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<p>Abstract</p> <p>Background</p> <p>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 <it>RUNX </it>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.</p> <p>Results</p> <p>Analysis of the genome draft of the fugu pufferfish (<it>Takifugu rubripes</it>) reveals the existence of a fourth runt domain gene, <it>FrRUNT</it>, in addition to the orthologs of human <it>RUNX1</it>, <it>RUNX2 </it>and <it>RUNX3</it>. The tiny <it>FrRUNT </it>packs six exons and two putative promoters in just 3 kb of genomic sequence. The first exon is located within an intron of <it>FrSUPT3H</it>, the ortholog of human <it>SUPT3H</it>, and the first exon of <it>FrSUPT3H </it>resides within the first intron of <it>FrRUNT</it>. The two gene structures are therefore "interlocked". In the human genome, <it>SUPT3H </it>is instead interlocked with <it>RUNX2</it>. <it>FrRUNT </it>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 <it>RUNT </it>locus was lost in the tetrapod lineage, together with <it>FrFSTL6</it>, a member of a novel family of follistatin-like genes.</p> <p>Conclusions</p> <p>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.</p>