.

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The new data indicate that the genome contains very little unused sequences; genes are just one of

many types of DNA sequences that have a functional impact.

The consortium identified many previously unrecognised start sites for transcription and new

regulatory sequences that contrary to traditional views are located not only upstream but also

downstream of transcription start sites.

“Our results reveal important principles about the organisation of functional elements in the human

genome, providing new persp-ectives on everything from DNA transcription to mammalian

evolution,” said Ewan Birney, head of genome annotation at EMBL-EBI.

Until recently, researchers had thought that most DNA sequences with important biological function

would be constrained by evolution making them likely to be conserved as species evolve.

But about half of the functional elements in the human genome do not appear to have been

constrained during evolution, suggesting that many species’ genomes contain a pool of functional

elements that provide no specific benefits in terms of survival or reproduction.

Over the next couple of years the ENCODE project will be scaled up to the entire genome. The

Ensembl project, a joint EMBL-EBI and Sanger Institute project, jointly headed by Ewan Birney, has

already generated some initial genome wide datasets with early full scale datasets. This integration

has led to the identification of just over 110,000 regulatory elements across the human genome.

'Junk' DNA makes compulsive reading13 June 2007 NewScientist.com news service Andy Coghlan

The central dogma of genetics could hardly be simpler: DNA makes RNA makes protein. Except that now this tidy picture of how genes work has been muddied by a mammoth investigation of human DNA.

It turns out that DNA generates far more RNA than the standard dogma predicts it should - even some "junk" DNA gets transcribed. The Encyclopedia of DNA Elements (ENCODE) project has quantified RNA transcription patterns and found that while the "standard" RNA copy of a gene gets translated into a protein as expected, for each copy of a gene cells also make RNA copies of many other sections of DNA. None of the extra RNA fragments gets translated into proteins, so the race is on to discover just what their function is.

"One of the critical questions is whether they're important or not, and we simply don't know," says Ewan Birney, head of genome annotation at the European Bioinformatics Institute in Cambridge, UK, and analysis coordinator for the ENCODE project, which involves many labs from around the world.

Birney says that while the central dogma still holds, the discovery of so much extra RNA could mean there are hitherto unrecognised subtleties of gene regulation that now need to be explained. "It's no longer the neat and tidy genome we thought we had," says John Greally of the Albert Einstein College of Medicine in New York City.

ENCODE labs analysed 30 million bases or "letters" of human DNA - about 1 per cent of the total - covering 44 different and randomly chosen sites in our genome, and measured the associated RNA transcription in living cells. The whole sample was analysed independently by a range of methods in 38 labs, then cross-checked.

With around 400 known genes in the chosen sample, researchers expected an equal number of different RNA transcripts according to the central dogma of one RNA copy per gene. Instead, they found about twice the predicted quantity of RNA transcripts. Moreover, they also found almost 10 times the expected number of gene switches - the points in DNA where transcription can be activated (Nature, vol 447, p 799).

Many of the RNA transcripts were copies of sections lying across genes and their adjacent stretches of "junk" DNA (see Diagram). Even more surprising, many transcripts were copies of junk DNA situated further from genes. The researchers speculate that the unexpected glut of gene switches might explain the extra RNA.

Birney says that the additional switches may be mutations that appear by accident and then generate new slugs of RNA, but because they are produced randomly, most are evolutionarily neutral "passengers" in the genome. There might be rare occasions, however, when a new RNA does confer an advantage.

Tom Gingeras of genomics firm Affymetrix in Santa Clara, California, and a co-leader of ENCODE, disagrees. He first reported transcription of non-coding DNA three years ago (New Scientist, 21 February 2004, p 10), and is convinced that the extra RNAs have a function, perhaps to help transport molecules around the cell or fine-tune and modulate the activity of genes themselves. "We don't think

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they're produced by accident," he says.

Whatever the truth, the results pose fresh puzzles about how genes work. "It would now take a very brave person to call non-coding DNA junk," says Greally. From issue 2608 of New Scientist magazine, 13 June 2007, page 20

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Nature Published online: 13 June 2007; | doi:10.1038/447760a

Genome project turns up evolutionary surprises

Findings reveal how DNA is conserved across animals

Erika Check

The latest studies of the instructions embedded in the human genome are revealing how evolution has shaped our species. In 'Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project'1, 2, and in a themed issue of Genome Research3, scientists report the first findings from a project called ENCODE. This 'encyclopedia of DNA elements' attempts to discover how our cells make sense of the DNA sequence in the human genome. Already, ENCODE is up-ending one piece of conventional scientific wisdom: the idea that biologically relevant DNA resists change over evolutionary time. ENCODE aims to catalogue all the "functional elements" in the genome — the DNA sequences that control how and when our cells use our genes. Most of these controls seem to be written into so-called non-coding DNA, which does not make a detectable protein product. Because organisms depend on functional elements working correctly, scientists have long thought that such elements should not change much over evolutionary time. So researchers have mostly looked for key functional elements in non-coding DNA that is the same across species, known as conserved or constrained DNA.

But ENCODE is the first project to compare long stretches of non-coding DNA across many mammals, from mice to monkeys to humans. This comparison suggests that evolutionary

The ENCODE project aims to catalogue all the 'functional elements' in the human genome.

ARCTIC-IMAGES/CORBIS

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processes don't always freeze functional DNA in place. "The fact that we found so much functional sequence that did not seem to be evolutionarily constrained across all mammals is really surprising," says Elliott Margulies of the National Human Genome Research Institute in Bethesda, Maryland, who co-chaired one of the ENCODE analysis groups. The finding comes from the ENCODE pilot project, which used multiple methods to collect and analyse data on just 1% of the human genome — not an easy task (see 'Scaling up to a monumental task'). In one part of the project, groups of experimental biologists used a suite of laboratory techniques to find out what portions of the genome might be functional. Meanwhile, groups of computational biologists compared the ENCODE sequences across humans and 28 other animals to find constrained regions of DNA that had changed little throughout evolution. But when the different groups compared their results, they found that their predictions about key portions of the genome didn't always agree: the biologists' list of functional sequences didn't match the computational group's list of constrained sequences. At first, many were sceptical of this result, says John Stamatoyannopoulos of the University of Washington in Seattle, a co-chair of one of the ENCODE analysis groups. "It raised some eyebrows," he says. "But eventually all the ENCODE groups started coming out with the same thing." Overall, biologists found no evidence of function for about 40% of the constrained ENCODE regions. On the flipside, about half of the functional elements found in non-coding DNA were totally unconstrained. The finding that many constrained regions weren't considered to be functional is not too surprising, because it is unlikely that ENCODE included enough tests on enough different types of cells to capture every major aspect of biology. But the idea that important DNA might also be unstable is newer, and intriguing, because it undermines the assumption that biological function requires evolutionary constraint. "We're generalizing this principle over mammals, and over many functional elements," says Ewan Birney, head of genome annotation at the European Bioinformatics Institute in Cambridge, UK, and a leader of ENCODE. "We're coming out quite strongly that this is not merely a curiosity of our genome — it's a really important part of the way our genome works." But how can major components of the mammalian genome change essentially randomly over time? That is not entirely clear. The authors of the ENCODE paper speculate that the unconstrained genomic regions are evolving "neutrally" — that is, they are constantly changing in ways that are neither good nor bad for the individual. This means that, on the whole, many genetic changes simply don't affect overall biology. This has major consequences for understanding the relationship between genetics and biology, Birney says. "It means, for example, that if you look at some conserved piece of biology — say, how the kidneys work in mice and humans — not all of those bits of biology will be conserved or constrained at the level of the DNA bases, and that's quite a strong shift." But not everyone agrees with that take. For example, John Mattick at the University of Queensland in Brisbane, Australia, argues that the widely accepted calculation of the baseline, or neutral, rate of mammalian evolution is flawed. Because measurements of constraint rely on a comparison with the neutral rate, it is possible that many of ENCODE's so-called unconstrained regions really aren't unconstrained, Mattick argues. "I would have said that this finding suggests that many regions of our genome are evolving



under weak selection pressure, or that our measurements of the neutral rate of evolution are incorrect," says Mattick, who is an author on the ENCODE paper. In fact, Mattick thinks scientists are vastly underestimating how much of the genome is functional. He and Birney have placed a bet on the question. Mattick thinks at least 20% of possible functional elements in our genome will eventually be proven useful. Birney thinks fewer are functional. The loser will buy the winner a case of the beverage of his choice. Meanwhile, other scientists are gathering data to answer new questions raised by ENCODE. Many hope that other ongoing studies, such as comparable genome sequences from additional primate species, will help decide which parts of the ENCODE data to study first. Article brought to you by: Nature

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References

1. The ENCODE Project Consortium Nature 447, 799–816 (2007). | Article | 2. Greally, J. M. Nature 447, 782–783 (2007). | Article | 3. Genome Res. 17, Issue 6 (2007). 4. Nature 447, 361 (2007). | Article |

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RNA Really New Advances Jun 14th 2007 From The Economist print edition

Molecular biology is undergoing its biggest shake-up in 50 years, as a hitherto little-regarded chemical called RNA acquires an unsuspected significance

IT IS beginning to dawn on biologists that they may have got it wrong. Not completely wrong, but wrong enough to be embarrassing. For half a century their subject had been built around the relation between two sorts of chemical. Proteins, in the form of enzymes, hormones and so on, made things happen. DNA, in the form of genes, contained the instructions for making proteins. Other molecules were involved, of course. Sugars and fats were abundant (too abundant, in some people). And various vitamins and minerals made an appearance, as well. Oh, and there was also a curious chemical called RNA, which looked a bit like DNA but wasn't. It obediently carried genetic information from DNA in the nucleus to the places in the cell where proteins are made, rounded up the amino-acid units out of which those proteins are constructed, and was found in the protein factories themselves.

All that was worked out decades ago. Since then, RNA has been more or less neglected as a humble carrier of messages and fetcher of building materials. This account of the cell was so satisfying to biologists that few bothered to look beyond it. But they are looking now. For, suddenly, cells seem to be full of RNA doing who-knows-what.

And the diversity is staggering. There are scnRNAs, snRNAs and snoRNAs. There are rasiRNAs, tasiRNAs and natsiRNAs. The piRNAs, which were discovered last summer, are abundant in developing sex cells. No male mammal, nor male fish, nor fly of either sex, would be fertile without them. Another RNA, called XIST, has the power to turn off an entire chromosome. It does

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so in females because they, unlike males, have two X chromosomes and would otherwise get an unhealthy double dose of many proteins. There is even a “pregnancy-induced non-coding RNA”, cutely termed PINC. New RNAs are rushing forth from laboratories so rapidly that a group called the RNA Ontology Consortium has been promised half a million dollars to prune and tend the growing thicket of RNA-tailed acronyms.

In the light of this abundance, perceptions about what a gene is need to change. Genes were once thought of almost exclusively as repositories of information about how to build proteins. Now, they need to be seen for what they really are: RNA factories. Genes for proteins may even be in the minority. In a human, the number of different microRNAs, one of the commonest of the newly discovered sorts of RNA, may be as high as 37,000 according to Isidore Rigoutsos, IBM's genome-miner in chief. That compares with the 21,000 or so protein-encoding genes that people have.

Philosophers of science love this sort of thing. They refer to it as a paradigm shift. Living through such a shift is confusing for the scientists involved, and this one is no exception. But when it is over, it is likely to have changed people's views about how cells regulate themselves, how life becomes more complex, how certain mysterious diseases develop and even how the process of evolution operates. As a bonus, it also opens up avenues to develop new drugs.

Increase and multiply

Not everyone agrees with Dr Rigoutsos about how many microRNAs there are. But the results of a project called the Encyclopaedia of DNA Elements (ENCODE), published in this week's Nature, suggest he is on the right track. The project looked in detail at 1% of the human genome. When ENCODE started, four years ago, the conventional wisdom was that only a few percent of this 1%, corresponding mainly to the protein-coding genes, would actually be transcribed into RNA. In fact, most of it is. What this means is unclear—just how unclear being shown by the fact that although the consortium was willing to identify only eight places where this transcription definitely results in an RNA molecule with a job other than passively carrying the code for a protein, they found another 268 where there was likely to be one, and several thousand more where the data hinted there might be one. That compares with 487 protein-coding genes in the same sequence.

Other evidence suggests that microRNAs regulate the activity of at least a third of human protein-encoding genes. This means there are very few cellular processes that do not happen under their watch. Around 20 microRNAs, for instance, are made only in human embryonic stem cells. These molecules could turn out to be the key to understanding how such cells remain in a state from which they can become any other type of cell—the very reason embryonic stem cells hold such great medical promise.

The existence of microRNAs may also help to explain why some creatures are more complex than others. Until their discovery, this was something of a paradox. Knowing that DNA stores data that then get translated into living organisms, and that the complexities of development must require lots of information, biologists naturally expected that the more intricately formed an organism is, the more genes it would have in its cells. They therefore struggled when they found that C. elegans, a tiny worm that lacks a proper brain but is nevertheless widely studied by geneticists, has about 20,000 genes—only a little bit short of the number in a human. Indeed, this seems to be a general number for animals. Another geneticists' favourite, the fruit fly Drosophila, has a similar number. But, of course, the genes in question are protein-coding genes. Add in the genes whose RNA does other things and the balance changes.

It changes even more if exactly what those RNA molecules do is examined. Single microRNAs, for example, often regulate the levels of hundreds of different proteins. They are like powerful strings controlling copious protein puppets. Super-imposed on this, some types of regulatory RNA edit



other kinds of RNA. The effect of extra genes for both of these sorts of RNA molecules is therefore multiplicative rather than additive.

The picture that is emerging is thus one of “hard-wired” simple organisms, which mostly stick to using RNA for fetching and carrying, and “soft-wired” complex ones that employ it in a management capacity. In the complexity stakes, it is not how many protein-coding genes you have, but how you regulate them, that counts.

What's up, Doc?

Another consequence of RNA's rise to prominence is that researchers have a new source of explanations for illness. Small RNAs have been linked to many types of cancer, to genetic diseases of the central nervous system, and even to infections. Some scientists, for instance, think that RNA molecules help the protein that causes Creutzfeldt-Jakob disease to recruit non-infectious proteins to join its ranks.

The new RNA world is also a source of ideas about how diseases might one day be treated. In this line of work it is best to start simple, which is why the main hunt for new drugs centres on a technology called RNA interference, or RNAi (see article). This, in theory at least, promises to turn down the production of any single protein to very low levels. That distinguishes it from microRNAs, which control many proteins simultaneously.

A hypothetical RNAi drug might, for instance, become the ultimate analgesic by affecting the activity of SCN9A, a gene recently pinpointed as the reason why a Pakistani street performer—who put knives through his arms and walked on burning coals—could not feel pain. The technology has also helped over-eating mice stay slim and live a fifth longer. That was done by choking an insulin-receptor gene in the animals' fat cells. This made the cells less inclined to store every calorie. The technique has even created edible cottonseed (for anyone who might want to try it) by eliminating cotton's gossypol toxin. Not least, it can claim to have produced allergy-friendly soya beans, by turning off the gene that encodes the protein that provokes the reaction.

It is also a technology that can be used at one remove. Recently, Michael White of the University of Texas and his colleagues used RNAi not to treat lung cancer directly, but to convert tumorous cells that do not respond to Taxol, a widely used anti-cancer drug, into cells that are sensitive to it. They did this by silencing Taxol-suppressing genes that were usually active in those cancer cells.

RNAi drugs work by mugging another sort of RNA—one of the classes of the molecule discovered decades ago. These are the messenger-RNA molecules that shuttle information from DNA to the cell's protein factories. The drugs themselves are short pieces of RNA made of strands about 21 genetic letters long. What is unusual about these molecules is that they have two parallel strands, instead of a single one.

One of DNA's differences from RNA is that it comes as a double-stranded helix. Molecules of RNA usually have only a single strand. When a double-stranded RNAi drug enters a cell, an “argonaute” protein picks the molecule up and unzips it down the middle. It chops one strand in two and discards those remnants. The other strand acts as a guide for the argonaute. It can pair with a messenger-RNA molecule—at least, it can do so as long as this messenger contains a sequence of 21 letters that complement those of the drug.

When such RNA molecules do pair, the argonaute slices the messenger to oblivion like a sword-swinging samurai, just as it did with the other half of the original RNAi drug. Thus the gene whose message it was carrying is silenced. This is how RNAi drugs stop the production of disease-related



proteins at source—they hold the tap turned off whereas most medicines try to mop up a continuous leak. Messenger destruction is specific because 21 letters of code are nearly always enough to identify the instructions for one type of protein over another.

The most probable explanation for RNAi is that it evolved as a defence against viruses. Double-stranded RNA is rare in nature, but viruses often make it when they reproduce. This means that organisms which have evolved the ability to recognise and destroy double-stranded RNA molecules have a competitive advantage over those that do not.

That is one example of the role of RNA in evolution. But there are many more. The evolution of microRNAs, for instance, underlines their importance in the origin of complexity. Their number appears to have ballooned when land plants and vertebrates evolved. But it is early days in this research. Dave Bartel, of the Massachusetts Institute of Technology, is surveying grand lists of small RNAs in mosses, flowers, worms, flies and mice in the hope that he will learn when different families of microRNAs emerged and which genes these microRNAs are regulating.

Dr Bartel has already discovered microRNA genes interspersed among sets of protein-encoding genes called Hox clusters. Hox clusters contain basic instructions about body plans, and the genes within them are arranged in the order in which they influence their owner's shape during development. In short, a Hox gene at one end of a cluster contains the information: “Give this embryo a head”. The gene at the other end says: “And a tail, too”. The role of the interspersed microRNAs is to regulate these high-level commands.

Ronald Plasterk, of the University of Utrecht, in the Netherlands, suggests that microRNAs are important in the evolution of the human brain. In December's Nature Genetics, he compared the microRNAs encoded by chimpanzee and human genomes. About 8% of the microRNAs that are expressed in the human brain were unique to it, much more than chance and the evolutionary distance between chimps and people would predict.

Such observations suggest evolution is as much about changes in the genes for small RNAs as in the genes for proteins—and in complex creatures possibly more so. Indeed, some researchers go further. They suggest that RNA could itself provide an alternative evolutionary substrate. That is because RNA sometimes carries genetic information down the generations independently of DNA, by hitching a lift in the sex cells. Link this with the fact that the expression of RNA is, in certain circumstances, governed by environmental factors, and some very murky waters are stirred up.

It's evolutionary, my dear Watson

What is being proposed is the inheritance of characteristics acquired during an individual's lifetime, rather than as the result of chance mutations. This was first suggested by Jean Baptiste Lamarck, before Charles Darwin's idea of natural selection swept the board. However, even Darwin did not reject the idea that Lamarckian inheritance had some part to play, and it did not disappear as a serious idea until 20th-century genetic experiments failed to find evidence for it.

The wiggle room for the re-admission of Lamarck's ideas comes from the discovery that small RNAs are active in cells' nuclei as well as in their outer reaches. Greg Hannon, of the Cold Spring Harbor Laboratory in New York State, thinks that some of these RNA molecules are helping to direct subtle chemical modifications to DNA. Such modifications make it harder for a cell's code-reading machinery to get at the affected region of the genome. They thus change the effective composition of the genome in a way similar to mutation of the DNA itself (it is such mutations that are the raw material of natural selection). Indeed, they sometimes stimulate actual chemical changes in the DNA—in other words, real mutations.



Even this observation, interesting though it is, does not restore Lamarckism because such changes are not necessarily advantageous. But what Dr Hannon believes is that the changes in question sometimes happen in response to stimuli in the environment. The chances are that even this is still a random process, and that offspring born with such environmentally induced changes are no more likely to benefit than if those changes had been induced by a chemical or a dose of radiation. And yet, it is just possible Dr Hannon is on to something. The idea that the RNA operating system which is emerging into view can, as it were, re-write the DNA hard-drive in a predesigned way, is not completely ridiculous.

This could not result in genuine novelty. That must still come from natural selection. But it might optimise the next generation using the experience of the present one, even though the optimising software is the result of Darwinism. And if that turned out to be commonplace, it would be the paradigm shift to end them all.

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Landmark Genome Study Shows Complexity of Human 'Code' Human Genome More Complicated Than Ever Realized, Scientists Say

By JOSEPH BROWNSTEIN ABC News Medical Unit

June 14, 2007 —

In what is being hailed as a landmark in understanding the human genome, scientists from over 35 research centers around the world released a collaborative study Wednesday afternoon showing that our genetic makeup is much more complicated than previously thought.

The collaboration of researchers, known as the Encyclopedia of DNA Elements � or ENCODE � consortium, looked at roughly 1 percent of the entire human genome, concluding that the 95 percent of the genome previously believed to be superfluous actually plays a major role in regulating how DNA expresses itself.

The study brings a new dimension to determining both the impact of human genetics in clinical medicine and how humans evolved differently from animals.

When researchers announced they had mapped the human genome in 2003, they knew it was made up of over 3 billion base pairs of DNA.

However, only between 1.5 and 5 percent of that � encompassing the areas known as "genes" � was involved in actually making proteins. The rest was termed "junk DNA."

But researchers felt that the remaining part of the genome had to have a purpose. In a paper released in the journal Nature, scientists say they have found that much of that so-called junk DNA is actually involved in regulating how genes build and maintain the body.

"Several years ago, we had completion of the Human Genome Project, but we didn't know what to do with 95 percent of the DNA we'd found," said John Greally of the Albert Einstein College of Medicine, who reviewed the study in the same issue of Nature. "This is going to be a landmark."

Greally likens the genes to musical instruments, and the regulatory regions of the genome found in this study to an orchestral score � the instructions necessary to make the whole symphony come together.

Genes With Accessories

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While Greally said the study is an important milestone in understanding the human genome, the fact that the other parts of the DNA play a regulatory role is not surprising; rather, it is something many scientists had expected.

He also said that this study begins to answer a question scientists have been asking for a while: How do cells in the body operate differently when they all have the exact same DNA?

"What we've known for a long time ... is that every cell in the body has the same DNA, but every cell uses different genes, and that's what defined them," said Greally.

While the current study mapped 1 percent of the genome and took four years, scientists feel that the remaining 99 percent of the genome's regulatory regions will be mapped within the next four to five years.

"It's just a matter of money," said Zhiping Weng, a biomedical engineering professor at Boston University, who was one of the study leaders.

She said the accelerating pace of technology for sequencing DNA, and the number of labs that will be interested in adding to the research, would speed up the remainder of the process.

"This is an enormous step forward," said Charles DeLisi, director of bioinformatics at Boston University, who played a major role in the Human Genome Project, but was not involved in the research for this particular study.

DeLisi sees this paper as the start of a new direction in the study of the human genome, where we gain a broader understanding of how DNA really dictates human physiology.

"You'll learn a lot well before this project is completed," he said, referring to what he termed a continuum of medical advances that would take place as researchers learned more about how genetic defects contribute to various diseases like diabetes, heart disease and certain forms of cancer.

Clinicians would then have a more accurate way of diagnosing patients for their risk of developing specific diseases, DeLisi said.

Working in Harmony

One of the most important parts of this study, DeLisi said, is the fact that many research labs came together to work on it.

"We're all working together to make this happen a lot more rapidly than it would otherwise happen," he said. "To me, that is exhilarating."

Francis Collins, head of the National Human Genome Research Institute, and Michael Snyder of Yale University, echoed that sentiment at a press conference on the study Wednesday morning. They indicated that having so many researchers working together so smoothly was key to completing this important work.

This level of collaboration will continue as scientists aim to complete the mapping of the human genome.



"One of the important results is that we can do this," said Ewan Birney, head of genome annotation at the European Molecular Biology Laboratory's European Bioinformatics Institute. "We can gain this information genomewide."

Evolving Understanding

Birney said that the genome research will take a number of different directions, leading to a variety of discoveries.

"Depending on your level of biological geekiness, you get excited about these stories at a different level," said Birney.

For him, an important finding was how different human and animal DNA are.

As many as half of the functional parts of the genome varied between different mammals, said Birney, who has looked at genomes for mice, rats, hedgehogs, platypuses and baboons, among others.

Despite that diversity between humans and animals, Birney stresses that humans are still very alike from one person to the next.

"Not only are we incredibly similar, the only sensible way to view our genetics is as one population," he said. "We are far, far more similar to each other than we are different."

While the new advance adds to the understanding of the genome, researchers point out that completing the mapping will take time. The complexity of the genome, Collins said, is something he feels all the researchers are in awe of.

"We are intended to be complicated," he said, "and we obviously are."

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`Junk DNA' Isn't Junk; Purpose Seen in Genetic Silent Majority

By John Lauerman

June 13 (Bloomberg) -- The vast majority of human DNA, sometimes called ``junk'' because it isn't directly involved in making cellular proteins, is important after all, scientists said.

By looking at just 1 percent of the human genome, researchers found that at least half of the junk regions are biologically relevant. Those areas are storehouses of information that contain switches to regulate the actions of genes, according to a study released today by the journal Nature.

The finding reflects a $42-million research effort, involving 80 organizations in 11 countries, and is the first step in analyzing the 98 percent of the DNA that isn't responsible for encoding proteins, the building blocks of life. The approach brings genetic research to a new level, said Francis Collins, the director of the National Human Genome Research Institute in Bethesda, Maryland.

``I don't think it should be surprising that what we have discovered is complex,'' he said. Referring to humans, he said: ``We are intended to be complicated and we obviously are.''

Now researchers are trying to make sense out of the billions of components in DNA, the chain molecule that forms genes. The study group, called the Encyclopedia of DNA Elements consortium, or ENCODE, analyzed 44 sequences comprising 300 million components.

The findings help explain studies that have associated diseases such as prostate and breast cancer with areas that are devoid of genes, said Michael Snyder, a professor of molecular biophysics and biochemistry at Yale University in New Haven, Connecticut.

Zooming In

``These areas were thought to be junk DNA, and now it is clear that some of them encode regulatory information,'' Snyder, who helped lead the study, said today in a telephone conference with reporters. ``This will help us our ability to zoom in on the regions that allow us to understand human disease.''

While only a tiny portion of the genome can make protein, the study found that most of its sequences make RNA, the molecule that helps translate genetic information from DNA into proteins.

Once considered DNA's poor cousin, RNA has become an increasingly intriguing molecule. Researchers have found that RNA can also block protein from being made, a process called RNA interference.

The study expanded on the versatility of RNA, the researchers said. For example, each gene in the area studied by the international group made an average of five different kinds of RNA, Snyder said. Some of the RNA's are previously unknown promoters that increase the activity of other genetic sequences, he said.

`Much Better Map'

``We have a much better map of all the RNA's and the information that is expressed from the genome,'' he said. ``When you start prodding under the hood, it is very complicated and it is a lot of fun to try to figure this out.''

While about half of the sequences the researchers looked at were already well known, the other half were ``gene deserts'' that have no known function.

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The ENCODE scientists suspected that these areas held important information and purposes, said Ewan Birney, a senior scientist at the European Molecular Biology Laboratory's European Bioinformatics Institute in Hinxton, U.K., who also helped direct the study.

``People involved in genomics knew this stuff was not hanging around for the hell of it,'' he said. ``The junk is not junk. It is very active, it does a lot of things.''

Scientists from Australia, Austria, Canada, Germany, Japan, Singapore, Spain, Sweden and Switzerland also worked on the study.

To contact the reporter on this story: John Lauerman in Boston at [email protected] .

Last Updated: June 13, 2007 13:18 EDT

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DNA study challenges basic ideas in genetics Genome 'junk' appears essential

By Colin Nickerson, Globe Staff | June 14, 2007

A massive international study of the human genome has caused scientists to rethink some of the most basic concepts of cellular function. Genes, it turns out, may be relatively minor players in genetic processes that are far more subtle and complicated than previously imagined.

Among the critical findings: A huge amount of DNA long regarded as useless -- and dismissively labeled "junk DNA" -- now appears to be essential to the regulatory processes that control cells. Also, the regions of DNA lying between genes may be powerful triggers for diseases -- and may hold the key for potential cures.

The research, published in a set of papers in today's editions of the journals Nature and Genome Research, raised far more questions than it answered -- and in a sense was a rallying cry for more and deeper research into the functioning of the genome, often referred to as the "blueprint" for life.

"The instruction manual for life is written in a language we are only just beginning to understand," Francis Collins, director of the federal government's National Human Genome Research Institute , said at a news conference yesterday.

Collins' s institute was among the more than 80 research institutions in North America, Europe, Asia, and Australia that participated in the $42 million, four-year study, whose aim was to analyze 30 million units of human DNA -- just 1 percent of the entire human genome -- to create an inventory of biologically functional elements. The project is known as the Encyclopedia of DNA Elements, or ENCODE, and involved an exhaustive scrutiny of 44 broad "sites" in the human genome, probing not just genes, but all material in the samples.

"We're finding that a lot of the genome is as mysterious as 'dark matter' in physics; we know it is out there doing something. The challenge is to find out what and why," said Thomas D. Tullius , professor of chemistry at Boston University and one of the ENCODE researchers. "There were huge surprises; this research has upset a lot of thinking about how the genome works."

He added in an interview: "There now appear to be thousands of places in the genome that were long thought to be useless or meaningless, but which we now see to have a functional role. But we don't really understand what that role is."

Most startling, according to researchers, is that some areas of the genome looming as crucial are regions that don't contain specific instructions for making proteins. That recognition amounts to a sea change in basic biology.

There are about 20,000 genes in the human body. But they are surrounded by other DNA material whose exact purpose is unclear. Roughly 1 percent of the human genome is thought to be "protein-coding" -- that is, genes. Another 4 percent had been thought to be "non coding DNA" that serves as on-off switches for the genes, and the rest was seen as a sort of swamp with no clear purpose.

But the new work suggests that the "control regions" in the DNA are far more extensive, perhaps embracing more than half of all DNA. Functions thought to be carried out by genes alone now appear to be managed by multiple, overlapping segments of DNA. In addition, other portions of the genome are believed to be on standby, as a toolbag to be utilized as humans evolve.

"It's like clutter in the attic," said Collins. "Most of the time, the human genome is operating on the 'first and second floor,' with 5 percent of the genome doing what needs to be done on a daily basis. But over

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evolutionary time, a much larger part of the genome, the stuff in the attic, becomes important. It's waiting for natural selection to call for it."

The ENCODE research builds on the historic Human Genome Project, largely completed in 2003, which cataloged the genes. Instead of the "big picture" look at the entire structure, the ENCODE project fine-combed selected sites in the genome in extraordinary detail. Half the sites were known by scientists to affect gene replication and protein coding; the other half were random samples from across the genome, including swatches of "junk."

A long standing assumption in genetics has been that cellular organisms are run by genes, which instruct cells to produce proteins thought to be the main driving mechanism in cells. But according to the study, obscure sections of the genome, the "junk DNA," may play an even more critical role in health and evolution than genes themselves.

"We're reshaping our understanding of which regions of the genome produce the critical information" that allows organisms to function and evolve, said Michael Snyder, professor of molecular biophysics at Yale University and one of the researchers.

Recent research into heart attacks and diabetes has made the startling discovery that the roots of disease may lie in noncoding portions of DNA, not in the genes themselves.

In a significant finding, researchers discovered that "gene transcription" -- essential to the process by which DNA builds proteins indispensable to life -- is occurring in regions between genes. They found that ribonucleic acid, or RNA, long seen as another type of genetic code that directs cellular machinery to make proteins, is also produced in stretches of the genome not involved in protein production. That suggests that these regions have an important purpose, though still not understood, the scientists said.

"Transcription appears to be far more interconnected across the genome than anyone had thought," said Collins, adding that the ENCODE findings are "moving us into a deeper understanding of how life works and how, sometimes, things go wrong and disease occurs."

But untangling the tantalizing implications of the new findings will be the work of years.

"It's like reading a code, text jumbled together, and you're trying to make sense of it," said Zhiping Weng, professor of biomedical engineering at Boston University and a researcher in the study. "This project provides many new insights into the complex functional landscape of the human genome."

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Science: miracles and mysteries

June 18, 2007

SCIENTISTS keep pulling the rug out from under their own feet. They acquire new knowledge that makes the old, suddenly upended ideas seem quaintly uninformed.

After discoveries are made, there are surprised choruses of apparently we were wrong. One can only say apparently, because the whole point of science is that there's always more to learn.

Last week two discoveries ushered in new insights. There's the news that in China, scientists had found the fossil remains of Gigantoraptor erlianensis, a 3,100-pound, roughly 26-foot-long birdlike dinosaur that may have had feathers. The fossil was found in 2005, but scientists spent two years studying it before announcing its importance. The upset for science: Theories held that the more birdlike dinosaurs became, the smaller they got. That's not so in this case. Large as he was, this dinosaur didn't live long enough to reach its full size.

Then there's the news that researchers have made a huge leap in understanding the human genome. The old thinking was that genes, which are made of DNA, determine how a living body is cobbled together. The new thinking is that genes work with other kinds of DNA, so-called junk DNA, that had been seen as less important. Now scientists say junk DNA also plays an important role in regulating cells.

The finding is the result of a four-year, $42 million international effort that involved 80 institutions and looked at just 1 percent of the entire human genome, some 30 million units of DNA. What exactly does junk DNA do, and how does it function? These questions have yet to be answered. The goal is to create an encyclopedia of the various DNA elements of the human genome, a kind of instruction manual on how DNA works.

Such findings are an implicit invitation to children to become scientists and continue the work of their academic ancestors. But to take their rightful place in the world's laboratories, children need to be in schools with teachers who can engage them in the sciences, immersing them in current thought and enticing them to pursue what's not known. Children need a clear sense of the scientific mission and enough moxie to keep challenging conventional wisdom.

Scientific progress is also an implicit appeal to government to keep research funding flowing -- both to solve known problems such as chronic diseases, and to gather knowledge for knowledge's sake. Last week, the American Association for the Advancement of Science highlighted efforts in the US House to spend $21 billion more on federal research funding than President Bush has proposed.

It would be money well spent: on science and on the profound endeavor of pursuing the unknown.

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DNA Decoding Landmark June 13, 2007

(WebMD) Researchers announced they have decoded the first 1% of the human genetic code — and the results already are rewriting the rules of biology. The massive, four-year, $42 million effort, organized by the U.S. National Human Genome Research Institute, is called the Encyclopedia of DNA Elements, or ENCODE. It involved 35 researcher groups from 80 organizations scattered across 11 nations. It's a huge success, says NHGRI Director Francis Collins, M.D., Ph.D. The project builds on the Human Genome Project, which in 2003 finally pieced together the DNA sequences that make up the human genome. "But the genome is written in a language we are still trying to learn how to understand," Collins said in a news conference. "ENCODE is building an encyclopedia to tell us what functions are encoded in this remarkable 3-billion-letter script. That script ... somehow carries within it all of the instructions necessary to take a single-celled embryo and turn it into the very complex biological entity called a human being." Collins says that the success of this pilot project means that over the next four years, researchers will undertake a $100 million effort to decode the remaining 99% of the human genome. The early findings already rewrite the human biology rulebook — especially the rules about what genes are and what they do. The biggest surprises:

Human genes aren't discrete boxes of DNA. Instead, DNA from all over the genome contributes to the units of inheritance we call genes.

It was once thought that all functional genes encode protein molecules, the building blocks of the body. The rest of the DNA was called "junk DNA." Now it turns out that this "junk" is just as important as the rest of the genome.

Genes, once supposed to have only one specific function, are now shown to have, on average, at least five different functions.

Very few genes actually code for proteins. The vast majority of genes regulate the function of other genes, telling them when, where, and how they should work.

Many of our genes are just along for the ride, doing us neither good nor harm. But these "bystander" genes may be the stuff from which future human evolution will be made. It's all much more complicated than had been supposed, says Michael Snyder, Ph.D., director of the Yale University Center for Genetics and Proteomics. "I envision this like a sports car," Snyder said at the news conference. "When you first look at it, it looks pretty, simple, and elegant. But as soon as you start prodding under the hood, you find out how complicated it is." For medicine, the new findings hold a great deal of promise. Nearly all of the recently discovered genes linked to disease risk turn out to be the regulatory genes. "This may be a good thing, because there is only a subtle tweaking of a gene in a person with disease," Collins said. "Changing that with a small-molecule drug has a good chance of success. We will have some work to do to figure out how that works, and whether the gene is expressed too high, too low, in the wrong place, and so on." Finishing the human genome encyclopedia will give medical research an extraordinarily valuable tool, says Ewan Birney, Ph.D., leader of the Birney Research Group at the European Bioinformatics Institute in Cambridge, England. "We can now start to say why it is that a certain part of the genome is changing the risk for a certain disease," Birney said at the news conference. "And as we go across the genome, we will be providing researchers with a broader and broader set of annotations to understand how diseases really happen, and therefore get more insight into how to cure them." The ENCODE Project Consortium reports the findings in the June 14 issue of the journal Nature. Twenty-eight companion papers appear in the June issue of Genome Research.

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Posted: June 14, 2007, 4:50 PM ET

'Landmark' Study Changes Long-held DNA BeliefsA four-year international study of the human genome has prompted scientists to rethink some of their most basic ideas about

how DNA functions.

The researchers found that individual genes interact with one another in more complex ways than previously suspected. They also found that large stretches of DNA once called "junk DNA" because they had no known purpose may actually play a significant role in regulating biological processes.

The findings point to the need for much more research, the researchers say, and could influence the way scientists search for the genetic causes of diseases.

"This is a landmark in our understanding of human biology," Francis Collins, director of the National Human Genome Research Institute, said at a news conference Wednesday.

The institute was one of more than 80 research institutions from 11 countries that participated in the Encyclopedia of DNA Elements (ENCODE) project. The researchers published their findings Thursday in a series of articles in the journals Nature and Genome Research.

The human genome consists of a string of more than 3 billion DNA letters. However, only about 3 percent of those DNA letters are part of the approximately 20,000 genes that contain instructions for making proteins, which regulate the body's cellular processes. The protein-making is a two-step process. First, the DNA in the gene is transcribed into RNA, and then that RNA serves as a template to produce a protein.

Until now, most genome research has focused on investigating genes -- often the genes thought to cause or contribute to heritable diseases -- and has ignored the vast stretches of so-called "junk DNA."

The new study, in contrast, picked 44 sites on the genome to comb through in detail. Some were chosen because they already contained genes of interest, but others were randomly chosen to include large stretches of DNA with no known purpose.

The researchers found, to their surprise, that much of the supposedly purposeless DNA was transcribed into RNA -- leading them to believe that the DNA serves some purpose, although they don't yet know what that purpose might be.

"There now appear to be thousands of places in the genome that were long thought to be useless or meaningless, but which we now see to have a functional role," ENCODE researcher Thomas Tullius of Boston University told the Boston Globe. "But we don't really understand what that role is."

One role, the researchers say, may be to act as control regions that help regulate individual genes and turn them on and off. Researchers already knew that some sections of DNA performed this function, but the new research suggests that it might be more widespread than previously thought.

Other segments of DNA may simply be "clutter in the attic," according to Collins. However, even this clutter could serve a purpose, providing basic building blocks for evolution to call into use when needed.

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"Most of the time, the human genome is operating on the 'first and second floor,' with 5 percent of the genome doing what needs to be done on a daily basis," Collins said at the news conference. "But over evolutionary time, a much larger part of the genome, the stuff in the attic, becomes important. It's waiting for natural selection to call for it."

---- Compiled from wire reports and other media sources

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Human instruction book not so simple: studies Wed Jun 13, 2007 8:52PM BST

By Maggie Fox, Health and Science Editor

WASHINGTON (Reuters) - An in-depth examination of the human DNA map has turned basic biology concepts upside-down and may even rewrite the book on evolution and some causes of disease, researchers said on Wednesday.

They found there was far more to genetics than the genes themselves and determined there was no such thing as "junk DNA" but that some of the most useless-looking stretches of DNA may carry important information.

Thirty-five teams of researchers from 80 different organizations in 11 countries teamed up to share notes on just 1 percent of the human genome.

Their findings, the start of the Encyclopedia of DNA Elements or ENCODE Project, were published in the journals Nature and Genome Research.

"This is a landmark in our understanding of human biology," said Dr. Francis Collins, head of the National Human Genome Research Institute, which funded much of the work.

When the human genome was published in 2003, some scientists voiced surprise that human beings had only about 30,000 genes. Rice, for instance, has 50,000.

The new study confirms what many genetics experts had suspected -- the genes are important, but so is the other DNA, the biological code for every living thing.

What they discovered is that even DNA outside the genes transcribes information. Transcription is the process that turns DNA into something useful -- such as a protein.

ACTION OUTSIDE THE GENES

Much of this action is going on outside the genes in the so-called regulatory regions that affect how and when a gene activates, Collins said.

The researchers discovered 4,491 of these so-called transcription start sites, "almost tenfold more than the number of established genes," they wrote in the Nature paper.

Ewan Birney of the European Molecular Biology Laboratory's European Bioinformatics Institute in Cambridge said this helped explain how such a complex creature as a human arose from just four letters of code repeated over and over.

"The junk is not junk. It is really active," Birney told reporters. This could be useful in understanding and treating disease.

"One could imagine that that actually could be a good thing because it would tell you that there is a subtle

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tweaking of the expression of that particular gene, and therefore that particular protein in a person at high risk -- they are making a little too much or not quite enough," Collins added.

Drugs might easily be designed to compensate, he said.

The researchers did find some DNA that appears to do nothing, and it can mutate without causing any damage.

Collins likened these stretches of DNA to boxes in the attic.

"It is not the sort of clutter that you get rid of without consequences because you might need it. Evolution may need it," he said.

That little extra padding might be just what an animal needs to adapt to some unforeseen circumstance, the researchers said. "They may become useful in the future," Birney said.

© Reuters 2006. All rights reserved. Republication or redistribution of Reuters content, including by caching, framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.

Reuters journalists are subject to the Reuters Editorial Handbook which requires fair presentation and disclosure of relevant interests.

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Human Genome Yields Up More Secrets

By E.J. Mundell HealthDay Reporter Wednesday, June 13, 2007; 12:00 AM

WEDNESDAY, June 13 (HealthDay News) -- In what's being hailed as a milestone in human genetics research, an international consortium of scientists announced Wednesday new data that could revolutionize how scientists study health and disease.

An exhaustive look at only 1 percent of the human genome produced two major findings: a vast amount of seemingly useless genes formerly called "junk DNA" may, in fact, be crucial to regulatory processes governing cells; and "epigenetic" factors outside of genes are probably big players behind many diseases.

The results of the Encyclopedia of DNA Elements (ENCODE) Project, published in the June 14 issue ofNature, are "moving us into a deeper understanding of how life works and how, sometimes, things go wrong and disease occurs," Dr. Francis Collins, director of the U.S. National Human Genome Research Institute, told reporters at a morning news conference.

The completion of the Human Genome Project in April 2003 was an historic achievement, resulting in a catalog of more than 30,000 genes that make up the species' genetic blueprint. Those genes are comprised of 3 billion individual nucleotides -- labeled A, C, G, or T -- which combine to form genetic code. All of this is packed and bound into chromosomes as material collectively called chromatin.

"This script is written in this apparently simple alphabet with just four letters, but somehow carries within it all of the instructions necessary to take a single-cell embryo and turn it into a very complex biological entity called a human being," said Collins, whose institute is the major source of funding for the $41 million project.

It is one thing to map the whole genome on the "macro" level, the experts noted. But what the ENCODE team -- 35 groups from 80 organizations worldwide -- is seeking to do is examine, in much more detail, just 1 percent of the genome.

About half of this 1 percent involves areas that were known by scientists to influence gene replication and protein coding to make the building blocks of life. The other half was a random sample meant to include other aspects of the genome, including so-called "junk DNA."

"When they first sequenced the genome, [scientists] were surprised at how little DNA was involved in protein coding regions," explained Ewan Birney of the European Bioinformatics Institute in Hinxton, England.

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Birney, who headed up the two-and-a-half year analysis of the ENCODE data, noted that just 1.5 percent of the "letters" in the genome actually make cellular proteins. So, his team wondered, what was the other 98.5 percent doing?

"People rather dismissively called the rest of it 'junk DNA,' " he said. But the ENCODE data suggest that this genetic material is, in fact, very active.

"One of the big surprises is that the regions between genes seem to be alive, not only with regulatory regions -- which we suspected -- but also there's a lot of [gene] transcription," Birney said. Transcription is the process whereby DNA transcribes its information into usable proteins.

The researchers also discovered another, less obvious purpose to a lot of genetic material. They noticed that up to 70 percent of "functional regions" in the genomes of both humans and other mammals were what Birney called "neutral." These neutral genetic blips popped up frequently and didn't help or hinder the organism, in terms of activities needed to sustain life.

But Collins and other experts believe the neutral regions may, in fact, be key players in evolution and disease, swinging into action occasionally and triggering either helpful or harmful changes.

"It's like clutter in the attic," Collins said. "It's not the kind of clutter that you would get rid of without consequences, however, because you might need it."

"Most of the time the human genome is operating on the 'first and second floor,' with maybe 5 percent of the genome doing whatever needs to be done in terms of daily activities," Collins added. "But over evolutionary time, a much larger fraction of the genome -- this stuff up in the attic -- becomes important. In fact, it's probably responsible for getting us where we are in terms of [our] complexity. It's still there, waiting for natural selection to call upon it."

ENCODE is also revealing that epigenetics -- factors that modify the function of DNA but don't change its sequence -- are a major player in disease.

For example, a team at the University of Virginia has found that the degree to which DNA is bound within the chromosome's chromatin structure strongly influences whether that gene can express, or produce, a protein.

While smaller studies have hinted at that before, "this genome-wide survey really shows that these factors are beautifully coordinated," lead researcher Dr. Anindya Dutta, a professor of molecular genetics at the university, toldHealthDay. "Portions of the chromosome that are lightly packed are replicated early, and they also have the highest amount of gene expression."

That means that a too-loose or too-tight "packing" can cause changes in how a gene functions, much like a mutation would. The ENCODE survey found that, "in cancer cells, this happens in 20 percent of our genes," Dutta noted.

Indeed, revelations from ENCODE should, in the long run, greatly enhance research into a variety of diseases, the experts said. The findings come on the heels of a major study, released last week inNature, in which British scientists substantially increased the number of genes implicated in such common diseases as bipolar disorder, diabetes, heart disease and rheumatoid arthritis.



In many cases, the new complexity arising from ENCODE means that "it will take us a bit longer to sort out exactly what is the mechanism of disease risk," Collins said. "We will have some work to do to figure out exactly how [a genetic aberration] works and what is the consequence."

The results announced Wednesday, he added, are merely those of a pilot project. "We aim to scale this up in the not-too-distant future and apply these same approaches to the entire human genome," he said.

And, Collins noted, "I think that we are all, regardless of our philosophical perspective, rather awed by what we are seeing."

A host of related articles on the ENCODE project were also published Wednesday in the June issue ofGenome Research.

Moe information

For more on the human genome, visit the U.S. National Human Genome Research Institute.

SOURCES: June 13, 2007, news conference,Nature, including Francis Collins, M.D., Ph.D., director, U.S. National Human Genome Research Institute, Bethesda, Md., and Ewan Birney, Ph.D., head, genome annotation, European Molecular Biology Laboratory's European Bioinformatics Institute, Hinxton, England; Anindya Dutta, M.D., professor, biochemistry and molecular genetics, University of Virginia, Charlottesville

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Intricate Toiling Found In Nooks of DNA Once Believed to Stand Idle

By Rick Weiss Washington Post Staff Writer Thursday, June 14, 2007; A01

The first concerted effort to understand all the inner workings of the DNA molecule is overturning a host of long-held assumptions about the nature of genes and their role in human health and evolution, scientists reported yesterday.

The new perspective reveals DNA to be not just a string of biological code but a dauntingly complex operating system that processes many more kinds of information than previously appreciated.

The findings, from a project involving hundreds of scientists in 11 countries and detailed in 29 papers being published today, confirm growing suspicions that the stretches of "junk DNA" flanking hardworking genes are not junk at all. But the study goes further, indicating for the first time that the vast majority of the 3 billion "letters" of the human genetic code are busily toiling at an array of previously invisible tasks.

The new work also overturns the conventional notion that genes are discrete packets of information arranged like beads on a thread of DNA. Instead, many genes overlap one another and share stretches of molecular code. As with phone lines that carry many voices at once, that arrangement has prompted the evolution of complex switching, splicing and silencing mechanisms -- mostly located between genes -- to sort out the interwoven messages.

The new picture of the inner workings of DNA probably will require some rethinking in the search for genetic patterns that dispose people to diseases such as diabetes, cancer and heart disease, the scientists said, but ultimately the findings are likely to speed the development of ways to prevent and treat a variety of illnesses.

One implication is that many, and perhaps most, genetic diseases come from errors in the DNA between genes rather than within the genes, which have been the focus of molecular medicine.

Complicating the picture, it turns out that genes and the DNA sequences that regulate their activity are often far apart along the six-foot-long strands of DNA intricately packaged inside each cell. How they communicate is still largely a mystery.

Altogether, the new project shows that the simple sequence of DNA letters revealed to great

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fanfare by the $3 billion Human Genome Project in 2003 was but a skeletal version of the human construction manual. It is the alphabet, but not much more, for a syntactically complicated language of life that scientists are just now beginning to learn.

"There's a lot more going on than we thought," said Francis Collins, director of the National Human Genome Research Institute, the part of the National Institutes of Health that financed most of the $42 million project.

"It's like trying to read and understand a very complicated Chinese novel," said Eric Green, the institute's scientific director. "The take-home message is, 'Oh, my gosh, this is really complicated.' "

The findings come from the Encyclopedia of DNA Elements project, nicknamed Encode. While much of the decades-long effort to understand DNA's role in health and disease has been driven by scientists' interest in particular genes, Encode focused on a representative 1 percent of the genome. Using a variety of experimental and computational approaches, the researchers sought to catalogue everything going on there.

The 3 1/2 -year effort was designed as a pilot project to see whether it would be practical to study the entire genome in such depth and to hasten the development of cheaper tools to do so. Encode was so successful, Collins said, that the remaining 99 percent of the genome is expected to be studied the same way for $100 million.

The teams targeted 44 areas along the genome, half of them already of interest and half chosen at random to include gene-dense "urban" areas and expanses of seemingly inactive genetic "desert."

Perhaps most surprising was how much of the human genome is at work at any given time, the scientists said.

Researchers have long known that only about 2 percent of human DNA is involved in making proteins, the molecular workhorses inside cells. That involves a two-step process in which a stretch of DNA -- a gene -- serves as a template to produce a strand of RNA, which is then used as a template to produce a protein.

Recent studies had shown that some snippets of DNA between genes also are transcribed into RNA even though they do not go on to make proteins. Surprisingly, though, the new work shows that most of a cell's DNA gets transcribed, raising questions about what all that RNA is doing.

Some of it may be doing nothing. "It may be like clutter in the attic," Collins said, noting that clutter could be useful when conditions change and evolution needs new material to work with.

But much of it seems to be playing crucial roles: regulating genes, keeping chromosomes properly packaged or helping to control the spectacularly complicated process of cell division, which is key to life and also is at the root of cancer.

"We are increasingly being forced to pay attention to our non-gene DNA sequences," John M. Greally of the Albert Einstein College of Medicine in New York wrote in a commentary in today's issue of the journal Nature, where one of the new reports is being published. The 28



other papers appear in today's issue of Genome Research.

Greally noted that several recent studies have found that people are more likely to have Type 2 diabetes and other diseases if they have small mutations in non-gene parts of their DNA that were thought to be medically irrelevant.

Another aspect of Encode had researchers looking at the equivalent 1 percent of the genomes of more than 20 other mammals, and those results are forcing them to rethink the interplay between genetics and evolution.

The expectation was that many of the most active DNA sequences in humans would be prevalent in other mammals, too, because evolution tends to save and reuse what works best. But more than half were not found in other creatures, which suggests they may not be that important in people, either, said Ewan Birney of the European Bioinformatics Institute in Cambridge, England, a coordinator of the Encode effort.

"I think of them as gate-crashers at a party," Birney said. "They appeared by chance over evolutionary time . . . neither to the organism's benefit nor to its hindrance. That is quite an interesting shift in perspective for many biologists."

Although the new view of the genome may at first complicate efforts to identify DNA stretches of prime medical interest, Encode is sure to help in the long run, said Michael Snyder of Yale University, another coordinator.

"Defining the functional elements helps us zoom in to look for differences in sequence that might relate to disease," he said.

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Article Link: http://www.webmd.com/news/20070613/genetics-revolution-arrives

Genetics Revolution Arrives First Chapter of Human DNA ‘Encyclopedia’ Rewrites Biology

June 13, 2007 -- Researchers today announced they have decoded the first 1% of the human genetic code -- and the results already are rewriting the rules of biology.

The massive, four-year, $42 million effort, organized by the U.S. National Human Genome Research Institute, is called the Encyclopedia of DNA Elements, or ENCODE. It involved 35 researcher groups from 80 organizations scattered across 11 nations.

It's a huge success, says NHGRI Director Francis Collins, MD, PhD. The project builds on the Human Genome Project, which in 2003 finally pieced together the DNA sequences that make up the human genome.

"But the genome is written in a language we are still trying to learn how to understand," Collins said in a news conference. "ENCODE is building an encyclopedia to tell us what functions are encoded in this remarkable 3-billion-letter script. That script ... somehow carries within it all of the instructions necessary to take a single-celled embryo and turn it into the very complex biological entity called a human being."

Collins says that the success of this pilot project means that over the next four years, researchers will undertake a $100 million effort to decode the remaining 99% of the human genome.

The early findings already rewrite the human biology rulebook -- especially the rules about what genes are and what they do. The biggest surprises:

Human genes aren't discrete boxes of DNA. Instead, DNA from all over the genome contributes to the units of inheritance we call genes. It was once thought that all functional genes encode protein molecules, the building blocks of the body. The rest of the DNA was called "junk DNA." Now it turns out that this "junk" is just as important as the rest of the genome. Genes, once supposed to have only one specific function, are now shown to have, on average, at least five different functions. Very few genes actually code for proteins. The vast majority of genes regulate the function of other genes, telling them when, where, and how they should work. Many of our genes are just along for the ride, doing us neither good nor harm. But these "bystander" genes may be the stuff from which future human evolution will be made.

It's all much more complicated than had been supposed, says Michael Snyder, PhD, director of the Yale University Center for Genetics and Proteomics.

"I envision this like a sports car," Snyder said at the news conference. "When you first look at it, it looks pretty, simple, and elegant. But as soon as you start prodding under the hood, you find out how complicated it is."

For medicine, the new findings hold a great deal of promise. Nearly all of the recently discovered genes linked

By Daniel J. DeNoon WebMD Medical News

Reviewed by Louise Chang, MD

Health News

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to disease risk turn out to be the regulatory genes.

"This may be a good thing, because there is only a subtle tweaking of a gene in a person with disease," Collins said. "Changing that with a small-molecule drug has a good chance of success. We will have some work to do to figure out how that works, and whether the gene is expressed too high, too low, in the wrong place, and so on."

Finishing the human genome encyclopedia will give medical research an extraordinarily valuable tool, says Ewan Birney, PhD, leader of the Birney Research Group at the European Bioinformatics Institute in Cambridge,England.

"We can now start to say why it is that a certain part of the genome is changing the risk for a certain disease," Birney said at the news conference. "And as we go across the genome, we will be providing researchers with a broader and broader set of annotations to understand how diseases really happen, and therefore get more insight into how to cure them."

The ENCODE Project Consortium reports the findings in the June 14 issue of the journal Nature. Twenty-eight companion papers appear in the June issue of Genome Research. SOURCES: Birney, E. Nature, June 14, 2007; vol 447: pp 799-816. Greally, J.M. Nature, June 14, 2007; vol 447: pp 782-783. News conference, June 13, 2007, with Francis Collins, MD, PhD, director, National Human Genome Research Institute, NIH, Bethesda, Md. Michael Snyder, PhD, director, Center for Genetics and Proteomics, Yale University, New Haven, Conn. Ewan Birney, PhD, senior scientist, Birney Research Group, European Bioinformatics Institute, Cambridge, England. News release, NIH. News release, European Molecular Biology Laboratory. News release, European Bioinformatics Institute. © 2007 WebMD, Inc. All rights reserved.

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June 13, 2007

The 1 Percent Genome SolutionTiny slice of genome reveals bustling activity in the gaps between genes

The first results from a massive project to exhaustively catalogue all the functions of the human genome reveal a hotbed of activity in the gaps between genes. An international consortium of researchers sifted through 1 percent of the genome looking for pieces of DNA that are copied by the cell or help to control gene activity. The results indicate that most DNA is copied into molecules of RNA, including the long stretches between genes, and that genes overlap and interact with each other much more than researchers previously believed.

"We all suspected there was interesting stuff going on in these regions [between genes], and sure enough there is," says bioinformatician Ewan Birney of the European Bioinformatics Institute near Cambridge, England, a member of the project's computer analysis team.

Although researchers do not yet know the biological significance of these discoveries, they say that fully cataloguing the genome may help them understand how genetic variations affect the risk of contracting diseases such as cancer as well as how humans grow from a single-celled embryo into an adult. The next phase of the project, set to begin later this year, will attempt to inventory the full genome.

A genome consists of only four different nucleotide bases, or DNA subunits, arranged in a particular sequence. The publication of the human genome in 2001 revealed its sequence—the significance of which remains a mystery. In particular, genes account for only 1.2 percent of the genome's three billion bases. Once dismissed as "junk DNA," researchers have found that some of these so-called noncoding regions are shared among mammals, suggesting they play an important function.

To help uncover those functions and identify other important sequences, 35 research groups joined forces in 2003 to create the encyclopedia of DNA elements (ENCODE) project. This consortium selected 44 separate sections of the genome that included regions of high to low gene density and high to low similarity between mouse and human.

Like treasure hunters combing a vast beach with metal detectors, ENCODE researchers sifted through their patch of the genome in

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multiple ways that are described, along with the results, in a Nature paper published online today and in a special issue of Genome Research.

A major part of the project was identifying sequences that cells copy, or transcribe, into RNA molecules. Cells make proteins from RNA they copy from genes, but some RNAs play roles by themselves. In addition, some studies have found evidence that species from flies and worms to humans copy large amounts of RNA from noncoding DNA, with no apparent purpose. Nevertheless, "before ENCODE, I think a lot of people were skeptical of how real intergenic activity was," says bioinformatician and consortium member Mark Gerstein of Yale University.

Although genes make up only 3 percent of the ENCODE sequence, the consortium found that 93 percent of the sequence is transcribed. Some of the transcripts hail from noncoding DNA, the researchers report, but those that do match up with the 399 ENCODE genes overlap with each other extensively.

Transcripts from 65 percent of the genes incorporate pieces of DNA from relatively far outside of the genes or even from one or two other genes, says molecular biologist and consortium member Tom Gingeras of Affymetrix, a genome technology company in Santa Clara, Calif. Researchers know that cells chop single genes into shorter pieces called exons, which they mix and match into one transcript for creating a protein. Gingeras says the ENCODE findings confirm recent reports that humans and flies sometimes combine exons from two different genes.

Based on the transcript sequences, the researchers identified 1,437 new promoters—short DNA sequences where transcription begins—in or between genes, on top of the 1,730 promoters they knew of. That is nearly ten promoters per gene, Birney says. He adds that the abundance of transcripts that overlap each gene suggests that the very term "gene" should mean something different inside the cell nucleus, where transcription takes place, than outside of it, where finished proteins go.

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Project members also catalogued sequences that mark areas where DNA unwinds from the round histone proteins that maintain the shape of chromosomes, allowing the cell's transcription machinery to activate genes in those areas. They discovered some potentially unwound areas that are far from promoters and may therefore play some other role, Birney says.

The consortium found that 5 percent of the studied sequence has been conserved among 23 mammals, suggesting that it plays an important enough role for evolution to preserve while species have evolved. But of all the new ENCODE sequences identified as potentially important, only half fall into the conserved group.

These unconserved sequences may be "bystanders," Birney says—consequences of the genome's other functions—that neither help nor hurt cells and may have provided fodder for past evolution.

They could also simply maintain a useful DNA structure or spacing between pieces of DNA regardless of their particular sequence, says genomics researcher T. Ryan Gregory of the University of Guelph in Ontario, who was not part of the consortium.

"The biological insights are mainly incremental at this point," says genome biologist George Weinstock of the Baylor College of Medicine in Houston, which he says is to be expected of such a pilot study. "This is a 'community resource' project, like a genome project, that makes lots of new data available to the community, who then dig into it and mine it for discoveries."

Gregory says the results, although still cryptic, do hint at new functions and a more complicated genome. "This study shows us how far we are from a comprehensive understanding of the human genome."

© 1996-2007 Scientific American, Inc. All rights reserved. Reproduction in whole or in part without permission is prohibited.



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By Melissa Lee Phillips

NEWS First pages of regulation "Encyclopedia" Many regulatory sequences in the human genome are not conserved

[Published 13th June 2007 05:02 PM GMT]

Approximately half of the functional regulatory sequences in the human genome appear to lack conserved sequences, according to an analysis of functional elements in 1% of the genome. The finding comes from the four-year pilot ENCODE Encyclopedia of DNA Elements project, whose results are published in this week's Nature. This lack of evolutionary constraint is "clearly one of the most interesting findings in the paper," said Eric Schadt of Rosetta Inpharmatics in Seattle, Wash., who was not involved in the work. It's possible that variations in regulatory sequences between people could help explain individual differences in disease susceptibility, giving these findings "huge implications," Schadt told Nature. The ENCODE project also analyzed many other aspects of functional non-coding regions of the human genome. "Finally, we're going to be able to

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have some type of a map that will allow us to interpret the significance of any kind of human genetic variation, not just what is occurring in genes," said ENCODE co-chair John Stamatoyannopoulos of the University of Washington in Seattle. A series of papers on ENCODE data is also appearing this week in Genome Research. The pilot phase of the project combined more than 200 new experimental and computational data sets from a consortium of 35 research groups to identify functional elements encoded in about 30 megabases of the human genome. Researchers analyzed DNA from diverse regions throughout the genome, Stamatoyannopoulos said, so that researchers can confidently extrapolate results to the entire genome. "This is the first time that so many different data types have been analyzed over the exact same regions in the exact same cell types," he told Nature. The consortium's analyses revealed that most of the human genome is transcribed, even though just a small fraction of these transcripts are translated into protein. "The ENCODE work is really confirming that there is a significant amount of intergenic and intronic transcription," said Douglas Mortlock of Vanderbilt University in Nashville, Tenn., who was not involved in the work. "A lot of this has been suggested to exist, but it's sort of nice to see confirmation on a larger scale." However, the biological role of many of these transcripts is not yet clear, he added. "A lot of that transcription may not be functional." The data also showed that the same regions of DNA are often transcribed multiple times in an overlapping fashion, confirming a previous hypothesis. "What we think of as genes are actually overlapping each other to a much greater extent than was previously thought," Stamatoyannopoulos said. "The whole genome appears to be connected together in some kind of a transcriptional network."



The researchers found consistent differences between histone modifications of promoters and non-promoter functional elements like enhancers, and they also discovered that transcription factors are equally likely to bind downstream as upstream of a target gene. In general, many of the findings regarding chromatin structure, histone modifications, and transcription have been suggested by previous studies, Schadt said, but the size and depth of the ENCODE analyses provide "a tour-de-force, integrated analysis of all that information and [show] how an extensive annotation of the human genome might work," he told Nature. The consortium next combined new data from various types of analyses -- including transcription, DNA replication timing, chromatin accessibility, and histone modifications -- and used computational algorithms to look for patterns of organization across the entire genome, Stamatoyannopoulos said. They found that all of these data sets confirm a patchwork pattern of transcriptionally active and inactive domains, Stamatoyannopouloss said. This pattern does not differ much between different cell types. "This is a very satisfying finding, because it indicates that there's some global structure of the genome," he added. One of the project's most novel findings, Schadt and Mortlock agreed, is that about half of non-coding functional elements do not appear to be under evolutionary constraint, not only in humans, but across multiple mammalian species. (The researchers compared these regions with orthologous regions of 14 mammalian genomes.) Some researchers have suggested novel regulatory elements can be discovered by simply looking for conserved non-genic sequences between or within species, Stamatoyannopoulos said, but this result suggests that discovering them "really requires an experimental approach." If these regulatory regions are variable between



individual humans, they could be responsible for "common variations in disease and drug responses," Schadt told Nature. "I think it will be one of the more interesting things to explore" from the project's findings, he said. Melissa Lee Phillips [email protected] Links within this article C. Choi, "Regulatory DNAs may be missed," Nature, March 24, 2006. http://www.the-scientist.com/news/display/23246/ L. Pray, "Post-genome project launches," Nature, March 5, 2003. http://www.the-scientist.com/article/display/21158 The ENCODE Project Consortium, "Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project," Nature, June 14, 2007. http://www.nature.com/nature Eric Schadt http://www.rii.com/about/executives.html M.L. Phillips, "Non-coding DNA adapts," Nature, October 20, 2005. http://www.the-scientist.com/article/display/22805/ John Stamatoyannopoulos http://www.gs.washington.edu/faculty/stamj.htm Genome Research http://www.genome.org/ Douglas Mortlock http://phg.mc.vanderbilt.edu/content/mortlock J. Cheng et al., "Transcriptional maps of 10 human



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15 JUNE 2007 VOL 316 SCIENCE www.sciencemag.org1556

NEWS OF THE WEEK

Genes, move over. Ever since the early 1900s,biologists have thought about heredity prima-rily in terms of genes. Today, they often viewgenes as compact, information-laden gemshidden among billions of bases of junk DNA.But genes, it turns out, are neither compact noruniquely important. According to a pain-staking new analysis of 1% of the humangenome, genes can be sprawling, with far-flung protein-coding and regulatory regionsthat overlap with other genes.

As part of the Encyclopedia of DNA

Elements (ENCODE) project, 35 researchteams have analyzed 44 regions of the humangenome covering 30 million bases and figuredout how each base contributes to overallgenome function. The results, compiled in apaper in the 14 June issue of Natureand 28 papersin the June issue of Genome Research, providea litany of new insights and drive home howcomplex our genetic code really is. For exam-ple, protein-coding DNA makes up barely2% of the overall genome, yet 80% of the basesstudied showed signs of being expressed, saysEwan Birney of the European Molecular Biol-ogy Laboratory’s European BioinformaticsInstitute in Hinxton, U.K., who led theENCODE analysis.

Given the traditional gene-centric perspec-tive, that finding “is going to be very disturbingto some people,” says John Greally, a molecu-lar biologist at Albert Einstein College ofMedicine in New York City. On the other hand,

says Francis Collins, director of the NationalHuman Genome Research Institute (NHGRI)in Bethesda, Maryland, “we’re beginning tounderstand the ground rules by which thegenome functions.”

Once the human genome sequence was inhand by 2003, NHGRI set up ENCODE tolearn what those 3 billion or so bases were allabout. The initial 4-year, $42 million effort,which tackled 1% of the human genome,brought new and existing experimental andcomputational approaches to bear, mapping

not just genes but also regulatory DNA andother important features such as gene startsites. NHGRI now plans to spend about$23 million annually over the next 4 years toperform a similar analysis of the wholegenome, expecting that the lessons learnedfrom the pilot ENCODE and new sequencingtechnologies will greatly reduce the costs ofthis extended project (Science, 25 May,p. 1120). “The goal is to measure all the differ-ent kinds of features across the human genomeand ask which features go together to under-stand the whole package,” says George Weinstock,a geneticist at Baylor College of Medicine inHouston, Texas.

A key component of the pilot ENCODE isan analysis of the “transcriptome,” the reper-toire of RNA molecules that cells create bytranscribing DNA. For protein-coding genes,most of their RNA transcripts—the messen-ger RNA (mRNA)—get translated into

chains of amino acids by ribosomes. For othertypes of “genes,” RNA is the end product:Ribosomal RNAs become the backbone ofthe ribosome, for example.

Researchers used to think very little RNAwas produced beyond mRNA and a smatteringof RNA end products. But about half the tran-scripts that molecular biologist Thomas Gingerasof Affymetrix Inc. in Santa Clara, California,discovered in his RNA survey 2 years agodidn’t f it into these categories (Science,20 May 2005, p. 1149), a finding ENCODEhas now substantiated. The ENCODEresearchers knew going in that the DNA theywere studying produced about eight non-protein-coding RNAs, and they have now dis-covered thousands more. “A lot more of theDNA [is] turning up in RNA than most people

would have predicted,” says Collins.ENCODE has produced few clues as to

what these RNAs do—leaving some to wonderwhether experimental artifacts inflated the per-centage of DNA transcribed. Greally is satis-fied that ENCODE used enough differenttechniques to show that the RNA transcriptsare real, but he’s not sure they’re biologicallyimportant. “It’s possible some of these tran-scripts are just the polymerase [enzyme] chug-ging along like an Energizer bunny” and tran-scribing extra DNA, he suggests.

But in the 8 June issue of Science (p. 1484),Gingeras and his colleagues reported thatmany of the mysterious RNA transcripts foundas part of ENCODE harbor short sequences,conserved across mice and humans, that arelikely important in gene regulation. That thesetranscripts are “so diverse and prevalent acrossthe genome just opens up the complexity ofthis whole system,” says Gingeras.

DNA Study Forces Rethink of What It Means to Be a Gene

GENOMICS�

DNA work. For Ewan Birney, coordinating 300 authors to analyze1% of the humangenome (graphic, bluebars) was a rewardingchallenge.

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The mRNA produced from protein-codinggenes also held surprises. When AlexandreReymond, a medical geneticist at the Univer-sity of Lausanne, Switzerland, and his col-leagues took a close look at the 400 protein-coding genes contained in ENCODE’s targetDNA, they found additional exons—theregions that code for amino acids—for morethan 80%. Many of these newfound exons werelocated thousands of bases away from thegene’s previously known exons, sometimeshidden in another gene. Moreover, somemRNAs were derived from exons belonging totwo genes, a f inding, says Reymond, that

“underscores that we have still not trulyanswered the question, ‘What is a gene?’ ” Inaddition, further extending and blurring geneboundaries, ENCODE uncovered a slew ofnovel “start sites” for genes—the DNAsequences where transcription begins—manylocated hundreds of thousands of bases awayfrom the known start sites.

Before ENCODE started, researchers knewof about 532 promoters, regulatory DNA thathelps jump-start gene activity, in the humanDNA chosen for analysis. Now they have775 in hand, with more awaiting verification.Unexpectedly, about one-quarter of the pro-

moters discovered were at the ends of the genesinstead of at the beginning.

The distributions of exons, promoters, genestart sites, and other DNA features and the exis-tence of widespread transcription suggest that amultidimensional network regulates geneexpression. Gingeras contends that because ofthis complexity, researchers should look atRNA transcripts and not genes as the funda-mental functional units of genomes. ButCollins is more circumspect. The gene “is aconcept that’s not going out of fashion,” he pre-dicts. “It’s just that we have to be more thought-ful about it.” –ELIZABETH PENNISI

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NEWS OF THE WEEK

An activist group’s concern about maverickgenome sequencer J. Craig Venter’s intentionto patent an entirely synthetic free-livingorganism has thrown a spotlight on the emerg-ing intellectual-property landscape in this hotnew field. The protesters claim that Venterwants his company to become the Microsoftof synthetic biology, dominating the industry.

Venter hopes to use the artificial life form,which he says does not yet exist, as a carrierfor genes that would enable the bug to crankout hydrogen or ethanol to produce cheapenergy. Duke University law professor ArtiRai says the patent, if awarded, “could beproblematic” only if Venter’s product becamethe standard in the field. But Venter says thisapplication is just the start: He plans to patentmethods that would cover more than the sin-gle microbe described in the application.“We’d certainly like the freedom to operate onall synthetic organisms” that could serve as achassis for swapping out genes, says Venter,whose research team is at the nonprofitJ. Craig Venter Institute in Rockville, Mary-land, but who recently started a company tocommercialize the work.

Filed last October and published by theU.S. Patent and Trademark Office on 31 May,the application describes “a minimal set ofprotein-coding genes which provides theinformation required for replication of a free-living organism in a rich bacterial culturemedium.” The application cites work byHamilton Smith and others on Venter’s teamon a simple bacterium called Mycoplasma

genitalium that they are using to determinethe minimum number of genes for life. Theywant to synthesize this “minimal genome”from scratch, get it working inside a cell, thenadd genes to produce cheap fuels (Science,14 February 2003, p. 1006).

In a press release, the ETC Group, a tech-nology watchdog in Ottawa, Canada, calledVenter’s “monopoly claims … the start of ahigh-stakes commercial race to synthesize andprivatize synthetic life forms.” ETC calls forthe U.S. and international patent offices toreject the patent so that societal implicationscan be considered. ETC also cited a recentNewsweek interview in which the scientistsays he wants to create “the first billion- ortrillion-dollar organism.”

Venter says this is just one of several patentapplications that would give his company,Synthetic Genomics Inc., exclusive rights tomethods for making synthetic organisms. Theartificial Mycoplasma “may or may not be”the one used to generate hydrogen or ethanol,

he says; his team is working on severalspecies. “We haven’t given any thought to” thelicensing conditions, but in any case, theywould not impede work in academic labs, saysVenter, adding, “This is a problem that wehope will have hundreds of solutions.”

Rai says the notion that Venter’s Mycoplasma

strain will dominate the way Microsoft’s Win-dows did is tenuous because “about 10 thingswould have to happen,” among them that Venterwould create the organism, get the patent, andothers would adopt his technology as the stan-dard. Even if that happened, Venter “could dowell [financially] and do good,” she says, bylicensing the technology at low cost as aresearch tool, as happened with the originalpatents on recombinant DNA technology.

Other synthetic biologists don’t seemfazed. “He’s shooting an arrow in the generaldirection that things are going,” says FrederickBlattner of the University of Wisconsin,Madison, who has patented a stripped-downEscherichia coli and founded a companycalled Scarab Genomics that is commercializ-ing the technology while disbursing it to aca-demic researchers for a small cost. The morepertinent question, says Harvard’s GeorgeChurch, is whether the inventors’ claims tohave devised something useful will hold up,as there’s no obvious reason why a completelysynthetic Mycoplasma is needed rather than,say, modified E. coli to make hydrogen.

Massachusetts Institute of Technologysynthetic biologist Tom Knight, who haspointed out that anyone could get around thepatent simply by adding more than the450 genes stipulated, says his complaint isthat the application doesn’t explain how tobuild the artificial cell. “I think it’s rathertasteless,” Knight says.

–JOCELYN KAISER

Attempt to Patent Artificial Organism Draws a ProtestSYNTHETIC BIOLOGY

Future monopoly?

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Your Genome is Really, Really, REALLY Complicated By Brandon Keim June 14, 2007 | 10:22:58 AM Categories: Genetics

The ninety-five percent of the human genome that doesn't actively code for proteins and

was historically known as "junk" DNA is actually vital for regulating the activities of that

remaining five percent.

Those are the findings of researchers collaborating on the Encyclopedia of DNA

Elements, or ENCODE. The concept isn't exactly new -- quite a few scientists have long

felt that evolution didn't keep nine-tenths of the genome around just because it couldn't

be bothered to take out the trash -- but the researchers charted the nether regions of our

genome with unprecedented detail.

The ENCODE findings, derived from studying a small part of the genome and due to be scaled up in coming years, foreshadow

profound refocusing of our current low-resolution understanding of human genetics. Which isn't to say that earlier genetic

research is irrelevant: all those isolated gene findings, those associations of genes with proteins, of mutations with disease, are

important pieces of the puzzle. In some cases -- as with Tay-Sachs disease and Huntington's syndrome -- they're extremely

useful. But the findings do show just how preliminary our understanding of genetics is.

Since inveigling against genetic reductionism is an old hobby of mine, it's nice to see the genome's complexity getting some

overdue recognition. Not that this is big news to some scientists, but it's a revelation to the public at large. Indeed, the news

articles surrounding the ENCODE findings capture this well:

BBC: The study, which was carried out on just 1% of our DNA code, challenges the view that genes are the

main players in driving our biochemistry.

Boston Globe: Genes, it turns out, may be relatively minor players in genetic processes that are far more subtle

and complicated than previously imagined.

Guardian: The findings highlighted how scientists had become so blinded by the importance of genes that the

role of other parts of the genome had largely gone unappreciated....

Agence France-Presse: The most detailed probe yet into the workings of the human genome has led scientists

Page 1 of 5Wired Science - Wired Blogs

6/14/2007http://blog.wired.com/wiredscience/2007/06/your_genome_is_.html

to conclude that a cornerstone concept about the chemical code for life is badly flawed.

ABC: The study brings a new dimension to determining both the impact of human genetics in clinical medicine

and how humans evolved differently from animals.

For years, the public has been treated to a neverending stream of pronouncements surrounding the potential insights and

therapies that will follow from the finding of a gene or two associated with some disease or behavior. Science journalists are, by

and large, the people who've carried these findings to the public. This is understandable: they take their lead from journals and

the scientific PR machine. But from the latest round of news articles, it should follow that simplistic narratives of genes and

disease are at an end.

Let's see just how long that lasts....

Related Wired coverage here.

Image: Ami Shah

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National Public Radio (NPR)

SHOW: Talk of the Nation: Science Friday 2:00 PM EST

June 15, 2007 Friday LENGTH: 2438 words HEADLINE: Reading Between the Genomes ANCHORS: IRA FLATOW BODY: IRA FLATOW, host: And now, we're changing gears for the rest of the hour - reading between the genes. When scientists first began to decode the human genome, the big news was and still is, in many ways, the genes, parts of the DNA that held the blueprint for creating all our parts of our bodies or malfunction to create disease. And the race was on to find the genes that cause diabetes or cancer or depression. The bits between the genes, the repeating sequences that didn't seem to do anything, were referred to as junk DNA and not really worth anything. But the genes, it turns out, make up only a small part of the genome, and scientists are learning that much of that so-called junk DNA may play a major role in regulating how the not-junk DNA or regular DNA is expressed. And this week, a consortium of researchers from around the world released a study looking at a sample of that junk DNA. And joining me now to talk about what they found is John M. Greally - he is assistant professor at Albert Einstein College of Medicine in the Bronx, and he's here with in our New York studio. Thank you for coming in today. Dr. JOHN M. GREALLY (Epigenomics and Human Disease, Albert Einstein College of Medicine): Thanks for inviting me. FLATOW: So the junk is not really junk after all? Dr. GREALLY: It'd be a very brave person who would call it junk at this stage. FLATOW: Why? Dr. GREALLY: Well, even before this study, when people were looking at small areas of the genome, the regions that were neighboring the genes that we knew were doing functional things like producing the red pigment in our red cells to carry oxygen - what they realized was that there were - some of these sequences that were not genes were actually responsible for switching on or off the gene expression. So we knew that it wasn't all junk, but this is the first study to kind of formally look at a large region of the genome and be

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systematic in research. FLATOW: And did you discover that that was the function of the so-called junk DNA, switching the other DNA on and off? Dr. GREALLY: They found a lot of different things in this particular study, but possibly the most interesting one was the ability of the DNA that was neighboring the genes to have a regulatory role. There are - it seems like there's a lot more happening in the genome than just the expression of these genes. FLATOW: And this is most of what's in the genome (unintelligible)... Dr. GREALLY: That's exactly right. FLATOW: Give us some idea of how much of it is not that normal DNA we think of. Dr. GREALLY: Well, if you were to try to visualize this, it would be like driving on a highway. And every time you pass an exit, it's like a snippet of the gene, an exon of a gene as we'd call it. Most of the time, we're on the highway; we're not at exits. And in fact, the genome is very like that. About 96 percent, conservatively, of the genome is not genes, so it's a little bit of a shock, I think to realize just how much of it is stuff that we don't understand. FLATOW: Would this switching function and the presence of this other kind of DNA explain things that we've seen everyday life but really couldn't, you know, explain before about how things work, like why somebody gets a disease while somebody does not get disease. Dr. GREALLY: Yeah. There are a couple of ways of looking at this. One is that these sequences that sit between the genes or beside the genes are determining which genes should be switched on or off in a specific cell type because the DNA itself is the same in a liver cell or a muscle cell or a brain cell, but the exact repertoire of genes that we switch on or off in each of those cell types differs. And those instructions are mediated by these sequences that live nearby. In terms of disease, that - this is where it gets very interesting - because some of the recent studies that were performed, for example, to look at large numbers of patients with adult diabetes, they realized that there were certain genes that looked like they were associated with the disease, but when you look at their results, you realize that a lot of the changes that they were seeing in the DNA sequence were not in the genes themselves, they were nearby. And it's - you know that those sequences are very associated with diabetes. You're much more likely to see it in a diabetic individual than somebody else. But the precise function, the way that it might be causing the diabetes, is still a mystery. FLATOW: Do we have a name for this DNA, instead of calling it none or other or something? Have scientists given these genes a name and the sequences or these parts? Dr. GREALLY: It depends on their function, and this particular study didn't really try to assign a function to the sequences. The study was really to try to identify the subset of this 96 percent that might be doing something functionally. When you start studying these in more detail, which would presumably be a follow-up study, some of these sequences act to increase the local gene expression, and they would be known as enhancers. Others tend to dampen down local gene expression. They would be known as silencers or perhaps repressors. And there are others that have this amazing property where if you have two genes side by side and you want to regulate them independently, the sequence in between will actually act as an insulator, and that's how they are referred. FLATOW: Could these genes - whatever we're calling them now - might have great influence in early embryology? Dr. GREALLY: Absolutely. FLATOW: I mean, things on and off - might that be a good place to study what they do?



Dr. GREALLY: Yes, definitely. Yeah. FLATOW: Yeah. Dr. GREALLY: It's already known that there are huge changes in the expression of genes during early development. There have been human malformation syndromes - things where children have been born with, you know, limb problems or problems with the - the formation of their brain - where the events have occurred out in the wilderness between the genes but not in the genes themselves. So clearly, that is going to be a very important area. FLATOW: But we inherit these as the same way we inherit the other. Dr. GREALLY: It all comes as one package, one long string of DNA. It has all the intervening stuff and the genes. FLATOW: And so this may add a whole new layer of complexity; things are not as simple as we thought they used to be. Dr. GREALLY: Absolutely. And a further layer of complexity is when you impose epigenetics on top of that, which is an area of interest to a lot of people at the moment. FLATOW: Well, explain what that is. Dr. GREALLY: Yeah. What the ENCODE guys were doing - the consortium was doing - they were looking to see where the sequences are located that might be doing something. But having found those sequences, the - something has to mediate their role, and the broad group of regulatory mechanisms, biochemical mechanisms that do something to those sequences, have been loosely referred to as epigenetic. And what can happen at those sites is that sometimes, the epigenetic regulators can have one pattern that might be associated, perhaps, with strong activation of a gene nearby. And sometimes, it may have a different pattern where it may actually have exactly the opposite effect. And the reason that this becomes particularly interesting is that it's this epigenetic regulation that is our means of responding to the environment and to noxious stimuli and basically reorganize the way that we express genes in a way that will allow us to adopt to our environment. FLATOW: What does this mean for genetic testing? We do genetic testing - there are home genetic kits coming on the market. We're in an era where now we know what your genome is. Doesn't that make these genetic tests really inadequate? Because it may show you you have the gene, but we may not know if it gets - ever gets switched on or not by another gene. Dr. GREALLY: If you have a mutation in a gene, the gene is dead or the gene has got a problem. So it doesn't matter if the local regulatory mechanisms are acting inappropriately or not. Thinking very simplistically, you can put gas in the tank, you can put new brake pads on, but if the engine is blown, it's not going to go anywhere. And the engine, in this case, would be the gene, so it doesn't matter what you do nearby. However, in terms of the issue of DNA testing, what it does is it broadens the opportunities available to us. It may be that we are able to start focusing on these sequences that have regulatory functions in between the genes, look for the sequence changes that are occurring there, and actually be able to understand that they are as important as the changes in the genes and thus be able to do something predictive and accurate with our patients. FLATOW: So you'd have to look to those also. You just couldn't say you have this gene for, let's say, breast cancer or something. And you - you have to have the activator gene that might also turn on or switch it off. Dr. GREALLY: Well, the... FLATOW: That may be a bad example because of the... Dr. GREALLY: Yes. FLATOW: PrCA(ph).



Dr. GREALLY: It's actually not a bad example in term of another type of cancer, which is colon cancer. There are some familial cases of colon cancer where these are very unfortunate families. The individuals get a very difficult type of cancer to diagnose, and they get it early in life, and it's called hereditary nonpolyposis colon cancer. And that is due to mutations, generally, in a gene called MLH1. But recently, there was a very intriguing report where the gene was perfectly healthy. There was no mutation in either copy of the gene that this individual had. But what they had instead was a change in the regulation of the gene, so it was silenced. And it is important in this instance because it illustrates that silencing of both copies of the gene is as devastating to the cell or to the body as mutations of both of those copies. FLATOW: This is TALK OF THE NATION: SCIENCE FRIDAY from NPR News. I'm Ira Flatow, talking with John Greally, assistant professor at the Albert Einstein College of Medicine in the Bronx. So we're talking about rethinking the human genome with these - with these genes, these helper genes, the switcher genes, all kinds of genes. Well, maybe our listeners will come up with a name for what we can call the whole group of genes. Let's go to Jessica in Denver. Hi, Jessica. JESSICA (Caller): Hi. Nice to be on the show. FLATOW: Hi. Thank you. JESSICA: I was just going to point out that the idea there may have been junk DNA in the first place seems quite absurd to me. It seems as if shortly after the genome was mapped, that James Watson has formulated some sort of language for the genome, and it was quite simple at first. But after a year of the scientific discovery, we have discovered that the genome can play a lot of tricks on us, that things aren't initially what they first appear. And we are still discovering things like that every day. It seems like most mappings of the genome play a very important part in the human body. FLATOW: Dr. Greally? Dr. GREALLY: Jessica, I think it's a fair point that there's a lot more complexity to the genome than we have realized up to now. I think even Dr. Watson was probably surprised at how little of the genome-encoded genes and - you know, we've had to deal with that in terms of our emotional well-being. But at the end of the day, the challenge is not to throw our hands up and say we don't understand the challenges, to say all of this material is out there in the genome. It's there to be understood. Let's tackle the problem. And that's what this - that's why this recent publication was such a landmark that these guys went after it systematically. FLATOW: Well, you bring up a good point. If only just a few percentage of the genome encodes for genes, and let's say 95 - could be a 98 - yeah, 95 percent of it is these other kinds of genes? Dr. GREALLY: Other kinds of sequences. FLATOW: Sequences. Dr. GREALLY: Yeah. FLATOW: And we haven't encoded those? Dr. GREALLY: We haven't figured... FLATOW: And we haven't - so we haven't figured - it's like the universe. We don't know what 95 percent of the universe is. We don't know what 95 percent of this other dark - it's called the dark genes, you know? Dr. GREALLY: People have referred to it as the dark matter, the genome. FLATOW: Yeah. So our work has just begun. Dr. GREALLY: It's a good thing if you're - if you're in this line of business. (Soundbite of laughter) FLATOW: I mean, here we've been celebrating the deciphering of a human genome, but we haven't deciphered now, and now we see how important to know what it is - 95 percent of the genome.



Dr. GREALLY: If we didn't have the Human Genome Project, we wouldn't have this problem. So the Human Genome Project was a great foundation for discovery. And now, we're going to take that one step further. FLATOW: What made this breakthrough possible? Dr. GREALLY: The usual combination, intellectual curiosity and technology. It would have been very difficult to do this about 10 years ago. But there have been advances in technology that allow you to look at lots and lots of DNA sequences simultaneously, and particularly in areas such as microarray technology which is quite popular in the field at the moment. And because of the fact that people start to get clever about how they could use these microarrays and sequencing technologies, that, in particular, was a breakthrough. FLATOW: Was there one sequence that lit a light bulb up in someone's head and said, whoa - we can't explain it any other way but these dark genes? Dr. GREALLY: There - not in this particular project. This particular project was most notable for the sheer number of sequences it was pulling in simultaneously. So we have a bit of information overload to deal with. FLATOW: And so now, the work will go on to decipher. Dr. GREALLY: Absolutely. FLATOW: Are there any - could - how long do you think it would take? How many years? Dr. GREALLY: Well, through my retirement, I guess. (Soundbite of laughter) FLATOW: You're going to look very old. There's other - there's a lot of work to be shared and done by everybody. Dr. GREALLY: Absolutely. But it's an accelerating pace, so being a typical, cautious scientist, I'm not going to put a number on it. FLATOW: And we won't force you. Thank you for taking time to be with us. Dr. GREALLY: Thank you for inviting me. FLATOW: John M. Greally is assistant professor at the Albert Einstein College of Medicine right here in the Bronx in New York. (Soundbite of music) FLATOW: Have a great weekend. I'm Ira Flatow in New York. LOAD-DATE: June 16, 2007

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Sequence Search Paper10 mistakes to avoid before you run your next Gene Sequence Search. www.genomequest.com

Biblical Adam, First ManAdam, first man per Bible records, archaeology dates him to 14,000 BP www.accuracyingenesis.com

Gene InsSequence aDownload www.textc

ENCODE finds the human genome to be an active place By John Timmer | Published: June 13, 2007 - 12:28PM CT

A paper that will appear in today's edition of Nature starts off with a bang, its first sentence

being "The human genome is an elegant but cryptic store of information." The paper's goal is

nothing less than decrypting as much as we can about a one percent of that genome, in the

expectation that it will serve as an accurate model of the remaining 99 percent. It's an

audacious and very satisfying piece of work; my biggest qualm about it comes from the

accompanying press releases, which suggest that we're going to see some bafflingly incoherent

media coverage of the findings.

ENCODE stands for Encyclopedia of DNA Elements, and it is a multi-institutional consortium

dedicated to finding out what our DNA is up to. As a first step, 30 Megabases of DNA from 44

different locations in the genome were subjected to roughly 200 forms of biochemical and

computational analysis. These methods explored RNA production, DNA packaging, and other

aspects by several independent assays, providing a fair degree of confidence in the results.

A genome full of pervasive transcription The big surprise in this work is that the genome is pervasively made into RNA. Although the

view that RNA's primary function is to code for proteins went by the wayside with the discovery

of various forms of regulatory RNA, the regulatory RNAs still fit into the paradigm of consistent

and discrete RNA production. The new study finds that essentially every base in the genome

shows up in RNA at one point or another. This is despite the fact that most of these bases

aren't doing anything: 95 percent of the genome isn't under selective pressure, and most of

that 95 percent doesn't appear functional in an evolutionary sense.

The data indicate that the process of copying DNA into RNA, called transcription, is

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Page 1 of 4ENCODE finds the human genome to be an active place

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fundamentally noisy. The transcription factors that tell the cell where to start making RNAs are

rather promiscuous, often having affinities for DNA sequences that will appear at random every

1,000 bases. They also act against a background where the packaging of DNA in the cell, which

determines their access to such sequences, is dynamically changing. Apparently, wherever

these changing conditions allow, transcription will start.

This suggest that regulatory elements around genes act less to specifically start transcription

there and more to make gene transcription at the gene more probable than the general

background of RNA noise. That said, the study also found clear signals of defined transcription

start sites at a rate of nearly ten times the number of genes in the area, suggesting some

aspects of the excess transcription are nonrandom. Other examples of extra transcribed bases

result from a transcription stopping mechanism that also appears to be noisy. In several cases,

RNAs were found that started in one gene and plowed straight through to the next one down

the chromosome.

The study did find one factor that might explain the distribution of all the extra sites of

transcription when it looked into the process of duplicating the DNA prior to cell division. Areas

where this process starts appear to have less compact DNA, which favors transcript initiation as

well.

If there's a weakness to this study, it's that it used cells that grow rapidly in culture instead of

samples from normal tissue. These cultured cells generally have origins in cancer and so may

have aberrant control of a range of cellular processes. Hopefully, the study can be repeated

using cells that are a better approximation of normal.

Where does this leave us? There seems to be three possible interpretations for all these extra transcripts. One is that,

even though we haven't detected a biological function, and evolution doesn't conserve them,

they are actually specifically functional. This would be the "there is no junk DNA" take on

matters. The opposite extreme would be an "it's all junk" view of it. From this perspective, the

starting and stopping of transcription is just an inherently noisy process and doesn't do humans

enough harm to create a selective pressure to improve it.

Somewhere between the two would be the view that few of these extra transcripts are useful in

themselves, but it's useful having them present on the collective level. Reasons could include

anything ranging from excess RNA performing some sort of structural function through to the

random transcripts being a rich source of new genes.

Personally, I fall into the "it's all junk" end of the spectrum. If almost all of these sequences are

not conserved by evolution, and we haven't found a function for any of them yet, it's hard to

see how the "none of it's junk" view can be maintained. There's also an absence of support for

the intervening view, again because of a lack of evidence for actual utility. The genomes of

closely related species have revealed very few genes added from non-coding DNA, and all of

the structural RNA we've found has very specific sequence requirements. The all-junk view, in

contrast, is consistent with current data. We've wondered for decades how transcription factors

can act specifically and at long distances despite their relatively weak specificity for DNA. This

data answers that question simply: they don't.

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All of this brings me back to the press release, which has set my blood boiling nearly every time

I read it. It basically takes the hardcore "none of it is junk" view but then undercuts its own

arguments. It states that "the new data indicate that the genome contains very little unused

sequences; genes are just one of many types of DNA sequences that have a functional impact."

What is that functional impact? They have no idea: "many species' genomes contain a pool of

functional elements that provide no specific benefits in terms of survival or reproduction."

It looks like they're choosing to define functional as "made into RNA," even though they

recognize that much of the DNA that is made into RNAs clearly has no influence on survival or

fitness. They're then using that skewed definition to claim the data shows that most of the

genome is functional. Since most of the popular press produces accounts based on the press

release, the public is going to be receiving a very distorted view of this work.

hoottwo

I think I fall into the "all junk" camp. Was this a steady state analysis? It may be that

none of this extra transcribed junk is stable enought to be of any use. In other words,

only complete RNAs remain stable long enough to be translated or used structurally.

June 13, 2007 @ 01:36PM

Filed under: RNA, DNA, Transcription, Genomics, more...

Reader comments

Walshicus

How much CPU power are we talking about to simulate this kind of thing? Beyond the

scope of a large distributed net?

June 13, 2007 @ 01:23PM

name99

Do we know enough to say that that transcribed RNA just sits around randomly until it is

later broken into pieces? As opposed to, for example,

• acting as ribozymes

• acting as second order transcription factors

• (this is the most interesting one) acting as a store of parts --- ie the resultant long

tRNAs are broken into smaller pieces that are useful in various ways, and because this

isn't a very demanding process, there isn't much selection pressure. This is your

intermediate view.

Damn, this opens up so many questions.

Obviously just creating RNAs to then destroy them wastes energy. My understanding of

prokaryotes is that, as a corollary to the fact that they don't have exons/introns, they

don't have what is called junk DNA So that's no help But do we get this same behavior



rmongiovi

Sounds like it's a question of your definition of "functional". If all DNA makes some sort

of RNA, then it's definitely functional.

To borrow an analogy from the computer world - it's all data, but it's not all information.

June 13, 2007 @ 02:32PM

not afford to be simply creating then destroying RNA without it having some important

side effect.

June 13, 2007 @ 01:59PM

IdeaHamster

Actually, this sounds a lot like some results that I heard about a while back with E. coli

(don't know if they were ever published, hence the lack of linkage...guess you'll just

have to trust me ). Basically, if you turn the sensitivity of an E. coli genomic microarray all the way up, you find that every base on both strands ends up getting

translated at some basal level. So, this sort of leeds credence to the "just junk/noise"

argument.

On the other hand, one theory I've always liked is the idea that these stretches can

serve as emergency gap fillers during DNA damage, or even as templates for

recombinative repair mechanisms...but then you would expect the expression to be

much less random. So, maybe I do fall in the "just junk" camp after all?

EDIT: As for the press release...

If I do end up leaving science...and trust me, as a former 6 y.o. kid obsessed with his

Fischer-Price microscope, leaving science is not something I want to do...but if I do it will

be because of the "Hollywoodification" of research.

June 13, 2007 @ 02:35PM

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Chemical & Engineering News

Latest News June 13, 2007

Genomics

Finding Function In The Genome Consortium uncovers surprising features in the human genetic blueprint Amanda Yarnell

Following on the heels of the massive Human Genome Project, which revealed the sequence of the human genome, a huge consortium of scientists has unveiled its preliminary progress in analyzing the functions of various stretches of that genetic blueprint (Nature 2007, 447, 799 and entire issue of Genome Res. 2007, 17).

Vernon Doucette/Boston University ENCODE consortium members Tullius (from right) and graduate students Stephen Parker and Eric Bishop use a capillary DNA sequencer to determine DNA cleavage patterns that provide information about the shape of the DNA backbone

Participants in the ENCODE (Encyclopedia of DNA Elements) project devised and tested a wide variety of high-throughput experimental and computational methods for identifying functional elements in a representative fraction of the genome. Such functional elements include sequences that code for proteins, sequences that don’t code for proteins, regulatory sequences that control the transcription of DNA, and sequences that control the packaging of the genome.

The consortium’s effort has revealed quite a few surprises about the genomic landscape. For instance, the team reports that the majority of DNA—whether it encodes proteins or not—is transcribed into RNA. This pervasive pattern of transcription challenges the longstanding notion that the human genome consists of a relatively small number of discrete genes surrounded by a plethora of seemingly irrelevant "junk" DNA, the say.

"We are increasingly being forced to pay attention to our nongene DNA sequences," notes John M. Greally of Albert Einstein College of Medicine in a commentary in Nature accompanying the consortium’s report. He adds that the consortium’s observations follow recent reports that many single-nucleotide genomic variations associated with disease are found outside of genes.

Also, contrary to conventional wisdom, about half of the functional elements identified by consortium scientists

Page 1 of 2Chemical & Engineering News: Latest News - Finding Function In The Genome

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appear to have been under little or no evolutionary constraint. That is, their sequences don’t seem to be conserved across different species. One possible explanation for this observation comes from Boston University chemistry professor and consortium member Thomas Tullius, whose lab is surveying the local DNA-backbone structure of functional elements in the genome (Genome Res. 2007, 17, 940 and 947). "Maybe sequence isn’t thefinal answer," he says. "I suspect we might find that the structure, not the sequence, of these functional elements is, in fact, what’s been conserved during evolution."

The consortium’s first-stage report covers 1% of the human genome, or roughly 30 million base pairs, selected togive a representative cross-section of the genetic blueprint. In the future, its members hope to produce a comprehensive catalog of all functional elements in the human genome.

"The glimpse we are provided by the ENCODE consortium into the ordered complexity of 1% of the human genome is tantalizing," Greally notes. But, he adds, it remains to be seen whether the researchers’ findings duringthe pilot phase will extend to the other 99% of the human genome. Consortium scientists face not only the work oscaling up the project’s methods but also the challenge of proving that their insights, obtained from easy-to-culturehuman cell lines, are representative of the many different types of primary cells found in the human body.

In the meantime, "because of the hard work and keen insights of the ENCODE consortium, the scientific community will need to rethink some long-held views about what genes are and what they do, as well as how the genome’s functional elements have evolved," comments Francis S. Collins, director of the National Human Genome Research Institute at the National Institutes of Health in Bethesda, Md. "This could have significant implications for efforts to identify the DNA sequences involved in many human diseases."

Chemical & Engineering News ISSN 0009-2347 Copyright © 2007 American Chemical Society

Page 2 of 2Chemical & Engineering News: Latest News - Finding Function In The Genome

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APPLICATIONS

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Microarrays Proteomics

RNA Interference

Human Genome Not So Tidy After All, ENCODE Project Suggests

[June 13, 2007]

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) — The human genome may not be a “tidy collection of independent genes,“ but rather “a network in which genes, regulatory elements and other types of DNA sequences interact in complex, overlapping ways,” according to National Human Genome Research Institute, which today announced the publication of results from its ENCODE Project in the June issue of Nature, and 28 companion papers in Genome Research. The ENCODE consortium, which comprises 35 groups from 80 organizations around the world, debuted in 2003 to build a “parts list” of the biologically functional elements in 1 percent of the human genome, and is a pilot study meant to “test the feasibility of a full-scale initiative to produce a comprehensive catalog of all components of the human genome crucial for biological function.” In the papers, ENCODE partners describe “major findings” in gene transcription and regulation, chromatin and replication, and evolutionary constraint. These findings include the discovery that the majority of DNA in the human genome is transcribed into RNA, and that these transcripts extensively overlap one another. “This broad pattern of transcription challenges the long-standing view that the human genome consists of a relatively small set of discrete genes, along with a vast amount of so-called junk DNA that is not biologically active,” NHGRI said in a statement. The data also showed that the human genome contains “very little unused sequences” and is a “complex, interwoven network.” According to NHGRI, in this network genes are “just one of many types of DNA sequences that have a functional impact.”

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In the Nature paper, the authors write, "Our perspective of transcription and genes may have to evolve,” noting the network model of the genome "poses some interesting mechanistic questions" that have yet to be answered. Other “surprises” in the ENCODE data could have “major implications” in how researchers understand the evolution of genomes, particularly mammalian genomes. “Until recently, researchers had thought that most of the DNA sequences important for biological function would be in areas of the genome most subject to evolutionary constraint,” NHGRI said. However, the ENCODE effort found that about half of functional elements in the human to have been obviously constrained during evolution, at least when examined by currencomputational biologists.” According to the ENCODE researchers, this lack of evolutionary constraint may indicate genomes contain a “pool of functional elements,” including RNA transcripts, that “providterms of survival or reproduction.” Over time, this pool may serve as a "warehouse for natural selection" by acting as a “soelements unique to each species and of elements that perform the similar functions amohaving sequences that appear dissimilar,” the researchers speculated. Other ENCODE findings include the identification of numerous previously unrecognized stranscription; the discovery of evidence that, contrary to traditional views, regulatory seto be located downstream of a transcription start site on a DNA strand as upstream; thesignatures of change in histones, and correlation of these signatures with different genodeeper understanding of how histone modification coordinates DNA replication. The NHGRI said that taken together, these findings will “reshape our understanding of hfunctions.” The study focused on 44 targets, which together cover about 1 percent of the human geabout 30 million DNA base pairs. The targets were selected to provide a representative entire human genome. All told, the ENCODE consortium generated more than 200 datasthan 600 million data points. NHGRI Director Francis Collins said the ENCODE effort has “blazed the way for future effunctional landscape of the entire human genome.” The main portal for ENCODE data is the University of California, Santa Cruz's ENCODE Ganalysis effort is coordinated by Ensembl, a joint project of the European BioinformaticsWellcome Trust Sanger Institute. Much of the primary data have been deposited in databases at the NIH's National CenteBiotechnology Information and at EBI. Additional information on the ENCODE project can be found here.

Steven Verdooner, Rich

Kreatech Biotechnology

Mount Sinai Thoracic SmicroRNA Profiles in Es

Qiagen, Digene, eXege

Copyright © 2007 GenomeWeb LLC. All rights reserved.

Page 2 of 2Human Genome Not So Tidy After All, ENCODE Project Suggests

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DNA `junk' appears to have uses June 14, 2007

JOSEPH HALL HEALTH REPORTER

A groundbreaking study says scientists may have to substantially alter their long-held conception of life's basic blueprint, DNA.

In a departure from traditional thinking, the four-year study says that genes can no longer be considered the only active parts of DNA and that huge segments thought to be "junk" may play a significant role in such individual traits as susceptibility to diseases.

"A lot of these regions that previously we were thinking were junk DNA, or vast deserts of non-functionality, have been found to be a lot more active," says Steven Jones, associate director of the British Columbia Cancer Agency's Genome Sciences Centre, and one of numerous authors of the scientific paper published today in the journal Nature.

"This was the surprise ... they seem to be doing things from a biological level."

Human DNA is made up of some 3 billion base pairs of nucleotides arranged in a double helix. Genes, which carry the code for proteins necessary to build a human, are arranged on the rungs of the twisted ladder, but segments of DNA are interspersed that were previously dismissed as little more than rubbish – evolutionary remnants that merely gave structure to the ladder.

But the new study says many of these may, in fact, play an integral role in controlling some of our genes and determining traits such as risk for type 2 diabetes.

"These might be regions ... that may be functional elements within our genomes, but don't have the star status of the (genes)," Jones says.

Page 1 of 2TheStar.com - News - DNA `junk' appears to have uses

6/14/2007http://www.thestar.com/printArticle/225245

These segments might also be acting as a "warehouse" for genetic material that could be critical for future evolutionary steps, says Ewan Birney, lead author of the study and senior scientist with the European Molecular Biology Laboratory in Hinxton, England.

"And then evolution can kind of tap into them when it needs to ..."

Dr. Rod McInnes, scientific director of genetics at the Canadian Institutes of Health Research, who was not involved in the study, called the research "transformative" and "stunning."

"It's absolutely fundamental stuff which is telling us things about the genome ... that I don't think anybody realized before."

Jones says most of the DNA segments previously considered to be inactive junk are busily "transcribing" messages through RNA.

This RNA molecule, a single-strand copy of DNA, allows a segment of DNA to be translated into proteins.

It was long thought that only the gene segments of DNA, which is separated into 23 chromosome pairings in humans, were sending out these RNA messengers.

But it's not clear if this newly discovered RNA messaging is being heard and, if so, where.

"They are not silent parts of the genome ... but whether they are useful is the question that is outstanding," Birney says. He said it's possible many are acting on various genes in "very subtle" ways.

The four-year-study was published in Nature by an international team of genomic researchers known as ENCODE, on the occasion of the 50th anniversary of the discovery of the structure of DNA.

The ENCODE paper chronicles all functioning parts in 1 per cent of the human genome, based on input from 80 agencies, and researchers hope next to complete the job.

Page 2 of 2TheStar.com - News - DNA `junk' appears to have uses

6/14/2007http://www.thestar.com/printArticle/225245

France 24 - world science news

By AFP

WEDNESDAY, JUNE 13, 2007

PARIS, June 13, 2007 (AFP) - The ground-breaking study, published in more than two dozen papers in journals on both sides of the Atlantic, takes a small percentage of the genome to pieces to draw up a "parts list," identifying the biological role of every component. For the international team of investigators, the four-year project was the computer-equivalent of passing a fine-toothed comb through a mountain of raw data. Reporting in the British journal Nature and the US journal Genome Research on Thursday, they suggest that an established theory about the genome should be consigned to history. Under this view, the genome is rather like a ribbon studded with some 22,000 "nuggets" in the form of genes, which make proteins, the essential stuff of life. Genes -- deemed so valuable that some discoverers of them have been prompted to file patents over them for commercial gain -- amount to only around a twentieth, or even less, of the genetic code. In between the genes and the sequences known to regulate their activity are long, tedious stretches that appear to do nothing. The term for them is "junk" DNA, reflecting the presumption that they are merely driftwood from our evolutionary past and have no biological function. But the work by the ENCODE (ENCyclopaedia of DNA Elements) consortium implies that this nuggets-and-dross concept of DNA should be, well, junked. The genome turns out to a highly complex, interwoven machine with very few inactive stretches, the researchers report. Genes, it transpires, are just one of many types of DNA sequences that have a functional role. And "junk" DNA turns out to have an essential role in regulating the protein-making business. Previously written off as silent, it emerges as a singer with its own discreet voice, part of a vast, interacting molecular choir. "The majority of the genome is copied, or transcribed, into RNA, which is the active molecule in our cells, relaying information from the archival DNA to the cellular machinery," said Tim Hubbard of the Wellcome Trust Sanger Institute, a British research group that was part of the team. "This is a remarkable finding, since most prior research suggested only a fraction of the genome was transcribed." Francis Collins, director of the US National Human Genome Research Institute (NHGRI), which coralled 35 scientific groups from around the world into the ENCODE project, said the scientific community "will need to rethink some long-held views about what genes are and what they do."

Page 1 of 2Landmark study prompts rethink of genetic code

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Copyright © 2007 FRANCE 24. All rights reserved.

"(...) This could have significant implications for efforts to identify the DNA sequences involved in many human diseases," he said. Another rethink is in offing about how the genome has evolved, said Collins. Until now, researchers had thought that the pressure to survive would relentlessly sculpt the human genome, leaving it with a slim, efficient core of genes that are essential for biological function. But the ENCODE consortium were surprised to find that the genome appears to be stuffed with functional elements that offer no identifiable benefits in terms of survival or reproduction. The researchers speculate that there is a point behind this survival of the evolutionary cull. Humans could share with other animals a large pool of functional elements -- a "warehouse" stuffed with a variety of tools on which each species can draw, enabling it to adapt according to its environmental niche. The ENCODE endeavour flows from the Human Genome Project, which concluded in April 2003 with the publication of a polished draft of the human genetic code. But having the draft is not the same as knowing what is in it or how it works. And this is essential for unlocking knowledge about our evolutionary odyssey, just as it is needed for engineering new treatments for inherited disease. The collaborative study focussed on 44 strategically chosen targets which together account for about one percent of the genome, or about 30 million of the three billion "rungs" in the DNA double-helix ladder. The data is being placed in the public domain to help medical and other research.

Page 2 of 2Landmark study prompts rethink of genetic code

6/13/2007http://www.france24.com/france24Public/en/news/science/20070613-biothec-gen...

Ultimo aggiornamento giovedi 14.06.2007 ore 15.28

TECNOLOGIA & SCIENZA Dopo la mappatura, il passo più importante: come funziona il codice della vita E adesso si aprono nuove prospettive per le terapie mediche del futuro

Svolta nello studio del Dna decifrato il "manuale di istruzioni" di ALESSIA MANFREDI

ROMA - Dopo la mappatura del codice della vita, arrivano ora i primi chiarimenti sul funzionamento dei nostri geni. Il passo successivo alla lettura di quei tre miliardi di lettere che compongono il Dna, tanto atteso, è finalmente arrivato: un "manuale di istruzioni" che getta luce sull'attività del genoma. I risultati dell'impresa, nata dalla collaborazione internazionale di oltre 80 paesi e 35 équipe di ricerca, tutti parte del programma Encode (the Encyclopedia of Dna Elements), sono stati pubblicati su Nature. E la prosecuzione naturale del Progetto Genoma, a detta degli scienziati, apre la strada ad una rivoluzione che promette importanti ricadute anche per lo sviluppo di nuove terapie mediche. Oltre 200 analisi per descrivere il comportamento del nostro codice genetico, o meglio, di una

Page 1 of 3Svolta nello studio del Dna decifrato il "manuale di istruzioni" - Scienza & Tecno...

6/14/2007http://www.repubblica.it/2006/08/sezioni/scienza_e_tecnologia/genetica/enciclope...

sua piccola porzione, per ora: 30 milioni di basi nucleotidiche, pari all'1 per cento. Se qualche anno fa si è ottenuta la mappa dei geni, il significato del codice rimaneva per molti aspetti oscuro. Si sapeva che racchiude tutte le istruzioni per sintetizzare tutte le molecole cheformano le cellule del nostro corpo, ma il modo in cui operava rimaneva un mistero. Ora, con il progetto Encode, molti elementi del puzzle assumono un ruolo più preciso. I ricercatori sono riusciti a capire come e dove si svolgono determinate funzioni biologiche, mettendo in discussione certi dogmi e rivalutando quello che finora è stato chiamato "Dna spazzatura", considerato cioè silente o inutile. Per il genetista Bruno Dalla Piccola "l'annuncio rappresenta un progresso molto significativo". "Se la mappatura del genoma era una fase preliminare, quella di assoluto rilievo è la comprensione di come funzionano i geni", spiega a Repubblica.it. "Se è vero che molte malattie sono causate da un loro funzionamento anomalo, capire come agiscono gli interruttori che accendono e spengono queste anomalie significa avvicinarsi ad unsogno: trovare i sistemi che regolano questi meccanismi ed intervenire a livello di terapia, con effetti potenzialmente rivoluzionari. Certo non domani, ma è questa la prospettiva che si apre", dice ancora il genetista. Rivalutando certe sezioni del Dna finora tenute in secondo piano rispetto ai geni, questo studiorivela aspetti inediti e offre qualche sorpresa. "L'immagine tradizionale del nostro genoma come un insieme ben ordinato di geni indipendenti viene rimessa in discussione", annuncia il consorzio internazionale di ricerca. Frutto di quattro anni di ricerche, questi risultati "promettono di trasformare la nostra comprensione del funzionamento del genoma" annunciano ancora gli scienziati, rivelando una rete complessa in cui i geni, gli elementi che regolano la loro attività e altri tipi di sequenze di Dna interagiscono. Tra le novità, i ricercatori hanno compreso che il Dna non codificante - quello cioè che non serve a costruire le proteine all'interno della cellula, i mattoni elementari dell'organismo - e che è la maggior parte, è trascritto in molecole di Rna (acido ribonucleico) che svolgono una funzione fondamentale per la regolazione dell'attività del Dna stesso. Altro che spazzatura, insomma: "I nuovi dati indicano che il genoma contiene pochissime sequenze inutilizzate ed i geni sono solo uno dei numerosi tipi di sequenze di Dna che hanno un impatto fondamentale" chiarisce in un comunicato il consorzio e il Laboratorio Europeo di Biologia Molecolare e di Bioinformatica (EMBL-EBI) che ha guidato lo studio, insieme al National Human Genome Research Institute (NHGRI), parte del NIH statunitense. In alcune di queste sequenze "silenziose" del genoma sono state scoperte strutture di cromatina (insiemi di geni e proteine che formano i cromosomi) sostanzialmente analoghe a quelle che si trovano in regioni attive del Dna, che producono proteine. La presenza di aree simili nel Dna di altri mammiferi suggerisce, infine, così "la possibilità che esista un grande insieme di elementi neutrali biochimicamente attivi ma che non forniscono nessun beneficio specifico all'organismo". E la conclusione degli scienziati è che "questo insieme potrebbe servire come 'magazzino' della selezione naturale".



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(13 giugno 2007)



Portada > Salud > Biociencia

ESTUDIO EN 'NATURE'

Un nuevo 'manual de instrucciones' del genoma reinterpreta el ADN humano

'Nature' publica el proyecto ENCODE, que analiza todos los elementos del genoma

Además de los genes, numerosos elementos tienen un papel esencial en el ADN

CARLOS MARTÍNEZ

MADRID.- Tres de los grandes retos científicos y tecnológicos que se abordan estos días implican el desarrollo de nuevos sistemas capaces de definir, analizar y comparar gigantescas bases de datos. Así ocurre con internet, con el esfuerzo multidisciplinar en torno al cambio climático y con la interpretación del genoma.

En este último campo, un consorcio internacional ha desarrollado un nuevo sistema para caracterizar con precisión la abundante y heterogénea información que esconde el ADN humano, incluida una gran parte de la secuencia considerada hasta ahora secundaria o incluso inservible.

La fase piloto de la iniciativa, la identificación y análisis de los elementos con una función biológica en el 1% del ADN humano, se publica en la última edición de 'Nature' y en otros 28 trabajos que difunde de forma simultánea la revista 'Genome Research'. El estudio es un primer paso hacia la elaboración de una gramática completa del genoma.

A pesar de ser un trabajo exhaustivo, fruto de cuatro años de investigación de 35 grupos, los estudios publicados representan sólo la primera etapa de la Enciclopedia de Elementos del DNA (ENCODE, en sus siglas en inglés), el nombre de la iniciativa. En la empresa, desarrollada por un consorcio internacional encabezado por los Institutos Nacionales de la Salud de EEUU, participan la Universidad Pompeu Fabra, el Centro para la Regulación Genómica y el Departamento de Genética de la Universidad de Barcelona, los tres en Cataluña, y el Centro Nacional de Investigaciones Oncológicas, en Madrid.

No todo son genes

La investigación, diseñada como una prueba para evaluar si es posible la realización a gran escala de la iniciativa, cambia la concepción tradicional del ADN humano como una "colección ordenada de genes" por su descripción como una compleja red formada por diversos elementos que interactúan entre sí. Los científicos han trazado las líneas generales de este vasto mapa y descrito los principales elementos que lo componen, incluidos aquellos sobre los

Representación de la secuencia de ADN. (Foto: NCI)

Actualizado jueves 14/06/2007 20:49 (CET)

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que se sabía menos y que, al contrario de lo que se pensaba, tienen un papel esencial. Pero se ignoran en gran medida los detalles.

Las múltiples relaciones entre los distintos elementos que componen el ADN y el patrón de comportamiento de las redes que conforman el genoma no se comprenden. El llamado "libro de la vida" sigue siendo "un elegante pero críptico depósito de información" -reza 'Nature'- sobre el que todavía se sabe muy poco. El proyecto ENCODE abre nuevas vías para interpretarlo.

"Cuanto más sabemos del genoma humano, más apreciamos lo complicado que es trasladar la información genómica a la función celular", explica Chris Gunter, uno de los editores de 'Nature'. Es decir, no se sabe la clave del asunto: por qué el genoma humano culmina en la formación del organismo. Gunter confía en que se logre una descripción del proceso a lo largo de los próximos 10 años.

Para lograrlo hay que superar numerosos obstáculos. Por ejemplo, la mayor parte de los análisis se han centrado en los genes específicos que codifican proteínas y en los elementos que rodean a este proceso. El esquema básico es el siguiente: cada gen tiene como función codificar al menos una proteína; si se siguen linealmente los pasos, se entenderá la función de cada región del ADN.

Sin embargo, así se abarca una mínima parte de la secuencia: únicamente entre el 1,5% y el 2% del genoma responde a este ordenado modelo. La realidad es que el genoma es mucho más que los genes que lo conforman. ¿Qué función cumple todo lo que se está dejando fuera del análisis?

Nuevos descubrimientos

En la fase piloto del proyecto ENCODE se ha desarrollado un nuevo sistema que engloba todos los elementos del ADN a los que se atribuye una función biológica: los genes (incluidos tanto los que codifican proteínas como los que no cumplen esta función), los elementos que controlan la transcripción de los genes y los que tienen como responsabilidad mantener la estructura de los cromosomas y mediar en la dinámica de replicación del ADN.

A partir de este punto de vista global, el trabajo seleccionó 44 regiones. La selección representa alrededor del 1% del genoma completo, es decir, unas 30 millones de pares de bases nucleótidas, el elemento mínimo que compone la secuencia.

Algunos de los primeros hallazgos incluyen importantes descubrimientos sobre el papel de las regiones de ADN que no participan en la codificación de proteínas. ENCODE supera la vieja hipótesis que consideraba inactiva una gran parte del genoma, bautizado entonces como "genoma basura".

Los nuevos datos muestran que sólo una mínima parte de la secuencia no cumple una función biológica. El porcentaje del genoma desdeñado hasta ahora tiene en realidad "papeles reguladores esenciales", escribe en 'Nature' John M. Greally, de la Facultad de Medicina Albert Einstein (EEUU).

"Por ejemplo, en los intentos por encontrar las causas de enfermedades hereditarias los investigadores estudian cientos de variaciones en la secuencia del genoma, conocidas como poliformismos de un único nucleótido, para ver cuáles no se asocian de forma aleatoria con el trastorno", explica Greally.



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"Recientemente, estos estudios mostraron varias secuencias asociadas con la diabetes tipo 2 y sus manifestaciones relacionadas, pero sólo una minoría de las variaciones se encontraba dentro de los genes", añade el especialista. "La información clave estaba oculta en las regiones de ADN desdeñadas hasta ahora. Ahora tenemos que pensar cómo pueden estar contribuyendo estas modificaciones a los riesgos, incluso de forma pequeña o sutil", añade Chris Gunter.

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06/14/2007

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A biologia acaba de ficar mais complicada. Os genes -trechos de DNA que contém a 'receita' para produzir proteínas que compõem as células- podem não ser tão decisivos assim para a estrutura biológica das pessoas, revela um novo estudo. As partes do DNA não atreladas aos genes em si - já apelidadas de 'DNA-lixo'- são também vitais para a variabilidade das linhagens de célula, afirma o trabalho na revista 'Nature'. A descoberta é anunciada por um consórcio internacional, o Encode (Enciclopédia dos Elementos do DNA, na sigla em inglês), que analisou apenas 1% de todo o genoma humano, mas em 11 tecidos diferentes. O resultado, pelo visto, vai de encontro a um consenso. 'É impossível não dizer que esses resultados apontam para um lugar onde nós também chegamos', disse Sergio Verjovski-Almeida, da Universidade de São Paulo, à Folha. O estudo do grupo brasileiro, publicado em março, também exaltou a importância dos trechos não codificantes do DNA humano, ou seja, aqueles pedaços de DNA que um dia foram chamados de lixo. Os brasileiros analisaram 15% do genoma para apenas 3 tecidos. No caso do trabalho do consórcio Encode, eles optaram por mais tecidos, porque tudo indica que é essa variabilidade de linhagens celulares que realmente importa. 'Eles mostraram que 93% das bases [não só as dos genes] estudadas por eles foram de alguma forma transcritas para um tecido'. Do ponto de vista conceitual, explica Almeida, a genômica agora está caminhando para um diferenciação clara entre função bioquímica e papel biológico. Ou seja, não basta associar um determinado segmento do DNA a uma proteína. É preciso questionar, afinal, qual o papel que esse processo tem no organismo? É aí que entra em cena, no mesmo patamar de importância que os próprios genes, as regiões do DNA que estão entre esses genes. 'Sem dúvida, agora sabemos que tudo é muito mais complexo. Esse papel biológico está lá e tem um peso importante', disse ontem em entrevista coletiva o pesquisador Francis Collins, diretor do Instituto de Pesquisa do Genoma Humano dos Estados Unidos, integrante do Encode. Outra descoberta do grupo internacional com a pesquisa de apenas 1% do genoma humano - eles acham que tudo encontrado até aqui estará presente também nos demais 99%- é importante para se entender mais sobre o processo de evolução do homem. A tese mais corrente entre os cientistas é que os trechos do

DNA responsáveis pela transcrição da informação genética em proteínas seriam relativamente constantes ao longo do tempo. Mas não foi isso que apareceu agora. Os pesquisadores do grupo, definiram esse dado encontrado por eles, com o mais surpreendente de todos. Apenas 12% dos trechos responsáveis pelas transcrições guardam algum tipo de conservação. Texto Anterior: Próximo Texto:

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Grammatik der Gene viel komplexer als gedacht 13.06.2007

London (dpa) Nach dieser Arbeit müssen viele Biologiebücher neu geschrieben werden: Im Erbmaterial des Menschen sind viel mehr Informationen gespeichert, als bislang angenommen. Zudem ist die Grammatik beim Ablesen der Gene viel komplizierter als es den wissenschaftlichen Vorstellungen bislang entsprach. Das berichtet das Konsortium ENCODE aus 35 Forscherteams im Fachjournal

«Nature» (Bd. 447, S. 799) und in 28 Artikeln des Journals «Genome Research» (Juniausgabe). Die Reihenfolge der Erbgut-Bausteine wurde zwar schon im Jahr 2003 abschließend bestimmt, nun haben die Forscher aber bei einem Prozent des Erbmaterials systematisch untersucht, was diese Bausteine tun. Noch vor kurzem nahmen viele Wissenschaftler an, dass ein Großteil des Erbmaterials aus funktionslosem «Müll» (Junk-DNA) besteht, der zwischen den Genen liegt. Das ENCODE-Konsortium fand nun jedoch heraus, dass die «Mehrzahl» der DNA-Bausteine tatsächlich abgelesen wird. Die Funktion vieler dieser Abschriften kennen die Forscher allerdings noch nicht. Die neuen Daten zeigen, dass das Genom nur «sehr wenig» ungenutzte Sequenzen enthält, schreibt das beteiligte Europäische Bioinformatik-Institut (EMBL-EBI) im britischen Hinxton. Es hat die Daten der Forscherteams aus 80 Organisationen zusammengefasst. Nach den Erkenntnissen des ENCODE-Konsortiums gilt nicht mehr die Vorschrift: Ein Gen ergibt ein Produkt. Denn ein Erbgut-Abschnitt kann demnach zu verschiedenen Abschriften führen mit jeweils unterschiedlichen Funktionen. «Es ist alles sehr viel komplizierter, als

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man sich das vor ein bis zwei Jahren vorgestellt hat», sagte der beteiligte Bioinformatiker Prof. Peter Stadler vom Fraunhofer- Institut für Zelltherapie und Immunologie in Leipzig. Das ENCODE-Konsortium hat viele zuvor unbekannte Startschalter zum Genablesen identifiziert und zudem neue Sequenzen, die die Aktivität der Gene regulieren. Außerdem fand es oft Genschalter hinter den Genen und nicht wie bislang gedacht nur davor. «Wir kennen jetzt im Wesentlichen die Mitspieler der Genregulation», sagte Stadler. «Der nächste Schritt wird sein, weitere Spielregeln herauszukriegen.» Das habe große Auswirkungen für die Diagnostik und Therapie von Krankheiten. «Es gibt die Hoffnung, künftig Fehlregulationen von Genen besser zu erkennen.» Man könne die Arbeit von ENCODE jedoch nicht isoliert betrachten, da das Wissen anderer Forscher auch eine große Rolle bei den Erkenntnissen spiele. Besondere Bedeutung hat die ENCODE-Arbeit auch für die Evolutionsforschung: «Eine der größten Überraschungen war, dass wir viele Kontrollelemente nicht mit anderen Arten teilen», sagte Manolis Dermitzakis vom Wellcome Trust Sanger Institute. Das Erbgut sei innerhalb der Evolution daher viel weniger stabil als bislang gedacht. Zudem haben die Forscher entdeckt, dass auch das Verpackungsmaterial der DNA, die Histone, eine wichtige Rolle beim Ablesen des Erbguts und vor allem bei der Zellteilung spielt. Die Wissenschaftsgemeinde müsse nun einige grundsätzliche Betrachtungsweisen über Gene, ihre Funktion und die Evolution des Erbguts überdenken, sagte der US-Genpionier Francis Collins, Direktor des National Human Genome Research Institute (NHGRI). Er hatte die Arbeit zur Entzifferung des Menschengenoms geleitet und hat jetzt eine führende Rolle bei ENCODE. Die Abkürzung steht für ENCyclopedia Of DNA Elements. Das Konsortium ist ein Nachfolger des Humangenomprojekts, das das menschliche Erbgut entziffert hat. Die Forscher haben in dem Pilotprojekt zu ENCODE nun insgesamt ein Prozent des Erbguts aus 44 DNA-Regionen ausgewählt, die repräsentativ seien. Die Einzeldaten sollen demnächst öffentlich zugänglich werden. Betrachtet man das Erbgut des Menschen als ein Buch mit drei Milliarden Bausteinen, so haben die Forscher nun neue Abschriften davon gefunden und können mit ihren Arbeiten die Grammatik und Zeichensetzung des Textes besser verstehen. Von einem Verständnis des Gesamtwerkes sind sie jedoch noch weit entfernt. Internet: www.genome.gov/ENCODE

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New research challenges understanding of human genome

[Date: 2007-06-14]

Results from a huge international effort to identify the functional components of the human genome are challenging established views about how the genome works. Among other things, the concept of 'junk' DNA looks set to be binned, as the findings reveal that most of the genome has a function of some kind. The research, which was funded by a range of bodies including the EU, is published by the journal Nature, with 28 companion papers appearing in the journal Genome Research. The work was carried out within the framework of the ENCODE (Encyclopedia of DNA Elements) project, which has spent the past four years identifying and cataloguing the functional elements of 1% of the human genome. The human genome was sequenced in April 2003. Together, the three billion base pairs ('letters') of the genome contain all the information needed to turn a fertilised egg cell into an adult human being. While we have some understanding of the parts of the genome that code for proteins, the function of the rest of the genome remains a mystery. 'The problem is it is written in a language we are still trying to learn to understand,' said Francis Collins, Director of the US' National Human Genome Research Institute (NHGRI). The goal of the ENCODE project is to investigate the genome to find out what it is doing and why. In this initial pilot phase, 30,000 base pairs, equivalent to 1% of the total genome, were targeted. Half of these were in regions of the genome which are relatively well characterised, and the other half were picked at random. Scientists from 80 organisations in 11 countries and representing a range of disciplines ran a battery of tests on the target DNA sequences, sharing information, technology and data along the way. The result was over 200 datasets and over 600 million data points. 'This was a prime example of team science at its best,' commented Dr Collins. 'None of this data would have been as rich without this sharing.' 'Our results reveal important principles about the organisation of functional elements in the human genome, providing new perspectives on everything from DNA transcription to mammalian evolution,' said Ewan Birney of the European Molecular Biology Laboratory, who led the data analysis work. 'In particular, we gained significant insight into DNA sequences that do not encode proteins, which we knew very little about before.' One of the most exciting findings was the fact that most of the DNA in our cells is active in some way, challenging the idea that the genome consists of active protein-coding genes surrounded by vast amounts of inactive, so-called 'junk' DNA. Furthermore, many of these non-protein coding sequences overlap with protein-coding sequences.

News

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'The junk is not junk. It is active. It does a lot of different things,' said Dr Birney. Many of the regions which were once thought to be junk have turned out to be regulatory sequences, which tell genes when and where they should be active. This finding will have implications for medicine, as many genetic mutations associated with diseases are found in regulatory regions. Another surprise for the scientists was the identification of 'neutral' sequences, which are being actively copied but provide neither a benefit nor a problem to the organism. These neutral sequences have not been conserved during evolution. The researchers speculate that these could be a source for new genetic variation in the future. 'It's like clutter in the attic,' explained Dr Collins. 'You wouldn't throw it away because you might need it.' One of the goals of the project was to develop the tools to carry out the analysis and ensure the feasibility of the project concept, which involved developing standards so that data from different laboratories and different experimental processes could be compared properly. 'We are now in a position to scale this up!' said Dr Collins. 'We are prepared to go from 1% to the whole thing.' 'The goal for the next five years is delivering a more complete understanding across our genome,' added Dr Birney. 'The ENCODE pilot project is the first step towards this goal.'

ENCODE: http://www.genome.gov/encode/ Nature: http://www.nature.com/nature/focus/encode/index.html Genome Research: http://www.genome.org/ All the articles are open access

Category: Projects Data Source Provider: ENCODE project consortium, Nature Document Reference: The ENCODE Project Consortium (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447: 799-816. Programme or Service Acronym: MS-SE C, MS-A C, MS-D C, MS-E C, MS-UK C, FP6-INTEGRATING, FP6-LIFESCIHEALTH, FRAMEWORK 6C Subject Index: Biotechnology; Coordination, Cooperation; Medicine, Health; Scientific Research

RCN: 27851

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BEIJING, June 14 (Xinhuanet) -- An in-depth examination by 35 teams of researchers from 80 different organizations in 11 countries who shared notes on 1 percent of the human genome has revealed there is no such thing as "junk DNA" and that some of what was considered "useless-looking" stretches of DNA may rewrite the book on evolution and causes of some diseases.

Their findings, the start of the Encyclopedia of DNA Elements or ENCODE Project, were published in the journals Nature and Genome Research.

"This is a landmark in our understanding of human biology," said Dr. Francis Collins, head of the National Human Genome Research Institute, which funded much of the work.

Some scientists were surprised that human beings had only about 30,000 genes after the human genome was published in 2003. Rice, for instance, has 50,000. The new study confirms what many genetics experts had suspected — the genes are important, but so is the other DNA, the biological code for every living thing.

What they discovered is that even DNA outside the genes transcribes information. Transcription is the process that turns DNA into something useful — such as a protein.

Much of this action is going on outside the genes in the so-called regulatory regions that affect how and when a gene activates, Collins said. The researchers discovered 4,491 of these so-called transcription start sites, "almost tenfold more than the number of established genes," they wrote in the Nature paper.

Ewan Birney of the European Molecular Biology Laboratory's European Bioinformatics Institute in Cambridge said this helped explain how such a complex creature as a human arose from just four letters of code repeated over and over.

"The junk is not junk. It is really active," Birney told reporters. This could be useful in understanding and treating disease.

(Agencies)

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ENCODE Nature Publicaiton Selected Media and Web Clippings 6

Documents

Transcript of ENCODE Nature Publicaiton Selected Media and Web Clippings 6