Dark Matter of the Genome Revealed

Dark Matter of the Genome Revealed

  10:29:00 AM    Science Lover

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An international team of researchers has discovered the vast majority of the so-called "dark matter" in the human genome, by means of a sweeping comparison of 29 mammalian genomes. The team, led by scientists from the Broad Institute, has pinpointed the parts of the human genome that control when and where genes are turned on. This map is a critical step in interpreting the thousands of genetic changes that have been linked to human disease.

Rendering of DNA. Researchers have discovered the vast majority of the so-called "dark matter" in the human genome, by means of a sweeping comparison of 29 mammalian genomes. (Credit: iStockphoto/Martin McCarthy)

Their findings appear online October 12 in the journal Nature.

Early comparison studies of the human and mouse genomes led to the surprising discovery that the regulatory information that controls genes dwarfs the information in the genes themselves. But, these studies were indirect: they could infer the existence of these regulatory sequences, but could find only a small fraction of them. These mysterious sequences have been referred to as the dark matter of the genome, analogous to the unseen matter and energy that make up most of the universe.

This new study enlisted a menagerie of mammals -- including rabbit, bat, elephant, and more -- to reveal these mysterious genomic elements.

Over the last five years, the Broad Institute, the Genome Institute at Washington University, and the Baylor College of Medicine Human Genome Sequencing Center have sequenced the genomes of 29 placental mammals. The research team compared all of these genomes, 20 of which are first reported in this paper, looking for regions that remained largely unchanged across species.

"With just a few species, we didn't have the power to pinpoint individual regions of regulatory control," said Manolis Kellis, last author of the study and associate professor of computer science at MIT. "This new map reveals almost 3 million previously undetectable elements in non-coding regions that have been carefully preserved across all mammals, and whose disruptions appear to be associated with human disease."

These findings could yield a deeper understanding of disease-focused studies, which look for genetic variants closely tied to disease.

"Most of the genetic variants associated with common diseases occur in non-protein coding regions of the genome. In these regions, it is often difficult to find the causal mutation," said first author Kerstin Lindblad-Toh, scientific director of vertebrate genome biology at the Broad and a professor in comparative genomics at Uppsala University, Sweden. "This catalog will make it easier to decipher the function of disease-related variation in the human genome."

This new map helps pinpoint those mutations that are likely responsible for disease, as they have been preserved across millions of years of evolution, but are commonly disrupted in individuals that suffer from a given disease. Knowing the causal mutations and their likely functions can then help uncover the underlying disease mechanisms and reveal potential drug targets.

The scientists were able to suggest possible functions for more than half of the 360 million DNA letters contained in the conserved elements, revealing the hidden meaning behind the As, Cs, Ts, and Gs. These revealed:

• Almost 4,000 previously undetected exons, or segments of DNA that code for protein
• 10,000 highly conserved elements that may be involved in how proteins are made
• More than 1,000 new families of RNA secondary structures with diverse roles in gene regulation
• 2.7 million predicted targets of transcription factors, proteins that control gene expression

"We can use this treasure trove of new elements to revisit disease association studies, focusing on those that disrupt conserved elements and trying to discern their likely functions," said Kellis. "Using a single genome, the language of DNA seems cryptic. When studied through the lens of evolution, words light up and gain meaning."

The researchers were also able to harness this collection of genomes to look back in time, across more than 100 million years of evolution, to uncover the fundamental changes that shaped mammalian adaptation to different environments and lifestyles. The researchers revealed specific proteins under rapid evolution, including some related to the immune system, taste perception, and cell division. They also uncovered hundreds of protein domains within genes that are evolving rapidly, some of which are related to bone remodeling and retinal functions.

"The comparison of mammalian genomes reveals the regulatory controls that are common across all mammals," said Eric Lander, director of the Broad Institute and the third corresponding author of the paper. "These evolutionary innovations were devised more than 100 million years ago and are still at work in the human population today."

In addition to finding the DNA controls that are common across all mammals, the comparison highlighted areas that have been changing rapidly only in the human and primate genomes. Researchers had previously uncovered two hundred of these regions, some of which are linked to brain and limb development. The expanded list -- which now includes more than 1,000 regions -- will give scientists new starting points for understanding human evolution.

The comparison of many complete genomes is beginning to offer a clear view of once indiscernible genomic regions, and with additional genomes, that resolution will only increase. "The power of this resource is that it continues to improve with the inclusion of more species," said Lindblad-Toh. "It's a very systematic and unbiased approach that will only become more powerful with the inclusion of additional genomes."

Other Broad researchers who contributed to this work include Manuel Garber, Or Zuk, Michael F. Lin, Pouya Kheradpour, Jason Ernst, Evan Mauceli, Lucas D. Ward, Michele Clamp, Sante Gnerre, Jessica Alföldi, Jean Chang, Federica Di Palma, Mitchell Guttman, David B. Jaffe, Irwin Jungreis, Marcia Lara, Jim Robinson, Xiaohui Xie, Michael C. Zody, and members of the Broad Institute Sequencing Platform and Whole Genome Assembly Team.

This project was supported by the National Human Genome Research Institute, National Institute for General Medicine, the European Science Foundation, National Science Foundation, the Sloan Foundation, an Erwin Schrödinger Fellowship, the Gates Cambridge Trust, Novo Nordisk Foundation, University of Copenhagen, the David and Lucile Packard Foundation, the Danish Council for Independent Research Medical Sciences, and The Lundbeck Foundation.

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Finding Variants in the Human Genome : HapMap 3 Points the Way Forward for Human Genetics Studies

Finding Variants in the Human Genome : HapMap 3 Points the Way Forward for Human Genetics Studies

  8:59:00 PM    Science Lover

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New findings show the value of genetic studies across human populations and the value of the latest DNA sequencing technologies to interrogate genetic variation. The results, from the latest phase of the international HapMap Project, are reported in Nature.

An international consortium today published a third-
generation map of human genetic variation, called the 
HapMap, which includes data from an additional seven 
global populations, increasing the total number to 11
populations. The improved resolution will help researchers 
interpret current genome studies aimed at finding common
and rarer genetic variants associated with complex
diseases. (Credit: Jane Ades , NHGRI)

The researchers' extensive study of genetic variation in multiple populations will form a framework for future genetic studies of variation and disease: their findings highlight the need to examine various populations in order to tease out the widest collection of genetic variants, as well as the requirement to deploy sequencing technologies to find as many variants as possible.

The HapMap Project seeks to identify signposts on the human genome that will simplify the search for important genetic variants. In the latest phase -- HapMap 3 -- the researchers looked for variants across the genome in 1184 samples from 11 populations. They chose the large sample set and the wide range of populations to maximize the variation they could capture. The project includes both single-letter differences (single-letter polymorphisms, or SNPs) as well as large differences from the loss, gain or duplication of regions, called copy-number polymorphisms, or CNPs.

"Despite the remarkable achievements following from the Human Genome Project, our knowledge of human genetic variation remains limited," says Professor Richard Gibbs, professor of molecular and human genetics at Baylor College of Medicine in Houston, Texas, and director of the BCM Human Genome Research Center. "Here we have studied more populations and were able to include CNPs in genomewide studies.

"These results tell us more about human genetic variation and about how to study variation successfully."

The results show that rarer variants are distributed more unevenly among populations. This might be expected -- evolutionary theory implies that the common variants are generally the older ones, having had greater time to spread through a population -- but also cautions that genetic studies should include a wide range of population groups to maximise discovery of more recent, population-specific variants.

"The closer we look at human genetic variation, the greater the granularity," explains Professor Manolis Dermitzakis, from the University of Geneva and one of the project coordinators, and formerly at the Wellcome Trust Sanger Institute. "An important task in genetics is to discriminate between the variants that are important for health and those that are part of the background.

"This new version of the HapMap will help us design ways to do that -- to sort the wheat from the chaff."

In addition to the genotyping studies described above, HapMap 3 also sequenced ten segments of 100,000 bases from well-characterized regions of the human genome. Unlike discovery using DNA chips -- as used in most studies to date -- direct sequencing is not biased towards more common variants, but gives a direct estimate of the frequencies of variants.

The researchers found that most variants were relatively uncommon (found in less than one person in ten), but they also found a large number of rare variants (each found in less than one in 100 people) or 'private' variants (found in only one person). Almost eight of ten variants were new and almost four of ten of those seen in less than one in 100 people were found in only one population.

From the results, the researchers suggest that variants in some genes, including genes involved in the immune system, wound healing and sense of smell, are under selection in different populations. These genes can now be studied to learn about how these systems work and about disease resistance. These findings show the value of having large studies that include many populations and samples to achieve comprehensive understanding of human variation.

"Some have talked about how little has come from the Human Genome Project over the past ten years, but perhaps they forget how little we knew then," says Professor David Altshuler of Massachusetts General Hospital in Boston and the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University in Cambridge, Mass. "It is amazing that we have gone from a genome less than 90 per cent completed to looking at genetic changes in one in 200 people or rarer. A few years ago, we had no idea of the extent of structural variation or how we might sample variants present at low frequency.

"The HapMap and other large-scale projects have transformed our understanding of the human genome and its relation to health and disease."

The HapMap 3/ENCODE 3 data set is publicly available at http://www.hapmap.org.

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Inefficient Selection: New Evolutionary Mechanism Accounts For Some Of Human Biological Complexity

Inefficient Selection: New Evolutionary Mechanism Accounts For Some Of Human Biological Complexity

  10:29:00 PM    Science Lover

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A painstaking analysis of thousands of genes and the proteins they encode shows that human beings are biologically complex, at least in part, because of the way humans evolved to cope with redundancies arising from duplicate genes.

Genomic and proteomic analysis has found a new evolutionary mechanism that accounts for some of the biological complexity of human beings. (Credit: iStockphoto/Liang Zhang)

"We have found a specific evolutionary mechanism to account for a portion of the intricate biological complexity of our species," said Ariel Fernandez, professor of bioengineering at Rice University. "It is a coping mechanism, a process that enables us to deal with the fitness consequences of inefficient selection. It enables some of our proteins to become more specialized over time, and in turn makes us more complex."

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The synthetic genome

The synthetic genome

  2:56:00 PM    Science Lover

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From Frankenstein’s monster through I, Robot to the lost young cyborg of Steven Spielberg’s AI, the idea of creating artificial life from inert matter has long inspired human imagination.

Last week that thrilling but unsettling goal appeared to have come a step closer with the announcement by Craig Venter, the maverick scientist, that his laboratory had constructed the world’s first completely synthetic genome.

He described how he had used laboratory chemicals to recreate an almost exact copy of the genetic material found inside a tiny bacterium - and was now attempting to slot it into an empty cell in the hope of creating a new life form.

For the layman, he compared his work with the building of a computer. His breakthrough was the equivalent of creating the software for a computer’s operating system. Now what he had to do was insert it into the computer itself - the empty cell - and “boot it up”.

What’s more, he announced, he was already working on the next stage of his great project. He would build an entirely synthetic organism, which he would then use to save the world from global warming.

For Venter, the showman of the world of science, the result could hardly have been better. Details of the breakthrough went around the world generating positive headlines. The prospect that a painless way of solving the problems of climate change might have been found was particularly attractive.

As the fuss dies down, however, questions remain. Has Venter really come close to creating a new life form? Will the benefits really be so powerful and clear cut? What might the acquisition of such godlike powers actually mean for humanity?

VENTER himself has long been a man of supreme immodesty. Since the 1990s he has scorched his way through the burgeoning science of genomics, leaving a trail of enemies in his path as he set about mapping the human genome.

The feelings he provokes are so intense that one profile in The New Yorker magazine from 2000 began with a quote from a string of fellow scientists, saying: “Craig Venter is an asshole. He’s an idiot. He is a thorn in people’s sides and an egomaniac.”

Venter’s first breakthrough was in developing what is now known as shotgun sequencing, a method for analysing the human genome faster and more cheaply than ever before.

At the time, however, it was unproven and too risky for the government-funded institution where he worked so, after many rows, Venter left and raised the money himself.

An instinctive entrepreneur, he might have expected to feel more at home mixing with fast moving risk-takers like himself, but instead the rows became even more intense. His first business partnership collapsed and his relationship with Celera Genomics, with whom he completed the genome, also proved tempestuous.

Even the publication of the genome itself proved controversial. Fearing that Venter would patent the genome and charge for access, a consortium of scientists launched their own publicly funded rival effort.

The race became so bitter that Bill Clinton, then US president, had to step in to negotiate a truce, with both teams agreeing to publish their findings simultaneously in 2001.

It was supposed to mark the end of hostilities but when Venter held a party his fellow scientists boycotted the event, leaving Venter glowering over a near-empty dance floor.

Soon after he was sacked by Celera. Insiders made clear the firm could no longer sustain such a huge ego.

Again Venter bounced back, using his £100m share of Celera’s stock to found the J Craig Venter Institute. It now has more than 400 scientists and staff based in Rockville, Maryland, and La Jolla, California. For Venter, however, perhaps its most priceless asset is that he controls it.

The years since then have seen Venter repeatedly in the headlines. Last June he announced success in transplanting the entire genome of one bacterium into another, effectively causing the recipient to change species.

Then, in September, he published his own genome, the first time any individual person’s DNA had been sequenced. It was perhaps a mixed blessing, revealing that Venter is at risk of Alzheimer’s, diabetes and hereditary eye disease.

For scientists the benefits of his institute’s synthetic genome are, however, much clearer. Although they have long been able to make synthetic DNA they have only been able to produce it in short lengths. This is because the chemical “bases” that make up the building blocks of DNA – adenine, thy-mine, cytosine and guanine – are very difficult to work with.

DNA chains are built from pairs of these bases all linked together to form the familiar “twisted ladder” shape. In the test tube, however, the chains become increasingly brittle the longer they get. This means that the largest synthesised DNA chain contained only 32,000 base pairs until now.

Dr Jim Haseloff, a Cambridge University expert in synthetic biology said: “The true breakthrough here is that Venter has built a DNA sequence containing 583,000 base pairs. There is a very good chance that if he can transplant it into a bacterial cell it will start working.”

This event may be far closer even than Venter is saying. The paper published last week was actually written five months ago, since when it has been undergoing peer review by other researchers. In that time the research has intensified.

Dan Gibson, who led the research, and Hamilton Smith, the Nobel prize-winning biologist who worked with him, said: “We are now working towards the ultimate goal of inserting a synthetic chromosome into a cell and booting it up to create the first synthetic organism.”

What it means is that pretty soon we are likely to see the first truly synthetic microbes – and that will be sure to spark fierce debate. Some will accuse Venter of playing God. Others will raise fears of new bioweap-ons. The simple question is: just what will humanity be able to do with this new technology? ONE thing that is clear is that there is no chance of Venter’s techniques being applied to create synthetic human genomes. Or indeed of it leading to the halting of the human ageing process, as some scientists have speculated.

Mycoplasma genitalium, the bacterium on which Venter’s team worked, was chosen purely because it has a relatively tiny genome. Most bacteria have far more – typically up to 10m base pairs long, while fungi have around 38m and plants 115m. Mammals are thousands of times more complex again with humans having around 3 billion base pairs.

Professor Paul Freemont, head of molecular biosciences at Imperial College, London, said: “There are just 485 genes in Mycoplasma, while humans have 20,000. It is science fiction to think Venter’s work could give scientists control of the human genome.”

There are, however, many other possibilities, some of which were set out by Venter himself in a telling article published last autumn. He described how, in 2003, his team had synthesised the first artificial genome, of an obscure virus called phi-X174.

As news of the breakthrough got out, he was invited to a meeting with John Marburger, the president’s chief scientific adviser. Venter said: “We told him now we had achieved this goal, we could begin to move to creating new types of microorganisms that could be used in numerous ways, as green fuels to replace oil and coal, digest toxic waste or absorb greenhouse gases.”

Alongside these attractive benefits, Venter also set out a more sinister possibility. “We could now probably also syn-thesise any virus with a genetic code of fewer than 10,000 ‘letters’ of DNA in under a week in the lab, and larger viruses such as the Marburg or Ebola virus [both very unpleasant] in a month or so.”

For Marburger the implications were clear and, soon after, Venter’s research was put under scrutiny by the National Science Advisory Board for Biosecurity which oversees research deemed potentially dangerous.

In public, however, little was said about such fears. Perhaps the only clue came at a press conference when Hamilton Smith blurted out: “We could make the smallpox genome.” Venter later spoke of his relief when only one reporter repeated Smith’s reference to the “possibility of making deadly pathogens”.

It is a worry that plays on people’s minds. Literature and films are littered with the human race being imperilled by biological innovations that have spiralled out of control. Such fears will never go away. Synthetic biology is after all a powerful technology and, just like genetic modification, crossbreeding and every other method for altering the genetic make-up of other living things, can be used for good or evil.

For now, however, the biggest barrier for making any use of such techniques at all lies in our limited understanding of how DNA works.

The researchers who praise Venter’s breakthrough also warn that predicting how a given sequence of synthetic DNA will actually perform is a far harder task.

Jason Chin, who leads a synthetic biology research group in Cambridge, said: “DNA communicates with a cell by prompting it to make proteins, but we have a long way to go in understanding the relationship between a given DNA sequence, the proteins it generates and the final properties of an organism.”

So, for now at least, scientists will be limited to producing synthetic versions of DNA sequences found in nature and tinkering with them.

When will we see the benefits? The history of biotechnology is littered with other reminders that we may have to wait a long time. Stem cells, gene therapy and cloning were all great scientific discoveries but the practical benefits are taking much longer to emerge.

Venter’s ecological claims for his breakthrough have been greeted with cautious optimism by his peers. But they note that there would be significant regulatory hurdles surrounding the release of a new organism into the environment to overcome. The benefits would most likely not been seen within a decade.

For Venter, however, such cautionary notes are simply a challenge. His vision, he told Newsweek magazine last year, is of creating the first “trillion-dollar organisms” - patented bugs that could excrete bio-fuels, generate clean energy in the form of hydrogen and even produce tailor-made foods.

It is a startling vision of a brave new world, but it also sounds like a world that would be largely controlled by J Craig Venter.

SOURCE : http://www.timesonline.co.uk/tol/news/uk/science/article3257051.ece

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Human genome further unravelled

Human genome further unravelled

  8:05:00 PM    Science Lover

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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".

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

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".

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

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."..

SOURCE : BBC NEWS

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