| Summary: | <p>Abstract</p> <p>Background</p> <p>The human <it>6–16 </it>and <it>ISG12 </it>genes are transcriptionally upregulated in a variety of cell types in response to type I interferon (IFN). The predicted products of these genes are small (12.9 and 11.5 kDa respectively), hydrophobic proteins that share 36% overall amino acid identity. Gene disruption and over-expression studies have so far failed to reveal any biochemical or cellular roles for these proteins.</p> <p>Results</p> <p>We have used <it>in silico </it>analyses to identify a novel family of genes (the <it>ISG12 </it>gene family) related to both the human <it>6–16 </it>and <it>ISG12 </it>genes. Each <it>ISG12 </it>family member codes for a small hydrophobic protein containing a conserved ~80 amino-acid motif (the ISG12 motif). So far we have detected 46 family members in 25 organisms, ranging from unicellular eukaryotes to humans. Humans have four <it>ISG12 </it>genes: the <it>6–16 </it>gene at chromosome 1p35 and three genes (<it>ISG12(a)</it>, <it>ISG12(b) </it>and <it>ISG12(c)</it>) clustered at chromosome 14q32. Mice have three family members (<it>ISG12(a)</it>, <it>ISG12(b1) </it>and <it>ISG12(b2)</it>) clustered at chromosome 12F1 (syntenic with human chromosome 14q32). There does not appear to be a murine <it>6–16 </it>gene. On the basis of phylogenetic analyses, genomic organisation and intron-alignments we suggest that this family has arisen through divergent inter- and intra-chromosomal gene duplication events. The transcripts from human and mouse genes are detectable, all but two (human <it>ISG12(b) </it>and <it>ISG12(c)</it>) being upregulated in response to type I IFN in the cell lines tested.</p> <p>Conclusions</p> <p>Members of the eukaryotic <it>ISG12 </it>gene family encode a small hydrophobic protein with at least one copy of a newly defined motif of ~80 amino-acids (the ISG12 motif). In higher eukaryotes, many of the genes have acquired a responsiveness to type I IFN during evolution suggesting that a role in resisting cellular or environmental stress may be a unifying property of all family members. Analysis of gene-function in higher eukaryotes is complicated by the possibility of functional redundancy between family-members. Genetic studies in organisms (e.g. <it>Dictyostelium discoideum</it>) with just one family member so far identified may be particularly helpful in this respect.</p>
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