The Gene Encoding Protein Kinase SEK1 Maps to Mouse Chromosome 11 and Human Chromosome 17

We report the mapping of the human and mouse genes encoding SEK1 (SAPK/ERK kinase-1), a newly identified protein kinase that is a potent physiological activator of the stress-activated protein kinases. The human SERK1 gene was assigned to human chromosome 17 using genomic DNAs from human–rodent somatic cell hybrid lines. A specific human PCR product was observed solely in the somatic cell line containing human chromosome 17. The mouseSerk1gene was mapped to chromosome 11, closely linked toD11Mit4,using genomic DNAs from a (C57BL/6J ×Mus spretus)F₁×M. spretusbackcross.     

Aryl Hydrocarbon Hydroxylase Induction by Benzo[a]anthracene: Regulatory Gene Localized to the Distal Portion of Mouse Chromosome 17

Aryl hydrocarbon (benzo[a]pyrene) hydroxylase inducibility by benzo[a]anthracene was studied in 29 somatic cell hybrid clones, developed by fusing mouse spleen or peritoneal cells from four different inbred strains with hypoxanthine phosphoribosyltransferase-deficient Chinese hamster E36 cells. Karyotype analysis plus 25 markers assigned to 16 autosomes and the X chromosome were examined. In 28 of the 29 clones, the presence or absence of inducibility is associated with the presence or absence, respectively, of mouse chromosome 17.—Liver microsomal aryl hydrocarbon hydroxylase induction by 3-methylcholanthrene or benzo[a]anthracene was assessed in appropriate backcrosses with the Mus musculus molossinus, M. m. castaneus, MOR/Cv, PL/J, SM/J and DBA/2J inbred strains and in 13 NX8 recombinant inbred lines. Twenty-seven biochemical genetic markers representing all but four autosomes were tested for possible linkage with the hydroxylase inducibility, and no linkage was found. The hepatic Ah receptor was quantitated in 26 BXD recombinant inbred lines; the Ah phenotype did not match exactly any of the more than 70 genes with established strain distribution patterns representing 12 autosomes and at least five unlinked markers.—It is concluded that a major gene controlling aryl hydrocarbon hydroxylase inducibility by benzo[a]anthracene is located on chromosome 17. Because there is no significant linkage with any of three biochemical markers in the upper third of the chromosome, we conclude that the inducibility gene is located in the distal 40% of mouse chromosome 17. Whether this trait represents the Ah locus, i.e., the gene encoding the cytosolic Ah receptor, will require further study.     

The Protein Tyrosine Phosphatase ? Gene Maps to Mouse Chromosome 7 and Human Chromosome 10q26

We have mapped the mouse protein tyrosine phosphatase ? (PTP?, gene symbolPtpre) gene to the distal region of chromosome 7 by linkage analysis using two sets of multilocus genetic crosses. The humanPTP? gene (gene symbolPTPRE) was mapped to chromosome 10q26 by fluorescencein situhybridization. We have previously documented the existence of two isoforms ofPTP?—a transmembranal, receptor-type isoform and a shorter, cytoplasmic one. Both isoforms have been suggested to arise from a single gene through the use of alternative promoters and 5′ exons. The identification of a singlePTP? locus in both organisms is consistent with this suggestion.     

Multiple Mechanisms Regulate Imprinting of the Mouse Distal Chromosome 7 Gene Cluster

Genomic imprinting is an epigenetic process that results in the preferential silencing of one of the two parental copies of a gene. Although the precise mechanisms by which genomic imprinting occurs are unknown, the tendency of imprinted genes to exist in chromosomal clusters suggests long-range regulation through shared regulatory elements. We characterize a 800-kb region on the distal end of mouse chromosome 7 that contains a cluster of four maternally expressed genes, H19, Mash2, Kvlqt1, and p57^Kip2, as well as two paternally expressed genes, Igf2 and Ins2, and assess the expression and imprinting of Mash2, Kvlqt1, and p57^Kip2 during development in embryonic and extraembryonic tissues. Unlike Igf2 and Ins2, which depend on H19 for their imprinting, Mash2, p57^Kip2, and Kvlqt1 are unaffected by a deletion of the H19 gene region, suggesting that these more telomeric genes are not regulated by the mechanism that controls H19, Igf2, and Ins2. Mutations in human p57^Kip2 have been implicated in Beckwith-Wiedemann syndrome, a disease that has also been associated with loss of imprinting of IGF2. We find, however, that a deletion of the gene has no effect on imprinting within the cluster. Surprisingly, the three maternally expressed genes are regulated very differently by DNA methylation; p57^Kip2 is activated, Kvlqt1 is silenced, and Mash2 is unaffected in mice lacking DNA methyltransferase. We conclude that H19 is not a global regulator of imprinting on distal chromosome 7 and that the telomeric genes are imprinted by a separate mechanism(s).     

Mapping of theARIXHomeodomain Gene to Mouse Chromosome 7 and Human Chromosome 11q13

The recently described homeodomain protein ARIX is expressed specifically in noradrenergic cell types of the sympathetic nervous system, brain, and adrenal medulla. ARIX interacts with regulatory elements of the genes encoding the noradrenergic biosynthetic enzymes tyrosine hydroxylase and dopamine β-hydroxylase, suggesting a role for ARIX in expression of the noradrenergic phenotype. In the study described here, the mouse and human ARIX genes are mapped. Using segregation analysis of two panels of mouse backcross DNA, mouseArixwas positioned approximately 50 cM distal to the centromere of chromosome 7, nearHbb.HumanARIXwas positioned through analysis of somatic cell hybrids and fluorescencein situhybridization of human metaphase chromosomes to chromosome 11q13.3–q13.4. These map locations extend and further define regions of conserved synteny between mouse and human genomes and identify a new candidate gene for inherited developmental disorders linked to human 11q13.     

Integration of Gene Maps: Chromosome X

Omitting 1137 loci that are included in the location database but have only cytogenetic assignment, there are 605 loci in the integrated map that synthesizes physical and genetic data and subsumes a composite physical location, cytogenetic and regional assignments, mouse homology, rank, and references. With error filtration and allowance far interference the genetic length is 211 cM, to which the p arm contributes 100 cM. The physical length is 164 Mb, with 62 Mb in the p arm. Current problems in map integration are discussed and some solutions proposed.     

N-Cadherin Gene Maps to Human Chromosome 18 and Is Not Linked to the E-Cadherin Gene

cDNA clones encoding the human N-cadherin cell adhesion molecule have been isolated from an embryonic muscle library by screening with an oligonucleotide probe complementary to the chick brain sequence and chick brain cDNA probe lambda N2. Comparison of the predicted protein sequences revealed greater than 91% homology between chick brain, mouse brain, and human muscle N-cadherin cDNAs over the 748 amino acids of the mature, processed protein. A single polyadenylation site in the chick clone was also present and duplicated in the human muscle sequence. Immediately 3' of the recognition site in chick a poly(A) tail ensued; however, in human an additional 800 bp of 3' untranslated sequence followed. Northern analysis identified a number of major N-cadherin mRNAs. These were of 5.2, 4.3, and 4.0 kb in C6 glioma, 4.3 and 4.0 kb in human foetal muscle cultures, and 4.3 kb in human embryonic brain and mouse brain with minor bands of 5.2 kb in human muscle and embryonic brain. Southern analysis of a panel of somatic cell hybrids allowed the human N-cadherin gene to be mapped to chromosome 18. This is distinct from the E-cadherin locus on chromosome 16. Therefore, it is likely that the cadherins have evolved from a common precursor gene that has undergone duplication and migration to other chromosomal locations.     

A Mammalian Homolog of the Bacterial Monomeric Sarcosine Oxidases Maps to Mouse Chromosome 11, Close toCryba1

We have cloned a cDNA from a mouse gene,Pso(peroxisomal sarcosine oxidase).Psoappears to encode a homolog of the single-subunit (40 kDa) bacterial sarcosine oxidases. The mousePsogene product would contain a peroxisomal localization sequence, like that of the recently reported rabbit enzyme. MousePsolies between 20 and 50 kb upstream of the promoter of theSez6gene, close toCryba1on chromosome 11.Psois expressed very strongly and specifically in liver and kidney. The gene appears to be present widely in eutherian mammals.     

Isolation of the Mouse Homologue of BRCA1 and Genetic Mapping to Mouse Chromosome 11

The BRCA1 gene is in large part responsible for hereditary human breast and ovarian cancer. Here we report the isolation of the murineBrca1homologue cDNA clones. In addition, we identified genomic P1 clones that contain most, if not all, of the mouseBrca1locus. DNA sequence analysis revealed that the mouse and human coding regions are 75% identical at the nucleotide level while the predicted amino acid identity is only 58%. A DNA sequence variant in theBrca1locus was identified and used to map this gene on a (Mus m. musculusCzech II × C57BL/KsJ)F1 × C57BL/KsJ intersubspecific backcross to distal mouse chromosome 11. The mapping of this gene to a region highly syntenic with human chromosome 17, coupled with Southern and Northern analyses, confirms that we isolated the murineBrca1homologue rather than a related RING finger gene. The isolation of the mouseBrca1homologue will facilitate the creation of mouse models for germline BRCA1 defects.     

Replication Timing Properties within the Mouse Distal Chromosome 7 Imprinting Cluster

Genomic imprinting is characterized by allele-specific expression of genes within chromosomal domains. Here we show, using fluorescence in situ hybridization (FISH) analysis, that the large chromosomal domain of the mouse distal chromosome 7 imprinting cluster, approximately 1 Mb in length between p57^Kip2 and H19 genes, replicates asynchronously between the two alleles during S-phase. At the telomeric side of this domain, we found a transition from asynchronous replication at the imprinted p57^Kip2 gene to synchronous replication at the Nap2 gene. Two-color FISH suggested that the paternal allele of this whole domain replicates earlier than its maternal allele. Treatment of the cells with a histone deacetylase inhibitor abolished this allele-specific feature accompanied with accelerated replication of the later-replicating allele at a domain level. Allele-specific asynchronous replication was observed even in ES cells. These results suggest that this imprinting cluster consists of a large replication domain which is already found at the early stage in development.     

Dissection of a QTL Hotspot on Mouse Distal Chromosome 1 that Modulates Neurobehavioral Phenotypes and Gene Expression

A remarkably diverse set of traits maps to a region on mouse distal chromosome 1 (Chr 1) that corresponds to human Chr 1q21–q23. This region is highly enriched in quantitative trait loci (QTLs) that control neural and behavioral phenotypes, including motor behavior, escape latency, emotionality, seizure susceptibility (Szs1), and responses to ethanol, caffeine, pentobarbital, and haloperidol. This region also controls the expression of a remarkably large number of genes, including genes that are associated with some of the classical traits that map to distal Chr 1 (e.g., seizure susceptibility). Here, we ask whether this QTL-rich region on Chr 1 (Qrr1) consists of a single master locus or a mixture of linked, but functionally unrelated, QTLs. To answer this question and to evaluate candidate genes, we generated and analyzed several gene expression, haplotype, and sequence datasets. We exploited six complementary mouse crosses, and combed through 18 expression datasets to determine class membership of genes modulated by Qrr1. Qrr1 can be broadly divided into a proximal part (Qrr1p) and a distal part (Qrr1d), each associated with the expression of distinct subsets of genes. Qrr1d controls RNA metabolism and protein synthesis, including the expression of ∼20 aminoacyl-tRNA synthetases. Qrr1d contains a tRNA cluster, and this is a functionally pertinent candidate for the tRNA synthetases. Rgs7 and Fmn2 are other strong candidates in Qrr1d. FMN2 protein has pronounced expression in neurons, including in the dendrites, and deletion of Fmn2 had a strong effect on the expression of few genes modulated by Qrr1d. Our analysis revealed a highly complex gene expression regulatory interval in Qrr1, composed of multiple loci modulating the expression of functionally cognate sets of genes.     

The Gene for Death Agonist BID Maps to the Region of Human 22q11.2 Duplicated in Cat Eye Syndrome Chromosomes and to Mouse Chromosome 6

Cat eye syndrome (CES) is associated with a duplication of a segment of human chromosome 22q11.2. Only one gene,ATP6E, has been previously mapped to this duplicated region. We now report the mapping of the human homologue of the apoptotic agonistBidto human chromosome 22 near locus D22S57 in the CES region. Dosage analysis demonstrated thatBIDis located just distal to the CES region critical for the majority of malformations associated with the syndrome (CESCR), as previously defined by a single patient with an unusual supernumerary chromosome. However,BIDremains a good candidate for involvement in CES-related mental impairment, and its overexpression may subtly add to the phenotype of CES patients. Our mapping of murineBidconfirms that the synteny of the CESCR and the 22q11 deletion syndrome critical region immediately telomeric on human chromosome 22 is not conserved in mice.Bidand adjacent geneAtp6ewere found to map to mousechromosome 6, while the region homologous to the DGSCR is known to map to mouse chromosome 16.