EVOLUTIONARY CONSERVATION OF PUTATIVE FUNCTIONAL DOMAINS IN THE HUMANHOMOLOG OF THE MURINE HIS-1 GENE

The mouse His-1 gene encodes a spliced and polyadenylated RNA with no long open reading frame (ORF), making it difficult to distinguish a fu nctional protein coding domain. To identify candidate protein coding O RFs, and other functionally significant regions, we have isolated and sequenced 8.5 kb of a human genomic DNA that is homologous to the mous e His-1 gene. Alignment of the mouse and human sequences required no e xtensive gapping, indicating that evolutionary constraints have mainta ined a requirement for colinearity in genomic organization. We have id entified the mouse transcriptional start point (tsp) and shown that th e sequence of the 5'-flanking region is highly conserved in the human homolog. Sequence comparisons between the mouse and human genes identi fied conservation of other putative functional domains in exon 3 and i n each of the two introns. Southern blot analysis with probes from eac h of these regions detected homologs in multiple other vertebrate spec ies. However, none of the multiple candidate ORFs in the mouse RNA wer e conserved in the human sequence, suggesting that the RNA is unlikely to encode a protein. These data suggest that the RNA may be the final and functional product from the mouse His-1 gene.