title: Deep vertebrate roots for mammalian zinc finger transcription factor subfamilies.
abstract: While many vertebrate transcription factor (TF) families are conserved, the C2H2 zinc finger (ZNF) family stands out as a notable exception. In particular, novel ZNF gene types have arisen, duplicated, and diverged independently throughout evolution to yield many lineage-specific TF genes. This evolutionary dynamic not only raises many intriguing questions but also severely complicates identification of those ZNF genes that remain functionally conserved. To address this problem, we searched for vertebrate "DNA binding orthologs" by mining ZNF loci from eight sequenced genomes and then aligning the patterns of DNA-binding amino acids, or "fingerprints," extracted from the encoded ZNF motifs. Using this approach, we found hundreds of lineage-specific genes in each species and also hundreds of orthologous groups. Most groups of orthologs displayed some degree of fingerprint divergence between species, but 174 groups showed fingerprint patterns that have been very rigidly conserved. Focusing on the dynamic KRAB-ZNF subfamily--including nearly 400 human genes thought to possess potent KRAB-mediated epigenetic silencing activities--we found only three genes conserved between mammals and nonmammalian groups. These three genes, members of an ancient familial cluster, encode an unusual KRAB domain that functions as a transcriptional activator. Evolutionary analysis confirms the ancient provenance of this activating KRAB and reveals the independent expansion of KRAB-ZNFs in every vertebrate lineage. Most human ZNF genes, from the most deeply conserved to the primate-specific genes, are highly expressed in immune and reproductive tissues, indicating that they have been enlisted to regulate evolutionarily divergent biological traits.
authors.affiliation: Center for Biophysics and Computational Biology, University of Illinois, Urbana.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Li-Hsin
authors.initials: LH
authors.lastname: Chang
authors.forename: Younguk
authors.initials: Y
authors.lastname: Sun
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Lu
authors.forename: Lisa
authors.initials: L
authors.lastname: Stubbs
mesh_terms: D000818:Animals; D002877:Chromosomes, Human / Q000235:genetics; D016000:Cluster Analysis; D016172:DNA Fingerprinting; D004268:DNA-Binding Proteins / Q000235:genetics; D019143:Evolution, Molecular; D056426:Genetic Loci; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008957:Models, Genetic; D010802:Phylogeny; D016415:Sequence Alignment; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics*; D014714:Vertebrates / Q000145:classification / Q000235:genetics*; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors
keywords: transcription factor evolution; vertebrate gene families; zinc finger genes