Comparative Genomics of the Zic Family Genes

Zic family genes encode five C2H2-type zinc finger domain-containing proteins that have many roles in animal development and maintenance. Recent phylogenetic analyses showed that Zic family genes are distributed in metazoans (multicellular animals), except Porifera (sponges) and Ctenophora (comb jellies). The sequence comparisons revealed that the zinc finger domains were absolutely conserved among the Zic family genes. Zic zinc finger domains are similar to, but distinct from those of the Gli, Glis, and Nkl gene family, and these zinc finger protein families are proposed to have been derived from a common ancestor gene. The Gli-Glis-Nkl-Zic superfamily and some other eukaryotic zinc finger proteins share a tandem CWCH2 (tCWCH2) motif, a hallmark for inter-zinc finger interaction between two adjacent C2H2 zinc fingers. In Zic family proteins, there exist additional evolutionally conserved domains known as ZOC and ZFNC, both of which may have appeared before cnidarian-bilaterian divergence. Comparison of the exon-intron boundaries in the Zic zinc finger domains revealed an intron (A-intron) that was absolutely conserved in bilaterians (metazoans with bilateral symmetry) and a placozoan (a simple nonparasitic metazoan). In vertebrates, there are five to seven Zic paralogs among which Zic1, Zic2, and Zic3 are generated through a tandem gene duplication and carboxy-terminal truncation in a vertebrate common ancestor, sharing a conserved carboxy-terminal sequence. Several hypotheses have been proposed to explain the Zic family phylogeny, including their origin, unique features in the first and second zinc finger motif, evolution of the nuclear localization signal, significance of the animal taxa-selective degeneration, gene multiplication in the vertebrate lineage, and involvement in the evolutionary alteration of the animal body plan.