title: A 1.1-Mb transcript map of the hereditary hemochromatosis locus.
abstract: In the process of positionally cloning a candidate gene responsible for hereditary hemochromatosis (HH), we constructed a 1.1-Mb transcript map of the region of human chromosome 6p that lies 4.5 Mb telomeric to HLA-A. A combination of three gene-finding techniques, direct cDNA selection, exon trapping, and sample sequencing, were used initially for a saturation screening of the 1.1-Mb region for expressed sequence fragments. As genetic analysis further narrowed the HH candidate locus, we sequenced completely 0.25 Mb of genomic DNA as a final measure to identify all genes. Besides the novel MHC class 1-like HH candidate gene HLA-H, we identified a family of five butyrophilin-related sequences, two genes with structural similarity to a type 1 sodium phosphate transporter, 12 novel histone genes, and a gene we named RoRet based on its strong similarity to the 52-kD Ro/SSA lupus and Sjogren's syndrome auto-antigen and the RET finger protein. Several members of the butyrophilin family and the RoRet gene share an exon of common evolutionary origin called B30-2. The B30-2 exon was originally isolated from the HLA class 1 region, yet has apparently "shuffled" into several genes along the chromosome telomeric to the MHC. The conservation of the B30-2 exon in several novel genes and the previously described amino acid homology of HLA-H to MHC class 1 molecules provide further support that this gene-rich region of 6p21.3 is related to the MHC. Finally, we performed an analysis of the four approaches for gene finding and conclude that direct selection provides the most effective probes for cDNA screening, and that as much as 30% of ESTs in this 1.1-Mb region may be derived from noncoding genomic DNA.
authors.affiliation: Mercator Genetics, Menlo Park, California 94025, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Ruddy
authors.forename: G S
authors.initials: GS
authors.lastname: Kronmal
authors.forename: V K
authors.initials: VK
authors.lastname: Lee
authors.forename: G A
authors.initials: GA
authors.lastname: Mintier
authors.forename: L
authors.initials: L
authors.lastname: Quintana
authors.forename: R
authors.initials: R
authors.lastname: Domingo
authors.forename: N C
authors.initials: NC
authors.lastname: Meyer
authors.forename: A
authors.initials: A
authors.lastname: Irrinki
authors.forename: E E
authors.initials: EE
authors.lastname: McClelland
authors.forename: A
authors.initials: A
authors.lastname: Fullan
authors.forename: F A
authors.initials: FA
authors.lastname: Mapa
authors.forename: T
authors.initials: T
authors.lastname: Moore
authors.forename: W
authors.initials: W
authors.lastname: Thomas
authors.forename: D B
authors.initials: DB
authors.lastname: Loeb
authors.forename: C
authors.initials: C
authors.lastname: Harmon
authors.forename: Z
authors.initials: Z
authors.lastname: Tsuchihashi
authors.forename: R K
authors.initials: RK
authors.lastname: Wolff
authors.forename: R C
authors.initials: RC
authors.lastname: Schatzman
authors.forename: J N
authors.initials: JN
authors.lastname: Feder
mesh_terms: D000595:Amino Acid Sequence; D001324:Autoantigens / Q000235:genetics; D001419:Bacteria / Q000235:genetics; D001665:Binding Sites; D015152:Blotting, Northern; D000071797:Butyrophilins; D002352:Carrier Proteins / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods*; D002896:Chromosomes, Human, Pair 6; D003001:Cloning, Molecular; D017124:Conserved Sequence; D018076:DNA, Complementary; D006680:HLA Antigens / Q000235:genetics; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D020733:RNA, Small Cytoplasmic; D012261:Ribonucleoproteins / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D017386:Sequence Homology, Amino Acid; D016324:Sequence Tagged Sites; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D027981:Symporters; D014018:Tissue Distribution; D014157:Transcription Factors; D014158:Transcription, Genetic; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D000099207:SS-A Antigen
chemical_list: D001324:Autoantigens; D000071797:Butyrophilins; D002352:Carrier Proteins; D018076:DNA, Complementary; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D006657:Histones; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011506:Proteins; D020733:RNA, Small Cytoplasmic; D012261:Ribonucleoproteins; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D027981:Symporters; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D000099207:SS-A Antigen; C103673:HFE protein, human; C116006:RO60 protein, human; C063552:transcription factor BTF3; C106984:TRIM38 protein, human