The Deep Genome Project

Kent Lloyd ,Stephen A Murray,Robert E Braun,Martin Hrabě De Angelis,David J Adams,Ann‐Marie Mallon ,Colin Mckerlie,Stanislas Lyonnet,Ying Xu,Yann Hérault ,Gareth Baynam,Radislav Sedláček ,James R Lupski,Wolfgang Wurst,Yuichi Obata,Jason D Heaney,Lauryl M J Nutter,Jacqueline K White ,Calum A Macrae,Fabio Mammano,Sanjeev Galande,Chi-Kuang Leo Wang,Glauco P Tocchini‐Valentini ,Xiang Gao,Damian Smedley,Toshihiko Shiroishi,Michael Sean Pepper ,Paul Flicek,Ann M Flenniken,Terrence F Meehan,David Valle,Kym M Boycott,Michael S Dobbie,Fàtima Bosch ,Arthur L Beaudet,Sara Wells,Mary E Dickinson,Helen Parkinson,Mark J Caulfield ,Roderick R Mcinnes ,Je Kyung Seong,Ronald D Cohn ,Anne Grobler,Steve Brown

doi:10.1186/s13059-020-1931-9

Abstract

In vivo research is critical to the functional dissection of multi-organ systems and whole organism physiology, and the laboratory mouse remains a quintessential animal model for studying mammalian, especially human, pathobiology. Enabled by technological innovations in genome sequencing, mutagenesis and genome editing, phenotype analyses, and bioinformatics, in vivo analysis of gene function and dysfunction in the mouse has delivered new understanding of the mechanisms of disease and accelerated medical advances. However, many significant hurdles have limited the elucidation of mechanisms underlying both rare and complex, multifactorial diseases, leaving significant gaps in our scientific knowledge. Future progress in developing a functionally annotated genome map depends upon studies in model organisms, not least the mouse. Further, recent advances in genetic manipulation and in vivo, in vitro, and in silico phenotyping technologies in the mouse make annotation of the vast majority of functional elements within the mammalian genome feasible. The implementation of a Deep Genome Project—to deliver the functional biological annotation of all human orthologous genomic elements in mice—is an essential and executable strategy to transform our understanding of genetic and genomic variation in human health and disease that will catalyze delivery of the promised benefits of genomic medicine to children and adults around the world.

Highlights

In vivo research is critical to the functional dissection of multi-organ systems and whole organism physiology, and the laboratory mouse remains a quintessential animal model for studying mammalian, especially human, pathobiology
With over 80% conserved synteny and a high degree of gene orthology, the mouse and human genomes have provided a unique opportunity for comparative functional analysis and the use of genetically altered mice to interrogate the pathobiology of human disease [1]
Despite the incredible scientific advances in genetics at the single gene and genomic level, the collective biomedical community has only begun to scratch the surface of knowledge about the diverse and varied in vivo pathobiological roles of functional elements throughout the human genome