Human Genetics

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Human Genetics

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Scientists are closer to understanding the genetic causes of type 2 diabetes by identifying 111 new chromosome locations (‘loci’) on the human genome that indicate susceptibility to the disease, according to a UCL-led study in collaboration with Imperial College London. LONDON, 10-May-2017 — /EuropaWire/ — Type 2 diabetes is the world’s most widespread and devastating metabolic disorder and previously only 76 loci were known and studied. Very few these loci are found in the African American population where the prevalence of type 2 diabetes is almost twice that in the European American population (19% vs. 10%). Of the additional 111 loci identified by the team, 93 (84%) are found in both African American and European populations and only 18 are European-specific. The study, published today in The American Journal of Human Genetics, used a method developed at UCL based on highly informative genetic maps to investigate complex disorders such as type 2 diabetes. European and African American sample populations comprising 5,800 type 2 diabetes case subjects and 9,691 control subjects were analysed, revealing multiple type 2 diabetes loci at regulatory hotspots across the genome. “No disease with a genetic predisposition has been more intensely investigated than type 2 diabetes. We’ve proven the benefits of gene mapping to identify hundreds of locations where causal mutations might be across many populations, including African Americans. This provides a larger number of characterised loci for scientists to study and will allow us to build a more detailed picture of the genetic architecture of type 2 diabetes,” explained lead author, Dr Nikolas Maniatis (UCL Genetics, Evolution & Environment). “Before we can conduct the functional studies required in order to better understand the molecular basis of this disease, we first need to identify as many plausible candidate loci as possible. Genetic maps are key to this task, by integrating the cross-platform genomic data in a biologically meaningful way,” added co-lead author, Dr Toby Andrew (Imperial College London, Department of Genomics of Common Disease). The team discovered that the additional 111 loci and previously known 76 loci regulate the expression of at least 266 genes that neighbour the identified disease loci. The vast majority of these loci were found outside of gene coding regions but coincided with regulatory ‘hotspots’ that alter the expression of these genes in body fat. They are currently investigating whether these loci alter the expression of the same genes in other tissues such as the pancreas, liver and skeletal muscle that are also relevant to type 2 diabetes. Three loci present in African American and European populations were analysed further using deep sequencing in an independent sample of 94 European patients with type 2 diabetes and 94 control subjects in order to identify genetic mutations that cause the disease. The team found that all three loci overlapped with areas of the chromosome containing multiple regulatory elements and epigenetic markers along with candidate causal mutations for type 2 diabetes that can be further investigated. “Our results mean that we can now target the remaining loci on the genetic maps with deep sequencing to try and find the causal mutations within them. We are also very excited that most of the identified disease loci appear to confer risk of disease in diverse populations such as African Americans, implying our findings are likely to be universally applicable and not just confined to Europeans,” added Dr Winston Lau (UCL Genetics, Evolution & Environment). “We are now in a strong position to build upon these genomic results, and we can apply the same methods to other complex diseases such as Alzheimer’s disease,” concluded Dr Maniatis.


News Article | May 12, 2017
Site: www.biosciencetechnology.com

When a group of researchers in the Undiagnosed Disease Network at Baylor College of Medicine realized they were spending days combing through databases searching for information regarding gene variants, they decided to do something about it. By creating MARRVEL (Model organism Aggregated Resources for Rare Variant ExpLoration) they are now able to help not only their own lab but also researchers everywhere search databases all at once and in a matter of minutes. This collaborative effort among Baylor, the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Harvard Medical School is described in the latest online edition of the American Journal of Human Genetics. "One big problem we have is that tens of thousands of human genome variants and phenotypes are spread throughout a number of databases, each one with their own organization and nomenclature that aren't easily accessible," said Julia Wang, an M.D./Ph.D. candidate in the Medical Scientist Training Program at Baylor and a McNair Student Scholar in the Bellen lab, as well as first author on the publication. "MARRVEL is a way to assess the large volume of data, providing a concise summary of the most relevant information in a rapid user-friendly format." MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER, all separate databases to which researchers across the globe have contributed, sharing tens of thousands of human genome variants and phenotypes. Since there is not a set standard for recording this type of information, each one has a different approach and searching each database can yield results organized in different ways. Similarly, decades of research in various model organisms, from mouse to yeast, are also stored in their own individual databases with different sets of standards. Dr. Zhandong Liu, assistant professor in pediatrics - neurology at Baylor, a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children's and co-corresponding author on the publication, explains that MARRVEL acts similar to an internet search engine. "This program helps to collate the information in a common language, drawing parallels and putting it together on one single page. Our program curates model organism specific databases to concurrently display a concise summary of the data," Liu said. A user can first search for a gene or variant, Wang explains. Results may include what is known about this gene overall, whether or not that gene is associated with a disease, whether it is highly occurring in the general population and how it is affected by certain mutations. "MARRVEL helps to facilitate analysis of human genes and variants by cross-disciplinary integration of 18 million records so we can speed up the discovery process through computation," Liu said. "All this information is basically inaccessible unless researchers can access it efficiently and apply it to their own work to find causes, treatments and hopefully identify new diseases." This project started as a necessity for the Model Organism Screening Center for the Undiagnosed Disease Network at Baylor, but as it grew, the group began reaching out to researchers in different disciplines for feedback on how MARRVEL might benefit them. "This program is just the start. I think our tool is going to be a model for us to help clinicians and basic scientists more efficiently use the information already publicly available," Wang said. "It will help us understand and process all of the different mutations that researchers are discovering." "The most exciting part is how this project is bringing so many different researchers together," Liu said. "We are working with labs we might not have normally collaborated with, trying to put together a puzzle of all this data." Both Wang and Liu are thankful to the contributions from the genetics communities allowing them access to the databases as they developed MARRVEL. Others who contributed to the findings include Drs. Rami Al-Ouran, Seon-Young Kim, Ying-Wooi Wan, Michael Wangler, Shinya Yamamoto, Hsiao-Tuan Chao, and Hugo Bellen (Howard Hughes Medical Institute at Baylor) all with Baylor College of Medicine; Yanhui Hu, Aram Comjean, Stephanie E. Mohr, and Norbert Perrimon (Howard Hughes Medical Institute at Harvard Medical School) all with Harvard Medical School. For full funding and acknowledgements please see full publication (available after embargo lifts)


News Article | May 11, 2017
Site: www.eurekalert.org

HOUSTON - (May 11, 2017) - When a group of researchers in the Undiagnosed Disease Network at Baylor College of Medicine realized they were spending days combing through databases searching for information regarding gene variants, they decided to do something about it. By creating MARRVEL (Model organism Aggregated Resources for Rare Variant ExpLoration) they are now able to help not only their own lab but also researchers everywhere search databases all at once and in a matter of minutes. This collaborative effort among Baylor, the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Harvard Medical School is described in the latest online edition of the American Journal of Human Genetics. "One big problem we have is that tens of thousands of human genome variants and phenotypes are spread throughout a number of databases, each one with their own organization and nomenclature that aren't easily accessible," said Julia Wang, an M.D./Ph.D. candidate in the Medical Scientist Training Program at Baylor and a McNair Student Scholar in the Bellen lab, as well as first author on the publication. "MARRVEL is a way to assess the large volume of data, providing a concise summary of the most relevant information in a rapid user-friendly format." MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER, all separate databases to which researchers across the globe have contributed, sharing tens of thousands of human genome variants and phenotypes. Since there is not a set standard for recording this type of information, each one has a different approach and searching each database can yield results organized in different ways. Similarly, decades of research in various model organisms, from mouse to yeast, are also stored in their own individual databases with different sets of standards. Dr. Zhandong Liu, assistant professor in pediatrics - neurology at Baylor, a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children's and co-corresponding author on the publication, explains that MARRVEL acts similar to an internet search engine. "This program helps to collate the information in a common language, drawing parallels and putting it together on one single page. Our program curates model organism specific databases to concurrently display a concise summary of the data," Liu said. A user can first search for a gene or variant, Wang explains. Results may include what is known about this gene overall, whether or not that gene is associated with a disease, whether it is highly occurring in the general population and how it is affected by certain mutations. "MARRVEL helps to facilitate analysis of human genes and variants by cross-disciplinary integration of 18 million records so we can speed up the discovery process through computation," Liu said. "All this information is basically inaccessible unless researchers can access it efficiently and apply it to their own work to find causes, treatments and hopefully identify new diseases." This project started as a necessity for the Model Organism Screening Center for the Undiagnosed Disease Network at Baylor, but as it grew, the group began reaching out to researchers in different disciplines for feedback on how MARRVEL might benefit them. "This program is just the start. I think our tool is going to be a model for us to help clinicians and basic scientists more efficiently use the information already publicly available," Wang said. "It will help us understand and process all of the different mutations that researchers are discovering." "The most exciting part is how this project is bringing so many different researchers together," Liu said. "We are working with labs we might not have normally collaborated with, trying to put together a puzzle of all this data." Both Wang and Liu are thankful to the contributions from the genetics communities allowing them access to the databases as they developed MARRVEL. Others who contributed to the findings include Drs. Rami Al-Ouran, Seon-Young Kim, Ying-Wooi Wan, Michael Wangler, Shinya Yamamoto, Hsiao-Tuan Chao, and Hugo Bellen (Howard Hughes Medical Institute at Baylor) all with Baylor College of Medicine; Yanhui Hu, Aram Comjean, Stephanie E. Mohr, and Norbert Perrimon (Howard Hughes Medical Institute at Harvard Medical School) all with Harvard Medical School. For full funding and acknowledgements please see full publication (available after embargo lifts) Both Wang and Liu are thankful to the contributions from the genetics communities allowing them access to the databases as they developed MARRVEL. Others who contributed to the findings include Drs. Rami Al-Ouran, Seon-Young Kim, Ying-Wooi Wan, Michael Wangler, Shinya Yamamoto, Hsiao-Tuan Chao, and Hugo Bellen (Howard Hughes Medical Institute at Baylor) all with Baylor College of Medicine; Yanhui Hu, Aram Comjean, Stephanie E. Mohr, and Norbert Perrimon (Howard Hughes Medical Institute at Harvard Medical School) all with Harvard Medical School. For full funding and acknowledgements please see full publication (available after embargo lifts)


Cold Spring Harbor, NY - Cold Spring Harbor Laboratory (CSHL) has been awarded a research subcontract by Leidos Biomedical Research to lead a Cancer Model Development Center (CMDC) for pancreatic, breast, colorectal, lung, liver and other upper-gastrointestinal cancers. The project is 100% supported by U.S. federal funds (NCI Contract No. HHSN261201500003I, Task Order Number HHSN26100008). CSHL Cancer Center Director Dr. David Tuveson and CSHL Research Director Dr. David Spector will lead the multinational collaborative effort with Dr. Hans Clevers of the Hubrecht Institute, Dr. Aldo Scarpa and Dr. Vincenzo Corbo of the ARC-Net Centre for Applied Research on Cancer at the University of Verona, Italy, and Dr. James Crawford of Northwell Health and Dr. Peter Gregersen of Northwell's Feinstein Institute for Medical Research. The new center will generate three-dimensional organoid culture systems of cancers - next-generation models that improve upon current two-dimensional model systems used to study cancers and develop therapeutics. "CSHL is excited to lead this international team to develop more effective research models for cancer that can be shared broadly with the scientific community in order to accelerate discoveries for improved diagnosis and treatments for cancer patients," said Dr. Tuveson. Dr. Priya Sridevi from CSHL is the lead project manager for this CMDC. Under the contract, the CSHL-led CMDC will establish up to 150 organoid models in one and a half years, contributing to a larger international effort to generate 1,000 new cancer models. The Human Cancer Model Initiative (HCMI) was announced in July 2016 by the National Cancer Institute, Wellcome Trust Sanger Institute in the United Kingdom (UK), Cancer Research UK, and the foundation Hubrecht Organoid Technology. As part of NCI's Precision Medicine Initiative in Oncology, this new project is timed to take advantage of the latest cell culture and genomic sequencing techniques to create models that are representative of patient tumors and annotated with genomic and clinical information. This effort is a first step toward learning how to use these tools to design individualized treatments. Dr. Tuveson, the project's principal investigator, led an effort to develop pancreas cancer organoids, establishing CSHL as an instructional site offering courses in organoid development to the professional scientific community worldwide. Organoids can be established from healthy human tissue as well as from a variety of tumor tissue types. The power of the organoid is that it faithfully recapitulates the tissue from which it is derived. It can be genetically manipulated using technologies like shRNA (short hairpin RNA) that can turn genes on and off, or the revolutionary gene-editing tool CRISPR-Cas9. Moreover, organoid models are amenable to drug screening approaches so they can be used to validate therapeutics. The pioneer of the organoid model system, Dr. Clevers, is a key member of the new CSHL-led center. "We have laid the foundations for this collaborative program through informal exchanges of our young scientists," said Dr. Clevers. "It is very exciting that we can now turn this into a mature, well-funded endeavor that will create next-generation cancer models, as close as possible to what we find in individual patients." In support of the project, the ARC-Net team led by Dr. Scarpa and Dr. Corbo will leverage the biobanking infrastructure coordinated by Dr. Rita T. Lawlor at ARC-Net. "We are very proud to be part of this international research group," said Dr. Corbo. "This collaboration brings together world-leading expertise in cancer genomics and cancer modeling with the potential of accelerating the implementation of personalized medicine. We see an unprecedented opportunity to develop better models of cancers that will enable researchers to interrogate the wealth of genomic information available today for the rational development of cancer therapeutics." "Northwell Health and the Feinstein Institute for Medical Research are very excited to be part of this international effort, as it will help lay the foundation for new standards in clinical care that incorporate ex vivo studies of cancer tissues to guide cancer therapies," said Dr. Gregersen, Professor and Director of the Feinstein Institute's Boas Center for Genomics and Human Genetics. Dr. Crawford, Professor and Chair of the Department of Pathology and Laboratory Medicine at the Hofstra Northwell School of Medicine, noted: "Through this multi-institutional collaboration, Northwell Health will also be well-positioned to help advance the clinical trials necessary for bringing such advances into the realm of clinical care." CSHL entered into a strategic alliance with Northwell Health in April 2015, with the objective of providing CSHL researchers access to Northwell's growing network of clinical services encompassing more than 16,000 new cancer cases annually. For CSHL and Northwell Health, this CMDC project demonstrates the power of their strategic affiliation to establish closer links between research and the clinic for the benefit of cancer patients. The multinational HCMI effort aims to speed up development of new models and to make research more efficient by avoiding unnecessary duplication of scientific efforts. Genetic sequencing data from the tumors and derived models will be available to researchers, along with clinical data about the patients and their tumors. All information related to the models will be shared in a way that protects patient privacy. The goal is to give scientists around the world access to the best resources to be able to easily study all types of cancer. These new cell models could transform how we study cancer and could help to develop better treatments for patients,Scientists will make the models using tissue from patients with different types of cancer, potentially including rare and pediatric cancers, which are often under-represented or not available at all in existing cell-line collections. The new models will have the potential to reflect the biology of tumors more accurately and better represent the overall cancer patient population. The Hubrecht Institute, founded in 1916, is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), situated on Utrecht Science Park "The Uithof" of the largest university in the Netherlands (Utrecht). Research at the Hubrecht Institute focuses on developmental biology and stem cells at the organismal, cellular, and molecular level. A variety of biological processes are being studied, mainly concerning embryonic development and development and homeostasis of organs. Presently there are 19 research groups, including the research group of Hans Clevers, with a total of about 220 employees. Prof. Dr. Hans Clevers discovered methods to grow stem cell-derived human epithelial 'mini-organs' (organoids) from tissues of patients with various diseases including cancer. Clevers' international reputation has brought him numerous grants and prestigious awards. For more information, visit https:/ ARC-Net, Applied Research on Cancer Network, is a university research centre that was established in 2007 through a joint initiative between the University of Verona, the University Hospital Trust of Verona and the Cariverona Foundation. ARC-Net represents Italy in the International Cancer Genome Consortium where the Centre coordinates the effort of the Italian Pancreatic Cancer Genome Project to the molecular characterization of rare pancreatic tumors. ARC-Net is organized into 5 core facilities platforms, which include a cancer tissue biobank that collects biological material and associated clinical, pathological and epidemiological data. To date the biobank has material from over 5,000 consented patients and has produced over 150 patients-derived xenografts of pancreatic cancer and other cancer models. For more information, visit http://www. Northwell Health is New York State's largest health care provider and private employer, with 21 hospitals and over 550 outpatient facilities. We care for more than two million people annually in the metro New York area and beyond, thanks to philanthropic support from our communities. Our 61,000 employees - 15,000+ nurses and nearly 3,400 physicians, including nearly 2,700 members of Northwell Health Physician Partners -- are working to change health care for the better. We're making breakthroughs in medicine at the Feinstein Institute. We're training the next generation of medical professionals at the visionary Hofstra Northwell School of Medicine and the School of Graduate Nursing and Physician Assistant Studies. And we offer health insurance through CareConnect. For information on our more than 100 medical specialties, visit Northwell.edu. Founded in 1890, Cold Spring Harbor Laboratory has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL has been a National Cancer Institute designated Cancer Center since 1987. Home to eight Nobel Prize winners, the private, not-for-profit Laboratory employs 1,100 people including 600 scientists, students and technicians. The Meetings & Courses Program hosts more than 12,000 scientists from around the world each year on its campuses in Long Island and in Suzhou, China. The Laboratory's education arm also includes an academic publishing house, a graduate school and programs for middle and high school students and teachers. For more information, visit http://www.


News Article | May 19, 2017
Site: news.yahoo.com

The National Institute of Mental Health notes that scientists aren't entirely sure what causes attention deficit hyperactivity disorder. Anything from genes and brain injuries to low birth weight and exposure to environmental toxins at a young age may play a role. However, of these variables, experts tend to agree that genetics is the most likely link. But this isn't to say the other factors go entirely by the wayside. For example, one study, published in Human Genetics, mentions that although ADHD is "highly heritable," it's a "multifactorial disorder, in which many genes, all with a small effect, are thought to cause the disorder in the presence of unfavorable environmental conditions." The Centers for Disease Control and Prevention reinforces this notion, outlining that in addition to the "important role" genetics plays in ADHD, other possible risk factors and causes may include brain injury, exposure to lead during pregnancy or at a young age and premature delivery. [See: 10 Concerns Parents Have About Their Kids' Health.] According to James M. Swanson, professor of pediatrics at the University of California, Irvine, whether genetics is the main reason a person develops this disorder remains "a tricky question." He explains that while " ADHD does seem to run in families" and that the "statistical estimate of heritability is very high," he stresses that this does not necessarily mean that all ADHD cases have a genetic basis. "Interpretation of estimates of 'heritability' is complicated." "Simply put, the etiology of ADHD is complex and can involve multiple causes," says Russell A. Barkley, clinical professor of psychiatry, Medical University of South Carolina. "To date, all of the major ones fall in the realm of neurology and genetics -- biological causation -- with no evidence that social factors alone can account for the condition." He explains that head trauma or other neurological injuries, alcohol use during pregnancy, significant premature birth and biohazard exposure "might interact with genetic liability to the disorder to exacerbate it." Barkley explains that the closer someone's genetic relationship is to a child with ADHD, the more likely it is that the relative also shares the disorder. For example, he notes that 25 to 35 percent of parents of ADHD children are adults with ADHD, 25 to 50 percent of siblings of children with ADHD have the disorder and 70 to 92 percent of identical twins of a child with ADHD have ADHD. [See: 10 of the Biggest Health Threats Facing Your Kids This School Year.] Thomas E. Brown, director of the Brown Clinic for Attention and Related Disorders in Manhattan Beach, California, agrees that genetics play a role in ADHD. In his book, "Outside the Box: Rethinking ADD/ADHD in Children and Adults: A Practical Guide," he writes that "like eye color and height," ADHD starts with genes. "It runs in families." Yet he too, makes it clear that there are several variables, including the fact that some people's genes are less stable than others, sometimes not becoming "active until many years after the person is born." Here are some other ways genetics can influence ADHD development -- and it's not always strictly about inheritance. In some cases, new, or de novo, mutations occur in a child's genes despite the fact that they're not present in the parent's genome, Barkley says. "We think this may account for at least 10 percent of ADHD, especially if they are new cases arising in a family that has no increased risk among the relatives." Such mutations can occur in egg and sperm-producing cells, he explains, and arise simply by exposure to the mutation-causing agents that everyone experiences during their life, such as environmental toxins and the sun's radiation. Although the mutations are not present in the parent's DNA, the gene mutations may still be passed to a child. "Some genes turn on and off depending on other things going on in the body or in the environment," Brown writes. Barkley explains that such gene-by-environment interactions can give rise to a child's ADHD development. "A child inherits genes for ADHD that cause a susceptibility to the disorder and the expression of these genes then interacts with some other agent in the environment to magnify the risk for ADHD beyond the genes alone," he says. "For instance, maternal alcohol or tobacco use during pregnancy increases the risk for ADHD about 2.5 times the population risk. But should a child have one or two of the risk genes for ADHD, the occurrence may go up eight times that of the population risk." Exposure to infections, chronic elevated parental stress during pregnancy and malnutrition earlier on in childhood also fall into this category, he says. Swanson adds that "severe deprivation in early life may cause ADHD," referencing a large-scale study beginning in the 1990s involving Romanian orphans who "suffered different degrees of early environmental deprivation and then were adopted into families in the U.K." In addition to getting hardly any personal care or cognitive stimulation prior to adoption, these children also received insufficient food. According to The Lancet, those living in Romanian institutions for more than six months as children had higher rates of social problems -- which lasted into adulthood -- including inattention and overactivity. "These studies may be relevant to the question about additional plausible environmental causes of ADHD," Swanson says. Another way genetics can influence ADHD is through epigenetics, which Barkley says refers to "small chemical 'flags' (usually methylated tags) that get inserted or attached on to a gene during or after its transmission to an offspring." The flag affects timing of gene activation as well as whether the gene is even activated in the first place. He says these epigenetic effects have been discovered in some disorders such as autism, adding that "some evidence is just beginning to accrue that it might occur in ADHD as well." [See: 11 Simple, Proven Ways to Optimize Your Mental Health.] "All in all," Barkley says, "about 65 to 75 percent of all ADHD cases arise from these genetic factors, chiefly inheritance of ADHD gene variants." Despite the genetic links associated with ADHD, remember that every person is different and that obtaining a diagnosis is a detailed process. "Assessment for ADHD requires collection of information about how the person functions in a wide variety of complex daily tasks at many different times of day in many different settings," Brown notes. Jennifer Lea Reynolds is a Health freelancer at U.S. News. She draws on her life and career experiences, including losing 70 pounds and writing copy at health-centric advertising agencies. Her articles have been published online in Smithsonian, Reader's Digest, Woman's Day and The Huffington Post. She's also the owner of FlabbyRoad.com, where she writes about weight loss, fitness, nutrition and body image. You can follow her on Twitter @JenSunshine.


News Article | May 7, 2017
Site: www.sciencedaily.com

Researchers at the Sydney Brenner Institute for Molecular Bioscience and the Division of Human Genetics at Wits, in collaboration with peers in Europe, the US and Canada published this research in the May issue of the American Journal of Human Genetics.


News Article | May 4, 2017
Site: www.eurekalert.org

Scientists are closer to understanding the genetic causes of type 2 diabetes by identifying 111 new chromosome locations ('loci') on the human genome that indicate susceptibility to the disease, according to a UCL-led study in collaboration with Imperial College London. Type 2 diabetes is the world's most widespread and devastating metabolic disorder and previously only 76 loci were known and studied. Very few these loci are found in the African American population where the prevalence of type 2 diabetes is almost twice that in the European American population (19% vs. 10%). Of the additional 111 loci identified by the team, 93 (84%) are found in both African American and European populations and only 18 are European-specific. The study, published today in the American Journal of Human Genetics, used a method developed at UCL based on highly informative genetic maps to investigate complex disorders such as type 2 diabetes. European and African American sample populations comprising 5,800 type 2 diabetes case subjects and 9,691 control subjects were analysed, revealing multiple type 2 diabetes loci at regulatory hotspots across the genome. "No disease with a genetic predisposition has been more intensely investigated than type 2 diabetes. We've proven the benefits of gene mapping to identify hundreds of locations where causal mutations might be across many populations, including African Americans. This provides a larger number of characterised loci for scientists to study and will allow us to build a more detailed picture of the genetic architecture of type 2 diabetes," explained lead author, Dr Nikolas Maniatis (UCL Genetics, Evolution & Environment). "Before we can conduct the functional studies required in order to better understand the molecular basis of this disease, we first need to identify as many plausible candidate loci as possible. Genetic maps are key to this task, by integrating the cross-platform genomic data in a biologically meaningful way," added co-lead author, Dr Toby Andrew (ICL, Department of Genomics of Common Disease). The team discovered that the additional 111 loci and previously known 76 loci regulate the expression of at least 266 genes that neighbour the identified disease loci. The vast majority of these loci were found outside of gene coding regions but coincided with regulatory 'hotspots' that alter the expression of these genes in body fat. They are currently investigating whether these loci alter the expression of the same genes in other tissues such as the pancreas, liver and skeletal muscle that are also relevant to type 2 diabetes. Three loci present in African American and European populations were analysed further using deep sequencing in an independent sample of 94 European patients with type 2 diabetes and 94 control subjects in order to identify genetic mutations that cause the disease. The team found that all three loci overlapped with areas of the chromosome containing multiple regulatory elements and epigenetic markers along with candidate causal mutations for type 2 diabetes that can be further investigated. "Our results mean that we can now target the remaining loci on the genetic maps with deep sequencing to try and find the causal mutations within them. We are also very excited that most of the identified disease loci appear to confer risk of disease in diverse populations such as African Americans, implying our findings are likely to be universally applicable and not just confined to Europeans," added Dr Winston Lau (UCL Genetics, Evolution & Environment). "We are now in a strong position to build upon these genomic results, and we can apply the same methods to other complex diseases such as Alzheimer's disease," concluded Dr Maniatis.


News Article | May 4, 2017
Site: www.eurekalert.org

OTTAWA, ON - May 4, 2017 - A worldwide consensus co-authored by more than 40 scientists sets out ways to address research bottlenecks as the international community strives to diagnose most rare genetic diseases by 2020. A commentary paper by lead author Dr. Kym Boycott, Chair of the Diagnostics Committee of the International Rare Diseases Research Consortium (IRDiRC) and a clinical geneticist and senior scientist at the Children's Hospital of Eastern Ontario (CHEO) Research Institute, says international cooperation is needed now more than ever; despite advances in technology and decades of research, the genetic mutations behind half of the 7,000 known rare genetic diseases in the world remain a mystery. The paper, "International Cooperation to Enable the Diagnosis of all Rare Genetic Diseases", published in the American Journal of Human Genetics today, shows international enthusiasm and support for IRDiRC-recognized platforms, tools, standards and guidelines to streamline resources and accelerate progress for rare disease research. "We need new strategies to solve the unsolved," Dr. Boycott said. "Diagnosing the genes responsible for rare genetic diseases is a crucial first step towards informed patient care, giving patients a better understanding of what is causing their mysterious symptoms and helping doctors to better manage complications. We've made tremendous progress in linking rare genetic diseases to their causative biological pathways. However, the lack of data-sharing infrastructure is siloing data and hindering further discoveries. This paper for the first time sets out these pinch points so that they can be considered and addressed by the genetics community." The paper also describes the increasing challenge of discovering novel disease mechanisms and confirming their links to rare diseases. The arrival of genome-wide sequencing in 2010 resulted in a boom in the number of disease genes identified but the rate of new discoveries has plateaued or decreased in recent years. Whole Exome Sequencing, for example, allowed researchers to zone in on the exome, the portion of the genome which encodes for proteins and where 85% of mutations originate. However, as many 'straightforward' genetic links have been identified, rare diseases are getting rarer and more difficult to solve. Taila Hartley, operations director of Care4Rare based at CHEO, said some rare genetic diseases are one in a million rather than one in 300,000. Being able to confirm a genetic cause with a second patient from another country that may be recorded in a database makes a huge difference in building evidence. "With whole-exome sequencing, there was a huge boom in new genetic discoveries. We thought this was going to continue but what we've realized now is we're experiencing a plateau or even actually a decrease in the number of genes that are being identified each year. And it's because we didn't realize the international scale of data-sharing that would be necessary to solve these ultra-rare diseases," Ms. Hartley said. Dr. Boycott, co-founder of Care4Rare, a nation-wide network of doctors, scientists and clinical researchers dedicated to improving the diagnosis and treatment of rare diseases, also helped establish the Matchmaker Exchange with University of Toronto scientist Dr. Michael Brudno. The Matchmaker Exchange is a data platform that enables sharing of rare disease patient clinical and genomic information from around the world. The CHEO Research Institute coordinates the research activities of the Children's Hospital of Eastern Ontario (CHEO) and is affiliated with the University of Ottawa. Its three programs of research include molecular biomedicine, health information technology, and evidence to practice research; key research themes include cancer, diabetes, obesity, mental health, emergency medicine, musculoskeletal health, electronic health information and privacy, and genetics of rare disease. The CHEO Research Institute makes discoveries today for healthier kids tomorrow. For more information, visit http://www. . For the latest CHEO news, our Twitter handle is @CHEOhospital


News Article | May 4, 2017
Site: www.eurekalert.org

Research could lead to new genetic testing strategies for syndromes involving larger size and intellectual disability Researchers have undertaken the world's largest genetic study of childhood overgrowth syndromes - providing new insights into their causes, and new recommendations for genetic testing. Overgrowth syndromes describe conditions that cause children to be taller and to have a bigger head size than expected for their age, and also to have an intellectual disability or other medical problems. Scientists at The Institute of Cancer Research, London, found many of the children with overgrowth syndromes had mutations in one of 14 different genes. They also showed that many of the overgrowth genes are also involved in driving cancer growth, though intriguingly, the types of mutations involved in promoting human growth and cancer growth are often different. The researchers collected samples and information from 710 children with an overgrowth syndrome through an international study, funded by Wellcome. They used a technique called exome sequencing to analyse the DNA of all the genes in each child and discovered a genetic cause for their overgrowth syndrome in 50 per cent of the children. These children had genetic mutations in one of the 14 genes, and usually the mutation started in the child with the overgrowth syndrome and was not inherited from either parent. Amongst the 14 genes was HIST1H1E, which has not been previously linked to a human disorder. The other genes have been linked with human disorders before, but their contribution to overgrowth syndromes was not known. Importantly, the study showed that the major genes causing overgrowth syndromes are involved in epigenetic regulation, which means they control how and when other genes will be switched on and off. Mutations in epigenetic regulation genes were the cause of overgrowth in 44 per cent of the children in the study, which is published today (Thursday) in the American Journal of Human Genetics. Study leader, Professor Nazneen Rahman, Head of Genetics at The Institute of Cancer Research, London, and The Royal Marsden Hospital NHS Foundation Trust, said: "The control of growth is a fundamental process important in development and many diseases, including cancer. We are pleased our work has provided both new insights into the mechanisms that control growth and new strategies by which genetic testing can be used efficiently to diagnose children with overgrowth syndromes." Co-study lead Dr Katrina Tatton-Brown, Reader in Clinical Genetics at St George's, University of London, Consultant Geneticist at The Institute of Cancer Research, London, and the South West Thames Regional Genetics Service, St Georges University Hospitals NHS Foundation Trust, said: "Our study suggests that offering an exome sequencing genetic test to children with overgrowth and intellectual disability would be a practical and worthwhile way to try to identify the cause of their problems. This would allow us to provide children with more personalised management and to give better information to families about risks to other members of the family."


News Article | May 5, 2017
Site: www.eurekalert.org

Scientists have discovered the genetic mutation that causes the rare skin disease, keratolytic winter erythema (KWE), or 'Oudtshoorn skin', in Afrikaners Scientists have discovered the genetic mutation that causes the rare skin disease, keratolytic winter erythema (KWE), or 'Oudtshoorn skin', in Afrikaners. Researchers at the Sydney Brenner Institute for Molecular Bioscience and the Division of Human Genetics at Wits, in collaboration with peers in Europe, the US and Canada published this research in the May issue of the American Journal of Human Genetics. KWE causes a redness of the palms and soles with consecutive cycles of peeling of large sections of thick skin, often exacerbated during winter months. Oudtshoorn is a town in the Western Cape province of South Africa where the disorder was present in large families. KWE causes a redness of the palms and soles with consecutive cycles of peeling of large sections of thick skin, often exacerbated during winter months. Oudtshoorn is a town in the Western Cape province of South Africa where the disorder was present in large families. Afrikaners are Afrikaans-language speakers descended from predominantly Dutch, German and French settlers, who arrived in South Africa in the 17th and 18th centuries. Afrikaners have a high risk for several genetic disorders, the best known being familial hypercholesterolaemia (inherited high cholesterol leading to heart attacks early in life) and porphyria (sensitivity of the skin to ultra-violet exposure and adverse reactions to specific drugs). These disorders are common because of founder mutations brought to South Africa by small groups of immigrants who settled in the Cape of Good Hope and whose descendants are now spread throughout the country. KWE is one of these less well-known founder genetic disorders. KWE was first described as a unique and discrete skin disorder in 1977 by Wits dermatologist, Professor George Findlay. He noticed that it occurred in families and had a dominant mode of inheritance -- i.e., on average, if a parent has the condition about half the children inherit it in every generation. In addition to identifying the genetic mutation for scientific purposes, this research now enables dermatologists to make a definitive diagnosis of KWE in patients. It further enables researchers to understand similar skin disorders and is a starting point for developing possible treatments. Since the late 1980s, three MSc and three PhD students at Wits University researched the disorder, firstly under the supervision of Professor Trefor Jenkins and from about 1990 guided by Professor Michele Ramsay, Director and Research Chair in the Sydney Brenner Institute for Molecular Bioscience. In 1997, Wits MSc student Michelle Starfield and a group in Germany mapped the KWE trait to a region on the short arm of chromosome 8. The researchers showed that it was likely that the South African families all had the same mutation, but that the German family had a different mutation. This research preceded the sequencing of the human genome and subsequent research focused on characterising this region of the genome and examining good candidate genes. The KWE mutation remained elusive. In 2012 Thandiswa Ngcungcu, then a Wits MSc student in Human Genetics whom Ramsay supervised, chose KWE as a topic for her PhD. Ngcungu's research involved large-scale DNA sequencing during an internship on the Next Generation Scientist Programme in Novartis, Basel. The mutation was not detected by conventional data analysis so copy number variants (genetic changes) -- where regions of the genome are duplicated or deleted - were investigated. Ngcungcu and the researchers then discovered a mutation in a region between genes that was present in all South African KWE-affected individuals studied. During this time Dr Torunn Fiskerstrand, University of Bergen, Norway, independently discovered the genetic cause of KWE in Norwegians. Ramsay and Fiskerstrand collaborated. The different DNA duplications in the South African and Norwegian families overlapped at a critical genomic region called an enhancer (which 'switches on' the gene) - providing strong evidence that this was, in fact, the KWE mutation. For over a year the scientists researched how this duplicated enhancer caused KWE. They demonstrated that the mutation causes a nearby gene to produce more protein than normal and that this abnormal expression was the likely cause of the skin peeling. Exactly twenty years after determining that the KWE mutation lies on chromosome 8, the mutation that causes KWE was identified and published. Solving the mystery of KWE was a journey of data analysis, ancestry mapping, genomic comparison and global collaboration. Ngcungcu continues her work as a postdoctoral fellow examining the genetics of another skin disorder, albinism, and as a lecturer in the Division of Human Genetics at Wits from July 2017.

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