Caenorhabditis elegans DAF-2 as a Model for Human Insulin Receptoropathies

David A. Bulger*, Tetsunari Fukushige, Sijung Yun, Robert K. Semple, John A. Hanover, Michael W. Krause

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Human exome sequencing has dramatically increased the rate of identification of diseaseassociated polymorphisms. However, examining the functional consequences of those variants has created an analytic bottleneck. Insulin-like signaling in Caenorhabditis elegans has long provided a model to assess consequences of human insulin signaling mutations, but this has not been evaluated in the context of current genetic tools. We have exploited strains derived from the Million Mutation Project (MMP) and gene editing to explore further the evolutionary relationships and conservation between the human and C. elegans insulin receptors. Of 40 MMP alleles analyzed in the C. elegans insulin-like receptor gene DAF-2, 35 exhibited insulinlike signaling indistinguishable from wild-type animals, indicating tolerated mutations. Five MMP alleles proved to be novel dauer-enhancing mutations, including one new allele in the previously uncharacterized C-terminus of DAF-2. CRISPR-Cas9 genome editing was used to confirm the phenotypic consequence of six of these DAF-2 mutations and to replicate an allelic series of known human disease mutations in a highly conserved tyrosine kinase active site residue, demonstrating the utility of C. elegans for directly modeling human disease. Our results illustrate the challenges associated with prediction of the phenotypic consequences of amino acid substitutions, the value of assaying mutant isoform function in vivo, and how recently developed tools and resources afford the opportunity to expand our understanding even of highly conserved regulatory modules such as insulin signaling. This approach may prove generally useful for modeling phenotypic consequences of candidate human pathogenic mutations in conserved signaling and developmental pathways.

Original languageEnglish
Pages (from-to)257-268
Number of pages12
JournalG3: Genes | Genomes | Genetics
Issue number1
Publication statusPublished - 1 Jan 2017


  • DAF-2
  • Dauer
  • INSR
  • Million Mutation Project


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