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Mouse library set to be knockout

Investigators are on the home stretch of the largest international biological research initiative since the Human Genome Project. Launched in 2006 in North America and Europe, the effort aims to disable each of the 20,000-odd genes in the mouse genome and make the resulting cell lines available to the scientific community. Read full article on Nature website.

MRC Mouse Network Roadshows - Dates and venues announced

A series of talks are being held to promote the opportunities available through the in the MRC Mouse Network. These are being held at major academic centers across the UK, and will include information about the IMPC, the benefits of participating in the network and how to apply to form a consortium.  Roadshows information

The Bioinformatics of Mutant Mouse Resources - A two-day hands-on introduction

Mouse Genetics 2011 conference Washington, DC (26th and 27th June 2011)

In association with the Mouse Genetics 2011 conference, the Wellcome Trust Sanger Institute and MRC Harwell, we are pleased to announce a two day workshop "The Bioinformatics of Mutant Mouse Resources".

Each participant will be required to provide their own wireless enabled laptop for the duration of the course.

At the end of this training, participants will be able to find their favourite genes, understand their gene structures in detail, as well as the underlying experimental data supporting the annotation. They will gain basic understanding and usability of comparative genomics and be able to observe the synteny surrounding their regions of study. They will also be introduced to non-specialist data mining skills.

Participants will be able to find mutant mouse resources for their genes of interest using the IKMC (International Knockout Mouse Consortium) and similar resources. They will gain basic understanding of the different alleles available from various pipelines, identifying their strengths and weaknesses for different applications. They will be able to judge the quality of the KO strategies offered, draw their own vector maps and find key elements for the targeting strategy and genotyping.

Participants will be able to search IMPC (International Mouse Phenotype Consortium) phenotypic databases of IKMC mouse mutants such as EuroPhenome, gain an understanding of the high-throughput phenotype data generated and the statistical approaches required to analyse it. They will also be able to compare and interpret this data with other phenotype data sources and identify mouse models of relevance to their clinical domain of interest.

This course is limited to 40 participants and will be held in English. The course manual will be made available as a PDF and will be sent out to participants one week prior to the course, and will also be available online during the workshop.

Please visit the registration page

for further details. Ensure you select the 'Satellite workshop on Bioinformatics of mutant mouse resources' in the Optional Events section of the registration form.

There will be a course fee of $150 for all participants. Participants will be expected to arrange and fund their own travel and accommodation.

 

MRC cash boost to maximise discovery of mouse models of human diseases

The Medical Research Council (MRC) has announced today that it is to invest in excess of £60m over the next five years into mouse genetics research at MRC Harwell, Oxfordshire.

MRC Harwell is an international centre for mouse genetics: scientists work to create mouse models to study a wide range of human diseases from diabetes to Parkinson's disease.

It is hoped that this substantial investment into MRC Harwell’s research facilities; the Mammalian Genetics Unit (MGU) and Mary Lyon Centre (MLC), will deliver major advances and support collaborative research services in the UK and internationally.

The MGU will continue ongoing studies using mouse models for understanding basic mammalian biology and learning more about human disease pathology, informing advances in treatment and prevention. The unit will also be developing a new research program identifying mouse models with late on-set diseases associated with ageing. This is in line with the MRC’s strategy for investing in research to support lifelong health and wellbeing.

The MLC will use this investment to provide technical support services and develop new programs in transgenic mouse production, phenotyping, strain archiving and distribution - all essential to ensure that UK scientists are able to maintain their leading position in the field of mouse genetics and functional genomics.

A global approach to mouse genetics

On top of these developments, money is also being used to support MRC involvement in the new International Mouse Phenotyping Consortium (IMPC): a world-wide collaboration of large mouse centres with the capacity and expertise to create mutations of every gene in the mouse genome, for which the UK is taking the scientific and industry liaison lead. Analysis of these mice will be undertaken with the aim to produce an encyclopaedia of mammalian gene function. All mice and data will be made freely available to academic and commercial researchers, enabling immediate access for validation and further phenotypic analysis.

Dr Tom Weaver, Director of the MRC’s Mary Lyon Centre said: "The MRC’s strategy underlines our ambition to accelerate progress in international health research and exploit genetics research. Being a part of the IMPC will allow us to make a vital contribution towards fulfilling that ambition."

The creation of the IMPC follows a decade of huge international investment in mouse genetics. The US National Institute of Health (NIH) estimates that it spends around one billion US Dollars a year supporting the production of mouse models while the European Commission has contributed hundreds of millions of Euros. Such funding has already allowed scientists to complete the sequence of the mouse genome, develop transgenic research using embryonic stem cells and create tens of thousands of animal models.

Professor Steve Brown, Director of the MGU and Scientific Chair of the IMPC explained: "The field is ready to move forward – it is timely to begin the project now. The UK, particularly through our European pilot EUMODIC, has taken the lead in the development of large-scale phenotyping approaches in the mouse. Our research programmes have demonstrated the feasibility of IMPC, and our recognised leadership in the technology and science of mammalian genetics makes us very well equipped to participate in this consortium."

MRC CEO Professor Sir John Savill commented: "The MRC is absolutely committed to basic research and we understand the value of mouse genetics - that is why we continue to support the science and infrastructure at MRC Harwell. We firmly believe that the IMPC represents a unique opportunity to capitalize on our significant investment in Harwell and it will provide extraordinary insight into biological function over the long-term. This is a great opportunity for the MRC to get involved in an important worldwide effort that is both exciting and offers enormous potential to further our understanding of human disease and develop new approaches to treatment."

Drug development

It is hoped that the creation of the IMPC will result in the coordinated global development of thousands of pre-clinical models of human diseases, which can then be used by pharmaceutical and biotechnology companies to speed-up the development pipeline of new drugs.

Dr Tom Weaver, Director of the MLC, explained: "We are keen to establish closer links with industry, since the application of mouse genetics will be vital for bridging progress made in basic research to the arena of medical genetics and genomic medicine. The focus is on translating basic discoveries into improved drug development and clinical outcome."

He added: "Through our participation in IMPC there will be enormous value and opportunities delivered to the clinical and biopharma research communities in the UK via the networks that will grow up around Harwell. For example, the models we produce will be used for validating discoveries made in genome-wide association studies and identify novel drug targets and drugable pathways. Our models will also serve as tools to understand the mechanisms of action of drugs in vivo, as well as rapid testing of efficacy prior to expensive clinical trials. Our vision is to put the mice and data into the hands of the scientists making new drugs as soon as possible."

Scientists link sex development disorders to faulty gene

Mutations in a gene called MAP3K1 play a key role in sex development disorders, according to new research by the Medical Research Council (MRC). This new discovery adds to the genes already known to influence a range of sexual development disorders. Researchers hope that they will be able to intervene earlier with treatments that will enable healthy puberty and fertility in later life by screening for this range of genes.

PUBMED link http://www.ncbi.nlm.nih.gov/pubmed/21129722
Journal link http://www.cell.com/AJHG/abstract/S0002-9297(10)00590-2

Whether an embryo develops into a male or female depends upon a complex set of interacting genes. These genes trigger an embryo’s reproductive organ, the gonad, to turn into a testis or an ovary. The scientists at MRC Harwell, collaborating with New York University, found that a mutation in MAP3K1 can cause someone with a Y chromosome, predicted to develop as a male, to instead develop as a female or as a male with characteristics on the spectrum between the two sexes.

Scientists studied two families from France and New Zealand affected by a heritable form of sex development disorder, including several women who had the chromosome set that predicted they would be male (XY) and men who had problems with sex development. Detailed analysis of the families’ DNA located the position of the defective gene to a particular chromosome region. The scientists at MRC Harwell then used mice, which share 90 per cent of genes with humans, to investigate further and highlight one likely genetic culprit – MAP3K1. Scientists found affected individuals had a mutation of this gene.

Dr Andy Greenfield from MRC Harwell, who led the UK arm of the study, explains: “Disorders of sexual development affect approximately one person in every thousand worldwide and can lead to lifelong emotional and health problems. We’re extremely grateful to the families who have helped us to progress our understanding of these disorders. By unravelling the building blocks of how our sex is determined in the womb it can help us to combat disease such as infertility and gonadal tumours, which other research has shown are more common in patients with the faulty MAP3K1 gene.”

Dr Harry Ostrer from the New York University School of Medicine and the senior study author, said: “This discovery reassures patients and their families that there is a cause. It also means we’re a step closer to developing future treatments to prevent the cancers common to this group of patients.”

The paper, Mutations in MAP3K1 Cause 46,XY Disorders of Sex Development and Implicate a Common Signal Transduction Pathway in Human Testis Determination is published today in the American Journal of Human Genetics. The research was carried out by an international team of clinicians and geneticists at the MRC Mammalian Genetics Unit at Harwell, New York University School of Medicine, Murdoch Children’s Research Institute (Australia) and the Centre Hospitalier Universitaire de Nante in France.

For more information or to arrange an interview with Dr Andy Greenfield, please contact the MRC Press Office on 0207 395 2345 or email press.office@headoffice.mrc.ac.uk

Notes to Editors: 1. For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk

Genetic variants at the FTO gene are associated with obesity in humans

Overexpression of Fto leads to increased food intake and results in obesity Chris Church, Lee Moir, Fiona McMurray, Christophe Girard, Gareth T Banks, Lydia Teboul, Sara Wells, Jens C Bruning, Patrick M Nolan, Frances M Ashcroft & Roger D Cox Published online Nature Genetics: 14 November 2010 | doi:10.1038/ng.713

Press Coverage

Now, Roger Cox and colleagues analyze mice globally overexpressing Fto and show that increased Fto expression leads to obesity in mice. http://www.nature.com/ng/index.html

In lay terms, what is the main finding of your study?

Previous studies published by others in 2007 showed in humans that a chromosome region containing a gene called the Fat Mass and Obesity gene, FTO for short, was associated with increased body mass index. On average, measured across large populations of people,two copies of this version of the region made people 3kg heavier. The obvious question was which gene in this region, that contains a number of genes, causes this increase and how does it do that? Our study set out to answer this question and we found that the FTO gene does account for this difference in BMI and that this is because of increased food intake.

How significant are the findings?

The FTO gene was a candidate in the original studies because the DNA markers that showed the association with fat mass were within the FTO gene itself. However, these markers were within sequence that is not coding and that may be regulatory. These sorts of regulatory regions can have effects over long distances and therefore on other genes. Further, there is another gene right next door to the FTO gene that one might argue could be equally likely to be regulated by such a DNA element. The significance of our findings is that we know for sure that the FTO gene has a role in determining BMI. It is also significant that increasing the expression of FTO increases food intake and is consistent with a number of human studies that measured food intake against people's DNA marker genotype in this region. Because FTO is not an obvious candidate in the control of food intake our study and those that precede it open a new area of research.

In lay terms how did you conduct the experiment(s)?

We took the expressed FTO DNA sequence and introduced it into the mouse so that it was expressed in all cells in addition to the normal FTO gene that was already there. The result was increased expression of FTO with either one or two extra copies of the gene; thus we had mice that expressed two of their own copies that could be compared with mice that had one extra copy or two extra copies and consequently increasing expression of FTO. We measured the body weight of the mice, their body composition (fat and lean mass), the amount of food they ate, their metabolic rate and looked at glucose and lipids in their blood. We did this using normal mouse diet and a high fat version of the diet.

What are the clinical implications of your finding(s)?

Obesity is a major public health issue. The latest Health Survey for England shows that 1 in 4 adults and 1 in 10 children are obese, defined as a BMI (body weight in kg divided by the square of their height in meters) of 30 or higher. It is estimated that the cost of obesity to the NHS is around 1 billion pounds a year. Obesity is a key risk factor for Type 2 diabetes. This is the most common form of diabetes and is caused by problems with insulin resistance and insulin secretion. It is most common in people over the age of 40 although it is being increasingly observed in younger people because of obesity. The FTO gene increases the risk of Type 2 diabetes through its effect on BMI and specifically fat mass. Because the FTO gene has an enzyme activity we hope that it might be a good target for developing an anti-obesity therapy. However, there are a number of experiments that must be done to understand its physiological function, to prove whether the enzyme activity is required and to develop this gene further as a potential target before the long process of drug discovery can begin.

Does this study have implications for the treatment of diseases, disorders, and/or injuries?

Primarily in the treatment of obesity, food intake disorders and consequential conditions such as diabetes and diabetic complications.

Outside of the main finding(s), does this study suggest exciting ideas, concepts, etc.?

Food intake can at least partially be controlled or influenced by common variants in our genes.

New Declaration on Data Sharing in Mouse Functional Genomics

The CASIMIR consortium, which is jointly led by MRC Harwell, recently held a meeting in Rome attended by scientists, lawyers, journal editors and representative of funding organisations to discuss data release in mouse functional genomics. The group came to a clear statement of an agenda, the "Rome Agenda", which challenges the mouse functional genomics community to minimise impediments to the availability of both mouse lines and other resources and related data Nature Journal .

MGU Director wins Genetics Society Medal

Professor Steve Brown, Director of the Mammalian Genetics Unit at MRC Harwell, has been awarded the 2009 Genetics Society Medal for his outstanding research contribution in genetics. Steve, who is internationally recognised for his seminal contributions to mouse and mammalian genetics, played a leading role in the development of high-resolution genetic and physical maps of the mouse genome. Most notably, he was involved in initiating the large-scale mouse ENU mutagenesis programme at Harwell for the generation of new disease models.

His own research interests have focused on mouse deafness models, where he has made a number of pivotal contributions to our understanding of the genetic bases of hearing loss. Steve said of his award: "There has been enormous progress in mouse genetics over the last decade and Harwell has been at the forefront of these developments. It is a tremendous pleasure to receive this recognition."

New guidance on sharing and archiving genetically altered mice

MRC Harwell was part of a taskforce made up of the RSPCA, MRC, Cancer Research UK, BBSRC and NC3Rs in launching new guidance for sharing mouse resources in support of the 3Rs. This report, in the form of a short booklet can be downloaded directly from the NC3Rs at http://www.nc3rs.org.uk/resourcesharing

Clinical Fellow at Harwell highlights issues of unethical trade in healthcare purchasing

Mahmood Bhutta, a clinical research fellow at Harwell, has been in the national media reporting unethical labour conditions in the manufacture of surgical instruments used in the NHS. He reports that workers in Pakistan are exposed to poor health and safety, long hours and inadequate remuneration. There is also a significant use of child labour. He has been working with the NHS to develop ethical purchasing guidelines for all healthcare products, released for consultation on 8th December.

The Guardian report can be accessed at www.guardian.co.uk/society/2008/dec/08/nhs-instruments-child-labour

The NHS consultation document can be seen at http://wwww.pasa.nhs.uk/PASAWeb/NHSprocurement/Sustainabledevelopment/Ethicalprocurement/LandingPage.htm

Mahmood was a founding member of the British Medical Association Medical Fair and Ethical Trade Group, which was instigated in 2007. The group aims to investigate, promote and facilitate fair and ethical trade in the production and supply of commodities to the healthcare industry and is supported by UK Government.

www.bma.org.uk/ap.nsf/Content/fairandethicaltradegroup

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