Despite huge progress in genome sequencing and analysis significant portions of the human genome remain ‘dark’ and understudied. This lack of knowledge is a threat to developments in medicine. To counter this, a worldwide group of scientists, clinicians and academics is calling for a new effort to explore the dark genome – led by mouse genetics.

Of the approximately 22,000 genes in the human genome, approximately 18,000 have counterparts (orthologs) in mice. The International Mouse Phenotyping Consortium has used “knockout” mice to identify functions (phenotypes) for about 6,255 of these, and plans to phenotype another 2,925 in the next two years.

The IMPC’s catalog of mouse genes has already helped identify hundreds of potential models for human diseases including blindness, albinism and skin diseases. It could also help save endangered species.

The proposed Deep Genome Project would go further, engaging the global mouse genetics community to provide a comprehensive functional annotation of all the sequences in mouse and human that are involved with disease.

“The IMPC is already shining a powerful light on the function of the dark genome and its role in disease. We urgently need to now build on this programme and undertake an even deeper and more extensive analysis of the mammalian genome,” wrote Professor Steve Brown, Chair of the IMPC Steering Committee and Professor Kent Lloyd, director of the UC Davis Mouse Biology Program and a partner in the IMPC. Brown and Lloyd are among 44 coauthors on a white paper calling for the new effort published in Genome Biology.

The authors proposed four steps to go forward:

Complete the functional annotation of the protein-coding section of the mouse genome. The coding region – the part that is used to produce proteins and run key cellular processes – is only three to five percent of the mammalian genome. The International Mouse Phenotyping Consortium (IMPC) is building a complete functional catalogue by knocking out every mouse gene and undertaking comprehensive analyses of the disease phenotypes found in each mutant. The IMPC will have completed about half of this effort by 2021. Target the other 95 percent of the genome, which does not code for proteins. This DNA can also have a significant effect on how genes function and changes in this part of the genome often cause disease. Translate this knowledge into clinical applications. Clinicians will be able to use this information to study the role of genes in health and disease and find new targets for therapies. Ensure fast and easy access to this information so that it can be integrated in the clinical decision-making process.

Research institutions need continued funding, collaboration and support in order to reach these goals, the achievement of which would fundamentally enhance a vital resource that would be used to transform biology, medicine and global health.

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