Deep vertebrate roots for mammalian zinc finger transcription factor subfamilies

Hui Liu, Li Hsin Chang, Younguk Sun, Xiaochen Lu, Lisa Stubbs

Research output: Contribution to journalArticlepeer-review


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" bymining ZNFloci from eight sequenced genomes andthen aligning the patterns of DNA-bindingamino 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.

Original languageEnglish (US)
Pages (from-to)510-525
Number of pages16
JournalGenome biology and evolution
Issue number3
StatePublished - Mar 2014


  • Transcription factor evolution
  • Vertebrate gene families
  • Zinc finger genes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics


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