Abstract
The generation of a comprehensive catalog of null alleles covering all protein-coding genes is the goal of the International Mouse Phenotyping Consortium. Over the past 20 years, significant progress has been made towards achieving this goal through the combined efforts of many large-scale programs that built an embryonic stem cell resource to generate knockout mice and more recently employed CRISPR/Cas9-based mutagenesis to delete critical regions predicted to result in frameshift mutations, thus, ablating gene function. The IMPC initiative builds on prior and ongoing work by individual research groups creating gene knockouts in the mouse. Here, we analyze the collective efforts focusing on the combined null allele resource resulting from strains developed by the research community and large-scale production programs. Based upon this pooled analysis, we examine the remaining fraction of protein-coding genes focusing on clearly defined mouse–human orthologs as the highest priority for completing the mutant mouse null resource. In summary, we find that there are less than 3400 mouse–human orthologs remaining in the genome without a targeted null allele that can be further prioritized to achieve our overall goal of the complete functional annotation of the protein-coding portion of a mammalian genome.
Highlights
Animal models, including mouse knockouts, play an instrumental role in advancing our understanding of how disruption of normal gene function relates to human disease
What was once a long-term aspirational goal of the mouse genetics community is an achievable milestone? This raises several interesting and important questions: How many more genes remain to be knocked out? How should these genes be prioritized for systematic mutagenesis? Are there other features in the genome that merit further consideration as mutagenesis targets? Here, we explore the collective catalog of mutant mouse null alleles generated by the IMPC and the broader scientific community to address these questions and chart a course towards finalizing a blueprint for understanding the activity of the protein-coding fraction of the mammalian genome
We used the MouseMine query tool to obtain annotation information detailing the target gene, allele symbol, methodology, and associated publications (Motenko et al 2015). These queries identified 29,341 unique null alleles corresponding to 13,973 proteincoding genes with the majority of community-derived alleles generated using an ES-based resource and IMPC alleles a mixture of both ES and Cas9 derived. In addition to these targeted null mutations, we identified an additional 265 unique genes as having an annotated null allele resulting from random mutagenesis
Summary
Animal models, including mouse knockouts, play an instrumental role in advancing our understanding of how disruption of normal gene function relates to human disease. Completion of the mutant mouse null resource that promises to advance our understanding of novel genes and pathways, while reducing the research barriers to entry for individual investigators.
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