Researchers from ERIBA, Radboud UMC, XJTU, Saarland University, CWI and UMC Utrecht have made a big step towards a better understanding of the human genome. By identifying large DNA variants in 250 Dutch families, the researchers have clarified part of the ‘dark matter’, the great unknown, of the human genome. These new data enable researchers from all over the world to study the DNA variants and use the results to better understand genetic diseases.

Although our knowledge of the human DNA is extensive, it is nowhere near complete. For instance, our knowledge of exactly which changes in our DNA are responsible for a certain disease is often insufficient. This is related to the fact that no two people have exactly the same DNA. Even the DNA molecules of identical twins have differences, which occur during their development and ageing. Some differences ensure that not everybody looks exactly alike, while others determine our susceptibility to particular diseases. Knowledge about the DNA variants can therefore tell us a lot about potential health risks and is a first step towards personalized medicine. Many small variants in the human genome – the whole of genetic information in the cell – have already been documented. Although it is known that larger structural variants play an important role in many hereditary diseases, these variants are also more difficult to detect and are, therefore, much less investigated.

By comparing the DNA of 250 healthy Dutch families with the reference DNA database the researchers were able to identify 1.9 million variants affecting multiple DNA ‘letters’. These variants include large sections of DNA that have disappeared, moved or even appear out of nowhere. When this happens in the middle of a gene that encodes a certain protein, it is likely that the functionality of the gene, and thus the production of the protein, is compromised. However, large structural variants often occur just before or after the coding part of a gene. The effect of this type of variation is hard to predict.

In the paper two occasions are described in which an extra piece of DNA was found just outside the coding region of a gene. In these occasions the variants had a demonstrable effect on the gene regulation. This proves that even structural variants that occur outside the coding regions need to be monitored closely in future DNA screenings. The catalogue of variants provided by this research enables other scientists to predict the occurrence of large structural variants from the known profile of the smaller ones. This technique opens new possibilities for studying the effects of large structural changes in our genomes.

Additionally, the research resulted in the discovery of large parts of DNA that were not included in the genome reference. This ‘extra’ DNA does contain parts that could be involved in the production of proteins. One of the extra pieces of DNA that was described in the paper is a new ‘ZNF’ gene that has previously never been found in humans. Nevertheless it appears to be present in roughly half of the Dutch population. This particular gene is a member of the ZNF gene family that was known from the reference genomes of several species of apes. The new variant will now be added to the human reference database. Authors subsequently showed that this gene is also present in genomes of several other human populations, however its function remains unknown. The fact that these and other pieces of ‘dark matter’ now have been placed on the genetic map enables scientists worldwide to study them and use the results to better understand human genetic diseases.

EurekAlert www.eurekalert.org/pub_releases/2016-10/su-mt100716.php

ETH researchers have discovered a molecule in liver cells that controls the release of fat into the bloodstream. This “lock keeper” is present in large quantities in overweight people and leads indirectly to vascular narrowing.

Anyone attending Munich’s famous Oktoberfest will know it can leave physical traces; fatty foods and plenty of alcohol cause the liver to work overtime. This organ stores a portion of any fat consumed (and also converts alcohol to fat), but releases it again once the revelry is over.

However, should the excesses continue – and if they are not offset by exercise and sport – the person becomes overweight and diabetic, leading to a condition known as fatty liver. If corrective action is taken in time, the liver can usually recover completely from its fatty degeneration. In severe cases the organ becomes inflamed – a condition that is almost impossible to treat.

Fatty liver is also associated with elevated blood fat values. When the liver becomes fatty it seeks relief by releasing fat into the bloodstream, including “good” fat in the form of high density lipoprotein (HDL), but also “bad” fat, such as low density lipoprotein (LDL), and its precursor, very low density lipoprotein (VLDL).
If the concentration of LDL and VLDL in the blood is too high, vascular constriction forms through atherosclerotic plaques. Should a plaque detach itself, there is a real risk of a vascular blockage, which results in a heart attack or stroke.

Markus Stoffel, Professor of Molecular Health Sciences at ETH Zurich, has been working with his team in collaboration with other scientists in Switzerland, Germany and the US to gain a closer understanding of the connection between excess weight, fatty liver and vascular constriction. And this has led to a surprising discovery: the scientists succeeded to identify a protein in liver cells known as vigilin, which acts as a kind of “lock keeper”. It regulates the release of fats, including VLDL, from the liver into the bloodstream.

The researchers found vigilin in large quantities in the liver cells of overweight mice – and humans. “The level of vigilin in the liver cells of people with fatty livers bears a strong correlation with the percentage of fat in the liver,” explains Stoffel. “In other words, the more fat liver cells contain, the higher the quantity of vigilin.”

In a study the ETH professor and his co-workers demonstrate that the primary function of vigilin is to regulate proteins that transport fat out of the liver. However, the molecule does not bind directly to these transport proteins, but rather to certain points of the associated messenger RNA.
The messenger RNA is the transcription of a gene. It represents the construction plan for the associated protein and is transported from the cell nucleus to the ribosomes. These molecular machines use the messenger RNA to build the protein.

The assumption is that vigilin supplies the ribosomes with the messenger RNA to which it is bound. But it is not just a transport vehicle, it also accelerates production of the associated protein.

One of these proteins “promoted” by vigilin is apolipoprotein B (ApoB), which is responsible for exporting triglycerides from the liver. Triglycerides also promote vascular calcification when present in concentrated form in overweight people.

In order to establish the causal relationship between vigilin and vascular calcification, the researchers stemmed formation of this protein in the livers of mice using a new process of RNA interference. As a consequence of this intervention, these animals suffered far less from atherosclerosis than animals who processed vigilin normally. By contrast, increased vigilin formation led to substantial deposits in the vessels.

“Vigilin intervenes at the level of gene regulation, which has barely been investigated to date,” says Stoffel. Our knowledge of how genes are regulated at the level of DNA is improving all the time. And the regulatory processes by which DNA templates are transcribed into messenger RNA are increasingly understood. But regulation of the step from messenger RNA to protein is something we know much less about. This makes the knowledge that vigilin has a regulatory function at this level all the more valuable. And researchers are particularly excited by the fact that vigilin is the first RNA-binding protein found in the context of fatty livers and diabetes.

ETH Zurich www.ethz.ch/en/news-and-events/eth-news/news/2016/09/vigilin-the-lock-keeper.html

Thermo Fisher Scientific and HEALTH BioMed (HBM) have announced a collaboration to support HBM’s development of molecular diagnostic (MDx) kits for infectious disease and pharmacogenomics screening to serve the China market. Under the terms of a strategic agreement, HBM will submit all kits it develops on the Applied Biosystems 3500Dx Capillary Electrophoresis (CE) platform through the appropriate regulatory process with the China Food and Drug Administration (CFDA) following successful validation. “Our collaboration with Thermo Fisher Scientific will enable HBM to meet a critical need in the China market for a series of high accuracy kits designed to run on a single CE platform to improve human health outcomes,” said Jianwei Yu, Chairman and CEO of HEALTH BioMed. “Molecular diagnostics such as these can improve diagnosis and treatment strategies in hospital settings while also helping to decrease antibiotic abuse.” HBM intends to leverage its CE-based Advanced Fragment Analysis (AFA) technology and reagents, which are currently CE-IVD-and cFDA-marked as is the ABI 3500Dx platform, to develop multiple assays under its SureX brand of multiplex kits. HBM’s current offering for human papillomavirus (HPV) screening, for example, is designed to target 25 high- and low-risk markers with high sensitivity, specificity and low hands-on-time. Development of its pharmacogenomics kits under the agreement will be designed to further support precision medicine initiatives in the country. “As a world leader in serving science, we are proud to be an enabling partner to help HEALTH BioMed build its portfolio of molecular diagnostics designed to better manage human health in China,” said Mark Smedley, president of genetic sciences at Thermo Fisher. “We are committed to working with diagnostic partners around the world who share our vision to drive the era of precision medicine.”

www.thermofisher.com        www.nb-health.com/HGT

EKF Diagnostics announces that its newly introduced Glycated Serum Protein (GSP) LiquiColor diabetic biomarker test has been verified for use on the Siemens Vista chemistry analyser. In a scientific poster published by scientists at the Memorial Healthcare System, Hollywood, USA, it was demonstrated that EKF’s GSP assay enhances the versatility of the Vista system for the specialized glycemic monitoring of diabetics with hemoglobinopathies, or conditions that affect red blood cell (RBC) lifespan. Daily blood glucose and HbA1c are used as short and long term (3-4 month) measures of glycemic control respectively. However, HbA1c values may be adversely affected by patients with hemoglobin variants or conditions that affect RBC lifespan such as anemia and dialysis to name a few, while GSP as a 2-3 week indicator of blood glucose, is unaffected. Traditional nitroblue tetrazolium (NBT) assays for fructosamine (or GSP), used as an alternative test for diabetes patients with hemoglobinopathies and pregnant women, suffer from a variety of interferences. Due to these analytical issues, the Memorial Healthcare System scientists required a reliable alternative that could be adapted to their existing analyser. Therefore, the EKF Diagnostics GSP assay was evaluated and validated using an open channel user defined method. The scientific poster authors concluded that EKF’s GSP assay provides laboratories with a simple, sensitive and fast alternative glycemic monitoring test without the endogenous substance interference that are typically observed in NBT-based colorimetric assays. “We are pleased with the recognition by the Memorial Health System of the value of our GSP diabetic biomarker test which is based on a double enzymatic degradation method. This provides superior specificity, accuracy and reliability compared to the older non-enzymatic fructosamine NBT method,” said Al Blanco, Business Unit Director – Central Lab at EKF Diagnostics. He added, “As a 2-3 week indicator of average blood glucose which is unaffected by RBC half-life, GSP closes the information gap between daily blood glucose and HbA1c testing. This means that GSP serves as an accurate intermediate marker of glycemia in instances where HbA1c may be of limited value, such as pregnancy, reduced RBC lifespan and hemodialysis.” The Memorial Health System scientific poster presented at the American Association for Clinical Chemistry (AACC) Annual Scientific Meeting 2016 is available to view at: http://www.ekfdiagnostics.com/glycated-serum-protein.html.

www.ekfdiagnostics.com info@ekfdiagnostics.com

Researchers have identified a gene (CYFIP2) associated with binge eating.

This finding represents one of the first examples of a genome-wide significant genetic factor to be identified for binge eating in model organisms or humans. In addition, the researchers discovered a network of down-regulated genes involved in myelination (the process of forming a sheath around a nerve fibre to allow nerve impulses to move quickly) that also was associated with binge eating.

These findings could potentially lead to treatments targeted to normalize eating behaviours.

Eating disorders are among the most lethal of neuropsychiatric disorders. Compulsive binge eating affects millions of people suffering from eating disorders and obesity in the United States. It is characterized by episodes of eating large quantities of food, often very quickly and to the point of discomfort. Binge eaters often experience a loss of control during the binge as well as shame, distress or guilt afterwards.

Genome-wide association studies of eating disorders in humans have been limited in their power to detect significant associations between genotype and disease or disease traits such as binge eating.

Using gene mapping and gene validation, researchers  were able to identify cytoplasmic FMR1-interacting protein 2 (CYFIP2) as a major genetic risk factor for binge eating. In addition, they observed that decreased myelination could be a neuropathological consequence of binge eating. Camron Bryant“Because we found changes in the brain as a consequence of binge eating that were predictive of decreased myelination, therapeutically promoting remyelination may represent a novel treatment avenue for promoting recovery from negative feeding behaviours in eating disorders,” explained corresponding author Camron Bryant, PhD, assistant professor of Pharmacology and Experimental Therapeutics & Psychiatry at BUSM.

Bryant and his colleagues believe these findings may lead to new therapeutic treatments which could ultimately save lives and restore healthy eating behaviours in conditions such as compulsive overeating, bulimia nervosa, anorexia nervosa and even substance use disorders.

Boston University Medical Center www.bumc.bu.edu/busm/2016/10/26/genetic-risk-factor-for-binge-eating-discovered/