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Creating an encyclopaedia of mammalian gene function

Creating an encyclopaedia of mammalian gene function

The International Mouse Phenotyping Consortium (IMPC) is working to provide freely available information about the function of every gene in the mouse genome, based on the focused efforts of its 18 member organisations.

Understanding health and disease in humans depends on knowing the function of some 20,000 protein-coding genes – yet the scope of our knowledge is limited to only a small fraction of these. To increase our understanding in this area, scientists at 18 research organisations in 11 countries have joined forces to systematically determine the function of every protein-coding gene in the mouse genome. The knowledge generated based on this resource will inform more targeted research into human disease.

IMPC researchers are cataloguing gene function by creating knock-out mouse lines, in which a single gene has been inactivated, and collecting key molecular and phenotypic (i.e., physical features, health status) information in a consistent manner. For each knock-out, they conduct a series of tests to identify any abnormal characteristics relating to factors such as development, anatomy and behaviour. This provides valuable insights into the potential function of the inactivated gene.

Over the past five years the IMPC has produced data for more than 5,000 genes, and determined that approximately one third of all mammalian genes are essential for life.

Sharing the data with everyone

Anyone visiting the IMPC web portal can search for data by gene, phenotype or human disease. Mouse lines and embryonic stem cells can be ordered for research through established repositories. To date more than 650 publications have used IMPC resources in their research with the list growing every week.

If you are interested in a particular gene that the IMPC has not yet studied, you can register your interest, which helps the consortium prioritise. As the data resource grows and new findings emerge, it will be increasingly important for the IMPC to ensure the interface and software are clear, intuitive and fit for purpose. For example, they recently updated their web interface to offer landing pages for different disciplines (e.g., bone, cardiovascular), which helps users find relevant information more quickly.

IMPC researchers have also developed software for comparing images of embryos, both in 2D cross-sections and in 3D that can be rotated and zoomed in. The interface allows users to view embryos with inactivated genes alongside healthy embryos, which makes it easier to spot differences.

Making the link with human disease

IMPC researchers are also developing automated algorithms that identify associations between mouse and human data. So far, they have discovered 129 human disease models – this is where the mice display many of the features of a certain human disease. 81 associations have been found between ‘lethal’ knock-out genes in mice and humans, further exploration of these will help bridge an important gap in the study of rare and developmental disorders.

The IMPC resource has also enabled new discoveries, for example very little was known about the gene FAM53B in mice or humans. Mice in which this gene had been deactivated had a decreased number of red blood cells and other phenotypes, which suggests that FAM53B is involved in growth and maturation of blood cells – and could be involved in certain types of anaemia.

The researchers have also found links between this gene and Diamond-Blackfan anaemia, for which the genetic causes are unknown in 46% of patients.

Building on the data

The data is now being harnessed by other scientists to identify genes implicated in specific areas and then look at them with ‘secondary phenotyping’ – that is performing more specific tests relevant to their research area.

DMDD (Deciphering the Mechanisms of Developmental Disorders) is a project dedicated to understanding the genetic causes of developmental disorders and rare diseases. DMDD takes lethal lines produced by the IMPC and performs in-depth phenotyping, identifying abnormalities ranging from organ malformations down to problems at the level of individual nerves and blood vessels. Their image and phenotype data is also freely available online for further study.

The 3i project (Infection, Immunity, Immunophenotyping) is performing in-depth analysis of the immune system and looking at responses to infection. In both cases, hundreds of strains have been analysed.

Going forwards

The IMPC plans to generate 3,000 new mouse lines in the next five years. Using powerful gene editing technologies such as CRISPR/Cas9, they will accelerate progress at reduced cost and higher efficiency than ever before. In addition, they will be phenotyping mice at later stages of life to better understand diseases associated with ageing.

As the IMPC’s data resource grows, it will become an increasingly important tool for precision medicine – customising healthcare for individuals based on their genetic make-up. The IMPC is a good example of what can be achieved when scientists collaborate to achieve a common goal. The results of their efforts are freely available to spur exploration and discoveries that benefit humankind.

Find out more about the IMPC and the DMDD

www.mousephenotype.org

dmdd.org.uk

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