Fishing for evolutionary clues to globin gene regulation

The pufferfish has a compact genome that is well suited for finding many protein-coding genes by fish-mammal sequence comparison. In this issue Gillemans and colleagues (page 2842) also turn to pufferfish for insights into the evolution and function of long-range regulatory elements, such as the locus control region (LCR) found upstream of mammalian beta-globin genes and the major regulatory element (MRE) found upstream of mammalian and avian alpha-globin genes. They find that matters are more complex than anticipated, but they also uncover clues that may prove productive in the long run. Pufferfish have 2 globin-gene loci, one with only alpha-globin genes (Flint et al, Hum Mol Genet. 2001;10:371-382) and one with an active beta-globin gene plus an active and a likely inactive alpha-globin gene (the alpha/beta locus). Gillemans et al searched the latter for a long-range regulatory element similar to a mammalian LCR, but none was found by sequence searches, DNase hypersensitive site mapping, or gene transfer into transgenic mice. Thus, either pufferfish do not have a regulatory element similar to the mammalian beta-globin LCR, or it is considerably further away on the chromosome. Interestingly, detailed analysis of the genes flanking the pufferfish globin loci showed a homologue to theRhomboid gene of Drosophila close to the globin genes in both loci, as well as upstream to the human alpha-globin genes and close to a recently discovered, widely expressed globin gene (encoding cytoglobin) on human chromosome 17. ThisRhomboid-globin gene arrangement appears to be ancient, predating the gene duplications leading to the genes encoding hemoglobins. Such conservation of synteny and breaks from it likely will be helpful guides to better understanding the evolution of globin gene families and deriving clearer insight into the origins of long-range regulatory elements.