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Two major papers from the International Mouse Phenotyping Consortium have been published today in Nature Genetics and Nature Communications. The research marks a vital step forward in the IMPC’s goal of creating a comprehensive catalogue of mammalian gene function.

Mouse genes could help decipher human disease

The first study in Nature Genetics reveals hundreds of new insights into gene function and human disease. The paper describes the analysis of 3,328 genes by the IMPC, representing approximately 15% of the mouse genome. 360 new disease models were identified. Moreover, the team identified new candidate genes for diseases with unknown molecular mechanisms. More than half of the genes analysed have never been investigated in a mouse before, and, for 1,092 genes no molecular function or biological process were previously known.

        

Uncovering the role of sex in biological studies

The second study in Nature Communications studied the differences between males and females – sexual dimorphism. Historically, a woman has been thought of as a small man in medicine and biomedical research. Even today, in medical practice the evidence-base for women is poor compared to men, reflecting a bias towards the study of males in biomedical research. In the largest study of its kind, IMPC scientists analysed up to 234 physical characteristics of more than 50,000 mice, including over 40,000 mutant mice. Surprisingly, IMPC found that around one-sixth of the parameters measured in mouse mutants varied significantly between males and females. The results have profound implications for the design of future animal studies which crucially underpin medical research into treatments for human diseases, as well as underlining the need to take into account sex in the development of therapies.

             

Pushing back the boundaries of knowledge

Later this year, the IMPC will meet its target of having analysed a third of the mouse genome, further pushing back the boundaries of our knowledge of gene function and disease. Together these two papers illustrate the profound insights into our understanding of the landscape of the mammalian genome that are emerging from the international research effort of the IMPC.
 

Study of unprecedented size reveals how sex ‘blindspot’ could misdirect medical research

                 

Scientists at MRC Harwell, as part of the International Mouse Phenotyping Consortium suggest that sex should be a mandatory consideration in the design of animal research studies.

It is well known that the prevalence, course and severity for many diseases including cardiovascular diseases, autoimmune diseases and asthma is heavily influenced by whether we are male or female, yet up until now the role of sex in animal research has not been fully explored. In fact, for consistency most animal research is only done on males and in two thirds of the research that does use two sexes, the results are not analysed by sex.

Many papers and funding bodies have raised the need to consider sex as an important variable, with the National Institute of Health going as far to make it a mandatory requirement in a recent policy change. This was however met with some resistance with many arguing that scientists should be trusted to know when sex plays a role, and with concerns being raised over the cost associated with duplicating experiments in both sexes.

To address this problem, researchers at the IMPC have performed one of the largest studies to date on the effect of sex on biomedical research, analysing up to 234 physical characteristics of more than 50,000 mice.

Burrowing into the data, the team found that in the standard group of mice – the control mice – their sex had an impact on 56.6 per cent of quantitative traits, such as body weight, and on 9.9 per cent of qualitative traits, such as the shape of the whiskers. In mice that had a gene switched off – the mutant mice – their sex modified the effect of the mutation in 13.3 per cent of qualitative traits and up to 17.7 per cent of quantitative traits. Importantly, in many of these cases the sex of the animal was not expected to have an effect, refuting the idea that researchers could simply address sex when it was predicted to be an issue in advance of the study.

This research supports the idea that regardless of research field or biological system, sex should be an important consideration in the design and analysis of animal studies. Dr Natasha Karp, lead author who carried out the research at the Wellcome Trust Sanger Institute, and now works in the IMED Biotech Unit at AstraZeneca, said: “This was a scientific blindspot that we really thought needed exploration. A person’s sex has a significant impact on the course and severity of many common diseases, and the consequential side effects of treatments – which are being missed.”

This study presents implications for the design of future animal studies and clinical trials. It has been more than twenty years since it became a requirement that women were included within clinical trials in the US [1]. Whilst more women are taking part in clinical trials, increasing from 9 per cent in 1970 to 41 per cent 2006 [2], women are still under-represented.

The bias is even stronger in the earlier stages of biomedical research. A review of international animal research between 2011 and 2012 found that 22 per cent of studies did not state the sex of the animals, and of those that did, 80 per cent of studies used solely males and only 3 per cent included both males and females [3].

The consequence of under-representing of females in biomedical research is evident. In the past 10 years, 8 out of 10 drugs were withdrawn from the market due to unexpected adverse effects in women, some of them life threatening [4].

MRC Harwell's Director and an author on the paper Professor Steve Brown, commented: “It is likely that important scientific information is missed by not investigating more thoroughly how males and females differ in biomedical research. Rather than extrapolate the results to account for the opposite sex, these results suggest designing experiments to include both sexes in the study of disease. This study is a major step to highlighting the impact of sex differences in research and will help in accounting for those differences in the future of biomedicine.”

To find out more, click here

Publication:
Natasha Karp et al. (2017) Prevalence of sexual dimorphism in mammalian phenotypic traits. Nature Communications. DOI: Ncomms15475 

Further Links:
1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624369/pdf/12905_2015_Article_251.pdf

2 https://www.ncbi.nlm.nih.gov/pubmed/20160159

3 https://www.ncbi.nlm.nih.gov/pubmed/25175501

4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535645/

MRC Harwell 2017 Festival events

For the 2017 Festival of medical research we will be having two events at MRC Harwell: a Year 12 Open Day and a Patient Open Day. See below for more information about these two events. 

Year 12 Open Day – Wednesday 21st June 

This event is aimed at students who are interested in a career in biomedical research. On their visit, they will have the opportunity to find out about genetics research, how mice are used to study disease, and the different types of careers in biomedical science. The visit will include a lab tour, a practical scientific skills session, a careers fair, and a visit to our world class animal facility – the Mary Lyon Centre. 

Patient Open Day – Friday 23rd June 

For this event would like to invite patients, their families, and representatives who are interested to find out more about primary scientific research, the relationship between genes and disease, and how mice are used in medical research. The visit will include an interactive tour of our working scientific laboratories, a first-hand opportunity to talk to scientists, and a visit to our world class animal facility – the Mary Lyon Centre.  

Please note this open day is not disease or condition specific, we will therefore not be able to offer clinical advice. 

To apply

Please note, for both events there is a morning and an afternoon session. Places are limited. If you are interested or would like more information please email us at openday@har.mrc.ac.uk

                                                                                               

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MRC Harwell 2017 Festival events

For the 2017 Festival of medical research we will be having two events at MRC Harwell: a Year 12 Open Day and a Patient Open Day. See below for more information about these two events. 

Year 12 Open Day – Wednesday 21st June 

This event is aimed at students who are interested in a career in biomedical research. On their visit, they will have the opportunity to find out about genetics research, how mice are used to study disease, and the different types of careers in biomedical science. The visit will include a lab tour, a practical scientific skills session, a careers fair, and a visit to our world class animal facility – the Mary Lyon Centre. 

Patient Open Day – Friday 23rd June 

For this event would like to invite patients, their families, and representatives who are interested to find out more about primary scientific research, the relationship between genes and disease, and how mice are used in medical research. The visit will include an interactive tour of our working scientific laboratories, a first-hand opportunity to talk to scientists, and a visit to our world class animal facility – the Mary Lyon Centre.  

Please note this open day is not disease or condition specific, we will therefore not be able to offer clinical advice. 

To apply

Please note, for both events there is a morning and an afternoon session. Places are limited. If you are interested or would like more information please email us at openday@har.mrc.ac.uk

                                                                                               

Attachment(s): 

Gene found to play prominent role in central nervous system foundation and function

Researchers at the MRC Harwell Institute have gained new insights into the function of the gene Katnal1. Katnal1 is one of a small family of genes that have been linked with intellectual disability, autism and schizophrenia in humans. In mice, loss of function of the gene leads to poor learning and memory while the growth, migration and shape of neurons in the brain are all disturbed. This research highlights Katnal1 as a prime candidate for further study of the mechanisms underlying diseases of cognitive dysfunction.

We have approximately one billion nerve cells in our brain. These neurons form a complex architecture of networks, which communicate with each other and with other areas of the body through chemical signals. Very early in development, neurons migrate from their birthplace to their final destination in the brain. During this period they develop and form numerous elaborate branches enabling crucial connections to be made with many other neurons. Defects in these processes have been associated with many cognitive disorders.

Image at top shows neurons in normal mice (left) and mutant mice (right). In the mutant mice it can be seen that the neuron branches are shorter and thinner. The gene Katnal1 codes for a protein which determines the shape of microtubule structures within cells. In neurons, microtubules are important for directing neuronal migration and branching. Katnal1 and its family of genes enable the reshaping of microtubule structures at the appropriate time in developing neurons and the termination of branch growth so new ones can be formed.

This gene previously has not been well characterised, although in a small patient study loss of the gene was related to intellectual disability while one rare gene alteration has been linked to schizophrenia.

In this study, mice with a coding sequence error in Katnal1 were identified as part of a large scale genetic study. The error, or mutation, resulted in a non-functional gene – it was essentially ‘switched off’. When the behaviour of the (mutant) mice was compared to normal mice (with the correct gene) a range of behavioural abnormalities were seen including poor learning and memory.

Changes in the brain, detectable only at a microscopic level, seemed to underlie these behavioural disturbances. Analysis of different brain sections showed that the patterns of neurons in the hippocampus (a region of the brain associated with memory) and cortex (the outermost layer of the brain) were different in mutants. The cortex has well defined cell layers so anomalies are easy to spot. More neurons were seen in the outer layers of the cortex in mutants, suggesting that the neurons may have migrated too far.

Furthermore the neurons from mutants had a different shape and fewer synaptic spines – these are the structures on neurons that enable communication with other neurons.

Defects were also seen in the cilia of the mutant mice. Cilia are hair-like protrusions that stick out from all cells and are vital in early development. In the brain cilia are thought to maintain the circulation of chemicals and nutrients in the cerebrospinal fluid – a colourless fluid which maintains a healthy environment for the brain and its neurons. Defective cilia have been linked to many brain disorders including intellectual disability.

Dr Pat Nolan, one of the authors on the paper, commented:

“Our findings highlight the importance of this small group of genes in establishing the neuronal connections that are critical for precise brain functions”.  

Further study of this gene and its role in neuron growth and development may provide insight into the cognitive dysfunction underlying intellectual disability and conditions such as autism. This will increase the likelihood of being able to identify therapeutic targets and potential treatments in the future.

To read the research in Molecular Psychiatry click here

Images show neurons in normal mice (left) and mutant mice (right). In the mutant mice it can be seen that the neuron branches are shorter and thinner. 

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CRISPR/Cas9 Quality Control

Joffrey Mianné and colleagues at the MRC Harwell Institute have published new research in Elsevier Methods outlining their proposed protocols for effectively screening the results of CRISPR/Cas9 gene editing technology. 

CRISPR/Cas9 is a new gene editing technology that has revolutionised research in the field. The technology allows for faster, cheaper, and more precise gene editing than was previously possible. It is increasingly used in the field of mouse genetics to help study the relationship between genes and human disease. It is now the chosen method for the International Mouse Phenotyping Consortium (IMPC), a global project to identify the function of every gene in the mouse genome.

Despite the acceleration of the technology – the results obtained with CRISPR/Cas9 can often be unpredictable. Frequently the genetic change made is not present uniformly throughout the organism (known as mosaicism) and other unwanted changes can be found at the site where the gene has been altered. It is essential that mice taken forwards carry only the desired change so that any physiological changes seen are because of that and not something else on the genome. The ability to correctly select mice with the desired mutation requires robust and accurate methods.

The technology allows many types of genetic changes to be made, including deletions and even swapping the individual molecules making up the code of the DNA. Here the researchers have proposed a framework to analyse the results of CRISPR/Cas9 activity according to the type of genetic alteration intended. They have ascertained that due to the high level of unpredictability in the first generation it is better to definitively characterise the following generation and establish the mutant mouse line from there.

This research will contribute to the current debate on best practice for the use of CRISPR/Cas9 in biomedical research.

How CRISPR/Cas9 works

The CRISPR-Cas9 system is made up of two key molecules – the enzyme Cas9 and a piece of guide RNA. In brief, the guide RNA locates and binds to the target DNA where the change is going to be made. Its sequence is complementary to that of the target DNA. The Cas9 then acts as molecular scissors and makes a cut across both strands of DNA in the double helix. The cell then recognises that the DNA is damaged and attempts to repair it. Scientists have been able to harness the cell’s own DNA repair machinery to introduce changes into the genome. 

PhD opportunities in 2017

 There are four vacancies available at the MRC Harwell Institute for 4 year MRC funded PhD/DPhil Studentships starting in October 2017.

The MRC Harwell Institute is an International Centre for Mouse Genetics at the forefront of studies in mouse functional genomics and mouse models of human disease. We are engaged in lifetime studies – from developmental abnormalities through to diseases of ageing.

There are several research themes offering PhD projects at the MRC Harwell Institute for 2017:

  • Genetic basis of type 2 diabetes
  • Genetics of circadian rhythms and sleep in health and disease
  • The genetics and pathology of deafness
  • The role of cilia in development and disease
  • Disorders of sex development
  • Bioinformatics of mouse models of disease
  • Statistical genomics
  • Investigating Novel Stress Response Pathways in Neurological Disease
  • Novel and bespoke mouse models for dissecting neurodegenerative disease

Click here for more information and details about how to apply.

Closing date Tuesday 7th February

Royal Society hosts tribute to Mary Lyon

         

In tribute to the eminent geneticist Mary Lyon and her role in developing the theory of X chromosome inactivation, a process implicated in disease inheritance, 100 researchers from nine countries attended a scientific meeting hosted by the Royal Society. As part of the event researchers attended a one day meeting at the MRC Harwell Institute where Mary developed her theory. The event brought together worldwide experts in this dynamic field to discuss the latest research advances and reflect on the life and work of Mary Lyon, who first proposed the theory of X chromosome inactivation 55 years ago. ​

The meeting marked the opening of a brand new Mary Lyon exhibition at Harwell. The exhibition includes a timeline of Mary’s life surrounded by panels exploring her education, career at Harwell, and major discoveries. A map of the world pinpoints the many places she visited during her career, bringing to life her global network of researchers.

Mary’s career at Harwell spanned a period of more than 50 years and it was during this time that she made many remarkable discoveries. Mary developed the theory of X chromosome inactivation in 1961 while studying mice with different coloured patches of fur. She hypothesised that one of the two X chromosomes in the cells of female mammals is randomly inactivated during early development so that females don’t have twice the number of X chromosome gene products as males, a potentially toxic double dose. Her hypothesis, now accepted and supported by subsequent research, has had profound implications in understanding the genetic basis of X-linked diseases as well as being one of the first descriptions of epigenetic phenomena.

Mary went to Cambridge in the early 1940s, at a time when women were not official members of the university. Despite taking the same courses as men women were awarded a ‘titular’ degree. In 1998 Mary and other women from her era were officially awarded a full undergraduate degree. WW2 served to change the position of women in the world and had a strong influence on Mary’s career. Much of her research involved looking at the effects of radiation in mice as result of the events of WWII. Most of the important discoveries Mary made were offshoots of studying radiation induced mutations in mice.

 

Speaking at the event Dr Sohaila Rastan, one of Mary’s PhD students commented: “Now 55 years after the hypothesis was first described, Mary Lyon would have found it very gratifying to see how much research it has spawned. Although the X inactivation field has advanced so significantly some basic questions still remain unanswered.

Professor Steve Brown, Director of the MRC Harwell Institute, said: “Mary would have relished the cut and thrust of the scientific discussion at the meeting, and would have joined in the excitement of the many new developments that were reported. She laid the groundwork for all that has followed, and the meeting was a fitting tribute to her scientific legacy.”

11/10/2016

Genes essential for life discovered in mouse embryos ​

Scientists at the MRC Harwell Institute and a team spanning eight different centres across the world have collaborated in an effort to identify and decipher the function of genes that are essential for life. The animal study, published in Nature, is the first of its kind to use high-throughput phenotyping, and provides novel insights into a variety of gene functions, many of which are known to be involved in human diseases.


Gene expression patterns in E12.5 embryos captured after lacZ wholemount staining. Targeted genes are from left to right, top row: Ngfr, Eomes, Adam11, Col9a2; bottom row: Fgf8, Atp1a3, Trpm2, Casz1.

The goal of the International Mouse Phenotyping Consortium (IMPC) is to elucidate the function of every gene in the mouse genome (~20,000 genes). Centres across the world have collaborated to do this by breeding mouse lines where the gene of interest has been inactivated or “knocked out”, this gives us insights into gene function by seeing what happens when the gene is rendered inactive. To date, almost 5,000 new knockout mouse lines have been created by the IMPC. Mice share 85% of their genes with humans. Studying the genes of mice therefore is crucial for helping us to understand human gene function. 

Approximately one third of all mammalian genes are essential for life, mice which have had these genes knocked out are not able to survive beyond an embryo stage or for very long after birth. Many of these genes have not been well characterised. Abnormalities in essential genes have been found to be involved in many human conditions, particularly developmental and rare diseases. Improving our understanding of these genes is therefore vital.

What was done

The IMPC has already developed a phenotyping pipeline for mice that survive to adulthood, this is a range of procedures to identify and quantify the characteristics or “phenotypes” seen when a gene has been knocked out. As mice with essential genes knocked out generally don’t survive to adulthood, the IMPC have developed a pipeline specifically to look at these essential genes, thus allowing us to see what might be going on at specific developmental stages. Features of the pipeline include establishing a window of lethality (working out the time of embryo death) and an analysis of gross morphology to observe phenotypes in freshly dissected embryos.

High resolution, high throughput 3D imaging was also used for the first time in the pipeline. A high throughput system means that images can be analysed quickly and on a large scale, this is important considering the number of genes being looked at (there are around 7,000 essential genes). Imaging techniques are also amenable to automated computational analysis, allowing for the identification of aberrant anatomical phenotypes – which may not have been possible to notice or picked up by manual inspection.

What was found

A strong correlation was found between genes causing lethality in mice and genes causing diseases in humans. Here, scientists found that of 593 essential mouse genes also shared with humans, that 183 of these were associated with human diseases.

Identification of novel phenotypes

The pipeline has enabled novel phenotypes that had not previously been seen to be reported for 86 genes. In all cases the 3D imaging revealed additional phenotypes that may have been missed by gross inspection.

Surprising findings

One of the most surprising findings was that many of the phenotypes seen with essential genes were seen in some embryos and not others. This was unexpected as the mice are almost genetically identical to each other and reared in identical environments. In addition, as these genes have such core functions usually very little variation is seen between organisms when they are disrupted. These findings have opened up a new avenue for further exploration in future studies.

Why is this study important?

The work so far has helped to identify novel human genes that are associated with diseases. This will be crucial going forwards for helping to improve our understanding of the biological mechanisms underlying these disorders. It will reveal unique insights into how things can go wrong at very early stages of development, before an organism is even born, to better understand the process of development. 

Performing these studies on a large scale using standardised and quality controlled procedures helps to ensure accurate and reliable data. All data and knockout mice produced by IMPC are freely available, thus reducing the need for replication and the number of animals used in research.

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