Systems Biology World

What Flies And Worms Have In Common

meson — Sat, 14 Mar 2009 02:51:45 +0900

ScienceDaily (Mar. 12, 2009) — Researchers at ETH Zurich and the University of Zurich have, for the first time, compared the proteomes of two different multi cellular organisms. They found surprising correlations between two animals that, at first sight, couldn’t be more different.

In a new publication in PloS Biology, researchers at the University of Zurich and ETH Zurich have, for the first time, undertaken a comparison of the proteomes of two different multi cellular organisms. The researchers compared the protein catalogue of the tapewormCaenorhabditis elegans with that of the fruit fly Drosophila melanogaster.

This comparison was possible because, over the past few years, the researchers have been cataloguing the fly’s proteins, with the data being systematically collected in Zurich’s specialist centre for proteome analysis, the “Center for Model Organism Proteomes” (C-MOP) at the University of Zurich.

Investigating the worm

The protein catalogue for the fruit fly was also sourced from a previous study published in 2007. In this study, an international team of researchers, including members of the University of Zurich and ETH Zurich, were able to record and index nearly two thirds of the predicted Drosophila melanogaster proteome – a total of over 9,100 proteins.

The protein makeup of the worm has now been recorded by a team led by Michael Hengartner, Professor of Molecular Biology at the University of Zurich. During the investigation, the university researchers found nearly 11,000 proteins and 10,600 gene loci. Some of the genes have been “rediscovered” as a result of this study. Although they had been predicted by computer calculations, experimental proof has only now been possible with this extended mapping. This allows researchers to refine their genome annotations, i.e. to say more precisely which genes of the genome are active and where within the genome they lie. So far, over 19,000 genes were known for the worm, with 22,000 assigned proteins.

Many proteins overlap

In order to compare the two protein catalogues, the researchers only used a part of the discovered genes with regard to the protein products. They focused on roughly 2,700 orthologous genes. These genes stem from the same ‘parent’ genes and are kept in the newly created organisms. They also keep the same function throughout the process of evolution.

For the majority of such orthologous proteins, the researchers found major parallels between the fly and the tapeworm. “The correlation between the two organisms is surprisingly high”, stresses Michael Hengartner. This despite the fact that the two organisms have developed separately for hundreds of millions of years.

The big differences between the two species, despite their great protein similarity, is due to the many interim steps necessary in the translation of a section of the DNA to the complete protein, with countless possible variations, such as the different regulation of the genes. According to the molecular biologist, “Evolution is able to play with the interim steps”.

As the C. elegans and Drosophila proteins are also similar to human proteins, the researchers suspect that a human/worm proteome comparison would bring similar results

Unique equipment

Such comparisons require protein databases such as the C-MOP, where data are collected and recorded according to uniform standards by various research groups. This expert centre for proteome data of model organisms is currently deemed to be the world’s only such institution, founded by the predecessor to the current SystemsX.ch, the “old” SystemsX. The ultimate goal is to make the data available, free of charge, to researchers who are also interested in proteomics, thus offering great value for fundamental biological research.

Together with the protein catalogues for Drosophila and C. elegans, the Center for Model Organism Proteomes also has proteome data for Arabidopsis thaliana, the epitome of the model plant. C-MOP has therefore created a unique database on proteins for model organisms.

Simplify the proteome analysis

Proteome research is still very laborious and complex. Whilst genomes can now be completely sequenced relatively quickly and cheaply, it is still difficult to catalogue proteins – the gene products. Ruedi Aebersold would therefore like to further simplify proteome analysis. The idea is to search for proteins that sufficiently characterise the genome, without the proteome having to be fully known.

In order to do this, the ETH professor would, for example, require certain peptide fragments that characterise the proteins. He says, “It’s like a simplified map. You only need a few pointers to find the right way.” He claims that it is important for system biology to be able to gauge proteomes more quickly and cheaply, as biological research also wants to measure changes in an organism. For example, if a gene is blocked, this can create stress at a cellular level. The big question, however, is how the system behaves as a whole, and not just as a faulty signal path.

Difference between humans and chimpanzees

And after all, the researchers want – as in the comparison between worms and flies – to use proteomics to get to the bottom of evolution and the line of descent. For example, chimpanzees and humans have numerous gene sequences in common, yet the two species are still very different, particularly in terms of brain functionality. “The sequence comparison alone does not sufficiently explain this difference”, explains the ETH professor. In order to explain the big differences in development of the phenotype, we would require extensive analysis of the proteins and the networks they form.

Journal references:

Schrimpf et al. Comparative Functional Analysis of the Caenorhabditis elegans and Drosophila melanogaster Proteomes. PLoS Biology, 2009; 7 (3): e48 DOI:10.1371/journal.pbio.1000048
Brunner et al. A high-quality catalog of the Drosophila melanogaster proteome. Nature Biotechnology, 2007; 25 (5): 576 DOI: 10.1038/nbt1300

Adapted from materials provided by ETH Life.

Five Thousand Bucks for Your Genome

meson — Tue, 07 Oct 2008 18:06:26 +0900

Monday, October 06, 2008

Five Thousand Bucks for Your Genome

A new sequencing service could change the face of human genomics.

By Emily Singer

Starting next spring, a complete human-genome sequence can be ordered for just $5,000, thanks to a new sequencing service announced by Complete Genomics, a startup based in Mountain View, CA. The stunning price drop--sequencing currently costs approximately 20 times that amount--could completely change the way that human-genomics research is done and open up new possibilities in personalized medicine. Researchers say that a $5,000 genome would enable new studies to identify rare genetic variants linked to common diseases, and it could open up the sequencing market to diagnostic and pharmaceutical companies, making genome sequencing a routine part of clinical drug testing.

Complete Genomics, which has received $46 million in venture funding to date and has largely stayed under the radar, plans to launch with a bang and anticipates the capacity to sequence 1,000 genomes in 2009 and 20,000 in 2010. That would represent a massive jump: with a price tag of $100,000 to $1 million over the past two years, only a handful of human genomes have been sequenced to date.

"Suddenly, these guys are talking about sequencing hundreds to thousands of genomes in the next couple of years," says Chad Nusbaum, codirector of the Genome Sequencing and Analysis program at the Broad Institute, in Cambridge, MA. "That opens up tremendous vistas for the kind of science we want to do. It's really by generating hundreds of human-genome sequences that you can start to ask hard questions about human genetics."

Complete Genomics says that it has already sequenced a human genome, although it has not yet released the data for independent review. "'Stunning' is not too strong a word, if they can do it in the very near term," says Jeffrey Schloss, program director for technology development at the U.S. National Human Genome Research Institute, on the possibility of a $5,000 genome. "But I haven't seen any data and I don't know anyone who has, which is of course critical."

J. Craig Venter, founder of the J. Craig Venter Institute, in Rockville, MD, is working with Complete Genomics to validate its technology, comparing the sequence that it generates with a reference sequence of his own genome.

Complete Genomics says that its cheap price tag comes thanks to two innovations: a way to densely pack DNA, developed by Rade Drmanac, the company's chief scientific officer, and a method to randomly read DNA letters, based on sequencing technology developed at George Church's lab at Harvard.

To start with, an 80-base-pair piece of DNA is inserted into a circular piece of synthetic DNA and replicated 1,000 times with a specialized enzyme. That large aggregate of DNA spontaneously compresses into a tightly packed ball, thanks to chemical characteristics engineered into the synthetic DNA. These DNA "nanoballs" are then packed onto specially fabricated arrays with unprecedented density--about a billion balls fit on a chip the size of a microscope slide. The high density of DNA allows large volumes to be sequenced quickly with few reagents, one of the most costly components of the process.

Next, as with other approaches, Complete Genomics determines the sequence of the target DNA using a series of fluorescently labeled DNA strands designed to bind to corresponding letters. But while advanced sequencing technologies currently in use--including those from Illumina, Applied Biosystems, and 454--read the sequence sequentially, letter by letter, Complete Genomics's labels bind to the target DNA randomly. Both the labels and the DNA circle are designed to allow scientists to deduce the position of each highlighted base--information that is then used to computationally reconstruct the sequence of the target DNA. (With both Complete Genomics's and other companies' methods, the short strands are computationally stitched together to generate the entire genome sequence.)

Because the identification of each base in the sequence does not depend on the correct identification of the previous one, individual errors have less impact on the overall result, generating a more accurate sequence with less repeat sequencing. (For a more detailed explanation and schematic of Complete Genomics's sequencing process, click here.)

A $5,000 genome is likely to open new arenas in genetic study of common disease. Most studies to date have analyzed carefully selected portions of individuals' genomes, linking common variations to risk of common ailments, such as diabetes and heart disease. However, even studies of thousands of patients have uncovered genetic variations that account for only a small percentage of the risk for disease. Scientists say that the ability to sequence many people's genomes will allow them to search for rare variations that likely account for remaining genetic risk. "I'd love to get my hands on [this technology] and think about how I can solve new problems with it," says Phil Sharp, MIT Institute Professor and winner of the 1993 Nobel Prize in Physiology or Medicine.

Beyond its unique technology, Complete Genomics has also chosen an unusual business model: rather than selling instruments, as most sequencing companies have done, it plans to offer sequencing services through a commercial-scale genome center. Cliff Reid, the company's president and chief executive officer, hopes that both the service model and the price tag will appeal to those who don't want to do their own sequencing, such as pharmaceutical companies. "They don't want to purchase an instrument; they want to purchase data," says Reid. In an effort to further pharmacogenomics--the ability to prescribe the right drug at the right dose to a patient based on his or her individual genetic profile--genomics is a growing component of clinical trials.

The company is now building a massive data center to manage the immense volume of information it expects to generate; it's planning to have a computer cluster containing 60,000 processors online by 2010. "No one has ever put together a data processing center this size for sequencing--because no one has ever been able to sequence this many genomes," says Reid. Complete Genomics will focus entirely on human-genome sequencing, unlike other companies, which use their technology for a variety of sequencing projects. And unlike Knome, a personal-genomics startup that offers individuals a complete genome sequence and personalized analysis for $350,000, Complete Genomics provides only the genome sequence.

The company has already made its first deal: to sequence 100 genomes in 2009 and 2,000 genomes in 2010 for Leroy Hood at the Institute for Systems Biology, in Seattle. Hood, who in the 1980s developed the first automated sequencing machine, sits on the Complete Genomics advisory board. Hood's project will comprise about ten percent of the facilities sequencing capacity in the first two years.

Even if Complete Genomics faces up to its promises, "they face a lot of competition," says J. Craig Venter. For example, Applied Biosystems, a veteran in the sequencing industry, recently announced a next-generation technology that it believes will be able to sequence genomes for $10,000.

A New MRSA Defense

meson — Sun, 14 Sep 2008 23:31:34 +0900

Friday, September 12, 2008

A New MRSA Defense

Marijuana extracts kill antibiotic-resistant MRSA without a high.

By Nora Schultz

Substances harvested from cannabis plants could soon outshine conventional antibiotics in the escalating battle against drug-resistant bacteria. The compounds, called cannabinoids, appear to be unaffected by the mechanism that superbugs like MRSA use to evade existing antibiotics. Scientists from Italy and the United Kingdom, who published their research in the Journal of Natural Products last month, say that cannabis-based creams could also be developed to treat persistent skin infections.

Cannabis has long been known to have antibacterial properties and was studied in the 1950s as a treatment for tuberculosis and other diseases. But research into using cannabis as an antibiotic has been limited by poor knowledge of the plant's active ingredients and by the controversy surrounding its use as a recreational drug.

Now Giovanni Appendino of the Piemonte Orientale University, in Italy, and Simon Gibbons of the School of Pharmacy at the University of London, U.K., have revisited the antibiotic power of marijuana by systematically testing different cannabinoids' ability to kill MRSA.

MRSA, short for methicillin-resistant Staphylococcus aureus, is a bacterium that can cause difficult-to-treat infections since it does not respond to many antibiotics. Many healthy people carry S. aureus on their skin, but problems arise when multi-drug-resistant strains infect people with weak immune systems through an open wound. In the worst cases, the bug spreads throughout the body, causing a life-threatening infection.

To make matters worse, resistance to antibiotics is rapidly increasing, and some strains are now even immune to vancomycin, a powerful antibiotic that is normally used only as a last resort when other drugs fail.

But when Appendino, Gibbons, and their colleagues applied extracts from five major cannabinoids to bacterial cultures of six strains of MRSA, they discovered that the cannabinoids were as effective at killing the bugs as vancomycin and other antibiotics.

"The cannabinoids even showed exceptional activity against the MRSA strain that makes extra amounts of the proteins that give the bugs resistance against many antibiotics," says Gibbons. These proteins, he explains, allow the bacteria to "hoover up unwanted things from inside the cell and spit them out again."

Conveniently, of the five cannabinoids tested by the researchers, the two most effective ones also happen to be nonpsychoactive, meaning that they cannot cause a high. "What this means is, we could use fiber hemp plants that have no use as recreational drugs to cheaply and easily produce potent antibiotics," says Appendino.

In an attempt to discover how the cannabinoids kill MRSA, the team manipulated several chemical groups within the compounds. Most of the changes did not affect the antibiotic activity at all, and those that did seemed to influence only how well the cannabinoid is taken up by the bacterial cells.

"Everything points towards these compounds having been evolved by the plants as antimicrobial defenses that specifically target bacterial cells," says Gibbons. "But the actual mechanism by which they kill the bugs is still a mystery. We've tested whether the cannabinoids affect common antibiotic targets like fatty acid synthesis or the [DNA-bending enzyme] DNA gyrase, but they don't. I really cannot hazard a guess how they do it, but their high potency as antibiotics suggests there must be a very specific mechanism."

Appendino and Gibbons say that cannabinoids could quickly be developed as treatments for skin infections, provided the nonpsychoactive varieties are used. "The most practical application of cannabinoids would be as topical agents to treat ulcers and wounds in a hospital environment, decreasing the burden of antibiotics," says Appendino.

Whether the cannabinoids could also be delivered in the form of an injection or in pills is less clear, the pair says, because they may be inactivated by blood serum.

Frank Bowling of the University of Manchester, who has had success treating MRSA-infected wounds with maggots, says that "any alternative treatment that removes MRSA from the wound and prevents it from spreading into the body is fantastic and preferable to using antibiotics that have strong side effects and against which resistance is already developing." He cautions, however, that the researchers still need to show that the cannabinoids are safe to use.

This is not something that Appendino is too concerned about: "The topical use of cannabis preparations has a long tradition in European medicine, and no allergies have been reported."

Mark Rogerson of GW Pharmaceuticals, a U.K.-based company that develops cannabinoid-based drugs to treat severe pain caused by multiple sclerosis and cancer, says that the discovery that cannabinoids kill MRSA "really underlines the potentially great diversity of medical applications that cannabis-based medicine can have. You can almost think of the cannabis plant as a mini pharma industry in its own right." But Rogerson says that it is unlikely that existing cannabis-based medicines could be used to treat MRSA because the exact effect will depend on the correct combination and dosage of cannabinoids.

Meanwhile, Appendino and Gibbons hope that antibacterial effectiveness could also make cannabinoids suitable preservatives for cosmetics and toiletries. "The golden standards of preservatives are parabens and chlorinated phenols," says Appendino, but these compounds do not degrade well in the environment and are strongly suspected to be hormonal modifiers. He also argues that, since all major cannabinoids are similarly effective, complete purification of a single compound isn't necessary. So semipurified cannabinoid mixtures extracted from nonpsychoactive plants could make a cheap and easy alternative to conventional preservatives.

Source: http://www.technologyreview.com/Biotech/21366/

Systems Biology: An Evolving Approach in Drug Discovery and Development

meson — Sat, 26 Jul 2008 04:43:46 +0900

Systems Biology: An Evolving Approach in Drug Discovery and Development

Authors: Ho, R.L.¹; Lieu, C.A.²

Source: Drugs in R&D, Volume 9, Number 4, 2008 , pp. 203-216(14)

Publisher: Adis International

Abstract:

Investments in systems biology approaches by the pharmaceutical industry have not yet yielded the payoffs envisaged by many. In most cases, a plethora of novel drug targets arising from genomics led to many more failed projects in the pipeline, suggesting that target-based drug discovery may not be an optimal strategy for the industry. Before high-throughput `-omics' technologies and computer analysis became commonplace, most drug candidates were laboriously screened in animal systems to identify compounds that produced useful responses. Interestingly, the targets of many of the compounds that became drugs are still uncertain to this day. It is likely that drugs act on multiple targets in concert over time, the identification of which will require not only system level cataloguing and measurements, but next generation multiscale systems modelling. The concept of a `differentiated drug response' - elucidating and integrating responses composed of a range of effects on different tissues and, importantly, different time scales - may eventually prove to be the dominant paradigm of systems biology research. In this article, we explore key relevant concepts and technologies that we believe are critical for the future of systems biology and its place in pharmaceutical research.

Keywords: Research and development; Research Tools; Systems biology

Document Type: Leading article

Affiliations: 1: 1 Rosa & Co., La Jolla, California, USA 2: 2 PRTM, Newport Beach, California, USA

Computational systems biology in drug discovery and development

meson — Fri, 27 Jun 2008 00:14:55 +0900

Computational systems biology is an emerging field in biological simulation that attempts to model or simulate intra- and intercellular events using data gathered from genomic, proteomic or metabolomic experiments. The need to model complex temporal and spatiotemporal processes at many different scales has led to the emergence of numerous techniques, including systems of differential equations, Petri nets, cellular automata simulators, agent-based models and pi calculus. This review provides a brief summary and an assessment of most of these approaches. It also provides examples of how these methods are being used to facilitate drug discovery and development.

Why Web 2.0 Is No Bubble

meson — Thu, 26 Jun 2008 15:55:36 +0900

Why Web 2.0 Is No Bubble: Corporations Are Willing to Pay for It

Posted by Josh Bernoff on June 9, 2008 11:18 AM

Everyone seems to want an answer to the question "When will Web 2.0 startups start making money?" The implication is that unless we can answer the question, the "bubble" of Web 2.0 will burst and all of us who believe in this stuff will be revealed as fantasists.

The fact is, it's incredibly hard to make money as a Web 2.0 startup aimed at consumers.

There are hundreds of these companies, and they all clamor to brief us at Forrester. Each has its own twist on blogs, social networks, ratings, user generated video, or whatever. It's hard to get people to pay attention to a new tool, and the value of the tool depends on lots of participation -- the classic chicken-and-egg problem. Your competitor is always one twist ahead of you. Some of these startups will succeed but the odds are one in a thousand -- you need just the right idea, at the right time, with the right push or set of potential customers, and you need to take off with such velocity that you leave the competition in the dust.

Once a startup like this does take off, there's that other pesky little problem -- monetizing the success. Google transformed the online world by first generating huge traffic, then finding a business model. But Google's success was based on a fantastically clever advertising mechanism that was automated, attracted new advertisers, and served searchers nearly as well as it served advertisers. Facebook hasn't yet unlocked that advertising gold mine, and flubbed up its most prominent try with Beacon. Twitter has no business model yet. Ning has hundreds of thousands of visitors, but still runs Google AdSense ads. And these are the successes. No wonder people are skeptical.

A few of these companies may (and likely will) unlock that genie as Google did and take off. But for any given startup, the odds are astronomical.

The amazing thing is that there are a class of startup companies making good money right now from Web 2.0. They're not flashy and they don't grow like mushrooms. But they've got all the business they can handle and they are growing. I am talking about companies that serve corporate social application needs. This isn't the typical Web 2.0 business paradigm, since serving corporate customers means lots of client service, which is people-intensive -- it doesn't lift off miraculously like a pure technology startup. In fact, in many of these companies, the technology itself is positively mundane. But the startups grow because they deliver value for which they can charge a premium and get customer loyalty. The customers of these companies don't defect when something shiny and new comes along, because they like the service they're getting.

Here are some examples, listed by the objectives they help companies accomplish (for more on these objectives see Chapters 4 through 9 of Groundswell).

Listening. Communispace now has hundreds of private communities that its client companies are using to learn about their customers. It succeeds because it's unlocked the key to running and moderating these communities effectively, and grows despite charging $150K or more per year per community. The other class of listening companies are the brand monitoring companies, and the track record here is great. Research giant Nielsen bought BuzzMetrics. Another research giant, TNS, bought Cymfony. J.D. Power & Associates bought Umbria. MotiveQuest, which is still independent, has typical clients happily paying $30K and up to work with it.

Talking. Talking with the Groundswell is tricky, but there are plenty of agencies ready to help you with it. After building dozens of campaigns and sites, Blast Radius was bought by mega-agency Wunderman. Brains on Fire ignited the spectacular success of Fiskateers. The digital divisions of companies like Edelman also compete in this space, as do the big Web service companies like Avenue A/Razorfish (now part of Microsoft).

Energizing. Ratings and reviews are the easiest way to energize customers to sell others, and the companies that provide them are taking off. Bazaarvoice's clients have generated over 10 billion customer reviews. PowerReviews works with over 200 retailers. And ExpoTV has built a business around consumers creating reviews on video.

Supporting. Support forums work -- they please customers and they reduce costs. Lithium has an impressive client list including Dell, AT&T, Comcast, and Sprint. The community space is crowded, but other companies with growing client lists include Jive Software, Awareness, and Mzinga/Prospero.

Embracing. Startups that enable clients to source ideas from their customers have a bright future, because customer-generated innovation is hot right now. Salesforce.com bought Crispy News and turned it into Salesforce Ideas, which powers idea sites for Dell and Starbucks. And Innocentive is growing rapidly, with 50 companies including Procter & Gamble offering prizes of $10,000 or more to innovators that can solve their problems.

While many were distracted by sparkly consumer-facing startups, these companies were building and growing solid businesses. Look how many of them were acquired! This is no bubble, because companies that deliver business value to clients have durable growth potential. Could this be the Web 2.0 business model everyone is looking for?

Synthetic biology aims to solve energy conundrum

meson — Wed, 25 Jun 2008 02:10:47 +0900

Anti-Bacterial Drug Discovery Using Systems Biology

meson — Mon, 23 Jun 2008 02:21:56 +0900

Anti-Bacterial Drug Discovery Using Systems Biology

Author: Kumble, K. D.¹

Source: Mini Reviews in Medicinal Chemistry, Volume 6, Number 11, November 2006 , pp. 1275-1283(9)

Publisher: Bentham Science Publishers

Abstract:

The pipeline for new antibacterials is bleak despite the fact that infectious diseases account for a quarter of all worldwide deaths due to disease. Bacteria are ideal organisms for a systems biology approach to understanding pathogenesis by combined use of genomic technologies and computer algorithms. This approach can be applied to identify control points in molecular networks, which could be targets for novel drugs.

Keywords: Genomics; systems biology; molecular networks; antibacterials; pathogens

Document Type: Research article

DOI: 10.2174/138955706778742803

Affiliations: 1: Genesis Research and Development Corporation Limited, One Fox Street, Parnell, Auckland, New Zealand.

DNA Deletion Linked to Autism

meson — Thu, 10 Jan 2008 15:40:08 +0900

Thursday, January 10, 2008

DNA Deletion Linked to Autism

A massive new study of the genetics of autism could lead to diagnostic tests and, eventually, to the identification of new drug targets.

By Emily Singer

A specific structural variation on chromosome 16 dramatically boosts the risk of autism, according to a study published today in the New England Journal of Medicine. The finding--one of the most significant to date--permits the development of new diagnostic tests to identify children at risk, and could ultimately point to specific biochemical pathways to target in drug development.

"This is one of the single largest [influences] and most frequent genetic causes for autism identified so far," says Bai-Lin Wu,director of the Genetics Diagnostic Laboratory at Children's Hospital Boston and one of the senior authors on the study.

Autism spectrum disorder--or autism, as it is commonly called--refers to a group of developmental disabilities with wide-ranging language, social, and behavioral symptoms. The disorder is known to have a strong genetic influence, with up to 90 percent of cases thought to have a genetic component. However, because the disorder is linked to a combination of genetic variations, each playing a minor role, identifying specific genetic triggers has been difficult. Now new microarray technologies, which allow scientists to screen a million or more genetic variations in thousands of patients, are enabling the much larger studies needed to pinpoint these triggers.

In the new paper, scientists say that they used microarrays to scour the DNA of more than 2,000 individuals with autism. They found that deletion or duplication of approximately 500 of the same DNA letters on chromosome 16 was strongly linked to autism, accounting for about one percent of cases. "While that doesn't sound like a huge number, the fact that these people carry the identical spontaneous deletion or duplication would be incredibly unlikely to happen by chance," says Mark Daly, a geneticist at Massachusetts General Hospital's (MGH) Center for Human Genetic Research, in Boston, and at the Whitehead Institute, in Cambridge, and one of the study's senior authors.

The results were independently identified by three different groups--at MGH; Children's Hospital Boston; and deCODE Genetics, in Iceland--that are studying three different populations, giving added weight to the work.

The findings build on previous reports that autism is linked to genetic deletions or duplications that arise spontaneously, rather than being passed down through generations. In almost all cases, parents of the affected people did not carry the chromosome 16 variation.

One of the most immediate clinical benefits of the research will be the development of inexpensive diagnostic tests. "Because the variation occurs so frequently, you could directly test for the presence or absence of a duplication or deletion as part of standardized genetic testing for autism," says James Gusella, a neurogeneticist at Harvard Medical School, in Boston, who participated in the research. For example, children who show developmental delays but are too young to undergo clinical autism testing could be screened for this variation, allowing parents and doctors to prescribe intervention for those who test positive. "We will be able to find at-risk children early on so that language and behavior problems can be treated much earlier," says Yiping Shen, director of research and development at Children's Hospital's Genetics Diagnostic Laboratory, who was also involved in the work.

Such testing could also predict if parents with one autistic child are at greater risk of having another; if their child's autism is linked to a spontaneous variation, they are at no greater risk than the general population. Researchers at Children's Hospital, which provides genetic testing to families, are already developing a clinical diagnostic test.

Scientists are also trying to pinpoint the specific gene or genes within this section of DNA that underlie the increased risk. Daly and his collaborators plan to sequence this region of the genome in another group of people with autism, in search of single-letter mutations that might disrupt the function of specific genes. "Genetics provides us with the only opportunity to gain insight into the biological mechanisms that underlie autism," says Daly. "We can look at individual gene discovery as a small first step in the overall path to develop treatments."

Previous studies have identified autism risk genes. However, these studies have focused on people with genetic disorders that often co-occur with autism, such as Fragile-X syndrome, complicating the role those genes play in the disorder. "Up until now, we haven't had the capacity to look at a single gene that is associated with pure autism," says Gusella.

The findings could point to additional spots in the human genome to search for autism risk genes. The variation on chromosome 16 lies within a genetic "hot spot," an area that is predisposed to undergoing structural duplications due to the architecture of the DNA, says Evan Eichler, a geneticist at the University of Washington in Seattle, who wrote an editorial accompanying the paper. "Every time we produce gametes, there's a finite probability of this region to duplicate," he says. In addition, the region has a high concentration of genes that are rapidly evolving in humans. While the significance of that finding is not yet clear, it may explain autism's status as a relatively young disease.

A Novel Approach to DNA Analysis

meson — Thu, 08 Nov 2007 17:23:14 +0900

Thursday, November 08, 2007

A Novel Approach to DNA Analysis

Comparing fruit flies reveals a new way to identify the functional elements of genomes.

By Anna Davison

In a milestone for the emerging field of comparative genomics, an international team of scientists has carried out a comparative analysis of the genome sequences of 12 different species of fruit flies. Not only did the researchers uncover patterns in the way that genes evolve as species adapt to different environments, but they also developed a new way of identifying the functional elements of the genome--a discovery with potentially far-reaching consequences.

For more than a hundred years, the fruit-fly species Drosophila melanogaster has been instrumental in the study of genetics, developmental biology, and animal behavior. Because a significant number of human genes have fruit-fly analogues, researchers have also used the insect to study many human diseases, including cancer, diabetes, and neurodegenerative disorders such as Alzheimer's. In 2000, scientists published the genome sequence for D. melanogaster; the sequence of a second fruit-fly species followed several years later.

There are 1,500 species of fruit flies, however, and they vary in appearance, behavior, and habitat. To fully understand the fruit-fly genome and how it has evolved, a consortium of more than a hundred labs around the world sequenced an additional 10 species and compared all 12 sequences. The group details its findings in two reports published in the November 8 issue of Nature.

"If you want to get a crystal-clear picture of how genes influence what an animal will look like, what it will eat, what behavior it will exhibit, this is a completely unparalleled resource for doing that," says Leslie Vosshall, a neurogeneticist at Rockefeller University, in New York.

The researchers selected species from all over the world--from Africa, Asia, the Americas, and the Pacific Islands. Some species are widespread and feed on a range of foods, whereas others are more limited. For instance, one species lives only on the Seychelles islands off the east coast of Africa and eats only one kind of fruit.

In one of the papers, a team led by Manolis Kellis, a computational biologist at MIT, compared the 12 sequences in order to identify all the functional elements in the fruit-fly genome. These include not only genes that code for proteins, but also sequences that help regulate gene expression by, for instance, encoding small RNA molecules that bind to other parts of the genome. To find these elements, researchers typically look for sequences that are common, and therefore highly conserved, among different genomes. "The basic premise of comparative genomics is that if something is conserved over millions of years in a dozen species, it's likely to do something useful," says Kellis.

But Kellis and his colleagues were also seeking an alternative strategy. They figured that by looking only for sequences that have remained roughly the same, they would miss a large number of functional elements. For instance, protein-coding genes can undergo extensive changes and yet retain their critical functions.

By looking at all 12 genomes, the team found that each type of functional element changes in characteristic ways over time, and those patterns of change serve as evolutionary signatures. For instance, a series of three-letter DNA sequences in which the first two letters are always conserved but the third one changes is likely to be a protein-coding gene, says Kellis. So the researchers designed computer algorithms to mine the sequence data and find the evolutionary signatures for each type of functional element. "This allowed us to find things that we would never have expected to find just by looking at a single genome," says Kellis.

Kellis's team found thousands of previously unidentified functional elements, including 150 protein-coding genes and more than a hundred microRNA genes. (MicroRNAs are short segments of RNA that silence genes by binding to specific sites in the genome.) The researchers also found that some genes, during their translation into proteins, ignore certain instructions and, as a result, acquire bits of protein encoded by other genes. "This is an entirely new mechanism," says Kellis, adding that his group has since found evidence of this mechanism in the human genome as well.

The second Nature paper describes research led by Andrew Clark, a population geneticist at Cornell University, who looked at known genes to see how they vary from one species to another and how they evolve, acquiring new functions as species adapt to their changing environments. Genes involved in the immune system, for instance, appear to evolve more rapidly than genes in the rest of the genome. The same was true for genes that regulate insecticide resistance.

Taste and smell receptor genes also undergo frequent changes. When the researchers compared species of flies that are generalists with those that have more specialized food preferences, they found that the specialists lose genes for different taste receptors at a much higher rate than the generalists do. "How you smell the world influences how you eat, and this will tell us an enormous amount about how genes that encode for smell and taste influence behavior," says Vosshall.

The studies of the 12 fruit-fly genomes will no doubt help scientists better understand the human genome, says Kellis. Not only do fruit flies and humans have so many genes in common, but now researchers have a systematic way of interpreting genomes that could lead to the discovery of entirely new kinds of functional elements, he says.