Category Archives: Gene Medicine

By Eric Sorensen, WSU science writer

SPOKANE, Wash. Washington State University researchers have seen how a particular gene is involved in the quality of sleep experienced by three different animals, including humans. The gene and its function open a new avenue for scientists exploring how sleep works and why animals need it so badly.

Sleep must be serving some important function, but as scientists we still dont understand what that is, said Jason Gerstner, assistant research professor in WSUs Elson S. Floyd College of Medicine and lead author of a paper in the open-access journal Science Advances. One way to get closer to that is by understanding how it is regulated or what processes exist that are shared across species.

As a doctoral student at the University of Wisconsin, Gerstner looked at genes that change expression over the sleep-wake cycle and found expression of the gene FABP7 changed over the day throughout the brain of mice.

He and colleagues saw that mice with a knocked out FABP7 gene slept more fitfully compared to mice with the gene intact. This suggested the gene is required for normal sleep in mammals.

To see if FABP7 is indeed required for normal sleep in humans, Gerstner and colleagues in Japan looked at data from nearly 300 Japanese men who underwent a seven-day sleep study that included an analysis of their DNA. It turned out that 29 of them had a variant of the gene responsible for the production of FABP7.

Like the mice, they tended to sleep more fitfully. While they would get the same amount of sleep as other people, their sleep was not as good, with more waking events when they should be sleeping.

Finally, the researchers made transgenic fruit flies. They inserted mutated and normal human FABP7 genes into star-shaped glial cells called astrocytes. Glial cells were long thought to be mere supporting characters to neurons, the processors of information in the brain. But researchers more recently have found that, like neurons, glial cells release chemical neurotransmitters and control behavior.

To monitor the flies sleep, the researchers used a commercial Drosophila activity monitor that automatically records activity changes using an infrared beam to determine if a fly is awake or asleep. If the beam is unbroken for five or more minutes, the machine concludes the fly is asleep.

It turned out that flies with the mutated FABP7 gene broke the beam more frequently during the normal sleep time. Like mice and humans without a properly functioning FABP7 gene, mutant FABP7 flies slept more fitfully.

This suggests that theres some underlying mechanism in astrocytes throughout all these species that regulates consolidated sleep, said Gerstner.

Moreover, he said, Its the first time weve really gained insight into a particular cells and molecular pathways roles in complex behavior across such diverse species.

Even more remarkable is that fruit flies have been on the planet for some 60 million years.

That suggests we have found an ancient mechanism that persisted over evolutionary time, he said. Evolution does not keep something around that long if it is not important.

While the researchers are excited about finding a gene with an apparently strong influence on sleep, they stress that other genes are almost certainly involved in the process.

FABP7 proteins are involved in what is called lipid signaling, shuttling fats to a cell nucleus to activate genes controlling growth and metabolism. Gerstner and his colleagues will now look to see how these functions might intersect with theories about why sleep matters. Among those theories are that sleep is important for neuronal activity, energy use and storage, and memory and learning.

Gerstners collaborators include scientists in Japan, Wisconsin and Pennsylvania, as well as WSU research intern Samantha Riedy, WSU professor Marcos Frank, and Hans Van Dongen, director of the WSU Sleep and Performance Research Center.

Funders include the National Institutes of Health and the U.S. Office of Naval Research.

The research is in keeping with WSUs Grand Challenges, major initiatives aimed at large societal problems. It is particularly relevant to the Sustaining Health challenge.

News media contact: Jason Gerstner, WSU Elson S. Floyd College of Medicine, 509-368-6660, j.gerstner@wsu.edu

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'Sleep gene' offers clues about why we need our zzzs - WSU News

Genetic testing company 23AndMe is back with a controversial new offering, after the U.S. Food and Drug Administration on Thursday green-lighted the companys request to market a fresh batch of direct-to-consumer tests. Soon, with a simple saliva swab dropped in the mail, customers will be able to get answers about their genetic risk for developing 10 maladiesincluding Parkinsons disease and late-onset Alzheimers.

The FDA approval will likely reignite a long-simmering debate about when and how such tests should be used. Even when there are strong links between certain gene variants and medical conditions, genetic information often remains difficult to interpret. It must be balanced against other factors including health status, lifestyle and environmental influences, which could sharpen or weaken risk. If disease risk news is delivered at homewithout a genetic counselor or doctor on hand to offer contextmany geneticists fear it can lead to unnecessary stress, confusion and misunderstandings.

Against that backdrop, the FDAs decision came with caveats: Results obtained from the tests should not be used for diagnosis or to inform treatment decisions, the agency said in a statement. It added that false positive and false negative findings are possible.

But geneticist Michael Watson, executive director of the American College of Medical Genetics and Genomics, thinks consumers will have trouble making such distinctions and says he doubts people will view them as a mere novelty. Watson also worries 23AndMes wares may create other problems: Follow-up testing for some of these conditions may be quite pricey, he says, and insurance companies might not cover that cost if a person has no symptoms. He also notes that some of the conditions involved may have no proved treatments, leaving consumers with major concernsand few options to address them, aside from steps like making some lifestyle changes.

The makeup of 23AndMes reports to consumers is still being finalized, but the company says it does not expect to grade or rank a persons risk of developing any of the 10 conditions approved for analysis. Instead it will simply report a person has a gene variant associated with any of the maladies and is at an increased risk, the company told Scientific American.

The FDA decision may significantly widen the companys market and top off a years-long debate about what sort of genetic information should be available to consumers without professional medical oversight. After the FDAs 2013 decision to stop 23AndMe from sharing data about disease risk with its customers, the company was still able to offer them information about their genetic ancestry. It has also been selling consumer tests for genes that would indicate whether people are carriers for more than 30 heritable conditions, including cystic fibrosis and Tay-Sachs disease.

This month 23AndMe plans to release its first set of genetic health-risk reports for late-onset Alzheimers disease, Parkinsons disease, hereditary thrombophilia (a blood-clotting disorder), alpha 1-antitrypsin deficiency (a condition that raises the risk of lung and liver disease), and a new carrier status report for Gauchers disease (an organ and tissue disorder). Reports for other tests will follow, the company says.

In considering whether to approve the tests, the FDA says it reviewed studies that demonstrated the 23AndMe procedures correctly and consistently identified variants associated with the 10 conditions. Further data from peer-reviewed scientific literature demonstrated the links between these gene variants and conditions, and supported the underlying science.

The FDA also announced on Thursday that it plans to offer the company exemptions for similar genetic tests in the future, without requiring them to be submitted for premarket review. That decision could leave the door open to offering tests for other conditions that have questionable reproducibility, says Jim Evans, a genetics and medicine professor at the University of North Carolina School of Medicine.

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Too Much Information? FDA Clears 23AndMe to Sell Home Genetic Tests for Alzheimer's and Parkinson's - Scientific American

April 4, 2017 Credit: George Hodan/Public Domain

A study of people from an isolated village in the Netherlands reveals a link between rare variants in the gene NKPD1 and depressive symptoms. The findings are published in the current issue of Biological Psychiatry. The study, led by co-first authors Najaf Amin, PhD, of Erasmus University Medical Center in the Netherlands and Nadezhda Belonogova of the Russian Academy of Sciences in Novosibirsk, Russia, helps researchers understand the molecular pathology of the disease, which could eventually improve how depression is diagnosed and treated.

Genetics play a strong role in risk for depression, but the identification of specific genes contributing to the disorder has eluded researchers. "By sequencing all of the DNA that codes for mRNA and ultimately, proteins, Dr. Amin and colleagues found a single gene that may account for as much as 4% of the heritable risk for depression," said Doctor John Krystal, Editor of Biological Psychiatry.

To identify the gene, the researchers assessed data from the Erasmus Rucphen Family study, which was composed of a collection of families and their descendents living in social isolation until the past few decades. In a population like this, genetic isolation leads to an amplification of rarely occurring variants with little other genetic variation, providing a more powerful cohort for the discovery of rare variants. Nearly 2,000 people who had been assessed for depressive symptoms were included in the analysis.

Using whole-exome sequencing to examine portions of DNA containing genetic code to produce proteins, Amin and colleagues found that several variants of NKPD1 were associated with higher depressive symptom scores. The association between depressive symptoms and NKPD1 were also replicated in an independent sample of people from the general population, although the replication sample highlighted different variants within NKPD1.

"The involvement of NKPD1 in the synthesis of sphingolipids and eventually of ceramides is interesting," said Dr. Amin, referring to the predicted role of NKPD1 in the body. Altered sphingolipid levels in blood have been associated with depression and have been proposed as a therapeutic target for major depressive disorder.

"We are the first to show a possible genetic connection in this respect," said Dr. Amin, adding that this implies that such a therapy might be beneficial for patients carrying risk variants in the NKPD1 gene.

As with other psychiatric disorders, depression lacks genetic or biochemical markers to aid diagnosis and treatment of the disorder. According to Dr. Amin, moving depression treatment into the era of precision and personalized medicine will require a transition to objective and unbiased measurements where patients are stratified based on the molecular pathology of the disease. "NKPD1 may be one such molecular mechanism," she said.

Explore further: Earlier and more severe depression symptoms associated with high genetic risk for major psychiatric disorders

More information: Najaf Amin et al. Nonsynonymous Variation inNKPD1Increases Depressive Symptoms in European Populations, Biological Psychiatry (2017). DOI: 10.1016/j.biopsych.2016.08.008

Journal reference: Biological Psychiatry

Provided by: Elsevier

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NKPD1 gene variant increases depression risk - Medical Xpress

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Scientists re-examine data exploring connection between serotonin gene, depression, stress

For years, scientists have been trying to determine what effect a gene linked to the brain chemical serotonin may have on depression in people exposed to stress. But now, analyzing information from more than 40,000 people who have been studied over more than a decade, researchers led by a team at Washington University School of Medicine in St. Louis have found no evidence that the gene alters the impact stress has on depression.

New research findings often garner great attention. But when other scientists follow up and fail to replicate the findings? Not so much.

In fact, a recent study published in PLOS One indicates that only about half of scientific discoveries will be replicated and stand the test of time. So perhaps it shouldnt come as a surprise that new research led by Washington University School of Medicine in St. Louis shows that an influential 2003 study about the interaction of genes, environment and depression may have missed the mark.

Since its publication in Science, that original paper has been cited by other researchers more than 4,000 times, and some 100 other studies have been published about links between a serotonin-related gene, stressful life events and depression risk. It indicated that people with a particular variant of the serotonin transporter gene were not as well-equipped to deal with stressful life events and, when encountering significant stress, were more likely to develop depression.

Such conclusions were widely accepted, mainly because antidepressant drugs called selective serotonin reuptake inhibitors (SSRIs) help relieve depression for a significant percentage of clinically depressed individuals, so many researchers thought it logical that differences in a gene affecting serotonin might be linked to depression risk.

But in this new study, the Washington University researchers looked again at data from the many studies that delved into the issue since the original publication in 2003, analyzing information from more than 40,000 people, and found that the previously reported connection between the serotonin gene, depression and stress wasnt evident. The new results are published April 4 in the journal Molecular Psychiatry.

Our goal was to get everyone who had gathered data about this relationship to come together and take another look, with each research team using the same tools to analyze data the same way, said the studys first author, Robert C. Culverhouse, PhD, an assistant professor of medicine and of biostatistics. We all ran exactly the same statistical analyses, and after combining all the results, we found no evidence that this gene alters the impact stress has on depression.

Over the years, dozens of research groups had studied DNA and life experiences involving stress and depression in the more than 40,000 people revisited in this study. Some previous research indicated that those with the gene variant were more likely to develop depression when stressed, while others didnt see a connection. So for almost two decades, scientists have debated the issue, and thousands of hours of research have been conducted. By getting all these groups to work together to reanalyze the data, this study should put the questions to rest, according to the researchers.

The idea that differences in the serotonin gene could make people more prone to depression when stressed was a very reasonable hypothesis, said senior investigator Laura Jean Bierut, MD, the Alumni Endowed Professor of Psychiatry at Washington University. But when all of the groups came together and looked at the data the same way, we came to a consensus. We still know that stress is related to depression, and we know that genetics is related to depression, but we now know that this particular gene is not.

Culverhouse noted that finally, when it comes to this gene and its connection to stress and depression, the scientific method has done its job.

Experts have been arguing about this for years, he said. But ultimately the question has to be not what the experts think but what the evidence tells us. Were convinced the evidence finally has given us an answer: This serotonin gene does not have a substantial impact on depression, either directly or by modifying the relationship between stress and depression.

With this serotonin gene variant removed from the field of potential risk factors for depression, Culverhouse and Bierut said researchers now can focus on other gene-environment interactions that could influence the onset of depression.

Culverhouse, RC, et al. Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression. Molecular Psychiatry. April 4, 2017.

This work was supported by the National Institute on Drug Abuse and the National Institute of Mental Health of the National Institutes of Health (NIH), grant numbers R21 DA033827, MH089995 and R01 DA026911. Other funding provided by the Wellcome Trust and other funding agencies from countries around the world. For a complete list of funding agencies and grants, please refer to the paper.

Potential conflicts of interest involving researchers who are authors of the study also are listed at the end of the paper. Some have received consultancy/speaking fees from various pharmaceutical companies and other business interests. LJ Bierut is one of the listed inventors on US Patent 8 080 371, Markers for Addiction, covering the use of certain DNA SNPs in determining the diagnosis, prognosis and treatment of addiction.

Washington University School of Medicines 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Study reverses thinking on genetic links to stress, depression - Washington University School of Medicine in St. Louis

Researchers have developed a method to swiftly screen the non-coding DNA of the human genome for links to diseases that are driven by changes in gene regulation. The technique could revolutionize modern medicine's understanding of the genetically inherited risks of developing heart disease, diabetes, cancer, neurological disorders and others, and lead to new treatments.

The study appeared online in Nature Biotechnology on April 3, 2017.

"Identifying single mutations that cause rare, devastating diseases like muscular dystrophy has become relatively straightforward," said Charles Gersbach, the Rooney Family Associate Professor of Biomedical Engineering at Duke University. "But more common diseases that run in families often involve lots of genes as well as genetic reactions to environmental factors. It's a much more complicated story, and we've been wanting a way to better understand it. Now we've found a way."

The new technique relies on the gene-hacking system called CRISPR/Cas9. Originally discovered as a natural antiviral defense mechanism in bacteria, the system recognizes and homes in on the genetic code of previous intruders and then chops up their DNA. In the past several years, researchers have harnessed this biologic system to precisely cut and paste DNA sequences in living organisms.

In the current study, researchers added molecular machinery that can control gene activity by manipulating the web of biomolecules that determines which genes each cell activates and to what degree.

With the new tool, Gersbach and his colleagues are exploring the 98 percent of our genetic code often referred to as the "dark matter of the genome."

"Only a small fraction of our genome encodes instructions to make proteins that guide cellular activity," said Tyler Klann, the biomedical engineering graduate student who led the work in Gersbach's lab. "But more than 90 percent of the genetic variation in the human population that is associated with common disease falls outside of those genes. We set out to develop a technology to map this part of the genome and understand what it is doing."

The answer, says Klann, lies with promoters and enhancers. Promoters sit directly next to the genes they control. Enhancers, however, which modulate promoters, can be just about anywhere due to the genome's complex 3D geometry, making it difficult to discern what they're actually doing.

"If an enhancer is dialing a promoter up or down by 10 or 20 percent, that could logically explain a small genetic contribution to cardiovascular disease, for example," said Gersbach. "With this CRISPR-based system, we can more strongly turn these enhancers on and off to see exactly what effect they're having on the cell. By developing therapies that more dramatically affect these targets in the right direction, we could have a significant effect on the corresponding disease."

That's all well and good for exploring the regions of the genome that researchers have already identified as being linked to diseases, but there are potentially millions of sites in the genome with unknown functions. To dive down the dark genome rabbit hole, Gersbach turned to colleagues Greg Crawford, associate professor of pediatrics and medical genetics, and Tim Reddy, assistant professor of bioinformatics and biostatistics. All three professors work together in the Duke Center for Genomic and Computational Biology.

Crawford developed a way of determining which sections of DNA are open for business. That is, which sections are not tightly packed away, providing access for interactions with biomachinery such as RNA and proteins. These sites, the researchers reason, are the most likely to be contributing to a cell's activity in some way. Reddy has been developing computational tools for interpreting these large genomic data sets.

Over the past decade, Crawford has scanned hundreds of types of cells and tissues affected by various diseases and drugs and come up with a list of more than 2 million potentially important sites in the dark genome -- clearly far too many to investigate one at a time. In the new study, Crawford, Reddy and Gersbach demonstrate a high-throughput screening method to investigate many of these potentially important genetic sequences in short order. While these initial studies screened hundreds of these sites across millions of base pairs of the genome, the researchers are now working to scale this up 100- to 1000-fold.

"Small molecules can target proteins and RNA interference targets RNA, but we needed something to go in and modulate the non-coding part of the genome," said Crawford. "Up until now, we didn't have that."

The method starts by delivering millions of CRISPR systems loaded into viruses, each targeting a different genetic point of interest, to millions of cells in a single dish. After ensuring each cell receives only one virus, the team screens them for changes in their gene expression or cellular functions.

For example, someone researching diabetes could do this with pancreatic cells and watch for changes in insulin production. Those cells that show interesting alterations are then isolated and sequenced to determine which stretch of DNA the CRISPR affected, revealing a new genetic piece of the diabetes puzzle.

The technique is already producing results, identifying previously known genetic regulatory elements while also spotting a few new ones. The results also showed it can be used to turn genes either on or off, which is superior to other tools for studying biology which only turn genes off. Different cell types also produced different -- but partially overlapping -- results, highlighting the biological complexity in gene regulation and disease that can be interrogated with this technology.

"Now that we have this tool, we can go in and annotate the functions of these previously unknown but important stretches of our genome," said Gersbach. "With so many places to look, and the ability to do it quickly and robustly, we'll undoubtedly find new segments that are important for disease, which will provide new avenues for developing therapeutics."

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Screening the dark genome for disease - Science Daily

April 4, 2017 Scanning electron micrograph of human T lymphocyte or T cell. Credit: NIAID/NIH

Scientists in Salford, U.K., have identified a gene which is 'revving the engine of cancer' against the world's most common breast cancer drug.

For reasons unknown, 50% of patients with breast cancer treated with the estrogen receptor-blocking drug tamoxifen eventually become resistant to the treatment.

In a paper published this week in the journal Oncotarget, biochemists tested a hypothesis that the mechanism of tamoxifen resistance is related to energy-generating mitochondria in cancer cells.

In doing so, they identified the protein NQ01 as the 'trigger' which determines whether cells would survive tamoxifen or not.

Michael P Lisanti, Professor of Translational Medicine in the Biomedical Research Centre at the University of Salford said: "In simple terms, the process of poisoning the cell (with tamoxifen) actually has the opposite effect, stimulating the cancer cells to respond by revving their engines in order to survive."

Lisanti and collaborators Dr Federica Sotgia and Dr Marco Fiorillo tested their idea that cancer cells were fighting against tamoxifen by using their mitochondria the 'powerhouse of the cell' - that produces all their energy.

In the laboratory they directly compared sensitive cells with tamoxifen-resistant cancer cells, and demonstrated that higher mitochondrial power is what distinguishes a drug-sensitive cell from a resistant cell.

Then they used a combination of protein profiling, genetics and metabolism to identify which genes were necessary to confer tamoxifen-resistance. They observed that by adding just a single gene, NQ01, the cells would survive.

Finally, they used a chemical inhibitor of NQ01 (dicoumarol), which is a relative of warfarin, to successfully sensitise tamoxifen-resistant cells.

Professor Lisanti concludes: "This is the first evidence that tamoxifen resistance is related to a specific metabolic behaviour, ie. increased mitochondrial power, which is important because this is not related to tamoxifen's effect on the estrogen receptor.

"It also confirms that tamoxifen resistance is not a mechanism related to estrogen."

Dr Marco Fiorillo suggests: "Now that we have identified the target, this will allow us and others to design new drugs to overcome tamoxifen resistance. There are already existing experimental drugs for targeting NQO1 and GCLC, for other reasons, so making inhibitors to target these enzymes is a practical reality."

Explore further: Researchers discover key to drug resistance in common breast cancer treatment

More information: Marco Fiorillo et al. Mitochondrial "power" drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer, Oncotarget (2017). DOI: 10.18632/oncotarget.15852

Journal reference: Oncotarget

Provided by: University of Salford

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New gene discovered driving drug resistance - Medical Xpress