Home genetic tests: how accurate are they?

Researchers at Ambry Genetics Corp analyzed how accurate direct-to-consumer genetic tests are in highlighting specific genetic variants. They found test raw data was incorrectly reported and could not be verified by further diagnostic laboratory tests in around 40% of the cases. These findings based on a small sample of 49 patients are reported in journal Genetics in Medicine.

Direct-to-consumer genetic tests (DTC) or home genetic tests are not diagnostic but are usually available to uncover information about ancestry, the risk of developing certain conditions and to check if they are a carrier to specific autosomal recessive conditions.  Home genetic tests are regulated by Food and Drug Administration, which currently prohibit these companies from offering diagnostic genetic tests. While they are not diagnostic some of the companies can provide raw data that can be interpreted by the third party for a fee.

Research led by Tandy-Connor and her colleagues set out to assess how accurate home genetic tests were in highlighting the presence of specific genetic variants. They analyzed the raw data of 49 patients that were referred to Ambry Genetics Corp for confirmatory testing, after sharing their home genetic tests raw data results with their medical providers. They found that two out of every five results were incorrectly reported and could not be further verified.

“Such a high rate of a false positives in this particular study was unexpected,” says Tandy-Connor, who believes that some of the discrepancies in the results can be explained by technical differences between the various testing methods used. “While direct-to-consumer genetic test results may lead to healthy changes in lifestyle or diet, these could also result in unwarranted emotions, including anxiety when someone obtains unexpected information, inaccurate information, or disappointment when receiving a lack of comprehensive diagnostic analysis.”

“The relatively small cohort simply reflects the reality that most people who get such direct-to-consumer genetic test results don’t seek confirmatory testing,” says Tandy-Connor. “People may assume that they are being provided accurate medical grade testing, so understandably do not go to the trouble and expense of seeking confirmation.”

Reference: Tandy-Connor, Stephany, Jenna Guiltinan, Kate Krempely, Holly Laduca, Patrick Reineke, Stephanie Gutierrez, Phillip Gray, and Brigette Tippin Davis. “False-positive Results Released by Direct-to-consumer Genetic Tests Highlight the Importance of Clinical Confirmation Testing for Appropriate Patient Care.” GENETICS in MEDICINE, 2018. doi:10.1038/gim.2018.38.

Adapted from press release by Springer.

Researchers find possible link between autism and nuclear receptor protein LXRβ

Research by University of Houston scientists discovered a possible link between nuclear receptor protein LXRβ (Liver X receptor Beta) and autism spectrum disorder. They found that nuclear receptor LXRβ deletion causes poor development of dentate gyrus, a part of brain’s hippocampus. The dentate gyrus, or DG, is responsible for emotion and memory and is known to be involved in autism spectrum disorders (ASD).

This study is led by Margaret Warner and Jan-Åke Gustafsson. The results are published in journal Proceedings of the National Academy of Sciences.”Our findings suggest early changes in dentate gyrus neurogenesis ultimately provide an aberrant template upon which to build the circuitry that is involved in normal social function,” said Warner.

Researchers conducted an animal study using LXRβ-deficient mice. Behavior analysis of these mice showed autistic-like behaviors, including social interaction deficits and repetitive behavior.”Knocking out LXRβ led to autistic behavior and reduced cognitive flexibility,” said Warner. “In this paper, we share our findings that that deletion of the LXRβ (Liver X receptor Beta) causes hypoplasia or underdevelopment in the dentate gyrus and autistic-like behaviors, including abnormal social interaction and repetitive behavior.”

Citation: Cai, Yulong, Xiaotong Tang, Xi Chen, Xin Li, Ying Wang, Xiaohang Bao, Lian Wang, Dayu Sun, Jinghui Zhao, Yan Xing, Margaret Warner, Haiwei Xu, Jan-Åke Gustafsson, and Xiaotang Fan. “Liver X receptor β regulates the development of the dentate gyrus and autistic-like behavior in the mouse.” Proceedings of the National Academy of Sciences, 2018, 201800184. doi:10.1073/pnas.1800184115.

Adapted from press release by the University of Houston.

Research shows key role of FoxO proteins in osteoarthritis development

Research from scientists at The Scripps Research Institute explains why the risk of osteoarthritis increases as we age and offers a potential avenue for developing new treatments. The study’s findings suggest that FOXO proteins are responsible for the maintenance of healthy cells in the cartilage of our joints. The results are published in journal Science Translational Medicine.

“We discovered that FoxO transcription factors control the expression of genes that are essential for maintaining joint health,” says Martin Lotz, MD, a TSRI professor and senior author of the study. “Drugs that boost the expression and activity of FoxO could be a strategy for preventing and treating osteoarthritis.”

Previous research from Lotz’ lab showed that as joints age, levels of FoxO proteins in cartilage decrease. Lotz and his colleagues had also found that people with osteoarthritis have a lower expression of the genes needed for a process called autophagy. Autophagy is a cell’s way of removing and recycling its own damaged structures to stay healthy.

For the new study, researchers used mouse models with FoxO deficiency in cartilage to see how the FoxO proteins affect maintenance of cartilage throughout adulthood. The researchers noticed a striking difference in the mice with “knockout” FoxO deficiency. Their cartilage degenerated at much younger age than in control mice. The FoxO-deficient mice also had more severe forms of post-traumatic osteoarthritis induced by meniscus damage (an injury to the knee), and these mice were more vulnerable to cartilage damage during treadmill running.

The FoxO-deficient mice had defects in autophagy and in mechanisms that protect cells from damage by molecules called oxidants. Specific to cartilage, FoxO-deficient mice did not produce enough lubricin, a lubricating protein that normally protects the cartilage from friction and wear. This lack of lubricin was associated with a loss of healthy cells in a cartilage layer of the knee joint called the superficial zone.

These problems all came down to how FoxO proteins work as transcription factors to regulate gene expression. Without FoxO proteins running the show, expression of inflammation-related genes skyrockets, causing pain, while levels of autophagy-related genes plummet, leaving cells without a way to repair themselves. “The housekeeping mechanisms, which keeps cells healthy, were not working in these knockout mice,” Lotz explains.

To determine whether targeting FoxO has therapeutic benefits, the investigators used genetic approaches to increase FoxO expression in cells of humans with osteoarthritis and found that the levels of lubricin and protective genes returned to normal. The next step in this research is to develop molecules that enhance FoxO and test them in experimental models of osteoarthritis.

Citation: Matsuzaki, Tokio, Oscar Alvarez-Garcia, Sho Mokuda, Keita Nagira, Merissa Olmer, Ramya Gamini, Kohei Miyata, Yukio Akasaki, Andrew I. Su, Hiroshi Asahara, and Martin K. Lotz. “FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis.” Science Translational Medicine 10, no. 428 (2018). doi:10.1126/scitranslmed.aan0746.

Research funding: NIH

Adapted from press release by The Scripps Research Institute.

Animal study finds MeXis gene protective against coronary artery disease

UCLA scientists have identified a gene called MeXis that may play a protective role in preventing heart disease. Their findings suggests that this gene acts within macrophages inside clogged arteries to help remove excess cholesterol from blood vessels by controlling cholesterol pump protein expression. Research is published in the journal Nature Medicine.

MeXis is an example of a “selfish” gene, one that is presumed to have no function because it does not make a protein product. However, recent studies have suggested that these so-called “unhelpful” genes can actually perform important biological functions without making proteins and instead producing a special class of molecules called long non-coding RNAs, or lncRNAs.

“What this study tells us is that lncRNAs are important for the inner workings of cells involved in the development of heart disease,” said Dr. Peter Tontonoz, senior author of the study. “Considering many genes like MeXis have completely unknown functions, our study suggests that further exploring how other long non-coding RNAs act will lead to exciting insights into both normal physiology and disease.”

In the study, researchers found that mice lacking MeXis had almost twice as many blockages in their blood vessels compared to mice with normal MeXis levels. In addition, boosting MeXis levels made cells more effective at removing excess cholesterol. In the next phase of the study, researchers will further explore how MeXis affects the function of cells in the artery wall and will test various approaches to altering MeXis activity. The researchers are interested in finding out if MeXis could be targeted for therapy of cardiovascular disease.

Citation: Sallam, Tamer, Marius Jones, Brandon J. Thomas, Xiaohui Wu, Thomas Gilliland, Kevin Qian, Ascia Eskin, David Casero, Zhengyi Zhang, Jaspreet Sandhu, David Salisbury, Prashant Rajbhandari, Mete Civelek, Cynthia Hong, Ayaka Ito, Xin Liu, Bence Daniel, Aldons J. Lusis, Julian Whitelegge, Laszlo Nagy, Antonio Castrillo, Stephen Smale, and Peter Tontonoz. “Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA.” Nature Medicine, 2018. doi:10.1038/nm.4479.

Funding: NIH/National Heart, Lung and Blood Institute, Burroughs Wellcome Fund Career Awards for Medical Scientists, UCLA Cardiovascular Discovery Fund, Lauren B. Leichtman and Arthur E. Levine Investigator Award.

Adapted from press release by the University of California Los Angles Health Sciences.

New cellular data recording technology utilizing CRISPR

Researchers at Columbia University Medical Center have modified bacterial immune system of human gut microbe Escherichia coli, enabling the bacteria to not only record their interactions with the environment but also time-stamp the events. They have turned bacteria into a microscopic data recorder, creating groundwork for a new class of technologies that could use bacterial cells for multiple uses like disease diagnosis to environmental monitoring.

Wang and members of his laboratory created this technology by taking advantage of CRISPR-Cas. CRISPR-Cas copies snippets of DNA from invading viruses so that subsequent generations of bacteria can repel these pathogens more effectively. As a result, the CRISPR locus of the bacterial genome accumulates a chronological record of the bacterial viruses that it and its ancestors have survived. When those same viruses try to infect again, the CRISPR-Cas system can recognize and eliminate them. CRISPR-Cas normally uses its recorded sequences to detect and cut the DNA of incoming phages.

To build their microscopic recorder, Ravi Sheth and other members of the Wang lab modified a piece of DNA called a plasmid, giving it the ability to create more copies of itself in the bacterial cell in response to an external signal. A separate recording plasmid, which drives the recorder and marks time, expresses components of the CRISPR-Cas system. In the absence of an external signal, only the recording plasmid is active, and the cell adds copies of a spacer sequence to the CRISPR locus in its genome. When an external signal is detected by the cell, the other plasmid is also activated, leading to insertion of its sequences instead. The result is a mixture of background sequences that record time and signal sequences that change depending on the cell’s environment. The researchers can then examine the bacterial CRISPR locus and use computational tools to read the recording and its timing. The current paper proves the system can handle at least three simultaneous signals and record for days.

Citation: Sheth, Ravi U., Sung Sun Yim, Felix L. Wu, and Harris H. Wang. “Multiplex recording of cellular events over time on CRISPR biological tape.” Science, 2017.

doi:10.1126/science.aao0958.

Funding: US Department of Defense, National Institutes of Health, Sloan Foundation.

Adapted from press release by Columbia University Medical Center.

National Institutes of Health to expand ENCODE project

The National Institutes of Health plans to expand its Encyclopedia of DNA Elements (ENCODE) Project, a genomics resource used by many scientists to study human health and disease. Funded by the National Human Genome Research Institute (NHGRI), part of NIH, the ENCODE Project is generating a catalog of all the genes and regulatory elements the parts of the genome that control whether genes are active or not in humans and select model organisms. With four years of additional support, NHGRI builds on a long-standing commitment to developing freely available genomics resources for use by the scientific community.

The genome in three dimensions folds up, forming loops and other shapes, to fit inside the nucleus.
Credit: Ernesto Del Aguila, NHGRI

“ENCODE has created high-quality and easily accessible sets of data, tools and analyses that are being used extensively in studies to interpret genome sequences and to understand the consequence of genomic variation,” said Elise Feingold, Ph.D., a program director in the Division of Genome Sciences at NHGRI. “These awards provide the opportunity to strengthen this foundation by expanding the breadth and depth of the resource.”

Since launching in 2003, ENCODE has funded a network of researchers to develop and apply methods for mapping candidate functional elements in the genome, and to analyze the enormous database of generated genomic information. The data and tools generated by ENCODE are organized by two groups: a data coordinating center, which houses the data and provides access to the resource through an open-access portal, and a data analysis center, which synthesizes the data into an encyclopedia for use by the research community.

Pending the availability of funds, NHGRI plans to commit up to $31.5 million in the fiscal year 2017 for these awards. With this funding, ENCODE will expand the scope of these efforts to include characterization centers, which will study the biological role that candidate functional elements may play and develop methods to determine how they contribute to gene regulation in a variety of cell types and model systems. Additionally, the project will enhance the ENCODE catalog by developing a way to incorporate data provided by the research community, and will use biological samples from research participants who have explicitly consented for unrestricted sharing of their genomic data.

More information about ENCODE project.
Adapted from press release by National Human Genome Research Institute.

Research in mice shows molecular mechanism underlying Oxycodone addiction

RGS9-2, a key signaling protein in the brain known to play a critical role in the development of addiction-related behaviors, acts as a positive modulator of oxycodone reward in both pain-free and chronic pain states, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published in the journal Neuropsychopharmacology. The mechanisms of oxycodone action uncovered through this study will help scientists and physicians develop strategies and tools to dissociate the analgesic (pain relief) actions of opioids from the addiction-related effects.

Pixabay images

Using mouse models of acute and chronic pain, Mount Sinai researchers found that RGS9-2, the intracellular protein that controls the function of opioid receptors in the brain reward center, promotes addiction to oxycodone in pain-free, acute, and chronic pain states. Mice that lacked the gene responsible for encoding RGS9-2 (RGS9KO mice) showed less propensity to develop addiction-related behaviors. Furthermore, the loss of RGS9-2 function does not affect the acute analgesic effects of oxycodone. The research team also found that RSG9-2 plays a protective role towards the development of oxycodone tolerance, as RGS9KO mice became tolerant to the analgesic effects of the drug earlier than those that had the gene. Researchers found that the same mechanisms control sensitivity to oxycodone addiction in pain-free as well as chronic pain states.

Oxycodone is a painkiller that is widely prescribed for acute and chronic pain conditions and is also among the most abused opioids. Oxycodone acts on the same brain receptors as morphine and heroin, the mu opioid receptors, which are present in many areas of the brain that mediate pain relief but are also expressed in the brain network associated with addiction. While there has been an extensive investigation into the mechanisms underlying the analgesia, dependence, and addiction potential of morphine, the mechanism by which oxycodone exerts its actions remained unknown.

“Although oxycodone produces similar analgesic and behavioral effects to those observed with morphine, our study demonstrates that the intracellular actions of morphine and oxycodone are distinct,” says Venetia Zachariou, Ph.D., Associate Professor in the Fishberg Department of Neuroscience and The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai. “Our work reveals that intracellular factors that prevent the actions of morphine may actually promote the actions of oxycodone. This information is particularly important for pain management strategies, as a common course is to have patients oscillate between oxycodone and morphine to achieve pain relief.”

This study provides new information on pathways involved in behavioral responses to oxycodone in pain-free and neuropathic pain states, which will help researchers and clinicians to determine the risks and benefits of oxycodone prescription for the treatment of pain. This knowledge may lead to the development of more efficacious and less addictive compounds for pain management.

Citation: Sevasti Gaspari, Valeria Cogliani, Lefteris Manouras, Ethan M Anderson, Vasiliki Mitsi, Kleopatra Avrampou, Fiona B Carr and Venetia Zachariou. “RGS9-2 Modulates Responses to Oxycodone in Pain-Free and Chronic Pain States.” Neuropsychopharmacology 2017.
DOI: 10.1038/npp.2017.4
Research funding: National Institute of Neurological Disorders and Stroke
Adapted from press release by The Mount Sinai Hospital.

Concussion and Alzheimer’s disease link

New research has found concussions accelerate Alzheimer’s disease-related brain atrophy and cognitive decline in people who are at genetic risk for the condition. The findings, which appear in the journal Brain, show promise for detecting the influence of concussion on neurodegeneration.

Brain. Ashton University

Moderate-to-severe traumatic brain injury is one of the strongest environmental risk factors for developing neurodegenerative diseases such as late-onset Alzheimer’s disease, although it is unclear whether mild traumatic brain injury or concussion also increases this risk.

Researchers from Boston University School of Medicine (BUSM) studied 160 Iraq and Afghanistan war veterans, some who had suffered one or more concussions and some who had never had a concussion. Using MRI imaging, the thickness of their cerebral cortex was measured in seven regions that are the first to show atrophy in Alzheimer’s disease, as well as seven control regions.

We found that having a concussion was associated with lower cortical thickness in brain regions that are the first to be affected in Alzheimer’s disease,” explained corresponding author Jasmeet Hayes, PhD, assistant professor of psychiatry at BUSM and research psychologist at the National Center for PTSD, VA Boston Healthcare System. “Our results suggest that when combined with genetic factors, concussions may be associated with accelerated cortical thickness and memory decline in Alzheimer’s disease relevant areas.”

Of particular note was that these brain abnormalities were found in a relatively young group, with the average age being 32 years old. “These findings show promise for detecting the influence of concussion on neurodegeneration early in one’s lifetime, thus it is important to document the occurrence and subsequent symptoms of a concussion, even if the person reports only having their “bell rung” and is able to shake it off fairly quickly, given that when combined with factors such as genetics, the concussion may produce negative long-term health consequences,” said Hayes.

The researchers hope that others can build upon these findings to find the precise concussion-related mechanisms that accelerate the onset of neurodegenerative diseases such as Alzheimer’s disease, chronic traumatic encephalopathy, Parkinson’s and others. “Treatments may then one day be developed to target those mechanisms and delay the onset of neurodegenerative pathology,” she added.

Citation: Hayes, Jasmeet P., Mark W. Logue, Naomi Sadeh, Jeffrey M. Spielberg, Mieke Verfaellie, Scott M. Hayes, Andrew Reagan, David H. Salat, Erika J. Wolf, Regina E. McGlinchey, William P. Milberg, Annjanette Stone, Steven A. Schichman and Mark W. Miller. ” Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer’s disease.” Brain 2017 vol: 83 pp: aww344.
DOI: 10.1093/brain/aww344
Research funding: US Department of Veterans Affairs, NIH/National Institute of Mental Health.
Adapted from press release by Boston University School of Medicine.

Similar epigenetic mark found in brain cells of different types of autism disorder

UCLA scientists and their colleagues have found evidence that an abnormal pattern of brain cells is common in people with different types of autism disorders. The abnormal pattern discovered in the study, reported in journal Cell, concerns a certain type of “epigenetic mark,” a chemical modification that occurs frequently on chromosomes and helps regulate the activity of nearby genes.

The findings suggest that although autism disorders have multiple causes, they mostly involve problems in a common set of biological pathways, which are actions among certain molecules within a cell that lead to specific changes such as turning genes on or off or assembling new molecules. The findings may lead to a better understanding of how autism disorders arise, and perhaps one day to the development of drugs that target some of these aberrant pathways. Researchers evaluated brain tissue of 45 people who had autism spectrum disorders and 49 who did not. The team mapped one specific type of epigenetic mark called “histone acetylation.”

In the study, mapping of histone acetylation marks revealed the same broad pattern or “signature” of abnormality in more than 80 percent of the samples from the cerebral cortexes of the autism cases, compared to the non-autism cases. The cortex, the most advanced brain region, is the one that appears to be most affected in autism disorders. The abnormal pattern, which did not appear in samples from other parts of the brain, involved changes at more than 5,000 locations on the human genome.

Scientists have only recently begun to conduct systematic investigations of epigenetic abnormalities in people, but they have already found that these abnormal chemical modifications contribute to cancers and other important diseases. This study was the first to map this type of epigenetic mark across the genome in a human disease.

“Thus, in addition to its value to autism research, this work paves the way for similar studies aimed at understanding other diseases,” Geschwind, study co-senior author and the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics at the David Geffen School of Medicine at UCLA.

The team now hopes to determine which of the many epigenetic abnormalities uncovered in the study are true causes of autism behaviors — and could thus be potential targets for future autism drugs. Drugs that affect histone acetylation have already been developed as potential cancer treatments, and some older psychiatric drugs also influence histone acetylation.

Citation: Sun, Wenjie, Jeremie Poschmann, Ricardo Cruz-Herrera del Rosario, Neelroop N. Parikshak, Hajira Shreen Hajan, Vibhor Kumar, Ramalakshmi Ramasamy, T. Grant Belgard, Bavani Elanggovan, Chloe Chung Yi Wong, Jonathan Mill, Daniel H. Geschwind and Shyam Prabhakar. “Histone Acetylome-wide Association Study of Autism Spectrum Disorder.” Cell 167, no. 5 (2016): 1385-1397.
DOI: 10.1016/j.cell.2016.10.031
Research funding: National Institutes of Health, Singapore’s Agency for Science Technology and Research.
Adapted from press release by UCLA.
Different types of autism disorders share abnormal pattern of brain cells

Understanding signaling pathway that creates brown fat to help in fight against obesity and diabetes

A signaling pathway in fat cells may one day provide the key to better treatments for obesity, according to new research by scientists at the Perelman School of Medicine at the University of Pennsylvania. They reported their findings in Genes & Development.

This image shows adipose tissue, with fat droplets in green
and blood vessels in red. Credit: The laboratory of
Zoltan Arany, MD, PhD, Perelman School of Medicine,
 University of Pennsylvania
Ordinary fat cells, also called white adipocytes, stuff themselves with fat molecules to store up energy, and their overloading leads to obesity and related conditions, including diabetes. Brown adipocytes, which are prevalent in children as “baby fat,” but much less so in adults, do virtually the opposite: they burn energy rapidly to generate heat and thereby protect the body from cold as well as obesity and diabetes. The signaling pathway discovered by the Penn scientists activates a “browning program” in white adipocytes, making them more like energy-burning brown adipocytes.
“It’s conceivable that one would be able to target this pathway with a drug, to push white fat to become brown fat and thereby treat obesity,” said the study’s senior author Zoltan P. Arany, MD, Ph.D., an associate professor of Cardiovascular Medicine. About 36 percent of American adults are considered obese and nearly 10 percent have type 2 diabetes.

Arany and colleagues found that the browning program in white adipocytes is normally suppressed by a protein called FLCN. It performs this function in cooperation with a major cellular signaling hub, a protein complex known as mTOR. The FLCN-mTOR interaction keeps the browning program switched off by preventing a protein called TFE3 from entering the cell nucleus.

The scientists showed that deleting the FLCN gene in the white adipocytes of mice allows TFE3 to migrate into the nucleus, where it binds to DNA and activates a key regulator of cellular metabolism called PGC-1β. It then turns on the set of genes for the browning program.

In the mice in which FLCN was deleted, white adipocytes became visibly browner as they produced more mitochondria–tiny, oxygen reactors that supply chemical energy within cells and convert energy to heat in brown adipocytes. In several other ways too, including their altered cellular structures, mitochondria’s higher capacity for consuming oxygen, and their distinctive pattern of gene expression, the cells became more like brown adipocytes.

Arany and his team showed that they could reproduce this browning effect merely by forcing the overexpression of PGC-1β in the white adipocytes of mice. “In principle, a drug that boosts the activity of PGC-1β or some of its target genes might serve as a therapeutic activator of the browning program to curb obesity and treat or prevent diabetes,” Arany said.

Aside from its potential medical relevance, the discovery is an important advance in understanding cell biology. “Cellular metabolism is regulated by major signaling pathways and with this study, we’re linking two of these major pathways, the mTOR, and the PGC-1 pathways,” Arany said. “The connection between them hasn’t been well understood, but here we’re clarifying it significantly.”

Arany and his team plan further studies of the pathway and its relation to other mTOR signaling pathways.

Citation:“The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue”. Shogo Wada, Michael Neinast, Cholsoon Jang, Yasir H. Ibrahim, Gina Lee, Apoorva Babu, Jian Li, Atsushi Hoshino, Glenn C. Rowe, James Rhee, José A. Martina, Rosa Puertollano, John Blenis, Michael Morley, Joseph A. Baur, Patrick Seale and Zoltan Arany. Genes & development 2016.
DOI: 10.1101/gad.287953.116
Research funding: National Institutes of Health.
Adapted from press release by Perelman School of Medicine at the University of Pennsylvania.