ZNF423 orthologs are highly constrained in vertebrates but show domain-level plasticity across invertebrate lineages

ZNF423 encodes 30 C2H2 zinc fingers that bind DNA and a variety of lineage- and signal-dependent transcription factors. ZNF423 genetic variants are proposed to cause neurodevelopmental and ciliopathy-related disorders in humans. Mouse models show midline brain defects, including cerebellar vermis hypoplasia, and defects in adipogenesis. Here I show strong protein sequence constraint among 165 vertebrate orthologs. In contrast, orthologs from invertebrate lineages, spanning larger time intervals, show substantial differences in zinc finger number, arrangement, and identity. A terminal zinc finger cluster common among other lineages was independently lost in vertebrates and insects. Surprisingly, a moderately-constrained non-C2H2 sequence with potential to form a C4-class zinc finger is a previously-unrecognized conserved feature of nearly all identified homologs. These results highlight evolutionary dynamics of a likely signal integration node across species with distinct developmental strategies and body plans. Functions of the newly identified C4-like sequence and lineage-specific fingers remain to be studied.