Origin of the MED, END-3 and END-1 factors. (A) Origin of all three factors at the base of the Elegans supergroup, followed by loss of a conserved intron in an ancestral med gene at the base of the Elegans group. (B) Hypothetical microhomology-mediated end joining (MMEJ) event that could delete the conserved zinc finger intron at the base of the Elegans group, using a 6-bp identity in-frame microhomology in an extant C. japonica med gene. At top, the microhomology is shown for the top strand. In the bottom part, complementary strands are shown pairing across the microhomology, which if resolved could result in an in-frame deletion of the intron, after (van Schendel and Tijsterman 2013). This would also require maintenance of the AAC codon for asparagine immediately to the right of the homology. (C) Speculative model for generation of the SKN-1/MED/END regulatory cascade through intercalation by serial duplications of an ancestral autoregulating elt-2 gene. A bent arrow indicates the transcription start site, with the regulatory activity of the protein product of the gene shown as a colored line from the bent arrow. The promoter is to the left of the bent arrow. The positions in the promoters are only meant to qualitatively convey positive regulation and not indicate number or position of binding sites.