TAG: "Genetics"

Cleft palate discovery in dogs to aid in understanding human birth defect


UC Davis study also shows that dogs have multiple genetic causes of cleft palate.

This puppy is a Nova Scotia Duck Tolling Retriever, the breed with the newly discovered genetic mutation for cleft palate.

UC Davis School of Veterinary Medicine researchers have identified the genetic mutation responsible for a form of cleft palate in the dog breed Nova Scotia Duck Tolling Retrievers.

They hope that the discovery, which provides the first dog model for the craniofacial defect, will lead to a better understanding of cleft palate in humans. Although cleft palate is one of the most common birth defects in children, affecting approximately one in 1,500 live human births in the United States, it is not completely understood.

The findings appear this week online in the journal PLOS Genetics and are available online at https://tinyurl.com/knr8wb3.

“This discovery provides novel insight into the genetic cause of a form of cleft palate through the use of a less conventional animal model,” said professor Danika Bannasch, a veterinary geneticist who led the study. “It also demonstrates that dogs have multiple genetic causes of cleft palate that we anticipate will aid in the identification of additional candidate genes relevant to human cleft palate.”

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Tweaking potassium levels in brain could be a key to fighting Huntington’s


UCLA findings could point to new drug targets for treating the devastating disease.

Astrocytes in brain tissue

By boosting the ability of a specific type of cell to absorb potassium in the brain, UCLA researchers were able to improve walking and prolong survival in a mouse model of Huntington’s disease.

Their findings, published March 30 in the online edition of the journal Nature Neuroscience, could point to new drug targets for treating the devastating disease, which strikes one in every 20,000 Americans.

Huntington’s disease is passed from parent to child through a mutation in the huntingtin gene. By killing brain cells called neurons, the disorder gradually deprives patients of their ability to walk, speak, swallow, breathe and think clearly. No cure exists, and patients with aggressive cases can die in as little as 10 years.

The laboratories of Baljit Khakh, a UCLA professor of physiology and neurobiology, and Michael Sofroniew, a UCLA professor of neurobiology, teamed up at the David Geffen School of Medicine at UCLA to unravel the role that astrocytes — large, star-shaped cells found in the brain and spinal cord — play in Huntington’s.

“Astrocytes appear in the brain in equal numbers to neurons yet haven’t been closely studied,” Khakh said. “They enable neurons to signal each other by maintaining an optimal chemical environment outside the cells. We used two mouse models to explore whether astrocytes behave differently during Huntington’s disease.”

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Kaiser, UCSF add genetic, health information to NIH online database


Information is largest-ever genetic resource for researchers.

Catherine Schaefer

Researchers worldwide will now have access to genetic data linked to medical information on a diverse group of more than 78,000 people, enabling investigations into many diseases and conditions. The data have just been made available to qualified researchers through the database of Genotypes and Phenotypes (dbGaP), the online database of the National Institutes of Health (NIH). The announcement was made today (Feb. 26) at the National Advisory Council on Aging by Richard Hodes, director of the National Institute on Aging (NIA).

The data come from one of the nation’s largest and most diverse genomics projects — the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort — which was developed collaboratively by the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH) and UC San Francisco. The addition of the data to dbGaP was made possible with $24.9 million in support from the NIA and the National Institute of Mental Health at NIH, as well as from the Office of the NIH Director.

“Data from this immense and ethnically diverse population will be a tremendous resource for science,” said NIH Director Francis Collins. “It offers the opportunity to identify potential genetic risks and influences on a broad range of health conditions, particularly those related to aging.”

Neil Risch

The GERA cohort is part of the RPGEH, which includes more than 430,000 adult members of the Kaiser Permanente Northern California health plan who volunteered to participate in the research program. Data on this larger cohort include electronic medical records, behavioral and demographic information from surveys, and saliva or blood samples from 200,000 participants obtained with informed consent for genomic and other analyses.

This work was made possible with the investment of an $8.6 million grant from the Robert Wood Johnson Foundation, which saw the potential to build a resource that would transform genomic research. “This massive influx of new, high quality data will help scientists discover bigger breakthroughs faster,” said Nancy Barrand, the foundation’s senior adviser for Program Development. “Researchers used to have to go through the painstaking process of collecting and studying genomic samples on their own. Now researchers worldwide can find valuable clues for improving health by studying the genetic information from a cohort of 78,000 diverse individuals in dbGaP.”

Additional support for development of the RPGEH resource was provided by the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, and Kaiser Permanente.

The genetic information on more than 78,000 individuals translates into over 55 billion bits of genetic data for the cohort. The researchers conducted genome-wide genotyping using the newly developed Affymetrix Axiom Gene Titan system employed in the UCSF Institute for Human Genetics Genomics Core Facility to rapidly scan selected markers of genetic variation called single nucleotide polymorphisms (SNPs) in the genomes of the people in the GERA cohort. The RPGEH then combined the genetic data with information derived from Kaiser Permanente’s comprehensive longitudinal electronic medical records, as well as extensive survey data on participants’ health habits and backgrounds, providing researchers with an unparalleled research resource. These data form the basis of genome-wide association studies (GWAS) that can look at hundreds of thousands to millions of SNPs at the same time in relation to many different health conditions.

“The transfer of this data will greatly accelerate research on genetic influences on health, disease and aging,” said Catherine Schaefer, Ph.D., executive director of the Research Program on Genes, Environment and Health and co-principal investigator for GERA. “Making these data on such a large diverse cohort broadly available will enable many more scientists to work at a much greater scale that is likely to help answer important questions concerning health.”

“It’s all about time and money,” added Neil Risch, Ph.D., director of the UCSF Institute for Human Genetics and co-principal investigator for GERA. “Collecting large amounts of health data from people — and processing it — is labor intensive and expensive. With this data set, no one has to collect clinical information, take bio samples, safeguard and store them, or conduct genome-wide genotyping of their DNA. They can simply sit at a computer, ask questions of the data, and extract information.”

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Personalized medicine a cost-effective way to tailor drug therapy after stents


Knowing patients’ genetic profiles can save money, improve outcomes.

Dhruv Kazi, UC San Francisco

Genetic testing can help doctors choose the most effective and economical drugs to prevent blood clots in the half a million patients in the U.S. who receive coronary stents each year, according to a new study led by a UC San Francisco researcher.

The work, reported in the Feb. 18 Annals of Internal Medicine, demonstrates that genetically guided personalized medicine, often perceived as pricier than traditional approaches, can both lower costs and increase the quality of health care.

“Our results counter the general perception that personalized medicine is expensive,” said Dhruv Kazi, M.D., M.Sc., M.S., assistant professor of medicine at UCSF and first author of the new study. “What we have shown is that individualizing care based on genotype may in fact be very cost-effective in some settings, because it allows us to target the use of newer, more expensive drugs to the patients who are most likely to benefit from them.”

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Genetic cue found for sudden cardiac death syndrome


UC Irvine discovery could lead to improved early detection and prevention strategies.

Geoffrey Abbott, UC Irvine

UC Irvine researchers have found a specific genetic flaw that is connected to sudden death due to heart arrhythmia – a leading cause of mortality for adults around the world.

While a number of genes have been linked with arrhythmias, UC Irvine’s Geoffrey Abbott and his colleagues discovered that the functional impairment of a gene called KCNE2 underlies a multisystem syndrome that affects both heart rhythm and blood flow and can activate chemical triggers that can cause sudden cardiac death.

“With these findings, we can now explore improved early detection and prevention strategies for people who are at higher risk of sudden cardiac death, such as those with diabetes,” said Abbott, a professor of pharmacology and physiology & biophysics in the UC Irvine School of Medicine.

Study results appear in the February issue of Circulation: Cardiovascular Genetics, a publication of the American Heart Association.

Distinct from a heart attack, in which the heart continues to beat but blood flow is blocked, sudden cardiac death occurs when the heart ceases to beat because of the uncontrolled twitching of muscle fibers in its ventricles. Without defibrillation within minutes, this type of event is fatal.

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Understanding the basic biology of bipolar disorder


Scientists from UCLA, UCSF take steps to ID genetic component to mental illness.

Brain regions

Scientists know there is a strong genetic component to bipolar disorder, but they have had an extremely difficult time identifying the genes that cause it. So, in an effort to better understand the illness’s genetic causes, researchers at UCLA tried a new approach.

Instead of only using a standard clinical interview to determine whether individuals met the criteria for a clinical diagnosis of bipolar disorder, the researchers combined the results from brain imaging, cognitive testing, and an array of temperament and behavior measures. Using the new method, UCLA investigators — working with collaborators from UC San Francisco, Colombia’s University of Antioquia and the University of Costa Rica — identified about 50 brain and behavioral measures that are both under strong genetic control and associated with bipolar disorder. Their discoveries could be a major step toward identifying the specific genes that contribute to the illness.

The results are published in today’s (Feb. 12) edition of the Journal JAMA Psychiatry.

A severe mental illness that affects about 1 to 2 percent of the population, bipolar disorder causes unusual shifts in mood and energy, and it interferes with the ability to carry out everyday tasks. Those with the disorder can experience tremendous highs and extreme lows — to the point of not wanting to get out of bed when they’re feeling down. The genetic causes of bipolar disorder are highly complex and likely involve many different genes, said Carrie Bearden, a senior author of the study and an associate professor of psychiatry and psychology at the UCLA Semel Institute for Neuroscience and Human Behavior.

“The field of psychiatric genetics has long struggled to find an effective approach to begin dissecting the genetic basis of bipolar disorder,” Bearden said. “This is an innovative approach to identifying genetically influenced brain and behavioral measures that are more closely tied to the underlying biology of bipolar disorder than the clinical symptoms alone are.”

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Global regulator of mRNA editing found


Protein controls editing, expanding the information content of DNA.

Model organism Caenorhabditis elegans

An international team of researchers, led by scientists from the UC San Diego School of Medicine and Indiana University, have identified a protein that broadly regulates how genetic information transcribed from DNA to messenger RNA (mRNA) is processed and ultimately translated into the myriad of proteins necessary for life.

The findings, published today (Feb. 6) in the journal Cell Reports, help explain how a relatively limited number of genes can provide versatile instructions for making thousands of different messenger RNAs and proteins used by cells in species ranging from sea anemones to humans. In clinical terms, the research might also help researchers parse the underlying genetic mechanisms of diverse diseases, perhaps revealing new therapeutic targets.

“Problems with RNA editing show up in many human diseases, including those of neurodegeneration, cancer and blood disorders,” said Gene Yeo, Ph.D., assistant professor in the Department of Cellular and Molecular Medicine at UC San Diego. “This is the first time that a single protein has been identified that broadly regulates RNA editing. There are probably hundreds more. Our approach provides a method to screen for them and opens up new ways to study human biology and disease.”

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Researchers ID more pesticides linked to Parkinson’s


They also find gene that increases risk.

Pesticides and Parkinson'sStudies have shown that certain pesticides can increase people’s risk of developing Parkinson’s disease. Now, UCLA researchers have found that the strength of that risk depends on an individual’s genetic makeup, which, in the most pesticide-exposed populations, could increase a person’s chance of developing the debilitating disease two- to six-fold.

In an earlier study, published January 2013 in Proceedings of the National Academy of Sciences, the UCLA team discovered a link between Parkinson’s and the pesticide benomyl, a fungicide that has been banned by the U.S. Environmental Protection Agency. That study found that benomyl prevents the enzyme aldehyde dehydrogenase (ALDH) from converting aldehydes — organic compounds that are highly toxic to dopamine cells in the brain — into less toxic agents, thereby contributing to the risk of Parkinson’s.

For the current study, UCLA researchers tested a number of additional pesticides and found 11 that also inhibit ALDH and increase the risk of Parkinson’s — and at levels much lower than they are currently being used, said the study’s lead author, Jeff Bronstein, a professor of neurology and director of the movement disorders program at UCLA.

Bronstein said the team also found that people with a common genetic variant of the ALDH2 gene are particularly sensitive to the effects of ALDH-inhibiting pesticides and are two to six times more likely to develop Parkinson’s when exposed to these pesticides than those without the variant.

The results of the new epidemiological study appear Feb. 5 in the online issue of Neurology, the medical journal of the American Academy of Neurology.

“We were very surprised that so many pesticides inhibited ALDH and at quite low concentrations — concentrations that were way below what was needed for the pesticides to do their job,” Bronstein said. “These pesticides are pretty ubiquitous and can be found on our food supply. They are used in parks and golf courses and in pest control inside buildings and homes. So this significantly broadens the number of people at risk.”

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Scientists discover new genetic forms of neurodegeneration


Several promising targets identified for development of new treatments.

Joseph Gleeson, UC San Diego

Joseph Gleeson, UC San Diego

In a study published in the Jan. 31issue of Science, an international team led by scientists at the UC San Diego School of Medicine report doubling the number of known causes for the neurodegenerative disorder known as hereditary spastic paraplegia. HSP is characterized by progressive stiffness and contraction of the lower limbs and is associated with epilepsy, cognitive impairment, blindness and other neurological features.

Over several years, working with scientific colleagues in parts of the world with relatively high rates of consanguinity or common ancestry, UC San Diego researchers recruited a cohort of more than 50 families displaying autosomal recessive HSP – the  largest such cohort assembled to date. The scientists analyzed roughly 100 patients from this cohort using a technique called whole exome sequencing, which focuses on mapping key portions of the genome. They identified a genetic mutation in almost 75 percent of the cases, half of which were in genes never before linked with human disease.

“After uncovering so many novel genetic bases of HSP, we were in the unique position to investigate how these causes link together. We were able to generate an ‘HSP-ome,’ a map that included all of the new and previously described causes,” said senior author Joseph G. Gleeson, M.D., Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of neurosciences and pediatrics and at Rady Children’s Hospital-San Diego, a research affiliate of UC San Diego.

The HSP-ome helped researchers locate and validate even more genetic mutations in their patients, and indicated key biological pathways underlying HSP. The researchers also were interested in understanding how HSP relates to other groups of disorders. They found that the HSP-ome links HSP to other more common neurodegenerative disorders, such as Alzheimer’s disease and amyotrophic lateral sclerosis.

“Knowing the biological processes underlying neurodegenerative disorders is seminal to driving future scientific studies that aim to uncover the exact mechanisms implicated in common neurodegenerative diseases, and to indicate the path toward development of effective treatments,” said Gleeson.

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Puzzling quesiton in bacterial immune system answered


Berkeley researchers uncover the key to self-awareness in genome editor.

Short DNA sequences known as “PAM” (shown in yellow) enable the bacterial enzyme Cas9 to identify and degrade foreign DNA, as well as induce site-specific genetic changes in animal and plant cells. The presence of PAM is also required to activate the Cas9 enzyme. (Illustration by KC Roeyer.)

Short DNA sequences known as “PAM” (shown in yellow) enable the bacterial enzyme Cas9 to identify and degrade foreign DNA, as well as induce site-specific genetic changes in animal and plant cells. The presence of PAM is also required to activate the Cas9 enzyme.

A central question has been answered regarding a protein that plays an essential role in the bacterial immune system and is fast becoming a valuable tool for genetic engineering. A team of researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and UC Berkeley have determined how the bacterial enzyme known as Cas9, guided by RNA, is able to identify and degrade foreign DNA during viral infections, as well as induce site-specific genetic changes in animal and plant cells. Through a combination of single-molecule imaging and bulk biochemical experiments, the research team has shown that the genome-editing ability of Cas9 is made possible by the presence of short DNA sequences known as “PAM,” for protospacer adjacent motif.

“Our results reveal two major functions of the PAM that explain why it is so critical to the ability of Cas9 to target and cleave DNA sequences matching the guide RNA,” says Jennifer Doudna, the biochemist who led this study. “The presence of the PAM adjacent to target sites in foreign DNA and its absence from those targets in the host genome enables Cas9 to precisely discriminate between non-self DNA that must be degraded and self DNA that may be almost identical. The presence of the PAM is also required to activate the Cas9 enzyme.”

With genetically engineered microorganisms, such as bacteria and fungi, playing an increasing role in the green chemistry production of valuable chemical products including therapeutic drugs, advanced biofuels and biodegradable plastics from renewables, Cas9 is emerging as an important genome-editing tool for practitioners of synthetic biology.

“Understanding how Cas9 is able to locate specific 20-base-pair target sequences within genomes that are millions to billions of base pairs long may enable improvements to gene targeting and genome editing efforts in bacteria and other types of cells,” says Doudna who holds joint appointments with Berkeley Lab’s Physical Biosciences Division and UC Berkeley’s Department of Molecular and Cell Biology and Department of Chemistry, and is also an investigator with the Howard Hughes Medical Institute (HHMI).

Doudna is one of two corresponding authors of a paper describing this research in the journal Nature. The paper is titled “DNA interrogation by the CRISPR RNA-guided endonuclease Cas9.” The other corresponding author is Eric Greene of Columbia University. Co-authoring this paper were Samuel Sternberg, Sy Redding and Martin Jinek.

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Advanced genetic technique yields novel antibiotic from ocean bacteria


Study may open new avenues for natural product discoveries, drug development.

Advanced genetic technique yields novel antibiotic from ocean bacteria.

Advanced genetic technique yields novel antibiotic from ocean bacteria.

Scientists at UC San Diego have developed a new genetic platform that allows efficient production of naturally occurring molecules, and have used it to produce a novel antibiotic compound. Their study, published this week in PNAS, may open new avenues for natural product discoveries and drug development.

According to lead investigator Bradley S. Moore, Ph.D., of the Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego, the findings demonstrate a “plug and play” technique to trigger previously unknown biosynthetic pathways and identify natural product drug candidates.

“In my opinion, the new synthetic biology technology we developed – which resulted in the discovery of a new antibiotic from a marine bacterium – is just the tip of the iceberg in terms of our ability to modernize the natural product drug discovery platform,” Moore said.

The ocean, covering 70 percent of the earth’s surface, is a rich source of new microbial diversity for the discovery of new natural products effective as drugs for treating infections, cancer and other important medical conditions. Most natural antibiotics are complex molecules that are assembled by a special group of enzymes genetically encoded in the microbe’s chromosome.

But it often proves difficult to grow the newly discovered ocean bacteria in the laboratory, or to get them to produce their full repertoire of natural products.

The UC San Diego scientists harvested a set of genes predicted to encode a natural product from ocean bacteria, then used the synthetic biology technology to identify and test a totally new antibiotic – taromycin A – found to be effective in fighting drug-resistant MRSA.

“Antibiotic resistance is critical challenge to the public health. Most antibiotics, such as penicillin, used in human medicine are natural molecules originally isolated from microbes in the soil or rainforest – part of the chemical warfare that microbes deploy to out-compete one another and secure their niche in the environment,” said co-investigator Victor Nizet, M.D., professor of pediatrics and pharmacy at UC San Diego.

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Study discovers therapy to correct a severe chromosome defect


Induced pluripotent stem cell reprogramming offers potential to correct abnormal chromosomes.

Anthony Wynshaw-Boris

Anthony Wynshaw-Boris

Geneticists from Ohio, California and Japan joined forces in a quest to correct a faulty chromosome through cellular reprogramming. Their study, published online Jan. 12 in Nature, used stem cells to correct a defective “ring chromosome” with a normal chromosome. Such therapy has the promise to correct chromosome abnormalities that give rise to birth defects, mental disabilities and growth limitations.

“In the future, it may be possible to use this approach to take cells from a patient that has a defective chromosome with multiple missing or duplicated genes and rescue those cells by removing the defective chromosome and replacing it with a normal chromosome,” said senior author Anthony Wynshaw-Boris, M.D., Ph.D., James H. Jewell M.D. ’34 Professor of Genetics and chair of Case Western Reserve School of Medicine Department of Genetics and Genome Sciences and University Hospitals Case Medical Center.

Wynshaw-Boris led this research while a professor in pediatrics, the Institute for Human Genetics and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UC San Francisco before joining the faculty at Case Western Reserve in June 2013.

Individuals with ring chromosomes may display a variety of birth defects, but nearly all persons with ring chromosomes at least display short stature due to problems with cell division. A normal chromosome is linear, with its ends protected, but with ring chromosomes, the two ends of the chromosome fuse together, forming a circle. This fusion can be associated with large terminal deletions, a process where portions of the chromosome or DNA sequences are missing. These deletions can result in disabling genetic disorders if the genes in the deletion are necessary for normal cellular functions.

The prospect for effective countermeasures has evaded scientists — until now. The international research team discovered the potential for substituting the malfunctioning ring chromosome with an appropriately functioning one during reprogramming of patient cells into induced pluripotent stem cells (iPSCs). iPSC reprogramming is a technique that was developed by Shinya Yamanaka, M.D., Ph.D., a co-corresponding author on the Nature paper. Yamanaka is a senior investigator at the UCSF-affiliated Gladstone Institutes, a professor of anatomy at UCSF, and the director of the Center for iPS Cell Research and Application (CiRA) at the Institute for Integrated Cell-Material Sciences (iCeMS) in Kyoto University. He won the Nobel Prize in Medicine in 2012 for developing the reprogramming technique.

Marina Bershteyn, Ph.D., a postdoctoral fellow in the Wynshaw-Boris lab at UCSF, along with Yohei Hayashi, Ph.D., a postdoctoral fellow in the Yamanaka lab at the Gladstone Institutes, reprogrammed skin cells from three patients with abnormal brain development due to a rare disorder called Miller-Dieker Syndrome, which results from large terminal deletions in one arm of chromosome 17. One patient had a ring chromosome 17 with the deletion, and the other two patients had large terminal deletions in one copy of chromosome 17, but not a ring. Additionally, each of these patients had one normal chromosome 17.

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