%0 Journal Article %J Genome Res %D 1997 %T Large-scale comparative sequence analysis of the human and murine Bruton's tyrosine kinase loci reveals conserved regulatory domains. %A Oeltjen, J C %A Malley, T M %A Donna M Muzny %A Miller, W %A Richard A Gibbs %A Belmont, J W %K Agammaglobulinaemia Tyrosine Kinase %K alpha-Galactosidase %K Animals %K Base Sequence %K Conserved Sequence %K Enhancer Elements, Genetic %K Genetic Variation %K Humans %K Mice %K Models, Genetic %K Molecular Sequence Data %K Promoter Regions, Genetic %K Protein-Tyrosine Kinases %K Recombinant Proteins %K Regulatory Sequences, Nucleic Acid %K Repetitive Sequences, Nucleic Acid %K Sequence Alignment %K Sequence Analysis, DNA %K Sequence Homology, Nucleic Acid %K Transcription Factors %K Transcription, Genetic %K Transfection %X

Large-scale genomic DNA sequencing of orthologous and paralogous loci in different species should contribute to a basic understanding of the evolution of both the protein-coding regions and noncoding regulatory elements. We compared 93 kb of human sequence to 89 kb of mouse sequence in the Bruton's tyrosine kinase (BTK) region. In addition to showing the conservation of both position and orientation of the five functionally unrelated genes in the region (BTK, alpha-D-galactosidase A, L44L, FTP-3, and FCI-12), the comparison revealed conservation of clusters of noncoding sequence flanking the first exon of each gene. Furthermore, in the sequence comparison at the BTK locus, the conservation of clusters of noncoding sequence extends throughout the locus; the noncoding sequence is more highly conserved in the BTK locus in comparison to the flanking loci. This suggests a correlation with the complex developmental regulation of expression of btk. To determine whether a highly conserved 3.5-kb segment flanking the first exon of BTK contains transcriptional regulatory signals, we tested various portions of the segment for promoter and expression activity in several appropriate cell lines. The results demonstrate the contribution of the conserved region flanking the first exon to the cell lineage-specific expression pattern of btk. These data show the usefulness of large scale sequence comparisons to focus investigation on regions of noncoding sequence that play essential roles in complex gene regulation.

%B Genome Res %V 7 %P 315-29 %8 1997 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/9110171?dopt=Abstract %R 10.1101/gr.7.4.315 %0 Journal Article %J Mamm Genome %D 1995 %T Sixty-nine kilobases of contiguous human genomic sequence containing the alpha-galactosidase A and Bruton's tyrosine kinase loci. %A Oeltjen, J C %A Liu, X %A Lu, J %A Allen, R C %A Donna M Muzny %A Belmont, J W %A Richard A Gibbs %K Agammaglobulinaemia Tyrosine Kinase %K alpha-Galactosidase %K Amino Acid Sequence %K Base Sequence %K Cosmids %K Fabry Disease %K Gene Library %K Humans %K Introns %K Molecular Sequence Data %K Protein-Tyrosine Kinases %K Repetitive Sequences, Nucleic Acid %K X Chromosome %X

Several disease loci have been mapped to the Xq21.3-Xq22 region of the human X Chromosome (Chr) including X-linked agammaglobulinemia (XLA), Fabry disease, Alport syndrome, and Pelizaeus Merzbacher disease. Upon cloning of the XLA gene, Bruton's tyrosine kinase (btk), both Fabry disease and XLA were mapped within the same 50- to 70-kb interval. In order to investigate the genomic organization of the region surrounding btk and the Fabry disease gene, alpha-galactosidase A (gla), we constructed a 6-cosmid contig spanning the region from 5' of gla to 3' of btk. Two of these cosmids spanning most of the coding sequence and the upstream region of btk and gla, U237D10 and U230D1, were sequenced by a random shotgun strategy combined with automated sequencing, resulting in 69 kb of contiguous genomic sequence. Sequencing of U237D10 showed btk to be comprised of 19 exons spanning over 35 kb. Sequencing of U230D1 showed that the 3' end of gla is 9 kb from the 5' end of btk and also demonstrated the presence of two additional genes in the region immediately 5' to btk. The surprisingly high gene density is similar to that seen previously only in the human major histocompatibility locus.

%B Mamm Genome %V 6 %P 334-8 %8 1995 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/7626884?dopt=Abstract %R 10.1007/BF00364796