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<p>The International Mouse Phenotyping Consortium (IMPC) has established a large-scale functional genomics resource by systematically generating and phenotyping knockout mouse lines, linking gene function to mammalian phenotypes. However, interpreting disease-associated non-coding variants remains particularly challenging due to their abundance, context-dependent activity, and the complexity of gene regulation. Genome-wide association studies (GWAS) have shown that many disease-associated loci map to non-coding regions. In addition, recent large-scale consortia have catalogued millions of candidate cis-regulatory elements (CREs) across mammalian genomes; however, predicting which elements contribute to disease-relevant gene regulation and organismal phenotypes remains difficult. Together, these observations highlight disease-relevant CREs as an important but still underexplored component of human disease mechanisms. In this white paper, we outline strategies to address this challenge: (i) prioritization of disease-relevant candidate CREs, (ii) genome editing in mice to functionally evaluate CREs, and (iii) the establishment of interdisciplinary working groups. By extending its activities beyond protein-coding sequences, the IMPC has a unique opportunity to define the functional and phenotypic impact of disease-relevant CREs in vivo at scale, thereby improving our understanding of how non-coding regulatory elements contribute to mammalian phenotypes and human disease.</p>

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The future objectives of the International Mouse Phenotyping Consortium (IMPC): functional evaluation of human disease-relevant cis-regulatory elements in the mouse genome

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月24日

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  • Naoki Kubo,
  • Akiko Oguchi,
  • Hiroshi Masuya,
  • Takanori Amano,
  • Akihiko Sakashita,
  • Hideya Kawaji,
  • Takeya Kasukawa,
  • Shinya Oki,
  • Shinya Ayabe,
  • Toyoyuki Takada,
  • Atsuo Ogura,
  • Kimiko Inoue,
  • Yasuhiro Murakawa,
  • Masaru Tamura,
  • Atsushi Yoshiki,
  • Toshihiko Shiroishi

摘要

The International Mouse Phenotyping Consortium (IMPC) has established a large-scale functional genomics resource by systematically generating and phenotyping knockout mouse lines, linking gene function to mammalian phenotypes. However, interpreting disease-associated non-coding variants remains particularly challenging due to their abundance, context-dependent activity, and the complexity of gene regulation. Genome-wide association studies (GWAS) have shown that many disease-associated loci map to non-coding regions. In addition, recent large-scale consortia have catalogued millions of candidate cis-regulatory elements (CREs) across mammalian genomes; however, predicting which elements contribute to disease-relevant gene regulation and organismal phenotypes remains difficult. Together, these observations highlight disease-relevant CREs as an important but still underexplored component of human disease mechanisms. In this white paper, we outline strategies to address this challenge: (i) prioritization of disease-relevant candidate CREs, (ii) genome editing in mice to functionally evaluate CREs, and (iii) the establishment of interdisciplinary working groups. By extending its activities beyond protein-coding sequences, the IMPC has a unique opportunity to define the functional and phenotypic impact of disease-relevant CREs in vivo at scale, thereby improving our understanding of how non-coding regulatory elements contribute to mammalian phenotypes and human disease.