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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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