Neuroscientists spot nature/nurture gene link

Neuroscientists at MIT's Picower Institute for Learning and Memory found that a previously unsuspected set of genes links nature and nurture during a crucial period of brain development

Nature--in the form of genes--and nurture--in the form of environmental influences--are fundamentally intertwined during this period.

"Our work points to how a disorder can be genetic and yet be dependent on the environment," said co-author Mriganka Sur, Sherman Fairchild Professor of Neuroscience at the Picower Institute and chair of MIT's brain and cognitive sciences department. "Many genes require activity to be expressed and make their assigned proteins. They alter their expression when activity is altered. Thus, we reveal an important mechanism of brain development that should open up a window into the mechanisms and treatment of brain disorders such as autism."

In the brain, some genes are only expressed, or turned on, in response to stimulus from the outside world. Like a panel of switches that turn lights on and off, genes that don't receive electricity don't "turn on" and express their particular proteins.

Sur and colleagues found a set of novel genes--including a calcium sensor called cardiac Troponin C, or cTropC--particularly sensitive to a critical period of development. The lack of proteins from these genes during a key phase of development could be one of the culprits in developing autism.

Researchers have long investigated the molecular mechanisms involved in monocular deprivation--when one eye is deprived of sight during a critical period of brain development, that eye becomes permanently blind, even after it is uncovered. This phenomenon is considered an important model for brain development because synapses for the covered eye--deprived of environmental stimulus, or what Sur calls "nurture"--shrivel up or get reassigned to other uses.

Sur and his colleagues looked at which genes are expressed, and which are not, when this phenomenon occurs. They hoped to pin down the correlation between nature--meaning the genes--and the external environment, or nurture. By identifying which genes are particularly apt to switch their expression patterns in response to "nurture," the researchers potentially narrowed down the ones that may be implicated in developmental disorders.

Researchers believe autism spectrum disorders are tied to brain changes that occur during critical periods of development. Different but overlapping critical periods are thought to exist for various cognitive functions affected in autism, such as language and social behaviors.

"Autism is a strongly genetic disorder: genes set up risk factors but by themselves simply make proteins," Sur said. "Genes work together with other influences. In the case of autism, these influences are unknown but could be molecules made by other genes or chemicals from the environment."

If scientists understood how genes changed in response to environmental influences during this crucial developmental period, they might be able to one day prevent or reverse the changes.

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New method devised for protecting private data

Companies and organizations that keep sensitive personal information on millions of Americans have become attractive targets for hackers in recent years, resulting in billions of dollars in losses for U.S. businesses and misery for countless consumers.

But now Amit Sahai, an associate professor of computer science at the UCLA Henry Samueli School of Engineering and Applied Science, and his colleagues have devised a new data-protection method they hope will put Internet criminals out of business.

"We want to change the rules of the game on hackers and even out the playing field," Sahai said.

Along with co-authors Brent Waters, a UCLA computer science alumnus, and Jonathan Katz of the University of Maryland, Sahai has come up with a mathematical system -- known as functional encryption -- that will not only help to simplify the encryption of data in servers but will also allow access to the data in an intuitive way, making it much harder for hackers to gain access to sensitive information but much easier for programmers to secure it.

While the method is not yet available for public use, it has received close attention from the data-encryption community. The authors' study, chosen as one of the top four papers at Eurocrypt 2008 -- one of two flagship international conferences in cryptography -- was presented this week at the conference in Istanbul.

In it, Sahai and his colleagues suggest that the biggest problem in data security today is that the world relies on "trusted servers" to store and secure data.

"This 'trusted server' model is a simple model," Sahai said. "It's easy to implement. It's easy to put into practice. Information is placed in the server at face value and the server itself is simply given the task of deciding who to give the data to. Because of the simplicity in programming, these servers have become ubiquitous and are prime targets -- everyone wants to attack them."

An additional problem with trusted servers, the authors say, is the current trend toward replicating data on a wide scale.

"To create robustness and availability, data is stored on several trusted servers as backups," said Waters, currently with the nonprofit research institute SRI. "If one server goes down, another can be accessed. There is a trade-off between data availability and security. The more replicated servers there are, the more targets there are for hackers."

The results of this lack of security speak for themselves. According to a 2007 FBI analysis, Internet crime costs U.S. businesses some $67 billion annually, including the indirect expense of repairing hacked systems. TJX, the parent company of discount clothing chains T.J. Maxx and Marshalls, revealed that during a recent 18-month period, hackers had stolen 45.6 million credit card numbers and other sensitive customer information. For every two Americans, one private record has been stolen through computer data breaches alone.

Cryptography, the practice and study of hiding information, is considered to be a branch of both mathematics and computer science and is closely tied to information theory, computer security and engineering. And while the technology of encryption has been around a long time, encrypting data and then deciding how to allow access to hundreds or even thousands of people has been a dilemma, Sahai said.

"Imagine current encryption technology as a lock and key -- the data is locked, and to allow different people access, many copies of the key need to be made," he said. "One record might need to be accessed by 10,000 people, so you make 10,000 copies of that key. With millions of documents and thousands of keys per document, you can imagine how very, very complicated it gets. It becomes much too complicated to manage. So even though we've had very strong encryption technology now for decades, it's just not used, or it is used incorrectly."

The study authors' new functional encryption method allows a programmer to simply plug in his criteria for the information. The mathematical system will then produce an encrypted record that only people matching the criteria can decrypt. The complex system of managing many keys is now simplified, and servers hold encrypted data that the servers themselves can't read. The information looks like gibberish to hackers.

In addition, the new mathematical system allows for keys to be personalized -- only one key is needed to unlock all the information that is available to that person.

"This is the key innovation in our system," Sahai said. "We have this mathematical method for randomization of personalizing keys so that your key doesn't just depend on what attributes you have, like what your name is. Further, there is some mathematical hardening that is personalized to you, so that you can't combine it with anyone else's keys to do anything meaningful."

The system severely restricts what a hacker can do. If he is an insider, he is limited by what access he legitimately has, and since keys are personalized, it becomes much easier to trace who accessed and released the information in the first place.

Sahai and Waters are considered the founders of the area of functional encryption. Sahai recently won a prestigious 2007 Okawa Research Grant Award from Japan's Okawa Foundation for his work in this area.

"Some of this work is already being implemented and is actually being incorporated into some research systems," Sahai said. "It's making its way closer to practice. Brent and I were able to apply for a patent on the very initial work we did, which was bought by a company called Voltage Security. There certainly is interest from the U.S. military and the U.S. Department of Homeland Security as well."

"Our goal is to rethink what encryption is," Waters said. "Over the years, people have taken on a somewhat rigid view of what encryption is. What we're hoping to do is show that we can build simpler and more powerful systems by changing the way we think. Eventually, we hope to get rid of complex infrastructures and do things in a simpler manner that is also more secure and cost-effective."

VIA

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Gene variant increases risk of asthma

A tiny variation in a gene known as CHI3L1 increases susceptibility to asthma, bronchial hyperresponsiveness and decline in lung function, researchers report early online in the New England Journal of Medicine. (The printed version will appear in the April 17 issue). The gene variant causes increased blood levels of YKL-40, a biomarker for asthma. A slightly different version of the genetic variation lowers YKL-40 levels and protects against asthma.

Although the original discovery came from a study of a genetically isolated population, the Hutterites of South Dakota, the researchers were able to confirm the same connections between the CHI3L1 variations, YKL-40 levels and asthma susceptibility in three genetically diverse Caucasian populations from Chicago; Madison, Wisconsin; and Freiberg, Germany.

This gene, "may have important implications in the early identification of, susceptibility to, and prevention and treatment of asthma,” said Elizabeth G. Nabel, M.D., director, the National Heart, Lung, and Blood Institute.

"This is exciting because it connects asthma susceptibility to a whole new pathway at the protein and the genetic levels," said study author Carole Ober, professor of human genetics at the University of Chicago Medical Center. "There is a good deal more we need to find out about this connection, but now we know where to look."

"This is also the most significant genetic discovery based on our years of gathering data on asthma in the Hutterites," Ober added. "This is a group with enormous potential to advance our understanding of the genetic underpinnings of disease. We now have a remarkable collection of data, which we expect will lead us to many more insights."

Ober and colleagues at the University of Chicago had long been searching for genetic factors that could influence the risk of common diseases, such as asthma. To simplify this quest, they have focused since 1994 on the Hutterites, a genetically isolated U.S. religious community descended from about 90 people. The Hutterites came to the United States in 1874 and settled in small communal farming colonies in what is now South Dakota. Today Hutterite communities are present in the Dakotas, Minnesota, Montana, Washington and Canada.

They provide an ideal community for genetic studies because they are all members of a large pedigree that is known back to the 1700's and they live communally, sharing resources and maintaining a traditional lifestyle. "They eat the same food, live off the same allowance and have the same education," said Ober, who has been working with them since 1979. They have similar, but not identical genomes. "So the genes that make a difference are easier to detect."

In 1996 and 1997, Ober's team gathered clinical data about asthma from more than 700 members of the Hutterite communities, and stored blood samples that were recently used to measure YKL-40 levels. About 11 percent of Hutterites had asthma and another 12 percent had bronchial hyperresponsiveness.

The genetic studies took on a sharper focus in 2007, when a team led by Geoffrey Chupp of Yale University showed that, on average, patients with asthma had higher levels of the protein YKL-40 in their blood than people without asthma, and that those with more severe asthma had even higher levels.

YKL-40, a natural suspect as a cause of asthma, belongs to a family of enzymes called chitinases. These enzymes are part of the innate immune system's response to chitin, a common biologic polymer found especially in insects – including dust mites and cockroaches, which have been associated with asthma – as well as in certain disease-causing organisms, including fungi and parasitic worms. The chitinases help break down chitin. They also trigger inflammation, which is a central component of asthma.

Working with Chupp's laboratory, Ober found that mean YKL-40 levels were also increased among Hutterites with asthma or hyperresponsive airways. Ober's group also showed that these elevated YKL-40 levels were handed down from generation to generation, indicating that differences between individuals were due nearly entirely to genetic differences.

So they began looking for variations in the CHI3L1 gene on chromosome 1 that codes for YKL-40. They found one very slight genetic difference between those with asthma and those without. Hutterites with asthma were more likely to have a small but consistent variation in one part of the gene, called a promoter, which regulates when the gene is expressed.

That variation changes one DNA base pair, out of the 3 billion in the human genome, at a location in the CHI3L1gene known as -131C/G. Those with asthma were more likely to have a cytosine (C), rather than guanine (G) at this location.

Those inheriting two copies of a C at -131 had higher YKL-40 levels and an asthma prevalence of 0.20. Those with CG had intermediate YKL-40 levels and an asthma prevalence of 0.12. Those with GG had the lowest YKL-40 levels and a prevalence of only 0.08, less than half that of the CC allele.

To see if these results could be generalized from the genetically isolated Hutterite population to a more diverse group, the researchers tested the same variations in the CHI3L1 gene in 178 Caucasian children enrolled in prospective birth cohort, known as COAST, a collaboration led by Robert Lemanske of the University of Wisconsin at Madison.

They also looked for correlations between asthma and SNP -131C/G in two clinical samples, one from the Children's University Hospital in Freiberg, Germany (344 children with asthma and 294 without), and one from the asthma clinics at the University of Chicago Medical Center (99 children and adults with asthma and 197 without).

In the two clinical samples, those with the CC configuration at position 131 were more likely to have asthma, with CG intermediate and GG the lowest risk of the disease. In the COAST cohort, many subject were still too young to have developed asthma, but the genetic patterns was closely associated with YKL-40 levels, and this association was already present at birth.

The authors suspect that the change from C to G at this site reduces expression of the gene, resulting in lower levels of YKL-40 and protection from asthma.

Although variation in CHI3L1 appears to be one of the most significant genetic triggers yet discovered for susceptibility to asthma, it is far from the sole cause of the disease, the researcher caution. In the Hutterites, it explains 9.4 percent of the variance in YKL-40 levels, suggesting that additional genetic variants also influence these levels. Finding those variations "could identify additional genes," they add, "with significant impact on asthma risk and lung function."

"This evolutionarily ancient pathway involving the innate immune system plays a surprisingly important role in asthma pathogenesis," said Ober, "and a single genetic variant in the CHI3L1 gene may account for most of this risk."

This could have a significant impact on drug development, she added. "For some people, if you block YKL-40 you might dramatically reduce the severity of the disease. Knowing the genotype at SNP -131C might identify those who most likely to benefit from such a treatment."

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Scientists show first 3-D image of antibody gene

Using a multidisciplinary mix of geometry, biological research and techniques developed to solve problems on supercomputers, scientists at the University of California, San Diego have shown for the first time how a genome is organized in three-dimensional space.

The 3-D structure of the immunoglobulin locus in B cells is shown, with the relative positions of the different portions of the immunoglobulin genes. Grey objects indicate constant regions. Blue objects indicate proximal variable regions. Green objects indicate distal variable regions. Red line indicates the linker connecting the proximal variable and joining regions.

Researchers led by Cornelis Murre, a professor of biology at UC San Diego, and Steve Cutchin, senior scientist for visualization services at the San Diego Supercomputer Center (SDSC), used the gene encoding the immunoglobulin heavy chain locus — responsible for generating diverse kinds of antibodies — to demonstrate the structure of the genome.

The observations, the researchers say, permit an insight into the structure of the human genome, which until now has remained elusive.

Their results, “The 3-D Structure of the Immunoglobulin Heavy Chain Locus: Implications for Long-Range Genomic Interactions,” are published in the April 18 issue of the journal Cell.

Because the genome is the most essential part of the cell for storing and accessing genetic information, the complete DNA sequence of a wide variety of genomes has been revealed in studies performed in a large number of laboratories — “a tremendous success that has provided insight into mechanisms that underpin the development of a wide variety of diseases,” the authors say.

However, Murre said, “it has remained unclear as to how the genome is organized in three-dimensional space. This is an important issue since the regulation of gene expression is controlled by interactions of genomic elements that are separated by large genomic distances. Thus, our team wanted to determine how the genome is structured within the nucleus.”

The experiments described in the Cell paper, he said, provide a first glimpse into this question. “As a model system, we used the gene encoding for the immunoglobulin heavy chain locus, because it is responsible for generating the wide diversity of antibodies.”

Having measured the distances that separate the various parts of the gene, Murre said, the researchers, in collaboration with Cutchin at the SDSC, then used geometry to resolve the first structure of a genetic locus.

His work, said Cutchin, involved computational geometry, scientific visualization, computational methods and numerical methods.

“The resulting structure shows that the antibody gene is organized into ‘flower-like’ structures that are connected by linkers,” said Murre. “These flowers contain the various parts that ultimately generate the wide variety of antibodies. This is the first time that geometry has been used to determine the structure of a genetic locus. Ultimately, the same approach should be used to elucidate the structure of the entire human genome.”

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