Next-generation human genetics for organism-level systems biology

[Display omitted] •Triple-target CRISPR efficiently produces bi-allelic KO mice without crossing.•ES-mouse method produces KI mice in a single generation from embryonic stem cells.•Humanized mice made without crossing can be key to understanding human diseases.•Mouse genetics without crossing can be useful for organism-level systems biology. Systems-biological approaches, such as comprehensive identification and analysis of system components and networks, are necessary to understand design principles of human physiology and pathology. Although reverse genetics using mouse models have been used previously, it is a low throughput method because of the need for repetitive crossing to produce mice having all cells of the body with knock-out or knock-in mutations. Moreover, there are often issues from the interspecific gap between humans and mice. To overcome these problems, high-throughput methods for producing knock-out or knock-in mice are necessary. In this review, we describe ‘next-generation’ human genetics, which can be defined as high-throughput mammalian genetics without crossing to knock out human-mouse ortholog genes or to knock in genetically humanized mutations.