Genetics
Massively parallel gene function assays aim to reduce uncertainty of genetic diagnoses
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Patients seeking certainty in genetic tests often receive a perplexing result. Many learn they carry a ‘variant of unknown significance’ of a disease-linked gene. Such variants might—or equally might not—increase disease risk.
A study published in the June issue of the journal Genetics characterized nearly 2000 variants of the breast cancer-associated gene BRCA1, demonstrating the potential of a new approach for sorting out which variants are harmful and which are harmless.
Because genetic tests increasingly use more comprehensive multi-gene and whole-genome sequencing methods, it’s becoming more common for patients to learn they carry a variant of unknown significance. For example, a 2014 study showed 42 percent of breast cancer patients who received results from a 25-gene hereditary cancer genetic test carried a variant of unknown significance in one of the scanned genes.
Drug improves measures of genetic disease that affects liver, spleen
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Among previously untreated adults with Gaucher disease type 1, a genetic disease in which there is improper metabolism due to a defect in an enzyme, treatment with the drug eliglustat resulted in significant improvements in liver and spleen size hemoglobin level, and platelet count, according to a study in the February 17 issue of JAMA.
Gaucher disease type 1 is characterized by enlargement of the spleen and liver, anemia, low blood platelets, chronic bone pain, and the failure to grow properly. Untreated Gaucher disease type 1 is a chronic and progressive disorder associated with disability, reduced life expectancy, and, in some patients, life-threatening complications. The current standard of care is enzyme replacement therapy, which requires lifelong intravenous infusions every other week. A safe, effective oral therapy is needed, according to background information in the article.
Pramod K. Mistry, M.D., Ph.D., F.R.C.P., of the Yale University School of Medicine, New Haven, Conn., and colleagues randomly assigned 40 untreated adults with Gaucher disease type 1 to receive eliglustat (twice daily; n = 20) or placebo (n = 20) for 9 months. Eliglustat is a novel oral medication, which showed favorable results for patients with this disease in a phase 2 trial. This phase 3 trial was conducted at 18 sites in 12 countries.
BGI study confirms accuracy of its NIFTY in nearly 147,000 pregnancies
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BGI has published a study tracking the clinical performance of its whole genome sequencing-based non-invasive prenatal test (the NIFTY® test) in nearly 147,000 pregnancies, the largest such study to date. The results showed high sensitivity and specificity and no significant difference between high-risk and low-risk pregnant women.
The study, published in the journal Ultrasound Obstetrics and Gynecology, reported on 146,958 samples from 508 medical centers in mainland China, which were collected between early 2012 and mid-2013 for trisomy 21, 18, and 13. Although NIFTY® measures other chromosomal abnormalities, these results were not included in the study.
According to the study’s results, NIFTY® identified 1,578 trisomy-positive and 145,380 negative samples. Comparing the results with follow-up confirmatory invasive testing, or by tracking patients’ eventual pregnancy outcomes, the study team then calculated the false positive (FPR) and false negative rate (FNR) for each tested trisomy, and the overall sensitivity, specificity, and positive predictive value (PPV).
Study Reveals Evolution at Work
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New research by UC Santa Barbara’s Kenneth S. Kosik, Harriman Professor of Neuroscience, reveals some very unique evolutionary innovations in the primate brain.
In a study published online today in the journal Neuron, Kosik and colleagues describe the role of microRNAs - so named because they contain only 22 nucleotides - in a portion of the brain called the outer subventricular zone (OSVZ). These microRNAs belong to a special category of noncoding genes, which prevent the formation of proteins.
“It’s microRNAs that provide the wiring diagram, dictating which genes are turned on, when they’re turned on and where they’re turned on,” said Kosik, who is also the co-director of UCSB’s Neuroscience Research Institute and a professor in the Department of Molecular, Cellular and Developmental Biology. “There’s a core set with which all kinds of really complex things can be built, and these noncoding genes know how to put it together.”
Testosterone-regulated genes may affect vaccine-induced immunity
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A new study has identified a link between certain genes affected by testosterone and antibody responses to an influenza vaccine. The findings, published in Proceedings of the National Academy of Sciences, suggest that testosterone levels may partially explain why men often have weaker responses to vaccines than women. The study, led by researchers at Stanford University, was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health.
Previous research has shown that men typically experience more severe viral and other microbial infections than women, who tend to mount stronger immune responses to infections and vaccinations. In the new study, researchers analyzed the antibody responses of 53 women and 34 men of various ages to the 2008-2009 seasonal influenza vaccine. Compared to the men, the women produced antibodies that in laboratory tests could more effectively neutralize the influenza virus.
To explain this difference, the scientists searched for patterns in gene expression, or the degree to which specific genes are turned on or off. They found that men with weak vaccine responses tended to have high expression levels of a certain cluster of genes involved in the metabolism of lipids (fats). Previous studies have suggested that testosterone may regulate the expression of many of these genes. The researchers found that men with high levels of testosterone and elevated expression of the gene cluster had weaker antibody responses to the vaccine than women and men with low testosterone. These results suggest that testosterone may suppress immune responses to vaccines by altering expression patterns of specific genes, but further research is needed to determine the mechanism.
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U.S. FDA panel backs BioMarin’s Morquio A Syndrome drug
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An experimental drug to treat Morquio A Syndrome, a rare genetic disorder that causes skeletal malformation and a variety of related lung, eye, ear and heart problems, should be approved, an advisory panel to the U.S. Food and Drug Administration concluded on Tuesday.
The 21-member panel voted overwhelmingly in favor of approval, saying the benefits of the drug, Vimizim, which is made by BioMarin Pharmaceutical Inc, outweigh its risks. The FDA is not obliged to follow the recommendations of its advisory panels but typically does so.
Morquio A Syndrome is characterized by a deficiency of an enzyme known as N-acetylgalactosamine-6-sulfatase, which causes excessive storage in the body of long chains of sugars known as glycosaminoglycans.
This build-up can lead to short stature and joint abnormalities that limit mobility and endurance. The disease can also cause hearing loss, eye problems and heart disease. Symptoms often appear before the age of five.
Steroid hormone receptor prefers working alone to shut off immune system genes
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Researchers at Emory University School of Medicine have obtained a detailed molecular picture that shows how glucocorticoid hormones shut off key immune system genes.
The finding could help guide drug discovery efforts aimed at finding new anti-inflammatory drugs with fewer side effects.
The results are scheduled for publication Sunday, Dec. 9 by the journal Nature Structural & Molecular Biology.
Synthetic glucocorticoid hormones - for example, prednisone and dexamethasone - are widely used to treat conditions such as allergies, asthma, autoimmune diseases and cancer. They mimic the action of the natural hormone cortisol, which is involved in the response to stress and in regulating metabolism and the immune system. For this reason, synthetic glucocorticoids have a variety of severe side effects such as increased blood sugar and reduced bone density.
Diet may treat some gene mutations
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Scientists have moved a step closer to correcting some unhealthy gene mutations with diet, according to a new research report appearing in the April 2012 issue of the journal GENETICS. Researchers from the University of California, Berkeley, determined variations and responses to vitamin treatment in the human cystathionine beta synthase gene, which when defective, causes the disease homocystinuria, an inherited metabolic disorder sometimes treatable with vitamin B6. After the analysis, scientists correlated specific gene mutations with severity of the disease, ranging from perfectly healthy and functional to severe and untreatable. Although the current study focused on homocystinuria, testing the effects of naturally occurring gene variations using surrogate organism genetics can be applied to other inherited disorders, such as neural tube defect, cleft palate, and blindness.
“The era of personal genome sequences is upon us, but there is a growing gap between the ability to sequence human genomes and the ability to understand the significance of variation in genome sequences,” said Jasper Rine, Ph.D., the principal investigator of this research in the Department of Molecular and Cell Biology at the California Institute of Quantitative Biosciences at the University of California, Berkeley. “This study demonstrates one way to close the gap; the data separate gene variants into distinct classes, including a group amenable to dietary intervention.”
To make their determination, scientists “swapped” the cystathionine beta synthase gene of baker’s yeast with the gene from humans to test which variants were healthy, treatable, or untreatable with additional vitamin B6. As a result, the study clarified the function of 84 DNA sequence variants in this gene, which will help physicians more effectively treat patients based on their particular genotypes. In addition, this approach opens doors for future studies examining other human genes that similarly cross over between humans and yeast.
Newly identified gene mutation adds to melanoma risk
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A major international study has identified a novel gene mutation that appears to increase the risk of both inherited and sporadic cases of malignant melanoma, the most deadly form of skin cancer. The identified mutation occurs in the gene encoding MITF, a transcription factor that induces the production of several important proteins in melanocytes, the cells in which melanoma originates. While previous research has suggested that MITF may act as a melanoma oncogene, the current study identifies a mechanism by which MITF mutation could increase melanoma risk.
The report from researchers from the U.S., the U.K. and Australia is receiving advance online publication in Nature. It is expected to appear in a print issue along with a study from French researchers finding that the same mutation increased the risk for the most common form of kidney cancer, for melanoma or for both tumors.
“We previously knew that MITF is a master regulator for production of the pigment melanin; and several years ago we identified a chemical modification, called sumoylation, that represses MITF activity,” says David Fisher, MD, PhD, chief of Dermatology at Massachusetts General Hospital (MGH), director of the MGH Cutaneous Biology Research Center and co-senior author of the Nature paper. “The currently discovered mutation appears to block sumoylation of MITF, and the resulting overactivity of MITF significantly increases melanoma risk.”
Eating your greens can change the effect of your genes on heart disease, say researchers
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A long-held mantra suggests that you can’t change your family, the genes they pass on, or the effect of these genes. Now, an international team of scientists, led by researchers at McMaster and McGill universities, is attacking that belief.
The researchers discovered the gene that is the strongest marker for heart disease can actually be modified by generous amounts of fruit and raw vegetables. The results of their study are published in the current issue of the journal PLoS Medicine.
“We know that 9p21 genetic variants increase the risk of heart disease for those that carry it,” said Dr. Jamie Engert, joint principal investigator of the study, who is a researcher in cardiovascular diseases at the Research Institute of the McGill University Health Centre (RI-MUHC) and associate member in the Department of Human Genetics at McGill University. “But it was a surprise to find that a healthy diet could significantly weaken its effect.”
Gene defect that predisposes people to leukemia discovered
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A new genetic defect that predisposes people to acute myeloid leukemia and myelodysplasia has been discovered. The mutations were found in the GATA2 gene. Among its several regulatory roles, the gene acts as a master control during the transition of primitive blood-forming cells into white blood cells.
The researchers started by studying four unrelated families who, over generations, have had several relatives with acute myeloid leukemia, a type of blood cancer. Their disease onset occurred from the teens to the early 40s. The course was rapid.
The findings will be reported Sept. 4 in Nature Genetics. The results come from an international collaboration of scientists and the participation of families from Australia, Canada, and the United States.
A question of gene silencing
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When investigating cancer cells, researchers discovered numerous peculiarities: Particular RNA molecules are present in large numbers, particular genes are overactive. Do these characteristics have a relation to cancer? Do they promote cell growth? Do they inactivate growth brakes or are they just a whim of nature? To find clues for answering these questions scientists perform what are called loss-of-function analyses. They knock out (silence) the gene of interest in living cells or whole organisms and subsequently look for any changes in the cells’ metabolism, physiology or behavior in order to find out whether specific cellular functions are lost.
“However, what was still missing was a method for selectively silencing those genes that do not code for proteins,” said Dr. Sven Diederichs, who is head of a Junior Research Group at DKFZ and at the Institute of Pathology of Heidelberg University. With his team, the molecular biologist has now developed a new method for selectively silencing such non-protein-coding genes and, thus, determining their function. “In many cancers we find that specific non- coding genes are particularly active. Therefore, we want to understand what the RNA molecules transcribed from these genes bring about in the tumor cells.”
Diederichs and his team have based their method on the use of zinc finger nucleases. These are engineered protein molecules that cut DNA at precisely defined sites and thus facilitate specific targeting and cutting of genes. Although the cell’s repair machinery will re-connect the two ends after the cutting process, silencing works well for protein-coding genes. The repair enzymes usually do not repair the site precisely and insert small defects. This destroys the protein information so that the proteins can no longer be formed.
PGD can permit the birth of healthy children to women carrying mitochondrial DNA disease
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Amsterdam, The Netherlands: Pre-implantation genetic diagnosis (PGD) can give women at risk of passing on a mitochondrial DNA disorder to their offspring a good chance of being able to give birth to an unaffected child, a researcher told the annual conference of the European Society of Human Genetics today (Monday). Dr. Debby Hellebrekers, from Maastricht University Medical Centre, Maastricht, The Netherlands, said that the scientists’ findings could have a considerable effect on preventing the transmission of mitochondrial diseases.
Mitochondria are cellular organelles involved in the conversion of the energy of food molecules into ATP, the molecule that powers most cellular functions. Disruptions of this energy-producing process, due to a defect in the mitochondrial DNA (mtDNA) or nuclear genes, can cause mitochondrial disorders which represent the most common group of inborn errors of metabolism. The manifestation of mtDNA disorders can be quite varied, but the diseases are almost always serious and, if they do not lead to death, they can result in life-long serious disability for children born with them. Symptoms of mtDNA disorders include loss of muscle co-ordination, visual and hearing problems, poor growth, mental retardation, heart, liver and kidney disease, neurological problems, respiratory disorders and dementia.
Prenatal diagnosis is in general not possible for mtDNA diseases, because the clinical signs cannot be reliably predicted from the mutation load (the relative amount of mutated mtDNA molecules) in chorionic villus sampling, so the team of scientists from The Netherlands, Australia, and the UK decided to look at whether PGD would be a better alternative. “If we could find a minimal level of mtDNA mutation load below which the chance for an embryo of being affected was acceptably low”, said Dr. Hellebrekers, “we could offer PGD to women who otherwise had little chance of giving birth to a healthy child.”
Dine or dash? Genes help decide when to look for new food
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For worms, choosing when to search for a new dinner spot depends on many factors, both internal and external: how hungry they are, for example, how much oxygen is in the air, and how many other worms are around. A new study demonstrates this all-important decision is also influenced by the worm’s genetic make-up.
In the simple Caenorhabditis elegans nematode, the researchers found that natural variations in several genes influence how quickly a worm will leave a lawn of bacteria on which it’s feeding. One of the genes, called tyra-3, produces a receptor activated by adrenaline - a chemical messenger involved in the ‘fight-or-flight’ response. The findings appeared online March 16, 2011, in the journal Nature.
“What’s encouraging to us about this story is that molecules related to adrenaline are implicated in arousal systems and in decision-making across a lot of different animals, including humans,” says Howard Hughes Medical Institute investigator Cornelia Bargmann of Rockefeller University in New York, who mentored the work of graduate student Andres Bendesky. These parallels between diverse species suggest that aspects of our decision-making abilities have ancient evolutionary roots.
Gonorrhea acquires a piece of human DNA
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If a human cell and a bacterial cell met at a speed-dating event, they would never be expected to exchange phone numbers, much less genetic material. In more scientific terms, a direct transfer of DNA has never been recorded from humans to bacteria.
Until now. Northwestern Medicine researchers have discovered the first evidence of a human DNA fragment in a bacterial genome – in this case, Neisseria gonorrhoeae, the bacterium that causes gonorrhea. Further research showed the gene transfer appears to be a recent evolutionary event.
The discovery offers insight into evolution as well as gonorrhea’s nimble ability to continually adapt and survive in its human hosts. Gonorrhea, which is transmitted through sexual contact, is one of the oldest recorded diseases and one of a few exclusive to humans.
