title: An enigmatic fourth runt domain gene in the fugu genome: ancestral gene loss versus accelerated evolution.
abstract: BACKGROUND
  The runt domain transcription factors are key regulators of developmental processes in bilaterians, involved both in cell proliferation and differentiation, and their disruption usually leads to disease. Three runt domain genes have been described in each vertebrate genome (the RUNX gene family), but only one in other chordates. Therefore, the common ancestor of vertebrates has been thought to have had a single runt domain gene.
  
  
  RESULTS
  Analysis of the genome draft of the fugu pufferfish (Takifugu rubripes) reveals the existence of a fourth runt domain gene, FrRUNT, in addition to the orthologs of human RUNX1, RUNX2 and RUNX3. The tiny FrRUNT packs six exons and two putative promoters in just 3 kb of genomic sequence. The first exon is located within an intron of FrSUPT3H, the ortholog of human SUPT3H, and the first exon of FrSUPT3H resides within the first intron of FrRUNT. The two gene structures are therefore "interlocked". In the human genome, SUPT3H is instead interlocked with RUNX2. FrRUNT has no detectable ortholog in the genomes of mammals, birds or amphibians. We consider alternative explanations for an apparent contradiction between the phylogenetic data and the comparison of the genomic neighborhoods of human and fugu runt domain genes. We hypothesize that an ancient RUNT locus was lost in the tetrapod lineage, together with FrFSTL6, a member of a novel family of follistatin-like genes.
  
  
  CONCLUSIONS
  Our results suggest that the runt domain family may have started expanding in chordates much earlier than previously thought, and exemplify the importance of detailed analysis of whole-genome draft sequence to provide new insights into gene evolution.
authors.affiliation: Institute for Systems Biology, 1441 N 34th St,, Seattle, WA 98103, USA. cgojp@systemsbiology.org
authors.forename: Gustavo
authors.initials: G
authors.lastname: Glusman
authors.forename: Amardeep
authors.initials: A
authors.lastname: Kaur
authors.forename: Leroy
authors.initials: L
authors.lastname: Hood
authors.forename: Lee
authors.initials: L
authors.lastname: Rowen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D050659:Core Binding Factor Alpha 1 Subunit; D050676:Core Binding Factor Alpha 2 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins / Q000235:genetics; D019143:Evolution, Molecular; D038681:Follistatin / Q000235:genetics; D017353:Gene Deletion; D016678:Genome; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics; D010455:Peptides / Q000235:genetics*; D010802:Phylogeny; D017434:Protein Structure, Tertiary / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D023741:Takifugu / Q000235:genetics*; D023721:Tetraodontiformes / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D050676:Core Binding Factor Alpha 2 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins; D038681:Follistatin; D009363:Neoplasm Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; C493729:Runx3 protein, human; C115819:SUPT3H protein, human; D014157:Transcription Factors