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December 2007 Posts
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December 20, 2007

Pinot Noir Genome Sequence Could Help Cut Costs of Wine Production

Good science, great wine, better prices--everybody wins!

Pinot Noir Genome Sequence Could Help Cut Costs of Wine Production December 20, 2007 By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – The newly published genome sequence of the pinot noir grape could reduce the cost of producing some popular wines, according to the research team that conducted the study.

The study, led by Riccardo Velasco and colleagues at Italy’s Agrario di San Michele all'Adige, was published in the open-access journal PLoS One this week. The research team used a combination of Sanger sequencing and 454 Life Sciences’ Genome Sequencer 20 to sequence the pinot noir plant’s 500 million base pairs.

The researchers used Sanger sequencing to generate 6.5X coverage and 454 sequencing to produce 4.2X coverage of the Vitis vinifera pinot noir clone ENTAV 115, a variety grown in a range of soils for red and sparkling wines.

Grape vines can be problematic to cultivate and are susceptible to a number of diseases caused by fungi, bacteria, and viruses.

The researchers expect that the pinot noir genome will provide insight into creating disease-resistant grape varieties without altering the quality of the resulting wine.

As part of the sequencing study Velasco and colleagues identified a number of genes that are related to disease-resistance, of which 289 contain one or more SNPs.

The study found that the grape plant has a relatively small genome for a crop plant, with more than two million SNPs and 28,585 genes.

“Pinot Noir has a highly complex heterozygous genome, which presents significant challenges to any sequence and assembly effort,? said 454’s VP of R&D, Michael Egholm, in a statement.

Although this complexity made the sequencing difficult, the researchers said it provided a “massive library of inherent variation? for studying how genes influence plant growth.

The genome also could provide information about pinot noir evolution, which has been complicated by its history of cultivation.

The researchers found that ten out of the plant’s 19 chromosomes resulted from a duplication that occurred shortly after the plant’s lineage diverged from that of the model plants Arabidopsis and poplar.

This genome sequencing “presents an opportunity to direct genetic improvement or disease resistance,? said Brian Dilkes of the University of California Davis’ Genome Center. It also could allow breeding for disease resistance without compromising grape flavor or quality, Dilkes added.

"The sequence of the grape genome, together with the large arsenal of SNP loci, now offers a tool to open a new era in the molecular breeding of grapes,? Velasco said.


Discovery Points to Treatment Approach for Fragile X Syndrome

This work has the potential to be a major breakthrough in the treatment of Fragile X Syndrome. Of course, this is just the first step. Understanding the mechanism for a condition does not mean we can cure them in most cases, but this does open the possibility for developing pharmacological or other interventions that may ameliorate the phenotype in affected individuals. The potential is really exciting to contemplate.

Discovery Points to Treatment Approach for Fragile X Syndrome

December 20, 2007 -- New research has found that many of the symptoms of fragile X syndrome, the most common cause of inherited mental retardation, can be eliminated in mice by reducing the expression of a single gene in the brain.

The study suggests that the gene is a prime target for drugs to alleviate symptoms of the disorder, for which there is currently no specific treatment.

Howard Hughes Medical Institute investigator Mark Bear and his colleagues reported their findings in the December 20, 2007, issue of the journal Neuron. Gül Dölen, a member of Bear's laboratory at Massachusetts Institute of Technology, was the lead author of the research article. Bear and Dölen collaborated with researchers at Brown Medical School, India's National Institute of Mental Health and Neuroscience, and the Tata Institute of Fundamental Research in Bangalore, India.

“The most exciting consequence of that theory was that it might be possible to correct fragile X by dialing back mGluR5 activation.?

Mark F. Bear

Fragile X syndrome is the most common inherited form of mental retardation and is estimated to affect approximately 90,000 people in the United States. The condition is caused by a mutation in the FMR1 gene on the X chromosome that prevents expression of a single protein, fragile X mental retardation protein (FMRP). The effects of fragile X vary between individuals, ranging from learning disability and hyperactivity to severe mental retardation. In addition to cognitive impairment and autistic behavior, children with fragile X can experience epileptic seizures and abnormal growth.

The disorder is caused by loss of a functional version of FMRP. Bear and his colleagues suspected that FMRP might suppress protein synthesis in the brain and work in opposition to metabotropic glutamate receptor-5 (mGluR5), which turns on protein synthesis. “The theory was that when FMRP was removed, protein synthesis was placed on a hair trigger, and that many pathologies of fragile X might be a consequence of that increase in protein synthesis,? he said. “The most exciting consequence of that theory was that it might be possible to correct fragile X by dialing back mGluR5 activation.?

To test this idea, the researchers knocked out one of the two copies of the gene for mGluR5 in mice that also lacked the gene for FMRP. The genetically engineered mice exhibited many of the symptoms observed in humans who have fragile X. By knocking out one copy of mGluR5, the researchers created mice that produced only half the normal amount of mGluR5 protein. And by cutting mGluR5 production in half, the researchers hoped that this would compensate for the lack of FMRP and eliminate the symptoms of fragile X.

“We decided to reduce the mGluR5 levels by 50 percent to reflect what might be a therapeutically relevant condition that would be achievable with carefully titrated drug treatment,? said Bear. “Total knockout of mGluR5 has deleterious effects, whereas reducing it by half is innocuous.?

The researchers found that reducing mGluR5 eliminated many of the symptoms of the disorder. Like humans with fragile X, mice without FMRP experience seizures, impaired memory, and accelerated body growth. When mGluR5 was diminished, these problems were corrected.

The reduction in mGluR5 also compensated for changes in the brain associated with increased protein synthesis. With less mGluR5, the brain of each mouse no longer formed an excessive number of neuronal connections. And the mice did not have a high density of dendritic spines that is characteristic of fragile X syndrome. Furthermore, the total rate of protein synthesis was reduced to normal levels in the brains of fragile X mice with reduced mGluR5.

The results of these experiments suggest drugs that block mGluR5 could prove to be the first effective treatment for fragile X syndrome, said Bear. Pharmaceutical companies have already developed a number of experimental drugs that block mGluR5, he said. Clinical trials are underway, but none of the drugs has yet been approved for humans. To speed drug development, Bear founded Seaside Therapeutics, a company that is now exploring the use of anti-mGluR5 drugs to treat fragile X syndrome.

Next on Bear's scientific agenda is an effort to determine which brain proteins are regulated by FMRP and mGluR5. Such information could help drug designers target pathologies of the disorder more precisely, he said. Bear and his colleagues are also exploring whether FMRP suppresses additional protein synthesis accelerators. These proteins might also make good targets for therapeutic drugs, Bear said.

Finally, he said, defects in the regulation of mGluR5 might also contribute to autism. “A picture is beginning to emerge that many single-gene disorders that cause autism might turn out to be genes that are similarly involved in the negative regulation of protein synthesis,? he said. “Thus, a significant fraction of cases of autism might be accounted for by excessive cerebral protein synthesis. If that were true, then mGluR5 antagonists might be therapeutically useful for much more than just fragile X.?

Source: http://www.hhmi.org


December 5, 2007

Gene Chips, SNP's and Mainstream Medicine

From today's Genome Web Daily News:

Coriell to Use Affy Chips to Genotype Thousands of Volunteers; Project Will Study Effect of Genetic Risk Factors on Treatment

December 5, 2007

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – The Coriell Institute for Medical Research yesterday kicked off the Delaware Valley Personalized Medicine Project, an initiative that plans to genotype up to 100,000 patient volunteers with the goal of studying the use of genetic risk factors in patient care.

The project will use Affymetrix’s Genome-Wide Human SNP Array 6.0 genotyping platform.

Coriell said the DVPMP will enroll 10,000 participants for the project over the next three years and eventually plans to reach 100,000 participants. Other partners in the program include the Fox Chase Cancer Center, Cooper University Hospital, and Virtua Health.

The initiative has so far raised $5 million from the William G. Rohrer Foundation, the William T. Read Legacy Fund, Eleanor Read, the Daniel J. Ragone Family Foundation, and Coriell's endowment.

In a statement, the DVPMP differentiated itself from “for-profit personal genome companies? because it “aims to explore use of genetic risk factors in clinical decision-making.?

Under the project, participants will be encouraged to consult with their physicians about their risk variants “and to make important decisions about preventative care and proper medical treatments,? Coriell said.

All patient volunteers “will control access to their genetic profiles and will determine whether they wish the information to become part of their medical records in the future,? the institute added. There is no charge to participate.

Erin O'Shea, a professor of molecular biology at Harvard University, will chair the project’s Informed Cohort Oversight Board, which will determine which risk variants are “appropriate? for use by patients and physicians to improve health.