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A new study uncovers a molecular mechanism that explains why joints fail to develop in embryos with paralyzed limbs. The research, published by Cell Press in the May issue of the journal Developmental Cell, answers a longstanding question about the influence of muscle activity on developing joints and underscores the critical contribution of movement to regulation of a signaling pathway that is important during development and beyond.

Joint development requires changes in gene expression that “commit” cells to becoming part of the developing joint and distinguish them from the surrounding cartilage tissue. Previous research has shown that the Wnt/-catenin signaling pathway plays a key role in maintaining this joint cell fate and preventing joint cells from differentiating into cartilage.

It is also clear that muscle contraction is involved in proper formation of the skeleton. “We have known for over a century that embryonic movement is intimately involved in development of the joints. However, the precise mechanism by which active musculature regulates joint formation has remained elusive,” explains senior study author Dr. Elazar Zelzer from the Department of Molecular Genetics at the Weizmann Institute of Science in Israel.

Dr. Zelzer and colleagues confirmed that the normal process of joint formation was disrupted in mouse models that lacked limb musculature or muscle contractility. They then noted that cells at the presumptive joint sites ceased to express classical joint markers and instead followed a pathway for developing cartilage. Local loss of ?-catenin activity explained why the joints failed to form.

“Prior to the current study, the mechanisms that underlie the contribution of movement to the process of joint development were mostly missing,” says Dr. Zelzer. “Our findings show that muscle contraction is necessary to maintain joint progenitor cell fate and explain how and why movement-induced mechanical stimuli play a key role during development.”

Importantly, the current results also establish joint formation as a context in which to study mechanical regulation of the Wnt/-catenin signaling more generally. The ability to respond to mechanical stimuli may also affect -catenin-related tumorigenesis in disorders such as colon cancer.

The researchers include Joy Kahn, Weizmann Institute of Science, Rehovot, Israel; Yulia Shwartz, Weizmann Institute of Science, Rehovot, Israel; Einat Blitz, Weizmann Institute of Science, Rehovot, Israel; Sharon Krief, Weizmann Institute of Science, Rehovot, Israel; Amnon Sharir, Weizmann Institute of Science, Rehovot, Israel, Hebrew University of Jerusalem, Rehovot, Israel; Dario. A. Breitel, Weizmann Institute of Science, Rehovot, Israel; Revital Rattenbach, INSERM-UPMC-Paris VI, Faculte?? de Medecine Pitie-Salpetriere, Paris, France; Frederic Relaix, INSERM-UPMC-Paris VI, Faculte?? de Medecine Pitie-Salpetriere, Paris, France; Pascal Maire, INSERM U567, CNRS UMR8104 Universite?? Paris Descartes, Paris, France; Ryan B. Rountree, Stanford University School of Medicine, Stanford, CA; David M. Kingsley, Stanford University School of Medicine, Stanford, CA; and Elazar Zelzer, Weizmann Institute of Science, Rehovot, Israel.

Source:
Cathleen Genova

Cell Press Continue reading →

An online tool to help educators teach the next generation of nurses and physician assistants about genetics and genomics has been launched by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. The tool is part of NHGRI’s effort to address the growing need among health care professionals for knowledge in this area, which is paving the way for more individualized approaches to detect, treat and prevent many diseases.

The Genetics/Genomics Competency Center (G2C2), developed by the University of Virginia in Charlottesville through a contract with NHGRI, is a free, Web-based collection of materials on genetics and genomics designed for educators who train nurses and physician assistants. To access this resource, visit g-2-c-2.

“As we enter the era of personalized medicine, establishing genetic and genomic literacy is an urgent concern for those who educate health professionals. This online resource will provide a valuable new tool for meeting that challenge,” said Jean Jenkins, R.N., Ph.D., NHGRI senior clinical advisor to the director. “In the future, we hope to expand this tool to include other health care professions, such as pharmacists and physicians.”

Dr. Jenkins announced the new resource at the 2010 American Association of Colleges of Nursing (AACN) Master’s Education Conference in New Orleans.

Nursing and physician assistant educators can use the Genetics/Genomics Competency Center to find and download materials for use in their classrooms. They also can share their favorite genomic and genetic teaching resources and materials with other educators by uploading material, which is regularly reviewed by the center’s editorial board to ensure quality control.

The Genetics/Genomics Competency Center was created under the guidance of an advisory group made up of representatives from a wide range of research and professional organizations. In addition to AACN, participating organizations included the American Academy of Physician Assistants, National Cancer Institute, National Coalition for Health Professional Education in Genetics, National League for Nursing, National Society of Genetic Counselors, Physician Assistant Education Association and Sigma Theta Tau International, the honor society of nursing.

“We’re very excited that physician assistants were included in this pioneering effort. Our profession has been at the vanguard of realizing the importance of genetics and genomics in the future of medicine, and encouraging efforts to incorporate more of these key concepts into education and training,” said physician assistant Michael Rackover, M.S., an advisory group member who directs the physician assistant program at Philadelphia University.

To encourage sharing and reduce duplication across health care disciplines, the Genetics/Genomics Competency Center helps to match existing educational resources with educational competencies for health professionals. The online center accomplishes this through sophisticated, cross-mapping of learning activities and assessments, outcome indicators and professional competencies, such as Genomics Nursing: Competencies, Curricula Guidelines and Outcome Indicators, (click here for more information), and similar guidelines for physician assistant education, paeaonline/index.php?ht=d/ContentDetails/i/60083.

NHGRI’s Genomic Healthcare Branch will host a webinar this spring to provide educators with a tutorial on using the tool and answer questions about the resource.

Source:
Omar McCrimmon
NIH/National Human Genome Research Institute Continue reading →

A study by Yale researchers offers a new view of what causes the greatest genetic variability among individuals – suggesting that it is due less to single point mutations than to the presence of structural changes that cause extended segments of the human genome to be missing, rearranged or present in extra copies.

“The focus for identifying genetic differences has traditionally been on point mutations or SNPs – changes in single bases in individual genes,” said Michael Snyder, the Cullman Professor of Molecular, Cellular & Developmental Biology and senior author of the study, which was published in Science Express. “Our study shows that a considerably greater amount of variation between individuals is due to rearrangement of big chunks of DNA.”

Although the original human genome sequencing effort was comprehensive, it left regions that were poorly analyzed. Recently, investigators found that even in healthy individuals, many regions in the genome show structural variation. This study was designed to fill in the gaps in the genome sequence and to create a technology to rapidly identify SV between genomes at very high resolution over extended regions.

“We were surprised to find that structural variation is much more prevalent than we thought and that most of the variants have an ancient origin. Many of the alterations we found occurred before early human populations migrated out of Africa,” said first author Jan Korbel, a postdoctoral fellow in the Department of Molecular Biophysics & Biochemistry at Yale.

To look at structural variants that were shared or different, DNA from two females – one of African descent and one of European descent – was analyzed using a novel DNA-based methodology called Paired-End Mapping (PEM). Researchers broke up the genome DNA into manageable-sized pieces about 3000 bases long; tagged and rescued the paired ends of the fragments; and then analyzed their sequence with a high-throughput, rapid-sequencing method developed by 454 Life Sciences.

“454 Sequencing can generate hundreds of thousands of long read pairs that are unique within the human genome to quickly and accurately determine genomic variations,” explained Michael Egholm, a co-author of the study and vice president of research and development at 454 Life Sciences.

“Previous work, based on point mutations estimated that there is a 0.1 percent difference between individuals, while this work points to a level of variation between two- and five-times higher,” said Snyder.

“We also found ‘hot spots’ – particular regions where there is a lot of variation,” said Korbel. “While these regions may be still actively undergoing evolution, they are often regions associated with genetic disorder and disease.”

“These results will have an impact on how people study genetic effects in disease,” said Alex Eckehart Urban, a graduate student in Snyder’s group, and one of the principal authors on the study. “It was previously assumed that ‘landmarks,’ like the SNPs mentioned earlier, were fairly evenly spread out in the genomes of different people. Now, when we are hunting for a disease gene, we have to take into account that structural variations can distort the map and differ between individual patients.”

“While it may sound like a contradiction,” says Snyder, “this study supports results we have previously reported about gene regulation as the primary cause of variation. Structural variation of large of spans of the genome will likely alter the regulation of individual genes within those sequences.”

According to the authors, even in healthy people, there are variants in which part of a gene is deleted or sequences from two genes are fused together without destroying the cellular activity with which they are associated. They say these findings show that the “parts list” of the human genome may be more variable, and possibly more flexible, than previously thought.

Authors from Yale in addition to primary authors Jan Korbel and Alex E Urban include Fabian Grubert, Philip Kim, Dean Palejev, Nicholas Carriero, Andrea Tanzer, Eugenia Saunders, Sherman Weissman, and Mark Gerstein. The research was funded the National Institutes of Health, a Marie Curie Fellowship, the Alexander von Humboldt Foundation, The Wellcome Trust, Roche Applied Science and the Yale High Performance Computation Center.

Citation: Science: Science Express (on line) September 28, 2007.

yale.edu Continue reading →

Three of the world’s pioneers in small RNA research–Victor Ambros, Gary Ruvkun and David Baulcombe–will lecture on their recent discoveries at a special half-day symposium at the University of Delaware from 9 a.m. to 12:30 p.m., Wednesday, April 16, in the Gore Recital Hall of the Roselle Center for the Arts.

The event will be held in their honor, as the 2008 winners of the Franklin Institute’s Benjamin Franklin Medal in Life Science.

UD’s symposium is part of a weeklong series of activities aimed at familiarizing students and the community with the accomplishments of the Franklin Institute laureates. The three will formally receive their awards, which are among science’s oldest and most prestigious honors, at a ceremony at the Philadelphia-based institute on April 17.

“The discovery of small RNAs and their regulatory roles is widely considered the most exciting development in biology in recent times,” said Pamela Green, the Crawford H. Greenewalt Endowed Chair in Plant Molecular Biology, who organized the event at UD. Green serves on the Franklin Institute’s Committee on Science and the Arts.

“The University of Delaware is honored to welcome three world-renowned scientists who are not only leaders in this field, but also pioneered it by discovering the very first examples of these interesting molecules that can turn off, or ‘silence,’ genes,” she noted.

Through their research, Ambros, Ruvkun and Baulcombe discovered tiny strands of RNA on the order of 20 nucleotides long, which can turn off genes, preventing them from functioning. Their pioneering work revolutionized the scientific understanding of RNA, which previously had been perceived as having an essential, but less interesting role than DNA. Their findings helped spawn a vast, new world of research on small RNAs, which is advancing the development of new genetic tools for basic research and for improving agriculture and human health.

Victor Ambros joined the faculty of the University of Massachusetts Medical School in January. Previously, he had been on the faculty at Dartmouth Medical School and Harvard.

His areas of research include microRNA biology and animal developmental genetics, with emphasis on the temporal control of cell division and cell fate during development.

Ambros received his bachelor’s and doctoral degrees in biology from the Massachusetts Institute of Technology, the latter with Nobel laureate David Baltimore. His postdoctoral research was at MIT with Nobel laureate H. Robert Horvitz. A member of the National Academy of Sciences, Ambros has received the American Association for the Advancement of Science’s Newcomb Cleveland Prize, Brandeis University’s Lewis S. Rosenstiel Award and the Genetics Society of America Medal for outstanding contributions in the past 15 years.

Gary Ruvkun is a professor of genetics at Harvard Medical School. He earned a bachelor’s degree in biophysics from the University of California at Berkeley and his doctorate from Harvard in biophysics. His postdoctoral research at Harvard was done with two Nobel Prize winners: Walter Gilbert at Harvard and H. Robert Horvitz at MIT.

In addition to microRNA and RNA interference, Ruvkun’s research interests include neuroendocrine control of metabolism, aging and molting, as well as microbial diversity.

Ruvkun has written more than 100 research papers and has several issued and pending patents. He is the recipient of a National Institutes of Health (NIH) Merit Award and the Rosenstiel Award from Brandeis University.

David Baulcombe earned a bachelor’s degree in botany from Leeds University and a doctorate from the University of Edinburgh. He was a postdoctoral researcher at McGill University and at the University of Georgia before establishing a research group at the Plant Breeding Institute in Cambridge. In 1988, he joined the Sainsbury Laboratory, where he did much of his world-renowned work. He is moving his laboratory to the University of Cambridge, where he is now professor of botany.

His research interests include the effect of RNA silencing on growth, development, evolution and defense in plants, and the development of virus-resistant crop plants.

Baulcombe is a Fellow of the Royal Society and a foreign associate member of the U.S. National Academy of Sciences. His awards include the Royal Medal, the Massry Prize, the M. W. Beijerinck Virology Prize, the Wiley Prize in Biomedical Science, the Ruth Allen Award and the Kumho Science International Award in Plant Molecular Biology and Biotechnology.

The symposium is free; however, seating is limited and registration is required. To register, visit the symposium Web site at [dbi.udel.edu/smallRNAsymposium.html]. Also, students and postdocs may apply via the Web site to join the speakers for lunch.

Minivans will be available to help shuttle registrants from the SEPTA station to the event if needed. Check the box on the registration page to request this service.

Sponsors include The Franklin Institute and the University of Delaware Office of the Provost and the College of Agriculture and Natural Resources, Delaware Biotechnology Institute, IDeA Network of Biomedical Research Excellence (INBRE) and the Experimental Program to Stimulate Competitive Research (EPSCoR). Awards week symposia are under Cephalon.

For more information, contact Sharon Bancroft at the Delaware Biotechnology Institute.

Source: Tracey Bryant

University of Delaware Continue reading →

For the first time, researchers have found five regions in the human genome that increase susceptibility to immunoglobulin A (IgA) nephropathy, a major cause of kidney failure worldwide – systematically identifying those that point to a tendency for IgA nephropathy, or a protection against it.

“The study is unique in identifying the biological pathways that mediate IgA nephropathy, mapping the way for further study that may reveal practical targets for diagnosis and treatment,” said Dr. Ali Gharavi, Division of Nephrology at Columbia University in New York City, the principal investigator.

“The cause and development of IgA nephropathy is poorly understood. Many biological pathways have been suggested, but none has been conclusive until now,” he said.

The ongoing genome-wide association study is funded by the National Institutes of Health’s Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Center for Research Resources, under an NIH Challenge Grant. The project is a part of the $10.4 billion provided to NIH through the Recovery Act. Results were published in the April issue of Nature Genetics.

Researchers looked at the genes of 3,144 people of Chinese and European ancestry, all of whom have IgA nephropathy. The disease occurs when abnormal IgA antibodies deposit on the delicate filtering portion of the kidney and form tangles. The immune system tries to get rid of the tangles, but the kidneys are caught in the crossfire, further destroying the delicate filters.

Worldwide prevalence of IgA nephropathy appears highest in Asia and southern Europe, and is responsible for most cases of kidney failure in those populations. The U.S. prevalence is much lower – up to 10 percent, although Native Americans from New Mexico have reported rates as high as 38 percent.

“IgA nephropathy is most common in Asia, intermediate in prevalence in Europeans and rare in Africans. We found that the frequency of genetic risk variants was similarly highest in Chinese people, intermediate in Europeans and lowest in Africans. This suggests that their higher frequency in Asians may in part account for increased prevalence in this population,” said Gharavi.

“Genetics are helpful if they tell you a story about the biology of disease. Here, we’re seeing a story unfold about the precise immune basis of IgA nephropathy, which also appears to be genetically associated with other rare kidney diseases – connections that were previously unsuspected,” said Dr. Rebekah Rasooly, an NIDDK scientist. “The beauty is that nobody had been looking in this direction, and now they are.”

Some of the genes implicated in the study are especially interesting because they play a role in other (not kidney-related) immune disorders. For example, the complement factor H region, called a locus, has been associated with macular degeneration, a progressive eye disease that can result in blindness; and susceptibility to meningococcal infection, the bacteria that causes meningitis.

Rasooly noted that since the genes identified in the Asian population were also found in North American and Mediterranean European populations, this suggests the genetic basis for the disease is similar in these populations. “It’s possible that this research might be relevant to all populations,” she said. “The study is also a great opportunity to conduct meaningful research with Recovery Act funding. Thanks to an NIH Challenge Grant, we now have a small but growing portfolio in this area, whereas we had nothing on it just a few years ago.”

IgA nephropathy appears to be a benign disease in some people, causing only occasional blood in the urine, while others need a kidney transplant, according to Dr. Marva Moxey-Mims, a pediatric kidney specialist at NIDDK.

“What’s the difference between these groups of people? This study begins to answer that question,” she said. “Although these gene locations by themselves do not unequivocally predict individual risk for disease or severity of it, now we can do more specific, prospective clinical studies to determine if they have predictive power about clinical outcomes in IgA nephropathy.”

Moxey-Mims added that the study also may one day point the way to a more accurate, less invasive way of diagnosing IgA nephropathy. Current diagnostic methods require a kidney biopsy, an invasive procedure that must be performed in a hospital.

The findings resulted from long-term collaborations among investigators in the United States, Italy and China. “This worldwide collaboration was critical to achieve sufficient momentum for the study and make progress in the field,” said Gharavi. He and study co-principal investigator, Dr. Richard Lifton at Yale University in New Haven, Conn., will recruit another 5,000 patients worldwide.

Source:
Bill Polglase
NIH/National Institute of Diabetes and Digestive and Kidney Diseases Continue reading →

Doctors can share confidential genetic information about patients in order to protect their relatives, even if patients object, says new GMC guidance on confidentiality, released today, 28th September.

For example, when a patient is diagnosed with a disease such as a hereditary form of cancer, doctors could tell their relatives about the potential risk their genetic link could carry.

The guidance also advises doctors to ask patients what personal or medical information they would like to share, with whom they would be like this information shared, and in what circumstances. This is especially important where patients have fluctuating or diminished capacity and may not be able to explain their condition or treatment.

Dr Henrietta Campbell, former CMO in Northern Ireland, who chaired the GMC’s working group on confidentiality, said,

“Confidentiality is central to trust between patients and doctors, but it is still an area of ethics which continues to challenge doctors more than any other.

“This guidance makes clear that, in the first instance, doctors should explain to a patient if their family might be at risk of inheriting a condition. In those circumstances, most will readily share information about their health. However, if a person refuses, it is the responsibility of the doctor to protect those who may be at risk.”

Other areas covered in the guidance also include:

- Reporting concerns about patients to the DVLA, when, due to ill health, a patient might be unfit to drive

- Responding to criticism in the press, which may involve inaccurate or misleading details of doctors’ diagnosis, treatment or behaviour

- Ensuring that school or college students on work experience understand the principles and implications of maintaining patient confidentiality

- Disclosing information for insurance, employment and benefit claims, including advice for occupational health or sports doctors who face ‘dual obligations’

- The use of confidential information for research or health service management, when it isn’t always practicable to use anonymised information or to get patients’ consent.

The new guidance – Confidentiality – was produced following a three-month consultation period, in which members of the public, the medical profession, employers and patients were asked for their views on draft guidance.

The guidance can be accessed here: gmc-uk/confidentiality

Source
General Medical Council Continue reading →

In organisms that reproduce sexually, sex cells (gametes) are produced by the specialized cell division called meiosis, which halves the number of
chromosomes from two sets (diploid) to one (haploid). During meiosis, homologous DNA molecules exchange genetic material (in a process called
homologous recombination), thereby contributing to genetic diversity. In addition, a subset of recombinants, called crossovers, creates connections
between chromosomes that are required for those chromosomes to be accurately segregated.

Accurate segregation ensures that gametes contain one and
only one copy of each chromosome. Recombination is initiated by chromosome breakage. A regulatory process then selects a subset of breaks to be healed
by a mechanism that forms crossover recombinants. Many of the remaining breaks are healed to form so-called “noncrossover” recombinants (also
referred to as “gene conversions”). Until recently it was thought that both crossovers and noncrossovers were formed by nearly identical pathways;
which form arose was thought to depend on how the last enzyme in the pathway attacked the last DNA intermediate.

However, more recent observations
suggested noncrossover recombinants might arise by a mechanism involving less stable intermediates than those required to make crossovers. In this
week’s issue of PLoS Biology Dr. Douglas Bishop, Dr. Melissa McMahill, and Dr. Caroline Sham show how a yeast strain was constructed that allowed
detection of a genetic signature of such unstable recombination intermediates. This strain provided evidence that meiotic crossovers and
non-crossovers do indeed form by quite different mechanisms.

Citation: McMahill MS, Sham CW, Bishop DK (2007) Synthesis-dependent strand annealing in meiosis. PLoS Biol 5(11): e299.
doi:10.1371/journal.pbio.0050299

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About half of prostate cancers have a genetic anomaly that appears to make tumor cells responsive to a new class of cancer-fighting drugs, a new study from the University of Michigan Comprehensive Cancer Center finds.

The drugs, called PARP inhibitors, are currently being tested in breast cancer patients with mutations in the BRCA1 and BRCA2 genes, which are found in up to 10 percent of all breast cancers.

Half of prostate cancers have a genomic rearrangement that causes the fusion of two genes called TMPRSS2 and ERG. This gene fusion, believed to be the triggering event of prostate cancer, was initially discovered in 2005 by U-M researchers led by Arul Chinnaiyan, M.D., Ph.D.

“This type of gene fusion occurs in about 50 percent of prostate cancers, but the genes involved have been notoriously difficult to target therapeutically. We found that instead of targeting the gene fusion product directly, we could block the function of critical interacting partners, such as PARP1,” says Chinnaiyan, a Howard Hughes Medical Institute researcher, director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at the U-M Medical School.

Chinnaiyan is the senior author of the current study, which appears in the May 17 issue of Cancer Cell.

“Our studies suggest that the total population of patients who could benefit from PARP inhibition could be significantly expanded,” says Chad Brenner, Ph.D. candidate at U-M, who is the first author on the study.

Working with prostate cancer models in cell lines and mice, researchers found that therapies using the PARP inhibitor Olaparib helped shrink tumors expressing the TMPRSS2:ERG gene fusion and blocked the ability of tumors to spread. Olaparib had no effect on tumors that did not have the gene fusion.

PARP inhibitors are not currently approved by the U.S. Food and Drug Administration, but initial trials in breast cancer patients indicate they can be administered safely and are well-tolerated.

Study authors Maha Hussain, M.D., and Felix Y. Feng, M.D., are currently working on two clinical trials based on these study findings to test if the TMPRSS2:ERG gene fusion could be used as to predict response to treatments, including a PARP inhibitor. These studies are not yet recruiting participants.

Prostate cancer statistics: 217,730 Americans will be diagnosed with prostate cancer this year and 32,050 will die from the disease, according to the American Cancer Society

Additional authors: Bushra Ateeq, Yong Li, Anastasia K. Yocum, Qi Cao, Irfan A. Asangani, Sonam Patel, Xiaoju Wang, Hallie Liang, Jindan Yu, Nallasivam Palanisamy, Javed Siddiqui, Wei Yan, Xuhong Cao, Rohit Mehra, Aaron Sabolch, Venkatesha Basrur, Robert J. Lonigro, Scott A. Tomlins, Christopher A. Maher, Kojo S.J. Elenitoba-Johnson, Kenneth J. Pienta, Sooryanarayana Varambally, all from U-M; Jun Yang, Nora M. Navone, from M.D. Anderson Cancer Center

Funding: National Institutes of Health, U-M Prostate Specialized Program in Research Excellence grant, Early Detection Research Network, U.S. Department of Defense, Prostate Cancer Foundation

Disclosure: The University of Michigan has received a patent on the detection of gene fusions in prostate cancer (US 7,718,369), on which Tomlins and Chinnaiyan are co-inventors. The diagnostic field of use has been licensed to Gen-Probe Inc. Chinnaiyan also has a sponsored research agreement with Gen-Probe. Gen-Probe has had no role in the design or experimentation of this study, nor has it participated in the writing of the manuscript.

Source:

University of Michigan Health System Continue reading →

Scripps Research Institute Professor Reza Ghadiri, Ph.D., has been awarded a four-year, $5.1 million grant as part of a National Institutes of Health (NIH) initiative to spur the development of the next generation of DNA sequencing technologies, which could enable biomedical researchers and health care workers to routinely sequence a person’s DNA.

With the new grant, funded by the NIH’s Human Genome Research Institute (NHGRI), the team will further develop an approach they call “nanopore strand sequencing.”

In nanopore strand sequencing, a single strand of DNA moves through a narrow pore and the bases are identified as they pass a reading head. Ghadiri notes that this is a rapid real-time technology; it does not require the time-consuming cyclic addition of reagents.

“After implementing a chip with a million pores, we expect nanopore sequencing to achieve a 15-minute genome by 2014 with a very short sample preparation time,” said Ghadiri, whose group will work with the laboratories of Hagan Bayley of the University of Oxford and Amit Meller of Boston University on the project. “In addition, nanopore sequencing will be able to identify modified bases and to sequence RNA directly.”

The new grant is part of an $18 million round of funding announced this week by the NHGRI, whose current goal is to make it possible to sequence a genome for $1,000 or less.

Over the past decade, DNA sequencing costs have fallen dramatically fueled in large part by tools, technologies and process improvements developed as part of the successful effort to sequence the human genome. NHGRI subsequently launched programs in 2004 to accelerate the development of sequencing technologies and the rate of reduction of genome sequencing cost. Last year, the program surpassed the goal of producing high quality genome sequence of 3 billion base pairs – the amount of DNA found in humans and other mammals – for $100,000. The cost to sequence a human genome has now dipped below $40,000.

The new grants will fund ten investigator teams to develop revolutionary technologies that would make it possible to quickly and cost-efficiently sequence a genome, enabling the use of sequencing as part of routine medical care.

Source:
Mika Ono
Scripps Research Institute Continue reading →

Scientists from the Burnham Institute for Medical Research (BIMR) and Illumina Inc., in collaboration with stem cell researchers around the world, have found that the DNA of human embryonic stem cells is chemically modified in a characteristic, predictable pattern. This pattern distinguishes human embryonic stem cells from normal adult cells and cell lines, including cancer cells. The study, which appears online today in Genome Research, should help researchers understand how epigenetic factors contribute to self-renewal and developmental pluripotence, unique characteristics of human embryonic stem cells that may one day allow them to be used to replace diseased or damaged cells with healthy ones in a process called therapeutic cloning.

Embryonic stem cells are derived from embryos that are undergoing a period of intense cellular activity, including the chemical addition of methyl groups to specific DNA sequences in a process known as DNA methylation. The methylation and demethylation of particular DNA sequences in the genome are known to have profound effects on cellular behavior and differentiation. For example, DNA methylation is one of the critical epigenetic events leading to the inactivation of one X chromosome in female cells. Failure to establish a normal pattern of DNA methylation during embryogenesis can cause immunological deficiencies, mental retardation and other abnormalities such as Rett, Prader-Willi, Angelman and Beckwith-Wiedemann syndromes.

Until recently, DNA methylation could only be studied one gene at a time. But a new microarray-based technique developed at Illumina enabled the scientists conducting this new study to simultaneously examine hundreds of potential methylation sites, thereby revealing global patterns. “Analyzing the DNA methylation pattern of hundreds of genes at a time opens a new window for epigenetic research,” says Dr. Jian-Bing Fan, director of molecular biology at Illumina. “Exciting insights into development, aging, and cancer should come quickly from understanding global patterns of DNA methylation.”

To examine global DNA methylation patterns in human embryonic stem cells, the researchers analyzed 14 human embryonic stem cell lines from diverse ethnic origins, derived in several different labs, and maintained for various times in culture. They tested over 1500 potential methylation sites in the DNA of these cells and in other cell types and found that the embryonic stem cells shared essentially identical methylation patterns in a large number of gene regions. Furthermore, these methylation patterns were distinct from those in adult stem cells, differentiated cells, and cancer cells.

“Our results suggest that therapeutic cloning of patient-specific human embryonic stem cells will be an enormous challenge, as nuclei from adult cells will have to be epigenetically reprogrammed to reflect the specific DNA methylation signature of normal human embryonic stem cells,” explains Dr. Jeanne Loring, co-director of the stem cell center at BIMR. “This reinforces the need for basic research directed at understanding the fundamental biology of human embryonic stem cells before therapeutic uses can be considered.”

Genome Research (genome/) is an international, continuously published, peer-reviewed journal published by Cold Spring Harbor Laboratory Press. Launched in 1995, it is one of the five most highly cited primary research journals in genetics and genomics.

Cold Spring Harbor Laboratory Press is an internationally renowned publisher of books, journals, and electronic media, located on Long Island, New York. It is a division of Cold Spring Harbor Laboratory, an innovator in life science research and the education of scientists, students, and the public. For more information, visit cshlpress/.

Contact: Maria Smit
Cold Spring Harbor Laboratory Continue reading →