Category Archives: Human Genetics

Although not widely known, RASopathies are among the most common genetic disorders, affecting approximately one child out of 1,000. RASopathies are caused by mutations within the RAS pathway, a biochemical system cells use to transmit information from their exterior to their interior.

Two Princeton University studies are opening important new windows into understanding an untreatable group of common genetic disorders known as RASopathies that affect approximately one child out of 1,000 and are characterized by distinct facial features, developmental delays, cognitive impairment and heart problems. The researchers observed in zebrafish and fruit fly embryos how cancer-related mutations in the RAS pathway a biochemical system cells use to transmit information from their exterior to their interior caused severe deformations. Fruit-fly embryos (above) showed how signals at the early stage of development (red in top photo) activate genes (purple in middle photo) and pattern structures in the fly larva (bottom photo.) (Photo courtesy of Stanislav Shvartsman, Department of Chemical and Biological Engineering)

Human development is very complex and its amazing that it goes right so often. However, there are certain cases where it does not, as with RASopathies, said Granton Jindal, co-lead author of the two studies. Both Jindal and the other co-lead author, Yogesh Goyal, are graduate students in theDepartment of Chemical and Biological Engineeringand theLewis-Sigler Institute for Integrative Genomics (LSI). Jindal and Goyal do their thesis research in the lab ofStanislav Shvartsman, professor of chemical and biological engineering and LSI.

Our new studies are helping to explain the mechanisms underlying these disorders, Jindal said.

These studies were published this year, one in the Proceedings of the National Academy of Sciences (PNAS) and the other in Nature Genetics online. The researchers made the discoveries in zebrafish and fruit flies animals commonly used as simplified models of human genetics and Jindal and Goyals specialties, respectively. Due to the evolutionary similarities in the RAS pathway across diverse species, changes in this pathway would also be similar. Thus, it is likely that significant parts of findings in animals would apply to humans as well, although further research is needed to confirm this.

The first paper published Jan. 3in PNAS presented a way to rank the severity of different mutations involved in RASopathies. The researchers introduced 16 mutations one at a time in developing zebrafish embryos. As each organism developed, clear differences in the embryos shapes became evident, revealing the strength of each mutation. The same mutant proteins produced similarly varying degrees of defects in fruit flies. Some of the mutations the researchers tested were already known to be involved in human cancers. The researchers noted that these cancer-related mutations caused more severe deformations in the embryos, aligning with the medical communitys ongoing efforts to adapt anti-cancer compounds to treat RASopathies.

Until now, there was no systematic way of comparing different mutation severities for RASopathies effectively, Goyal said.

Jindal added, This study is an important step for personalized medicine in determining a diagnosis to a first approximation. The study therefore suggested a path forward to human diagnostic advances, potentially enabling health care professionals to offer better diagnoses and inform caretakers about patients disease progression.

The study went further and examined the use of an experimental cancer-fighting drug being investigated as a possible way to treat RASopathies. The researchers demonstrated that the amount of medication necessary to correct the developmental defects in the zebrafish embryos corresponded with the mutations severity more severe mutations required higher dosages.

The more recent paper, published online by Nature Genetics Feb. 6, reports an unexpected twist in treatment approach to some RASopathies. Like all cellular pathways, the RAS pathway is a series of molecular interactions that changes a cells condition. Conventional wisdom has held that RASopathies are triggered by overactive RAS pathways, which a biologist would call excessive signaling.

The Nature Genetics study, however, found that some RASopathies could result from insufficient signaling along the RAS pathway in certain regions of the body. This means that drugs intended to treat RASopathies by tamping down RAS pathway signaling might actually make certain defects worse.

To our knowledge, our study is the first to find lower signaling levels that correspond to a RASopathy disease, Goyal said. Drugs under development are primarily RAS-pathway inhibitors aimed at reducing the higher activity, so maybe we need to design drugs that only target specific affected tissues, or investigate alternative, novel treatment options.

The Nature Genetics study also found that RAS pathway mutations cause defects by changing the timing and specific locations of embryonic development. For example, in normal fruit fly cells, the RAS pathway only turns on when certain natural cues are received from outside the cell. In the mutant cells, however, the RAS pathway in certain parts of fly embryo abnormally activated before these cues were received. This early activation disturbed the delicate process of embryonic development. The researchers found similar behavior in zebrafish cells.

Our integrative approach has allowed us to make enormous progress in understanding RASopathies, some of which have just been identified in the last couple of decades, Shvartsman said. With continued steps forward in both basic and applied science, as weve shown with our new publications, we hope to develop new ideas for understanding and treatment of a large class of developmental defects.

Princeton co-authors of the two papers includeTrudi Schpbach, the Henry Fairfield Osborn Professor of Biology and professor ofmolecular biology, andRebecca Burdine, an associate professor of molecular biology, as well as co-advisers to Goyal and Jindal; Alan Futran, a former graduate student in the Department of Chemical and Biological Engineering and LSI; graduate student Eyan Yeung of the Department of Molecular Biology and LSI; Jos Pelliccia, a graduate student in the Department of Molecular Biology; seniors in molecular biology Iason Kountouridis and Kei Yamaya; and Courtney Balgobin Class of 2015.

Bruce Gelb, a pediatric cardiologist specializing in cardiovascular genetics and the director of the Mindich Child Health and Development Institute at the Mount Sinai School of Medicine in New York, described the two new studies as wonderful in advancing the understanding of altered biology in RASopathies and developing a framework for comparing mutation strengths, bringing effective treatments significantly closer.

At this time, most of the issues that arise from the RASopathies are either addressed symptomatically or cannot be addressed, Gelb said. The work [these researchers] are undertaking could lead to true therapies for the underlying problem.

The paper, In vivo severity ranking of Ras pathway mutations associated with developmental disorders, was published Jan. 3 in the Proceedings of the National Academy of Sciences. The paper, Divergent effects of intrinsically active MEK variants on developmental Ras signaling, was published on Feb. 6 in Nature Genetics online. The research for both papers was supported in part by the National Institutes of Health and the National Science Foundation.

Media contact: Steven Schultz, 609-258-3617, sschultz@princeton.edu

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Studies point way to precision therapies for common class of genetic disorders - HealthCanal.com (press release) (blog)

HIV viral load is influenced by both virus and patient genetics

HIV sufferers experience varying rates of disease progression, depending in part on their viral load the amount of virus present in the body. Researchers collected patient and viral genetic data from 541 people with HIV and investigated the relative impacts of human and viral genetics on viral load. They found that HIV strain variation accounts for 29 percent of differences in viral load, and human genetic variation accounts for 8.4 percent. With a combined influence of just 30 percent, the results suggest that the effects of human genetics on viral load are caused mainly by its influence on which new genetic mutations arise in HIV as the virus multiplies inside the patient.

When top predators kill livestock, conflict can arise between pastoral communities and these endangered and rare species, impeding their conservation. A new study analyzed DNA and hair in the droppings of snow leopards and Himalayan wolves in Nepal, finding that a substantial 27 percent of the snow leopard diet and 24 percent of the wolf diet were made up of livestock. This highlights the need for further research into the impact of such predation on pastoral communities.

Six million people are diagnosed with new human papillomavirus (HPV) infections each year in the U.S. alone, but no specific cure for this family of viruses exists. Scientists have now used genetic engineering techniques to create a new high-throughput screening method that can identify potentially effective drugs and drug targets, considering the full viral genome and all its life cycle stages to increase the chance of success. When tested on 1,000 chemical compounds, the method identified several that were capable of blocking the growth of certain HPV strains, and the authors believe that their method could be an effective tool in drug development.

Image Credit: Madhu Chetri

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SciBites: Week of February 10th | PLOS Research News - PLOS Research News

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Genetics of both virus and patient work together to influence the ... Science Daily Viral and human genetics together account for about one third of the differences in disease progression rates seen among people infected with the human ... Patients and virus genetics account for a third of HIV viral loadInternational Business Times UK all 2 news articles »

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The Medical College of Wisconsin (MCW) appointed Raul A. Urrutia as director of the Human and Molecular Genetics Center and professor of the Department of Surgery, effective July 1.

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The Medical College of Wisconsin (MCW) appointed Raul A. Urrutia as director of the Human and Molecular Genetics Center and professor of the Department of Surgery, effective July 1.

Urrutia currently serves as professor in the departments of biochemistry and molecular biology, biophysics and medicine at the Mayo Clinic College of Medicine in Rochester, Minnesotaand director of epigenomics education and academic relationships in the epigenomics program, Mayo Clinic Center for Individualized Medicine.

Urrutia will relocatefrom Rochester, Minnesota, with his wifeGwen Lomberk, who will serve as associate professor, chief of the division of research, and director of basic research in the MCW Department of Surgery.

Read or Share this story: http://www.wauwatosanow.com/story/news/local/2017/02/09/medical-college-wisconsin-names-director-human-and-molecular-genetics-center/97714872/

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Medical College of Wisconsin names director of Human and Molecular Genetics Center - Wauwatosa Now

A few years ago, one of us (Ian) was lucky enough to be invited to visit the N.I. Vavilov Institute of Plant Industry in St Petersburg, Russia. Every plant breeder or geneticist knows of Nikolai Vavilov and his ceaseless energy in collecting important food crop varieties from all over the globe, and his application of genetics to plant improvement.

Vavilov championed the idea that there were Centres of Origin (or Diversity) for all plant species, and that the greatest variation was to be found in the place where the species evolved: wheat from the Middle East; coffee from Ethiopia; maize from Central America, and so on.

Hence the Centres of Origin (commonly known as the Vavilov Centres) are where you should start looking to find genotypes the set of genes responsible for a particular trait with disease resistance, stress tolerance or any other trait you are looking for. This notion applies to any species, which is why you can find more human genetic variation in some African countries than in the rest of the world combined.

By the late 1920s, as director of the Lenin All-Union Academy of Agricultural Sciences, Vavilov soon amassed the largest seed collection on the planet. He worked hard, he enjoyed himself, and drove other eager young scientists to work just as hard to make more food for the people of the Soviet Union.

However, things did not go well for Vavilov politically. How did this visionary geneticist, who aimed to find the means for food security, end up starving to death in a Soviet gulag in 1943?

Enter the villain, Trofim Lysenko, ironically a protg of Vavilovs. The notorious Vavilov-Lysenko antagonism became one of the saddest textbook examples of a futile effort to resolve scientific debate using a political approach.

Lysenkos name leapt from the pages of history and into the news when Australias Chief Scientist, Alan Finkel, mentioned him during a speech at a meeting of chief scientists in Canberra this week.

Finkel was harking back to Lysenko in response to news that US President Donald Trump had acted in January to censor scientific data regarding climate change from the Environmental Protection Agency. Lysenkos story reminds us of the dangers of political interference in science, said Finkel:

Lysenko believed that successive generations of crops could be improved by exposing them to the right environment, and so too could successive generations of Soviet citizens be improved by exposing them to the right ideology.

So while Western scientists embraced evolution and genetics, Russian scientists who thought the same were sent to the gulag. Western crops flourished. Russian crops failed.

The emerging ideology of Lysenkoism was effectively a jumble of pseudoscience, based predominantly on his rejection of Mendelian genetics and everything else that underpinned Vavilovs science. He was a product of his time and political situation in the young USSR.

In reality, Lysenko was what we might today call a crackpot. Among other things, he denied the existence of DNA and genes, he claimed that plants selected their mates, and argued that they could acquire characteristics during their lifetime and pass them on. He also espoused the theory that some plants choose to sacrifice themselves for the good of the remaining plants another notion that runs against the grain of evolutionary understanding.

Pravda formerly the official newspaper of the Soviet Communist Party celebrated him for finding a way to fertilise crops without applying anything to the field.

None of this could be backed up by solid evidence. His experiments were not repeatable, nor could his theories claim overwhelming consensus among other scientists. But Lysenko had the ear of the one man who counted most in the USSR: Joseph Stalin.

The Lysenko vs Vavilov/Mendel/Darwin argument came to a head in 1936 at the Conference of the Lenin Academy when Lysenko presented his -ism.

In the face of scientific opinion, and the overwhelming majority of his peers, Pravda declared Lysenko the winner of the argument. By 1939, after quite a few scientists had been imprisoned, shot or disappeared, including the director of the Lenin Institute, there was a vacancy to be filled. And the most powerful man in the country filled it with Trofim Lysenko. Lysenko was now Vavilovs boss.

Within a year, Vavilov was captured on one of his collection missions and interrogated for 11 months. He was accused of being a spy, having travelled to England and the United States, and been a regular correspondent with many geneticists outside the Soviet Union.

It did not help his cause that he came from a family of business people, whereas Lysenko was of peasant stock and a Soviet ideologue. Vavilov was sent to a gulag where, tragically, he died in 1943.

Meanwhile, his collection in Leningrad was in the middle of a 900-day siege. It only survived thanks to the sacrifice of his team who formed a militia to prevent the starving population (and rats) from eating the collection of more than 250,000 types of seeds, fruits and roots even growing the potatoes in their stock near the front to ensure the tubers did not die before losing their viability.

In 1948, the Lenin Academy announced that Lysenkoism should be taught as the only correct theory, and that continued until the mid-1960s.

Thankfully, in the post-Stalin era, Lysenko was slowly sidelined along with his theory. Today it is Vavilov who is considered a Soviet hero.

In 1958, the Academy of Science began awarding a medal in his honour. The leading Russian plant science institute is named in his honour, as is the Saratov State Vavilov Agrarian University. In addition, an asteroid, a crater on the Moon and two glaciers bear his name.

Since 1993, Bioversity International has awarded Vavilov Frankel (after Australian scientist Otto Frankel) fellowships to young scientists from developing countries to perform innovative research on plant genetic resources.

Meanwhile, research here in Australia, led by ARC Discovery Early Career Fellow Lee Hickey, we are continuing to find new genetic diversity for disease resistance in the Vavilov wheat collection.

In the post-Soviet era, students of genetics and agriculture in Russia are taught of the terrible outcomes of the applications of Lysenkoism to Soviet life and agricultural productivity.

Lysenkoism is a sad and terrible footnote in agricultural research, more important as a sadly misused -ism in the hands of powerful people who opt for ideology over fact. Its also a timely reminder of the dangers of political meddling in science.

Ian Godwin, Professor in Plant Molecular Genetics, The University of Queensland and Yuri Trusov, Plant molecular biologist, The University of Queensland

This article was originally published on The Conversation and republished here with permission. Read the original article.

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The tragic story of Soviet genetics shows the folly of political meddling in science - Cosmos

Alison Van Eenennaam, PhD, Animal Genomics and Biotechnology, University of California, Davis

HIGHLIGHTS:

Gene editing method has been developed to dehorn dairy cows It is unclear whether gene editing will be formally regarded as animal breeding which has not been traditionally regulated Gene edited animals should be evaluated on a case-by-case basis triggered by the novelty of the resulting attributes Regulatory frameworks should consider potential benefits of gene edited animals and the opportunity costs of precluding the use of this technology

Gene editing techniques are now being deployed by agricultural researchers to more precisely modify crops and animals without using foreign genes. This approach may quell some of the public skepticism of more classic transgenic products, often called GMOs. But questions remain about how these new products will be regulated.

The most dramatic advances are focused in the animal sector. Dairy cows, like those of the Holstein breed, naturally grow horns. They are often physically dehorned because they can pose a threat to other cows, as well as to farm workers handling the cattle. The team I lead at the University of California-Davis is collaborating with a company called Recombinetics, which has developed a method to produce dairy cattle that are genetically dehorned. The gene edited cattle are getting their new, horn-free alleles from the naturally hornless Angus breed to create hornless Holsteins.

Although this process mimics natural breeding in many key ways, questions remain about how or if the United States and governments around the world will regulate it. At the current time it is unclear whether gene editing of animals will be formally regulated in the same way as animals containing rDNA constructs that are the more traditional products of genetic engineering.

Animal breeding per se is not regulated by the U.S. government, although it is illegal to sell an unsafe food product regardless of the breeding method that was used to produce it. I am unaware of a unique food safety concern that has been associated with traditional animal breeding methods. Gene editing does not necessarily introduce any foreign rDNA or transgenic sequences into the genome, and many of the changes produced would be indistinguishable from naturally-occurring alleles and variations. As such, many applications will not fit the classical definition of genetic engineering.

For example, many edits are likely to alter alleles of a given gene using a template nucleic acid dictated by the sequence of a naturally-occurring allele from the same species (e.g. the hornless Holsteins carry a polled allele from Angus) [1]. As such, there will be no novel rDNA sequence present in the genome of the edited animal, and likewise no novel phenotype associated with that sequence. It is not evident what unique risks might be associated with an animal that is carrying such an allele given the exact same sequence and resulting phenotype would be observed in the closely-related breed from which the allele sequence was derived [2].

U.S. Regulators So Far Have Not Weighed In

Currently, the Food and Drug Administration (FDA) defines genetically engineered (GE) animals as those animals modified by rDNA techniques, including the entire lineage of animals that contain the modification [3]. The rDNA construct in the GE animal is considered a new animal drug and thus is a regulated article under the new animal drug provisions of the Federal Food Drug and Cosmetics Act. These two sentences are potentially contradictory as it is not clear if it is the use of rDNA techniques in the development of a product, or the presence of an rDNA construct (drug) in the product, that is the trigger for regulatory oversight. The use of rDNA techniques does not necessarily result in an rDNA construct in the animal.

It is possible that gene editing nucleases might introduce double stranded breaks at locations other than the target locus, and thereby induce alterations elsewhere in the genome [4]. Such off-target events are analogous to spontaneous mutations that occur in conventional breeding and are specifically induced in unregulated mutagenesis breeding, and can be minimized by careful selection of the guide sequence that targets the specific DNA sequence to be cut as well as the design of the gene editing reagents [5]. There are groups working on ways to rapidly identify and suppress such potential off-target effects [6]. Complete sequencing of polled calves derived from two independent cell lines to 20X coverage did not find any off-target introgression of the polled allele, nor any insertion- deletions (indels) ascribable to off-target DNA cleavage by the TALENs.[1].

Globally, governments and regulators are currently deliberating about how gene-edited animals should be regulated, if at all. It is no coincidence that there have been a slew of recent policy papers from normally unobtrusive public sector breeders and academicians from around the world discussing the need for regulation of genome editing to be science-based, proportional to risk, product focused and fit for purpose [2, 7-11].

Current Regulations of Transgenics Dont Clearly Apply

Many agencies around the world are involved with the regulation and governance of genetically engineered animals besides the U.S. FDA, including the European Medicine Agency (EMA), the European Food Safety Authority (EFSA), and the Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO). The definition of a genetically engineered animal differs among these different agencies.

The Codex Alimentarius (Codex), or Food Code, was established by FAO and WHO to develop harmonized international food standards, which protect consumer health and promote fair practices in food trade. In 2008 the Codex developed the science- based Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant-DNA Animals (GL68-2008) [12] which provides internationally-recognized recommendations for assessing the nutrition and safety of food from GE animals. In that document, a Recombinant-DNA Animal is defined as an animal in which the genetic material has been changed through in vitro nucleic acid techniques, including rDNA and direct injection of nucleic acid into cells or organelles.

The Cartagena Protocol on Biosafety (CPB) is an international agreement which aims to ensure the safe handling, transport and use of any living modified organism. The CPB defines Living modified organism to mean any living organism that possesses a novel combination of genetic material obtained through the use of modern biotechnology, and specifically excludes techniques used in traditional breeding and selection.

Likewise, the EU definition of a genetically engineered organism included in Directive 2001/18/EC encompasses an organism, with the exception of human beings, in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination..

Many applications of gene editing would result in products that have modifications that could occur by mating and/or natural recombination, and carry no novel combination of genetic material or rDNA construct. Additionally, many modifications would be indistinguishable from the naturally occurring variation that is the basis of all animal breeding programs and, in fact, evolution. The only way to tell the difference would be for the breeder to state whether the genetic variations in their germplasm was naturally occurring (which could include crossbreeding and mutation breeding induced by human intervention) or obtained via gene editing.

In this way it is somewhat analogous to cloning which makes an identical copy of an organism a genetic twin. The milk, meat and eggs from cloned animals are indistinguishable from the products produced by conventionally bred animals. In the United States the FDA determined there were no unique risks associated with products derived from clones and this process is allowed to be used in animal breeding programs. Conversely, animal cloning is prohibited in some countries in the EU where the process- based regulatory approach judged the process unacceptable on ethical grounds.

Lines Blurry as to What Constitutes Genetic Engineering

Most recently the U.S. National Academy of Sciences (NAS) [13] concluded that the distinction between conventional breeding and genetic engineering is becoming less obvious. Some emerging genetic engineering technologies (like gene editing) have the potential to create novel varieties that are hard to distinguish genetically from varieties produced through conventional breeding or processes that occur in nature.

The NAS reasoned that conventionally bred varieties are associated with the same benefits and risks as genetically engineered varieties. They further concluded that a process-based regulatory approach is becoming less and less technically defensible as the old approaches to genetic engineering become less novel and as emerging processes such as genome editing and synthetic biology fail to fit current regulatory categories of genetic engineering. They recommended a tiered regulatory approach focused on any intended and unintended novel characteristics of the end product resulting from the breeding methods that may present potential hazards, rather than focusing regulation on the process or breeding method by which that genetic change was achieved.

Ideally gene edited animals will be considered on a case-by-case basis using such a tiered regulatory approach triggered by the novelty of the resulting attributes or phenotypes displayed by the animal. There is a need to ensure that the extent of regulatory oversight is proportional to the unique risks, if any, associated with the novel phenotypes.

Given there is currently not a single genetically engineered animal being sold for food anywhere in the world despite more than 30 years since the first genetically engineered livestock were produced in 1985, animal breeders are perhaps the group most aware of the chilling impact that regulatory gridlock can have on the deployment of potentially valuable breeding techniques.

From a personal perspective I am agnostic as to which specific breeding method I use to achieve genetic progress in my research whichever works consistently, and enables the best rate of genetic progress is the one I would prefer to use if the regulations associated with the use of that technique are not prohibitive. Unfortunately, this has not been the case for genetic engineering for the past 20 years of my career. This has effectively precluded the use of this method in my research and by public sector breeders globally.

I have watched with growing frustration as the expensive regulatory system focused on the use of genetic engineering in agricultural breeding programs has wasted millions, if not billions, of dollars evaluating safe products. Those funds could have been better used to research to solve pressing agricultural problems. Agricultural production systems are complicated and complex and there are no black and white answers no forbidden or perfect solutions. Every solution has tradeoffs, also known as risk and benefits, as with every other decision we make in life.

If regulations around gene editing ultimately work to impede the seamless integration of gene editing methods with conventional animal breeding programs, they will effectively preclude the use of this technique in such programs. Idealistically, the best regulatory approach is one that allows new technologies to be used while preventing unacceptable risks to animal and human health or the environment. Here the definition of unacceptable becomes contentious, with some arguing that any level of risk is unacceptable.

However, in a world facing burgeoning animal protein demands, it important to ensure that regulatory frameworks also appropriately consider and weigh the potential benefits of gene edited animals to global food security. Perhaps as importantly should also be a careful evaluation of the opportunity cost associated with precluding the use of gene editing technology in animal breeding programs, something that has rarely been considered for genetically engineered crops. Doing nothing by forestalling progress on potential solutions to global problems is in fact doing something, and opportunity costs should also be a consideration in the evaluation of new plant and animal varieties.

This piece was adapted by the author and expanded from A. L. Van Eenennaam. 2017. Genetic Modification of Food Animals. Current Opinion in Biotechnology.

Alison Van Eenennaam is an Animal Genomics and Biotechnology Cooperative Extension Specialist in the Department of Animal Science at the University of California, Davis. Her publicly-funded research and outreach program focuses on the use of animal genomics and biotechnology in livestock production systems. She earned her B.S. from the University of Melbourne in Australia, and both her M.S. and Ph.D. degrees were earned from the University of California, Davis, in animal science and genetics, respectively.

References

The Genetic Literacy Project is a 501(c)(3) non profit dedicated to helping the public, journalists, policy makers and scientists better communicate the advances and ethical and technological challenges ushered in by the biotechnology and genetics revolution, addressing both human genetics and food and farming. We are one of two websites overseen by the Science Literacy Project; our sister site, the Epigenetics Literacy Project, addresses the challenges surrounding emerging data-rich technologies.

Excerpt from:
WillAnd ShouldGene Edited Animals Be Regulated? - Genetic Literacy Project

February 7, 2017 by Adam Hadhazy Two Princeton University studies are opening important new windows into understanding an untreatable group of common genetic disorders known as RASopathies that affect approximately one child out of 1,000 and are characterized by distinct facial features, developmental delays, cognitive impairment and heart problems. The researchers observed in zebrafish and fruit fly embryos how cancer-related mutations in the RAS pathway a biochemical system cells use to transmit information from their exterior to their interior caused severe deformations. Fruit-fly embryos (above) showed how signals at the early stage of development (red in top photo) activate genes (purple in middle photo) and pattern structures in the fly larva (bottom photo.) . Credit: Stanislav Shvartsman, Department of Chemical and Biological Engineering

Two Princeton University studies are opening important new windows into understanding an untreatable group of common genetic disorders known as RASopathies that are characterized by distinct facial features, developmental delays, cognitive impairment and heart problems. The findings could help point the way toward personalized precision therapies for these conditions.

Although not widely known, RASopathies are among the most common genetic disorders, affecting approximately one child out of 1,000. RASopathies are caused by mutations within the RAS pathway, a biochemical system cells use to transmit information from their exterior to their interior.

"Human development is very complex and it's amazing that it goes right so often. However, there are certain cases where it does not, as with RASopathies," said Granton Jindal, co-lead author of the two studies. Both Jindal and the other co-lead author, Yogesh Goyal, are graduate students in the Department of Chemical and Biological Engineering and the Lewis-Sigler Institute for Integrative Genomics (LSI). Jindal and Goyal do their thesis research in the lab of Stanislav Shvartsman, professor of chemical and biological engineering and LSI.

"Our new studies are helping to explain the mechanisms underlying these disorders," Jindal said.

These studies were published this year, one in the Proceedings of the National Academy of Sciences (PNAS) and the other in Nature Genetics online. The researchers made the discoveries in zebrafish and fruit fliesanimals commonly used as simplified models of human genetics and Jindal and Goyal's specialties, respectively. Due to the evolutionary similarities in the RAS pathway across diverse species, changes in this pathway would also be similar. Thus, it is likely that significant parts of findings in animals would apply to humans as well, although further research is needed to confirm this.

The first paper published Jan. 3 in PNAS presented a way to rank the severity of different mutations involved in RASopathies. The researchers introduced 16 mutations one at a time in developing zebrafish embryos. As each organism developed, clear differences in the embryos' shapes became evident, revealing the strength of each mutation. The same mutant proteins produced similarly varying degrees of defects in fruit flies. Some of the mutations the researchers tested were already known to be involved in human cancers. The researchers noted that these cancer-related mutations caused more severe deformations in the embryos, aligning with the medical community's ongoing efforts to adapt anti-cancer compounds to treat RASopathies.

"Until now, there was no systematic way of comparing different mutation severities for RASopathies effectively," Goyal said.

Jindal added, "This study is an important step for personalized medicine in determining a diagnosis to a first approximation." The study therefore suggested a path forward to human diagnostic advances, potentially enabling health care professionals to offer better diagnoses and inform caretakers about patients' disease progression.

The study went further and examined the use of an experimental cancer-fighting drug being investigated as a possible way to treat RASopathies. The researchers demonstrated that the amount of medication necessary to correct the developmental defects in the zebrafish embryos corresponded with the mutation's severitymore severe mutations required higher dosages.

The more recent paper, published online by Nature Genetics Feb. 6, reports an unexpected twist in treatment approach to some RASopathies. Like all cellular pathways, the RAS pathway is a series of molecular interactions that changes a cell's condition. Conventional wisdom has held that RASopathies are triggered by overactive RAS pathways, which a biologist would call excessive signaling.

The Nature Genetics study, however, found that some RASopathies could result from insufficient signaling along the RAS pathway in certain regions of the body. This means that drugs intended to treat RASopathies by tamping down RAS pathway signaling might actually make certain defects worse.

"To our knowledge, our study is the first to find lower signaling levels that correspond to a RASopathy disease," Goyal said. "Drugs under development are primarily RAS-pathway inhibitors aimed at reducing the higher activity, so maybe we need to design drugs that only target specific affected tissues, or investigate alternative, novel treatment options."

The Nature Genetics study also found that RAS pathway mutations cause defects by changing the timing and specific locations of embryonic development. For example, in normal fruit fly cells, the RAS pathway only turns on when certain natural cues are received from outside the cell. In the mutant cells, however, the RAS pathway in certain parts of fly embryo abnormally activated before these cues were received. This early activation disturbed the delicate process of embryonic development. The researchers found similar behavior in zebrafish cells.

"Our integrative approach has allowed us to make enormous progress in understanding RASopathies, some of which have just been identified in the last couple of decades," Shvartsman said. "With continued steps forward in both basic and applied science, as we've shown with our new publications, we hope to develop new ideas for understanding and treatment of a large class of developmental defects."

Princeton co-authors of the two papers include Trudi Schpbach, the Henry Fairfield Osborn Professor of Biology and professor of molecular biology, and Rebecca Burdine, an associate professor of molecular biology, as well as co-advisers to Goyal and Jindal; Alan Futran, a former graduate student in the Department of Chemical and Biological Engineering and LSI; graduate student Eyan Yeung of the Department of Molecular Biology and LSI; Jos Pelliccia, a graduate student in the Department of Molecular Biology; seniors in molecular biology Iason Kountouridis and Kei Yamaya; and Courtney Balgobin Class of 2015.

Bruce Gelb, a pediatric cardiologist specializing in cardiovascular genetics and the director of the Mindich Child Health and Development Institute at the Mount Sinai School of Medicine in New York, described the two new studies as "wonderful" in advancing the understanding of altered biology in RASopathies and developing a framework for comparing mutation strengths, bringing effective treatments significantly closer.

"At this time, most of the issues that arise from the RASopathies are either addressed symptomatically or cannot be addressed," Gelb said. "The work [these researchers] are undertaking could lead to true therapies for the underlying problem."

Explore further: New insight into RASopathy-associated lymphatic defects

More information: Granton A. Jindal et al. In vivo severity ranking of Ras pathway mutations associated with developmental disorders, Proceedings of the National Academy of Sciences (2017). DOI: 10.1073/pnas.1615651114

Yogesh Goyal et al. Divergent effects of intrinsically active MEK variants on developmental Ras signaling, Nature Genetics (2017). DOI: 10.1038/ng.3780

The RAS pathway is a cellular signaling pathway that regulates growth and development in humans. RASopathies are a group of diseases characterized by defects in RAS signaling.

Researchers have successfully targeted an important molecular pathway that fuels a variety of cancers and related developmental syndromes called "Rasopathies."

Investigators at Beth Israel Deaconess Medical Center (BIDMC) have identified a developmental cause of adult-onset cardiac hypertrophy, a dangerous thickening of the heart muscle that can lead to heart failure and death. ...

Different genetic mistakes driving skin cancer may affect how patients respond to the drug vemurafenib, providing grounds to screen people with melanoma skin cancer before treatment, a new study by Cancer Research UK scientists ...

May 5, 2016A cell-to-cell signaling network that serves as a developmental timer could provide a framework for better understanding the mechanisms underlying human heart valve disease, say University of Oregon scientists.

It's been more than 10 years since Japanese researchers Shinya Yamanaka, M.D., Ph.D., and his graduate student Kazutoshi Takahashi, Ph.D., developed the breakthrough technique to return any adult cell to its earliest stage ...

Two Princeton University studies are opening important new windows into understanding an untreatable group of common genetic disorders known as RASopathies that are characterized by distinct facial features, developmental ...

The world's biggest study into an individual's genetic make-up and the risk of developing lung disease could allow scientists to more accurately 'predict' - based on genes and smoking - your chance of developing COPD, a deadly ...

A poor diet during pregnancy can cause biological changes that last throughout life, according to research from Imperial College London.

UT Southwestern Medical Center researchers have identified a gene that protects the gut from inflammatory bowel disease (IBD).

In the largest, deepest search to date, the international Genetic Investigation of Anthropometric Traits (GIANT) Consortium has uncovered 83 new DNA changes that affect human height. These changes are uncommon or rare, but ...

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Medical College of Wisconsin names new director for human genetics center Milwaukee Business Journal At the Mayo college in Rochester, Minn., Urrutia is a professor in the departments of biochemistry and molecular biology, biophysics and medicine. He is director of epigenomics education and academic relationships in the epigenomics program of the Mayo ... and more »

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Medical College of Wisconsin names new director for human genetics center - Milwaukee Business Journal

Science Daily

GIANT study finds rare, but influential, genetic changes related to height Science Daily In the largest, deepest search to date, the international Genetic Investigation of Anthropometric Traits (GIANT) Consortium has uncovered 83 new DNA changes that affect human height. These changes are uncommon or rare, but they have potent effects ... The Genetics Of Human Height RevealedScience 2.0 Researchers Find New Genetic Variants that Influence Human Adult HeightSci-News.com all 14 news articles »

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GIANT study finds rare, but influential, genetic changes related to height - Science Daily

Ever wonder how much of your height you inherited from your parents?

A large-scale genetic study published recently in the journal Natureis helping shed some light on the factors that determine whether a person grows to be 6-feet-1 or 5-feet-2.

While scientists already had a good idea of the most common genetic factors that contribute to height, the new findings uncover a number of rare genetic alterations that can play a surprisingly major role in human growth.

Using data from the Genetic Investigation of Anthropometric Traits consortium (a group also known as GIANT), scientists from the Broad Instituteat MIT and Harvard analyzed genetic information from more than 700,000 people, discovering 83 DNA changes that play a part in determining a persons height.

In their previous work, the same research team identified nearly 700 common genetic factors linked with height. Now, theyve identified a number of rare genetic variants for human growth that have an even larger effect than most common factors. For some people, these rare DNA changes may account for height differences of up to a full inch.

Overall, common variants still contribute more to height than rare variants, Dr. Joel Hirschhorn, the studys lead author and a professor of pediatrics and genetics at Boston Childrens Hospital and Harvard Medical School, told The Huffington Post. But, for the person who happens to carry one of the rare variants, the impact can be much greater than for common variants. For the variants we looked at, this was up to almost an inch... as opposed to a millimeter or less for the common variants.

Using a new technology called the ExomeChip, the researchers were able to scan the genomes of large populations to find rare markers that correlated with a particular height. They identified 51 uncommon variants found in less than 5 percent of people, and 32 rare variants found in less than 0.5 percent of the population.

With the addition of these uncommon variants, geneticists can now account for 27 percent of the genetics determining height up from 20 percent based on earlier studies.

Heritability is by far the largest factor contributing to individual height.

Today, in places where most people get enough nutrition in childhood to grow to their potential, about 80 percent or more of the variability in height is due to genetic factors that we inherit from our parents, Hirschhorn explained.

According to the studys authors, this method of testing rare genetic variants could be used to investigate uncommon DNA changes involved in other aspects of human health.

Looking at rare variants in genes was helpful in understanding the biology of human growth, Hirschhorn said. With a big enough study, similar approaches could be valuable in understanding the biology of many diseases, which could help guide better treatments.

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Scientists Discover 83 Genetic Mutations That Help Determine Your Height - Huffington Post