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1.  Deep Vertebrate Roots for Mammalian Zinc Finger Transcription Factor Subfamilies 
Genome Biology and Evolution  2014;6(3):510-525.
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.
PMCID: PMC3971581  PMID: 24534434
zinc finger genes; transcription factor evolution; vertebrate gene families
2.  Rapid Sequence and Expression Divergence Suggest Selection for Novel Function in Primate-Specific KRAB-ZNF Genes 
Molecular Biology and Evolution  2010;27(11):2606-2617.
Recent segmental duplications (SDs), arising from duplication events that occurred within the past 35–40 My, have provided a major resource for the evolution of proteins with primate-specific functions. KRAB zinc finger (KRAB-ZNF) transcription factor genes are overrepresented among genes contained within these recent human SDs. Here, we examine the structural and functional diversity of the 70 human KRAB-ZNF genes involved in the most recent primate SD events including genes that arose in the hominid lineage. Despite their recent advent, many parent–daughter KRAB-ZNF gene pairs display significant differences in zinc finger structure and sequence, expression, and splicing patterns, each of which could significantly alter the regulatory functions of the paralogous genes. Paralogs that emerged on the lineage to humans and chimpanzees have undergone more evolutionary changes per unit of time than genes already present in the common ancestor of rhesus macaques and great apes. Taken together, these data indicate that a substantial fraction of the recently evolved primate-specific KRAB-ZNF gene duplicates have acquired novel functions that may possibly define novel regulatory pathways and suggest an active ongoing selection for regulatory diversity in primates.
PMCID: PMC2981486  PMID: 20573777
KRAB-ZNF genes; recently evolved primate genes; transcription factor; primate evolution; paralog divergence
3.  Gain, Loss and Divergence in Primate Zinc-Finger Genes: A Rich Resource for Evolution of Gene Regulatory Differences between Species 
PLoS ONE  2011;6(6):e21553.
The molecular changes underlying major phenotypic differences between humans and other primates are not well understood, but alterations in gene regulation are likely to play a major role. Here we performed a thorough evolutionary analysis of the largest family of primate transcription factors, the Krüppel-type zinc finger (KZNF) gene family. We identified and curated gene and pseudogene models for KZNFs in three primate species, chimpanzee, orangutan and rhesus macaque, to allow for a comparison with the curated set of human KZNFs. We show that the recent evolutionary history of primate KZNFs has been complex, including many lineage-specific duplications and deletions. We found 213 species-specific KZNFs, among them 7 human-specific and 23 chimpanzee-specific genes. Two human-specific genes were validated experimentally. Ten genes have been lost in humans and 13 in chimpanzees, either through deletion or pseudogenization. We also identified 30 KZNF orthologs with human-specific and 42 with chimpanzee-specific sequence changes that are predicted to affect DNA binding properties of the proteins. Eleven of these genes show signatures of accelerated evolution, suggesting positive selection between humans and chimpanzees. During primate evolution the most extensive re-shaping of the KZNF repertoire, including most gene additions, pseudogenizations, and structural changes occurred within the subfamily homininae. Using zinc finger (ZNF) binding predictions, we suggest potential impact these changes have had on human gene regulatory networks. The large species differences in this family of TFs stands in stark contrast to the overall high conservation of primate genomes and potentially represents a potent driver of primate evolution.
PMCID: PMC3126818  PMID: 21738707
4.  Lineage-specific transcription factors and the evolution of gene regulatory networks 
Nature is replete with examples of diverse cell types, tissues and body plans, forming very different creatures from genomes with similar gene complements. However, while the genes and the structures of proteins they encode can be highly conserved, the production of those proteins in specific cell types and at specific developmental time points might differ considerably between species. A full understanding of the factors that orchestrate gene expression will be essential to fully understand evolutionary variety. Transcription factor (TF) proteins, which form gene regulatory networks (GRNs) to act in cooperative or competitive partnerships to regulate gene expression, are key components of these unique regulatory programs. Although many TFs are conserved in structure and function, certain classes of TFs display extensive levels of species diversity. In this review, we highlight families of TFs that have expanded through gene duplication events to create species-unique repertoires in different evolutionary lineages. We discuss how the hierarchical structures of GRNs allow for flexible small to large-scale phenotypic changes. We survey evidence that explains how newly evolved TFs may be integrated into an existing GRN and how molecular changes in TFs might impact the GRNs. Finally, we review examples of traits that evolved due to lineage-specific TFs and species differences in GRNs.
PMCID: PMC3096533  PMID: 20081217
transcription factors; gene regulatory network; evolution; lineage-specific genes
5.  YY1 as a controlling factor for the Peg3 and Gnas imprinted domains 
Genomics  2006;89(2):262-269.
Imprinting Control Regions (ICRs) often harbor tandem arrays of transcription factor binding sites, as demonstrated by the identification of multiple YY1 binding sites within the ICRs of Peg3, Nespas, and Xist/Tsix domains. In the current study, we have sought to characterize possible roles of YY1 in transcriptional control and epigenetic modification of these imprinted domains. RNA interference-based knockdown experiments in Neuro2A cells resulted in overall transcriptional up-regulation of most of the imprinted genes within the Peg3 domain and also, concomitantly, caused significant loss in the DNA methylation of Peg3-DMR (Differentially Methylated Regions). A similar overall and coordinated expression change was also observed for the imprinted genes of the Gnas domain: up-regulation of Nespas and down-regulation of Nesp and Gnasxl. YY1 knockdown also resulted in changes in the expression levels of Xist and Snrpn. These results support the idea that YY1 plays a major role, as a trans factor, for the control of these imprinted domains.
PMCID: PMC1828871  PMID: 17067777
genomic imprinting; ICRs; YY1
6.  ECR Browser: a tool for visualizing and accessing data from comparisons of multiple vertebrate genomes 
Nucleic Acids Research  2004;32(Web Server issue):W280-W286.
With an increasing number of vertebrate genomes being sequenced in draft or finished form, unique opportunities for decoding the language of DNA sequence through comparative genome alignments have arisen. However, novel tools and strategies are required to accommodate this large volume of genomic information and to facilitate the transfer of predictions generated by comparative sequence alignment to researchers focused on experimental annotation of genome function. Here, we present the ECR Browser, a tool that provides easy and dynamic access to whole genome alignments of human, mouse, rat and fish sequences. This web-based tool ( provides the starting point for discovery of novel genes, identification of distant gene regulatory elements and prediction of transcription factor binding sites. The genome alignment portal of the ECR Browser also permits fast and automated alignments of any user-submitted sequence to the genome of choice. The interconnection of the ECR Browser with other DNA sequence analysis tools creates a unique portal for studying and exploring vertebrate genomes.
PMCID: PMC441493  PMID: 15215395

Results 1-6 (6)