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Archive - 2013

November 4th

New Method to Create Membrane Pores with DNA Nanotechnology

A new way to build membrane-crossing pores, using Lego-like DNA building blocks, has been developed by scientists at University College London (UCL), in collaboration with colleagues at the University of Cambridge and the University of Southampton. The approach provides a simple and low-cost tool for synthetic biology and the technique has potential applications in diagnostic devices and drug discovery. The research was published online on October 2, 2013 in Angewandte Chemie. Membrane pores are the gateways controlling the transport of essential molecules across the otherwise impermeable membranes that surround cells in living organisms. Typically made from proteins, pores of different sizes control the flow of ions and molecules both and in and out of the cell as part of an organism's metabolism. Our understanding of membrane pores comes both from the study of natural pores, and from equivalent structures built in the lab by synthetic biologists. But synthetic proteins are notoriously difficult to handle due to the complex and often unpredictable ways in which their structures can fold. Even minor protein misfolding changes a protein's properties, meaning that building synthetic pores out of proteins can be risky and time-consuming. A more straightforward approach is so-called 'rational engineering' using Lego-like DNA building blocks. Although generally known as life's genetic code, DNA strands, which are chemically much simpler than proteins, are far easier and more predictable to work with than proteins. As such they are a useful material for building nanoscale structures in the lab. "DNA is a construction material that follows very simple rules," said Dr. Stefan Howorka (UCL Chemistry). "New nanostructures can be easily designed using a computer program, and the elements fit together like Lego bricks.

Post-Treatment Mutations in Estrogen Receptor Gene Linked to Breast Cancer Treatment Resistance

Researchers at the University of Michigan (U-M) Comprehensive Cancer Center, together with colleagues, have used DNA and RNA sequencing to identify a type of mutation that develops after breast cancer patients take anti-estrogen therapies. The mutations explain one reason why patients often become resistant to this therapy. The discovery stems from a program at the U-M Comprehensive Cancer Center called Mi-ONCOSEQ in which patients with advanced cancer have their DNA and RNA sequenced to identify all types of genetic mutations that could play a role in the cancer. Researchers use the findings to help direct therapies they think will work best. But they also use the data to find new genetic links. The detailed analysis means that researchers can identify anomalies among a small number of patients. In this study, they looked at 11 patients with metastatic breast cancer that was classified as estrogen-receptor-positive, meaning the cancer is influenced by the hormone estrogen. This is the most common type of breast cancer. The study was published online on November 3, 2013 in Nature Genetics. The analysis found that six patients had mutations in the estrogen receptor. All of them had been treated with an aromatase inhibitor, a type of drug that blocks estrogen production. What’s more, the researchers found that the mutations were not present before the patients started their treatment, which implied it was the therapy itself that caused the mutations to develop or be selected. “This is the tumor’s way of evading hormonal therapy. These mutations activate the estrogen receptor when there is no estrogen – as is the case when a patient takes an aromatase inhibitor.

Transmitting Stress Response Patterns Across Generations

Children of survivors of extremely stressful life events face adjustment challenges of their own, as has been most carefully studied among the children of Nazi Death Camp survivors. This "intergenerational" transmission of stress response has been studied predominantly from the psychological perspective. However, recent research points to biological contributions as well. Indeed, a new study published in the November 1, 2013 issue of Biological Psychiatry demonstrates that offspring born to stressed mothers show stress-induced changes at birth, with altered behavior and gender-related differences that continue into adulthood. "The notion that biological traits that are not coded by the sequence of DNA can be transmitted across generations is the focus of a field of research called epigenetics. This new paper implicates epigenetic regulation of a well-studied contributor to stress response, CRF1 (corticotropin-releasing factor type 1), in the intergenerational transmission of patterns of stress response," said Dr. John Krystal, Editor ofBiological Psychiatry, who was not involved in the study. The researchers, led by Dr. Inna Gaisler-Salomon at University of Haifa in Israel, were interested in how stress modulates behavior and gene expression across generations. Previous studies in both humans and animals have shown that females exposed to stress even before they conceive can affect their children and even grandchildren. In this study, the researchers looked for a possible mechanism for these effects, focusing on the CRF1 gene. They studied adolescent female rats that went through a mild stress procedure before mating. Stress led to an increase in CRF1 expression in the frontal cortex, a brain region involved in emotional regulation and decision-making.

November 2nd

“Zone in with Zon”—DNA Sequencing on Mars?

Dr. Gerald Zon’s latest “Zone in with Zon” blog post, dated October 21, 2013, and published by TriLink BioTechnologies of San Diego, addresses the stimulating possibility of sequencing DNA on Mars. Although initially skeptical about this “far-out” idea, Dr. Zon did a little research and concluded that it might not be so far-fetched after all. He began by mentioning the long history of theories and research on how life, as we know it, began and evolved, noting that the subject has received considerable attention since 1924 when Soviet biologist Alexander Oparin proposed a theory of the origin of life on earth through the gradual chemical evolution of molecules that contain carbon in the “primordial soup.” Research continued, Dr. Zon said, with Stanley Miller’s now classic article “A Production of Amino Acids Under Possible Primitive Earth Conditions” in Science in 1953. Dr. Zon noted that recent identification of nucleobase analogs 2,6-diaminopurine and 6,8-diaminopurine has been reported by Dworkin and coworkers and suggested to strongly support extraterrestrial origin. In discussing what might be the origin of Martian genomes, Dr. Zon mentions the “common ancestry hypothesis” that proposes the natural transfer of viable microbes in space, such as from Mars to Earth and Earth to Mars. Scientists who have investigated this theory have concluded that “if microbes existed or exist on Mars, viable transfer to Earth is not only possible, but also highly probable, due to microbes’ impressive resistance to the dangers of space transfer and to the dense traffic of billions of Martian meteorites that have fallen on Earth since the dawn of our planetary system. Earth-to-Mars transfer is also possible but at a much lower frequency.” Dr.

October 28th

Awards, Newborn Screening, and Futuristic Presentations Highlight Last Day of ASHG Annual Meeting

The breakthrough-loaded 2013 annual meeting of the American Society of Human Genetics (ASHG) ended its five-day run in Boston with an awards session, followed by concurrent research presentation sessions, and ending with three riveting presentations on the future of genetics and systems biology by three world-leading researchers. The morning started with the presentation of the ASHG Victor A. McKusick Leadership Award presently jointly to Rochelle Hirschorn, M.D., and her husband, Kurt Hirschorn, M.D. The McKusick award honors the legendary Victor McKusick, M.D., who is often referred to as the “Father of Medical Genetics,” and his far-reaching and visionary contributions to genetics. Recipients are chosen for their enduring vision and leadership to ensure that human genetics will flourish and be successfully assimilated into the broader context of science, medicine, and health. In a moving moment, the award recipients were introduced by their son, Joel, M.D., Ph.D., from the Department of Genetics at Harvard Medical School. Dr. Rochelle Hirschorn was the Chief of Medical Genetics at New York University’s Langone Medical Center for 24 years. Her major discoveries include clarifying the sequence of acid alpha glucosidase and most of its defects in Pompe disease, and delineating the genetic structure and pathophysiology of adenosine deaminase (ADA ) deficiency, an autosomal recessive metabolic disorder that causes immunodeficiency. She also described the phenomenon of reverse mutations as a cause of “self-cure” in ADA deficiency patients and predicted the utility of gene therapy for ADA deficiency.

October 26th

Scientists ID Novel Mutation That Causes Aortic Aneurysms and Acute Aortic Dissection

Ascending thoracic aortic aneurysms can lead to life-threatening acute aortic dissections (TAADs). An example of this is the sudden death of popular actor John Ritter, who died from this problem. Subsequent examination of his brother Tommy showed that he had a dangerously large aortic aneurysm that was treated surgically to reduce his risk (see John Ritter’s father, Tex Ritter, known as the “Singing Cowboy,” had died suddenly while clutching his chest and is thus presumed to have died from the same problem as his son John. It is known that gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and aortic dissections. Using exome sequencing of distant relatives affected by thoracic aortic disease, followed by Sanger sequencing of additional probands with familial thoracic aortic disease, a research group presenting their results on Friday, October 25, at the American Society of Human Genetics (ASHG) 2013 annual meeting in Boston, reported identifying the same rare variant (c.530G>A) (p.Arg177Gln) in the gene PRKG1 in four families. This mutation segregated with aortic disease in the four families, with the majority (63%) of affected individuals presenting with acute aortic dissections at relatively young ages (mean 31 years, range 17-51 years). The PKRG1 gene encodes a type I cGMP-dependent protein kinase (PKG-1) that is activated upon binding of cGMP and controls SMC relaxation. Although the p.Arg177Gln alteration disrupts binding to the high-affinity cGMP binding site within the regulatory domain, the altered PKG-1 is constitutively activated even in the absence of cGMP.

Multiple, Distinct Y Chromosomes Associated with Significant Excess Risk of Prostate Cancer

An analysis of the genealogical and medical records of males in Utah's multi-generational families strongly supports the case that inherited variations in the Y chromosome, the male sex chromosome, play a role in the development of prostate cancer, according to a study presented on Friday, October 25, at the American Society of Human Genetics (ASHG) 2013 meeting in Boston. The study identified multiple, distinct Y chromosomes associated with a significant excess risk of prostate cancer, said Lisa Cannon-Albright, Ph.D., Professor and Chief of the Division of Genetic Epidemiology at the University of Utah School of Medicine. Dr. Cannon-Albright, who headed the study and presented the results, said that her lab plans to search these Y chromosomes for the genetic mutations that can predispose a man to develop prostate cancer, the second most frequently diagnosed cancer in the U.S. Because most of the Y chromosome does not recombine during cell division, it is passed virtually unchanged from father to son. “As a result, each male resident of Utah shares the Y chromosome of his father and his father’s father and so on,” she said. “This provided the ability to estimate the risk for prostate cancer in independent Y chromosomes represented in Utah.” The study relied upon the Utah Population Data Base (UPDB), which identifies over 6.5 million individuals, including many of the Utah pioneers in the 1800s. The pioneer genealogies in the UPDB are typically large, spanning 15 generations. The Utah population represented in the UPDB is genetically representative of Northern Europe. The database was created in the 1970s to define familial clustering and identify evidence for heritable contribution to cancer.

DNA Variants May Influence Response to Inhaled Bronchodilators by Patients with COPD

Several novel gene variants may help explain the response of patients with chronic obstructive pulmonary disease (COPD) to inhaled bronchodilators, according to a meta-analysis reported on Friday, October 25, at the American Society of Human Genetics (ASHG) 2013 meeting in Boston. The meta-analysis used statistical methods to combine results from four individual studies with a total of 6,500 Caucasian patients with moderate to severe COPD. Over 6.3 million unique single nucleotide polymorphisms (SNPs) were identified in the genotypes of the patients with COPD, which is a progressive breathing disorder that limits airflow in the lungs. The genotypes of over 800 African Americans with COPD were also analyzed. “Identifying single nucleotide polymorphisms associated with bronchodilator responsiveness may reveal genetic pathways associated with the pathogenesis of COPD and may identify novel treatment methods,” said Megan Hardin, M.D., Instructor of Medicine at Harvard Medical School and researcher in the Channing Division of Network Medicine at Brigham and Women's Hospital, Boston. Dr. Hardin, who presented the research, added that multiple genetic determinants likely influence bronchodilator responsiveness. Functional analysis of the SNPs will be conducted, she added. “As we continue to analyze the data, we expect to identify other important SNPs,” said Craig P. Hersh, M.D., who headed the study and is Assistant Professor, Harvard Medical School, and faculty member in the Channing Division of Network Medicine at Brigham and Women’s Hospital. All of the subjects studied had significant histories of smoking, with most (4,561), having smoking histories of over 10 pack-years (i.e., 10 years of smoking a smoking one pack of cigarettes per day.

October 24th

Gene-Diet Interaction Study Identifies Significant Variants Associated with Diet-Related Risk of Colorectal Cancer

A newly discovered potential gene-diet interaction for colorectal cancer was reported today (Thursday, October 24) at the American Society of Human Genetics(ASHG) 2013 meeting in Boston. The interaction may shed light on the statistically significant increased risk of colorectal cancer that is associated with consumption of red and processed meat, the researchers said. “If replicated, our findings have a relevant public health significance because diet is a modifiable risk factor for colorectal cancer,” said Jane Figueiredo, Ph.D., Assistant Professor of Preventive Medicine at the University of Southern California Keck School of Medicine, who presented the study this morning at the ASHG meeting. “It is conceivable that selected individuals at higher risk of colorectal cancer based on genomic profiling could be targeted for screening, diet modification and other prevention strategies,” added Dr. Figueiredo, one of the scientists collaborating in the international NIH-funded Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The scientists also determined that the lower colorectal cancer risk associated with vegetable, fruit, and fiber intake also was linked to genetic variants. The possibility that genetic variants may modify an individual’s risk for disease based on diet has not been thoroughly investigated but represents an important new insight into disease development, said Ulrike Peters, Ph.D., M.P.H, who headed the study and is a Member of the Fred Hutchinson Cancer Research Center’s Public Health Sciences Division in Seattle, Washington.

Scientists Identify First Gene for Most Common Form of Mitral Valve Prolapse

Research on the DNA of a large multi-generational family has provided a genetic clue that enabled scientists to pinpoint a gene that plays a role in mitral valve prolapse (MVP), a common cardiac disease that is the leading cause of heart valve surgery, according to a study presented today (Thursday, October 24) at the American Society of Human Genetics (ASHG) 2013 meeting in Boston. MVP affects 2.5% of the population and typically presents symptoms in adulthood, often leading to heart failure. 15% of the patients inherit the disease, but the remaining 85% of MVP incidence is sporadic. The scientists who located the gene, named DCSH1 (from the dachsous1 gene in Drosophila), also determined how mutations in this gene disrupt the normal embryonic development of the mitral valve, one of the valves that controls blood flow in the heart. “This work provides insights into the pathways regulating valve growth and development,” said Susan Slaugenhaupt, Ph.D., Professor of Neurology in the Center for Human Genetic Research at Massachusetts General Hospital (MGH) and Harvard Medical School and one of the lead scientists in the collaborative group that conducted the research. “The results implicate a previously unrecognized paradigm in the development of long-term structural integrity in the mitral valve,” said Ronen Y. Durst, M.D., former member of Dr. Slaugenhaupt’s lab and now a senior cardiologist at Hebrew University and Hadassah Medical Center in Jerusalem. Dr. Durst presented the study this afternoon at ASHG 2013. The researchers’ first step was to link MVP to a region on human chromosome 11 in the DNA of the group of relatives with the heart disorder. By sequencing that DNA region in family members, the scientists were able to link mutations in DCSH1 to MVP.