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News Archive
2007
December
Wellcome Trust Case Control Consortium named Researcher of the Year
From: Scientific American - www.sciam.com/article.cfm?id=sciam-50-research-leader
With genetic scientific advances reported almost daily, it sometimes seems as if we are merely waiting for researchers to discover the gene at fault for every human disease. The complex genetic basis of many common diseases, however, complicates prediction, diagnosis and treatment.
The Wellcome Trust Case Control Consortium (WTCCC), a constellation of more than 50 British research groups, took on the mammoth challenge of ferreting out the causes of diseases in which multiple genes are implicated. Last June they reported the findings of a study that scanned for specific gene variations among 17,000 British citizens: 2,000 each from patient groups diagnosed with bipolar disorder, coronary heart disease, Crohn’s disease, rheumatoid arthritis, hypertension and diabetes types 1 and 2, as well as 3,000 unafflicted who served as a control group. The large scale of the study was unprecedented and so was the payoff: 24 locations in the genome were found to be associated with six of the seven diseases.
The WTCCC compared the genomes of each affected group with those of the controls and zeroed in on locations where DNA bases differed between the two groups. The size of the study was essential in enabling the researchers to spot rare anomalies. Some of the signals were in coding regions of genes; some were in noncoding regions that might regulate other genes; and some were in “gene deserts”—noncoding regions with no identified function. The variants themselves may not actually be responsible for the diseases. But they serve as signposts for other researchers to investigate DNA at a fine scale.
Every person possesses a certain pattern of “polymorphisms” in
the six billion nucleotides of their genomic DNA—three billion for each of the
two sets of chromosomes. The statistical pattern of how these variations occur,
provided by studies such as the one conducted by the WTCCC, will help physicians
calculate the chances that a patient could develop symptoms of a hereditary
disorder. The ultimate goal of this research is personalized medicine in which
patients submit a blood sample and have their entire set of genes analyzed to
determine predisposition to chronic diseases, the best food and exercise
regimens to stay healthy, and which drugs and dosages will be most effective
when illness does strike.
—Kaspar Mossman
Researchers at the University of Oxford discover that genes determine the severity of Multiple Sclerosis
Researchers at the Wellcome Trust Centre for Human Genetics (WTCHG) at the University of Oxford have made a major new insight into the interaction of genes involved in Multiple Sclerosis (MS). They have discovered that the specific combination of two different versions of the same gene, one coming from each parent, determine the outcome for patients. It has long been known that MS is extremely variable, but this study is the first insight into why this is the case.
The research team at WTCHG, led by Professor George Ebers, undertook four independent but conceptually interlinked studies. The first study compared forms (alleles) of a specific gene, HLA-DRB1, in 160 MS patients with benign and malignant disease, representing the opposite extremes of long-term disease outcome. The second study was of benign and malignant MS sufferers in Sardinia, an island with an unusually high rate of the disease. The third study looked at siblings who both had MS, but with different versions of HLA-DRB1. The results of all three studies indicated that one allele of DRB1 was protective against the severe form of the disease. A fourth study, of a distinct but close relative of this allele, showed the same effect.
This research may have localised the molecular basis of MS to the short DNA stretch shared by the two protective alleles of the gene. The group had previously shown that one of these alleles is among several which are partially protective for risk. Now it appears that among those who have the allele from a parent and still get MS, the severe form of the disease is minimised. It seems to operate by somehow blocking the effects of the main MS susceptibility allele HLA-DRB1*1501 which would be inherited from the other parent.
Professor Ebers said: ‘The analysis of these studies has yielded the first clear insight into the mechanism of disease variability and we are very excited about the potential practical applications of our findings.’
There are few diseases in which the outcome varies between such extremes as MS. For some, the disease is mild and causes intermittent symptoms of a minor nature. But for others it can be fatal within 12 months. Evidence for genetic factors in disease outcome comes from sibling research, particularly studies on identical twins. The results of the studies undertaken by Prof Ebers’ team at the WTCHG may have far-reaching consequences for the future of MS research and treatment. There may some practical value in screening families to determine whether they have protective alleles and if MS is present there may be potential for practical prognostication. At present this would be only relative and apply to a minority of patients. However there is reason to think the gene-gene interaction identified will be part of a more general phenomenon and that more such observations will serve to refine information which can usefully be passed on to those with the disease. The results will also guide future research, as scientists can now focus on studying how the 01 allele interacts with other genes to reduce severity, suggesting new therapeutic strategies.
October
Consortium Publishes Phase II Map of Human Genetic Variation
The second phase of the HapMap www.hapmap.org Project – created to identify and catalogue genetic similarities and differences among populations around the world – has been completed by scientists from six countries, including Oxford researchers.
The International HapMap Consortium today published analyses of its second-generation map of human genetic variation, which contains three times more markers than the initial version unveiled in 2005.
Any two humans are more than 99 percent the same at the genetic level. However, it is important to understand the small fraction of genetic material that varies among people because it can help explain individual differences in susceptibility to disease, response to drugs or reaction to environmental factors. Variation in the human genome is organized into local neighbourhoods, called haplotypes, that usually are inherited as intact blocks of information. Consequently, researchers refer to the map of human genetic variation as a haplotype map, or HapMap.
In two papers in Nature www.nature.com, the consortium describes how the higher resolution map offers greater power to detect genetic variants involved in common diseases, explore the structure of human genetic variation and learn how environmental factors, such as infectious agents, have shaped the human genome. The first phase of HapMap is already revolutionising scientists’ ability to study the genetic basis of human disease.
The International HapMap Consortium is a public-private partnership of researchers and funding agencies from the United Kingdom, Canada, China, Japan, Nigeria and the United States. Much of the analyses of both phases of HapMap was undertaken at the University of Oxford, the only British university selected to be involved with the project.
One of the co-chairs of the analysis group, Professor Peter Donnelly, FRS, Director of Oxford University’s Wellcome Trust Centre for Human Genetics, said: ‘Understanding the differences between people’s genomes, and why those differences exist, is at the core of many questions in modern biomedical research. The HapMap project has transformed this area of research, giving new insights into areas as diverse as why some people are more susceptible to disease and our evolutionary history.’
The second-generation haplotype map, or Phase II HapMap, contains more than 3.1 million genetic variants, called single nucleotide polymorphisms (SNPs) – three times more than the approximately 1 million SNPs contained in the initial version. The more SNPs that are on the map, the more precisely researchers can focus their hunts for genetic variants involved in disease. The rapid growth of genome-wide association studies over the past year and half has been fuelled by the HapMap consortium’s decision to make its SNP datasets immediately available in public databases, even before the first and the second versions of the map were fully completed.
‘We are thrilled that the worldwide scientific community is taking advantage of this powerful new tool and we anticipate even more exciting findings in the future,’ says Professor Gil McVean of the University of Oxford’s Department of Statistics and Wellcome Trust Centre for Human Genetics, who co-led the analysis of Phase II HapMap and is one of two corresponding authors on the paper. ‘The improved SNP coverage offered by the Phase II HapMap, along with better statistical methods, promises to further increase the accuracy and reliability of genome-wide association studies.’
The Phase II HapMap was produced using the same DNA samples studied in the Phase I HapMap. That DNA came from blood collected from 270 volunteers from four geographically diverse populations: Yoruba in Ibadan, Nigeria; Japanese in Tokyo; Han Chinese in Beijing; and Utah residents with ancestry from northern and western Europe. No medical or personal identifying information was obtained from the donors, but the samples were labelled by population group.
To provide information on less common variations and to enable researchers to conduct genome-wide association studies in additional populations, there are plans to extend the HapMap even further. Among the populations donating additional DNA samples are Luhya in Webuye, Kenya; Maasai in Kinyawa, Kenya; Tuscans in Italy; Gujarati Indian in Houston; Chinese people in metropolitan Denver; people of Mexican ancestry in Los Angeles; and people of African ancestry in the southwestern United States.
In its overview paper in Nature, the consortium estimates that the Phase II HapMap captured 90 to 96 percent of common genetic variation in the populations surveyed. The consortium also confirmed that use of Phase II HapMap data has helped to improve the coverage of various commercial technologies currently being used to identify disease-related variants in genome-wide association studies. Researchers did note, however, that current technologies tend to provide better coverage in non-African populations than in African populations because of the greater degree of genetic variability in African populations.
The overview paper also reports that the Phase II HapMap has provided new insights into the structure of human genetic variation. One new finding was the surprising extent of recent common ancestry found in all the population groups. Taking advantage of the map’s increased resolution, the researchers identified stretches of identical DNA between pairs of donor chromosomes and then compared these stretches both within and across individuals. Their analysis showed that 10 to 30 per cent of the DNA segments analyzed in each population showed shared regions, indicating descent from a common ancestor within 10 to 100 generations.
Major research institution at University of Oxford gets new director
Professor Peter Donnelly FRS, one of the UK's leading statisticians and geneticists, today becomes the new Director of The Wellcome Trust Centre for Human Genetics (WTCHG) at the University of Oxford.
The WTCHG is one of the leading human genetics research centres in the world, perhaps best known for the identification of genes involved in asthma, language impairment, dyslexia, learning disabilities, infectious disease and diabetes. The WTCHG also participated in the Wellcome Trust Case Control Consortium (WTCCC), the largest ever study of the genetics of common disease, which recently attracted considerable interest when it announced the discovery of almost 20 new genes involved in human health, including obesity and diabetes. The Chairman of the Consortium, Professor Peter Donnelly, comes to the WTCHG as its new Director from the University of Oxford’s Department of Statistics, where he is Professor of Statistical Science.
Director of the Wellcome Trust, Dr Mark Walport, said: “Peter Donnelly is an outstanding statistical geneticist. His leadership of the Consortium has shown that he has the strength and vision to direct the WTCHG at an extremely exciting time for human genetic research”.
Professor Donnelly replaces Professor Anthony Monaco, who was the WTCHG’s Director from 1998. During his time as Director, Professor Monaco led the WTCHG from primarily human genetic research to expand into biological areas, in a multidisciplinary approach to human disease. The size of the WTCHG doubled and became an international leader in understanding the biological basis of common human disease. It seems only natural that Professor Donnelly be chosen as his successor.
Much of Professor Donnelly's work involves the development of mathematical models and statistical methods in studying genetics. He has been heavily involved in the ‘HapMap’ project, the successor to the human genome project, which studies patterns of variation in human populations. He has also been involved in developing statistical tools, which are widely used in population, conservation, human genetics and ecological studies.
Professor Donnelly said: “I am very enthusiastic about this position and having the opportunity to be involved in one of the leading human genetics research centres in the world, particularly at a time of much promise for human genetics and its impact on human health and disease.”
Professor Monaco is now Pro-Vice-Chancellor in charge of planning and resources at the University of Oxford. He continues his research programme at the WTCHG into the genetics of neurodevelopmental disorders such as autism, language impairment and dyslexia.
Oxford Mail, 3 October
August
Researchers at Oxford University find genetic link between body clocks and blood pressure
Scientists from the Wellcome Trust Centre for Human Genetics (WTCHG) at the University of Oxford have discovered a region of DNA involved in the body’s inbuilt 24 hour cycle (the circadian rhythm) is also involved in controlling blood pressure. The results indicate that altered circadian regulation of biological functions increases the risk of cardiovascular disease and diabetes. The results of the study are published on-line this week by the journal Proceedings of the National Academy of Sciences.
The research, funded mainly by the Wellcome Trust, used genetic studies in rat models and humans to demonstrate a link between changes in a gene involved with the body’s clock and risk of developing cardiovascular disease. Previous research from other institutions into the epidemiology of cardiovascular disease and diabetes has already shown they are somehow linked, but this is the first genetic evidence.
This study provides direct evidence that a genetic change in BMAL1 is linked to high blood pressure. This is the first evidence in humans for a direct causal link between changes in the body clock and increased risk of type 2 diabetes and high blood pressure. The research also highlights the importance of cross species studies to test new hypotheses. Study leader Professor Dominique Gauguier said: “The regulation of circadian rhythm is central to a wide range of biological processes and this type of genetic study should be extended to other disease areas”.
The results of the study may lead to changes in how the diseases involved are managed, as the body’s response to drugs used for treatment could also be linked to the body’s internal clock.
July
Researchers at Oxford University find gene for left-handedness
An international group of scientists, led by a team from the Wellcome Trust Centre for Human Genetics at the University of Oxford, have discovered a gene that increases the chance of being left handed. The study is published on-line today by the journal Molecular Psychiatry.
The research, which involved over 40 scientists from 20 research centres around the world, revealed a gene called LRRTM1; the first to be discovered which has an effect on handedness. Although little is known about LRRTM1, the Oxford team suspects that it modifies the development of asymmetry in the human brain. Asymmetry is an important feature of the human brain, with the left side usually controlling speech and language, and the right side controlling emotion. In left-handers this pattern is often reversed. There is also evidence that asymmetry of the brain was an important feature during human evolution; the brains of our closest relatives, the apes, are more symmetrical than humans’ and they do not show a strong handedness.
The researchers also discovered that LRRTM1 might slightly increase the risk of developing schizophrenia. People with schizophrenia often have unusual patterns of brain asymmetry and handedness, so the researchers were not surprised when LRRTM1 also showed a possible effect on the risk of developing schizophrenia. Schizophrenia is a disorder of the brain which results in impaired perception and thought. It affects roughly one percent of adults worldwide.
The study leader, Dr Clyde Francks, said: “People really should not be concerned by this result. There are many factors which make individuals more likely to develop schizophrenia and the vast majority of left-handers will never develop a problem. We don’t yet know the precise role of this gene.”
Some of the researchers involved in this discovery are now planning further study on the roles of LRRTM1 in the developing brain, and to find other genes with which LRRTM1 interacts. Dr Francks said: “We hope this study’s findings will help us to understand the development of asymmetry in the brain. Asymmetry is a fundamental feature of the human brain that is disrupted in many psychiatric conditions.”
London Metro 31 July
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May
New diagnostic tool could soon be searching for human diseases
Scientists have discovered a way to quickly test blood samples for a wide range of diseases, as part of a study funded by the Wellcome Trust, the UK’s largest medical research charity. The findings will ultimately allow early identification of disease risk, and reduce the time, cost and discomfort of current tests.
The study was led by the Wellcome Trust Centre for Human Genetics (WTCHG), at the University of Oxford, and also included scientists from Imperial College London and Novo Nordisk. The findings are published today in the prestigious journal Nature Genetics.
The team of researchers was led by Professor Dominique Gauguier, an expert in mammalian genetics at the WTCHG. Blood samples from 200 rats were analysed to find a link between chemical markers found in the blood plasma and potential diseases.
Nuclear Magnetic Resonance (NMR), a process which uses powerful magnets to identify individual molecules, was used to compare blood samples from rats with and without particular diseases. Over 38,000 individual molecules (known as metabolites) were quantified using NMR, including glucose, cholesterol and lipids, as well as metabolites processed by gut bacteria. The scientists then searched for regions of the rat genome to find areas corresponding to each metabolite. Using the results it is possible to match a disease to a particular group of metabolites, collectively known as a biomarker.
Professor Gauguier said: ‘This process is an important link between DNA and disease, and shows the value of the rat as a model for how diseases come about in humans’.
The technology, which requires just a pinprick of blood, is already being applied to human blood samples, from patients suffering from coronary artery disease. Professor Gauguier hopes that biomarkers for human diseases will be identified within a few years.
April
Major genetic study identifies clearest link yet to obesity risk
Scientists have identified the most clear genetic link yet to obesity in the general population as part of a major study of diseases funded by the Wellcome Trust, the UK's largest medical research charity. People with two copies of a particular gene variant have a 70% higher risk of being obese than those with no copies.
Obesity is a major cause of disease, associated with an increased risk of type 2 diabetes, heart disease and cancer. It is typically measured using body mass index (BMI). As a result of reduced physical activity and increased food consumption, the prevalence of obesity is increasing worldwide. According to the 2001 Health Survey for England, over a fifth of males and a similar proportion of females aged 16 and over in England were classified as obese. Half of men and a third of women were classified as overweight.
Scientists from the Peninsula Medical School, Exeter, and the University of Oxford, including the Wellcome Trust Centre for Human Genetics, first identified a genetic link to obesity through a genome-wide study of 2,000 people with type 2 diabetes and 3,000 controls. This study was part of the Wellcome Trust Case Control Consortium, one of the biggest projects ever undertaken to identify the genetic variations that may predispose people to or protect them from major diseases. Through this genome-wide study, the researchers identified a strong association between an increase in BMI and a variation, or "allele", of the gene FTO. Their findings are published online today in the journal Science.
The researchers then tested a further 37,000 samples for this gene from Bristol, Dundee and Exeter as well as a number of other regions in the UK and Finland.
The study found that people carrying one copy of the FTO allele have a 30% increased risk of being obese compared to a person with no copies. However, a person carrying two copies of the allele has a 70% increased risk of being obese, being on average 3kg heavier than a similar person with no copies. Amongst white Europeans, approximately one in six people carry both copies of the allele.
"As a nation, we are eating more but doing less exercise, and so the average weight is increasing, but within the population some people seem to put on more weight than others," explains Professor Andrew Hattersley from the Peninsula Medical School. "Our findings suggest a possible answer to someone who might ask 'I eat the same and do as much exercise as my friend next door, so why am I fatter?' There is clearly a component to obesity that is genetic."
The researchers currently do not know why people with copies of the FTO allele have an increased BMI and rates of obesity.
"Even though we have yet to fully understand the role played by the FTO gene in obesity, our findings are a source of great excitement," says Professor Mark McCarthy from the Wellcome Trust Centre for Human Genetics at the University of Oxford. "By identifying this genetic link, it should be possible to improve our understanding of why some people are more obese, with all the associated implications such as increased risk of diabetes and heart disease. New scientific insights will hopefully pave the way for us to explore novel ways of treating this condition."
The findings were welcomed by Dr Mark Walport, Director of the Wellcome Trust.
"This is an exciting piece of work that illustrates why it was so important to sequence the human genome," says Dr Walport. "Obesity is one of the most challenging problems for public health in the UK. The discovery of a gene that influences the development of obesity in the general population provides a new tool for understanding how some people appear to gain weight more easily than others. This discovery, along with further results expected from the Wellcome Trust Case Control Consortium later this year, will open up a wealth of new avenues to understand and treat common diseases."
The FTO gene was first discovered whilst studying the DNA of a cohort of patients with type 2 diabetes. The risk of developing type 2 diabetes increases significantly for obese people. Through its effect on BMI, having one copy of the FTO allele increases the risk of developing type 2 diabetes by 25%, having two by 50%.
"We welcome this result, which holds promise for tackling rising levels of obesity and the associated risk of developing type 2 diabetes," says Professor Simon Howell, Chair of Diabetes UK, which funded the original collection of samples from people with diabetes. "The discovery has been possible not only because of exemplary team work of scientists from a large number of institutions but also because of the cooperation of the 5,000 diabetes patients and 37,000 people without diabetes who gave blood samples for the study."
Professor Mark McCarthy has been interviewed for Sky News and Al Arabiya News.
February
Centre researchers are first to solve protein structure at Diamond
Just days after the Diamond Light Source opened its doors, scientists from The University of Oxford have successfully used it to solve a protein structure. Professor David Stuart, who heads the Medical Research Council (MRC) Structural Biology Division at the university’s Wellcome Trust Centre for Human Genetics, used Diamond to solve the 3-dimensional structure of a protein involved in cancer.
The work being undertaken by Professor Stuart’s research group is part of a large project, funded by the European Commission, which aims to solve the structures of protein clusters involved in human cellular signalling. The research group used Diamond to solve the structure of a cluster of proteins with crucial roles in organism development. The same proteins are also involved with the formation of cancerous tumours, learning and memory processes, and viral infection processes.
Major projects at the Structural Biology Division are funded by the MRC, Cancer Research UK and the European Commission, and investigate mechanisms to make drugs more effective at combating cancer and viral infections. An important part of such investigations is finding out the shape and structure of biological molecules, as these characteristics help determine their function.
Another member of the research team, Professor E. Yvonne Jones, said: “The resolution the Diamond facility gives has provided us with significant new information of vital importance to drug design. Diamond will keep the UK at the forefront of research into structural biology well into the next decade”.
Centre plays central role in international autism study
The first results of an international study into the DNA of families with autistic children have just been released, revealing two previously unknown genetic links to the disorder.
The Autism Genome Project (AGP), an international group of 120 researchers from 50 institutions across 19 countries, released the first results of the genetic study of autism in the Feb 18th online edition of Nature Genetics.
Funded by international, private and public partners, AGP has achieved its initial goals of assembling the world’s largest gene bank, with DNA from 1200 families where more than one child is affected with autism, and carrying out the world’s most comprehensive genome scan into the genetics of autism. This was jointly led by two academics from the University of Oxford, Professor Anthony Monaco, from the Wellcome Trust Centre for Human Genetics, and Professor Anthony Bailey, from the Department of Psychiatry.
The second phase of AGP is now underway, with $14.5m of funding over three years. This phase will involve searching the gene bank for variations in genes associated with autism. Professor Anthony Monaco is acting as principal investigator for this task, with his laboratory at the Wellcome Trust Centre for Human Genetics taking a leading role, together with other sites in Ireland, Canada and the US. The research in the UK has been funded by over £900k from the Medical Research Council (MRC) and £50k from Autism Speaks UK. Professor Monaco said: “I am really pleased that we have secured significant funds for phase two of the project. This will allow us to screen the genomes of thousands of families to identify any genes that increase an individual’s susceptibility to autism.”
Oxford University News Monday 19th February
Independent Monday 19th February
January
Centre researcher talks about why teenagers can't help sleeping in ...
Professor Russell Foster, an expert in body clocks, has written an article about teenagers' body clocks running slightly behind those of older people.
BBC Radio 4 'Today' - Friday 12th January 0741 am
London Metro Friday 12th January
Daily Mail Friday 12th January
Also Friday 12th January - BBC Radio Five Live and BBC Radio Wales
Telegraph Saturday 13th January
Ireland's RTE2 FM - Monday 15th January
The Centre reveals new gene involved in epilepsy and learning disability
Researchers from the Wellcome Trust Centre for Human Genetics at Oxford University have discovered a gene in mice which is involved in epilepsy and learning disabilities in humans.
The team of scientists, led by Professor Jonathan Flint, noticed that one of the mice they were studying was hyperactive and performed poorly on memory based tasks. They nicknamed this mouse ‘Jenna’ and examined its DNA. The scientists found that its unusual behaviour was due to change in a gene called alpha tubulin, which makes one of the protein building blocks of cells. This gene is present in almost all species, including sweetcorn, lobsters and roses. Intrigued by Jenna’s behaviour, the team decided to compare the alpha tubulin gene sequence to that in humans suffering from lissencephaly. Patients with this disease have a smooth brain, instead of being covered by the usual folds, and suffer from epilepsy and learning disabilities. The team found changes in alpha tubulin in patients with this disease. It is hoped that the discovery will provide further insight into how the brain functions and diseases such as epilepsy.
Professor Flint said: ‘Our work shows the value of the mouse as a model for finding genetic alterations in humans, which can lead to serious diseases. This is good example of how basic research can help in the clinic’.
The results of this research have been published in the prestigious journal, Cell.
Keays, D. A. et al (2007). Mutations in a-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell, Vol 128, 45-57.
The Oxford Times - Friday 19th January
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Page last updated on Mon Feb 9 12:12:41 2009 |