Characterization of TH1 and CTSZ, two non-imprinted genes downstream of GNAS1 in chromosome 20q13

The clustering and coordinate regulation of many imprinted genes justifies positional searches for imprinted genes adjacent to known ones. We recently characterized a locus on 20q13, containing GNAS1, which has a highly compl ex imprinted expression pattern. In a search for neighbouring genes, we hav e now characterized a new gene, TH1, downstream of GNAS1. TH1 and GNAS1 are separated by more than 70 kb consisting largely of interspersed repetitive DNA, TH1 is the homologue of a gene that, in Drosophila, lies adjacent to the DNA repair gene mei-41. We have determined the full-length structures o f human, mouse and Drosophila TH1. Though of unknown function, TH1 is highl y conserved and widely expressed. Nonetheless, there is no similar Caenorha bditis elegans protein. We have also determined the complete genomic struct ures of human and Drosophila TH1. The Drosophila gene has five exons spanni ng 2.6 kb. The last three introns have precise equivalents in the human gen e, which has 15 exons spanning 14 kb and is transcribed away from GNAS1. Us ing a single-nucleotide polymorphism in the 3' untranslated region, we have demonstrated biallelic TH1 expression in human fetal tissues, suggesting t hat, unlike GNAS1, TH1 is probably not imprinted. Immediately downstream of TH1 lies CTSZ, encoding the recently described cysteine protease, cathepsi n Z. We have also elucidated the genomic structure of this gene; it has sis exons spanning 12 kb and is oriented tail-to-tail with TH1, only 70 bp sep arating their polyadenylation sites. A polymorphism was again identified wi thin the CTSZ 3' untranslated legion and used to demonstrate biallelic expr ession in fetal tissues.