A linkage map of mouse chromosome 19: definition of comparative mapping relationships with human chromosomes 10 and 11 including the MEN1 locus.

A linkage map of mouse Chromosome (Chr) 19 was constructed using an interspecific cross and markers defined by restriction fragment length variants. The map includes 20 markers, 9 of which had not been mapped previously in the mouse. The data further defined the relationship between genes on mouse Chr 19 and those on the long arm of human Chr 10 and the pericentric region of the long arm of human Chr 11. The comparative mapping analysis suggests that the proximal segment of mouse Chr 19 may contain the MEN1 locus and that the current study has identified additional genes that may be useful for positional cloning of this putative tumor suppressor gene.     

A multipoint genetic linkage map of mouse chromosome 18

We have mapped 13 loci on mouse Chromosome 18 by Southern blot analysis of restriction fragment length polymorphisms among progeny from an interspecific backcross: (C57BL/6J X Mus spretus) X M. spretus. Complete haplotype analysis of 136 of these progeny was used to establish gene order and estimate genetic distances between loci. The gene order (from centromere to telomere) and recombination distances (in centimorgans) were as follows: PGK-1rs5-4.3-Tpi-10-11.8-(Egr-1, Hmg17-rs9)-2.1-Fgfa-2.2-Grl-1-10.1-(Cdx-1, Csfmr, Pdgfrb, Pdea, Rps14)-2.1-Adrb-2-22.9-Mbp. Pgk-1rs5, Tpi-10, Hmg17-rs9, and Rps14 had not been previously mapped in the mouse; Egr-1 had only been syntenically assigned to mouse Chr 18. Nine of the loci, spanning 18 cM, have homologs on the distal long arm of human Chr5--a region rich in genes encoding growth factors and receptors. An additional previously unmapped gene, Drd-1, predicted to be on mouse Chr 18 based on its human chromosomal location, was mapped to the middle region of mouse Chr 13.     

Establishment of the mouse chromosome 7 region with homology to the myotonic dystrophy region of human chromosome 19q

A number of genetic markers, including ATP1A3, TGFB, CKMM, and PRKCG, define the genetic region on human chromosome 19 containing the myotonic dystrophy locus. These and a number of other DNA probes have been mapped to mouse chromosome 7 utilizing a mouse Mus domesticus/Mus spretus interspecific backcross segregating for the genetic markers pink-eye dilution (p) and chinchilla (cch). The establishment of a highly syntenic group conserved between mouse chromosome 7 and human chromosome 19q indicates the likely position of the homologous gene locus to the human myotonic dystrophy gene on proximal mouse chromosome 7. In addition, we have mapped the muscle ryanodine receptor gene (Ryr) to mouse chromosome 7 and demonstrated its close linkage to the Atpa-2, Tgfb-1, and Ckmm cluster of genes. In humans, the malignant hyperthermia susceptibility locus (MHS) also maps close to this gene cluster. The comparative mapping data support Ryr as a candidate gene for MHS.     

A rat mutation producing demyelination (dmy) maps to chromosome 17

A recessive mutation exhibiting severe myelin breakdown, mainly at the level of the lumbar segments of the spinal cord and without any associated inflammation, was discovered in a partially inbred rat colony. Analysis of the segregation patterns of a set of polymorphic microsatellite markers in two inter-strain crosses allowed the mapping of this autosomal recessive mutation to rat Chromosome (Chr) 17, very close to the prolactin (Prl) locus, in a region homologous to human Chr 6p21.2-22.3 and mouse Chr 13. The pathology of the demyelination process and the chromosomal localization indicate that this mutation has no known equivalent in either mouse or human. Received: 21 March 1996 / Accepted: 22 July 1996     

Confirmation and refinement of the localisation of the c-MEL locus on chromosome 19 by physical and genetic mapping

Summary The human gene locus c-MEL was identified following transfection of genomic DNA from the human melanoma cell line NK14; it has previously been assigned to chromosome 19 (p13.2–q13.2) by analysis of somatic cell hybrids. We have further refined the position of this gene to the proximal region of 19p (cen-p13.2), using cell hybrids containing only fragments of human chromosome 19. We have confirmed this physical localisation by linkage analysis with a recently described restriction fragment length polymorphism for the c-MEL gene, and mapped the locus within the region of the low density lipoprotein receptor gene (LDLR) (Lod 4.43, ) and the anonymous marker D19S11 (13.1.25) (Lod 9.33, ). This gene thus maps to a region of chromosome 19 involved in karyotypic abnormalities in a variety of malignancies including melanomas and leukaemias.     

Fine mapping of Hyplip1 and the human homolog, a potential locus for FCHL

Familial combined hyperlipidemia (FCHL) is a common genetic dyslipidemia predisposing to premature coronary heart disease (CHD). We previously identified a locus for FCHL on human Chromosome (Chr) 1q21-q23 in 31 Finnish FCHL families. We also mapped a gene for combined hyperlipidemia (Hyplip1) to a potentially orthologous region of mouse Chr 3 in the HcB-19/Dem mouse model of FCHL. The human FCHL locus was, however, originally mapped about 5 Mb telomeric to the synteny border, the centromeric part of which is homologous to mouse Chr 3 and the telomeric part to mouse Chr 1. To further localize the human Hyplip1 homolog and estimate its distance from the peak linkage markers, we fine-mapped the Hyplip1 locus and defined the borders of the region of conserved synteny between human and mouse. This involved establishing a physical map of a bacterial artificial chromosome (BAC) contig across the Hyplip1 locus and hybridizing a set of BACs to both human and mouse chromosomes by fluorescence in situ hybridization (FISH). We narrowed the location of the mouse Hyplip1 gene to a 1.5-cM region that is homologous only with human 1q21 and within approximately 5–10 Mb of the peak marker for linkage to FCHL. FCHL is a complex disorder and this distance may, thus, reflect the well-known problems hampering the mapping of complex disorders. Further studies identifying and sequencing the Hyplip1 gene will show whether the same gene predisposes to hyperlipidemia in human and mouse. Received: 9 September 2000 / Accepted: 30 October 2000     

Human homeo box-containing genes located at chromosome regions 2q31----2q37 and 12q12----12q13

Four human homeo box-containing cDNAs isolated from mRNA of an SV40-transformed human fibroblast cell line have been regionally localized on the human gene map. One cDNA clone, c10, was found to be nearly identical to the previously mapped Hox-2.1 gene at 17q21. A second cDNA clone, c1, which is 87% homologous to Hox-2.2 at the nucleotide level but is distinct from Hox-2.1 and Hox-2.2, also maps to this region of human chromosome 17 and is probably another member of the Hox-2 cluster of homeo box-containing genes. The third cDNA clone, c8, in which the homeo box is approximately 84% homologous to the mouse Hox-1.1 homeo box region on mouse chromosome 6, maps to chromosome region 12q12----12q13, a region that is involved in chromosome abnormalities in human seminomas and teratomas. The fourth cDNA clone, c13, whose homeo box is approximately 73% homologous to the Hox-2.2 homeo box sequence, is located at chromosome region 2q31----q37. The human homeo box-containing cluster of genes at chromosome region 17q21 is the human cognate of the mouse homeo box-containing gene cluster on mouse chromosome 11. Other mouse homeo box-containing genes of the Antennapedia class (class I) map to mouse chromosomes 6 (Hox-1, proximal to the IgK locus) and 15 (Hox-3). A mouse gene, En-1, with an engrailed-like homeo box (class II) and flanking region maps to mouse chromosome 1 (near the dominant hemimelia gene). Neither of the class I homeo box-containing genes--c8 and c13--maps to a region of obvious homology to chromosomal positions of the presently known mouse homeo box-containing genes.     

Location of mouse and human genes corresponding to conserved canine olfactory receptor gene subfamilies

Olfactory receptors are G protein-coupled, seven-transmembrane-domain proteins that are responsible for binding odorants in the nasal epithelium. They are encoded by a large gene family, members of which are organized in several clusters scattered throughout the genomes of mammalian species. Here we describe the mapping of mouse sequences corresponding to four conserved olfactory receptor genes, each representing separate, recently identified canine gene subfamilies. Three of the four canine genes detected related gene clusters in regions of mouse Chromosomes (Chrs) 2, 9, and 10, near previously mapped mouse olfactory genes, while one detected a formerly unidentified gene cluster located on mouse Chr 6. In addition, we have localized two human gene clusters with homology to the canine gene, CfOLF4, within the established physical map of Chr 19p. Combined with recently published studies, these data link the four conserved olfactory gene subfamilies to homologous regions of the human, dog, and mouse genomes. Received: 10 September 1997 / Accepted: 29 December 1997     

Cloning of a novel member of the low-density lipoprotein receptor family

A gene encoding a novel transmembrane protein was identified by DNA sequence analysis within the insulin-dependent diabetes mellitus (IDDM) locus IDDM4 on chromosome 11q13. Based on its chromosomal position, this gene is a candidate for conferring susceptibility to diabetes. The gene, termed low-density lipoprotein receptor related protein 5 (LRP5), encodes a protein of 1615 amino acids that contains conserved modules which are characteristic of the low-density lipoprotein (LDL) receptor family. These modules include a putative signal peptide for protein export, four epidermal growth factor (EGF) repeats with associated spacer domains, three LDL-receptor (LDLR) repeats, a single transmembrane spanning domain, and a cytoplasmic domain. The encoded protein has a unique organization of EGF and LDLR repeats; therefore, LRP5 likely represents a new category of the LDLR family. Both human and mouse LRP5 cDNAs have been isolated and the encoded mature proteins are 95% identical, indicating a high degree of evolutionary conservation.     

Fine mapping of the circling (cir) gene on the distal portion of mouse chromosome 9

Circling mice manifest profound deafness, head-tossing, and bi-directional circling behavior, which they inherit in autosomal recessive manner. Histologic examination of the inner ear reveals abnormalities of the region around the organ of Corti, spiral ganglion neurons, and outer hair cells. A genetic linkage map was constructed for an intraspecific backcross between cir and C57BL/6J mice. The cir gene was mapped to a region between D9Mit116/D9Mit15 and D9Mit38 on mouse chromosome (Chr) 9. Estimated distances between cir and D9Mit116, and between cir and D9Mit38 were 0.70 +/- 0.40 and 0.23 +/- 0.23 cM, respectively. Order of the markers was defined as follows: centromere - D9Mit182 - D9Mit51/D9Mit79/D9Mit310 - D9Mit212/D184 - D9Mit116/D9Mit15 - cir - D9Mit38 - D9Mit20 - D9Mit243 - D9Mit16 - D9Mit55/D9Mit125 - D9Mit281. On the basis of genetic mapping, we constructed a yeast artificial chromosome (YAC) contig across the cir region. The cir gene is located between the lactotransferrin (ltf) and microtubule-associated protein (map4) genes. The distal portion of mouse Chr 9 encompassing the cir region is homologous with human chromosome 3p21, which contains the Deafness, form B: Autosomal Recessive Deafness (DFNB6) locus. Therefore, the circling mouse is a potential animal model for DFNB6 deafness in humans.     

Mapping of multiple subunits of the neuronal nicotinic acetylcholine receptor to chromosome 15 in man and chromosome 9 in mouse

The alpha 3, alpha 5, and beta 4 genes (human gene symbols CHRNA3, CHRNA5, and CHRNB4 respectively; mouse gene symbols Acra-3, Acra-5, and Acrb-4, respectively) are members of the nicotinic acetylcholine receptor gene family and are clustered within a 68-kb segment of the rat genome (Boulter et al., 1990, J. Biol. Chem. 265:4472). By somatic cell hybrid analysis, three cDNAs corresponding to these genes were used to map the homologous loci to human chromosome 15 and to mouse chromosome 9. Linkage analysis using CEPH pedigrees showed that the CHRNA5 gene was closely linked to the following chromosome 15 loci: D15S46, D15S52, D15S28, D15S34, and D15S35. Using interspecies crosses in mice, the Acra-5 gene was found closely linked to the Mpi-1 locus. The mapping of these members of a neurotransmitter receptor gene family may facilitate the identification of relationships between the neurotransmitter receptors and murine or human phenotypes.     

Human chromosome 21q22.2-qter carries a gene(s) responsible for downregulation of mlc2a and PEBP in Down syndrome model mice

Congenital heart disease (CHD) is a major clinical manifestation of Down syndrome (DS). We recently showed that chimeric mice containing a human chromosome 21 (Chr 21) exhibited phenotypic traits of DS, including CHD. Our previous study showed that myosin light chain-2a (mlc2a) expression was reduced in the hearts of chimeric mice and DS patients. We found that phosphatidylethanolamine binding protein (PEBP) was also downregulated in Chr 21 chimeras in this study. As mlc2a is involved in heart morphogenesis, and PEBP controls the proliferation and differentiation of different cell types, these genes are candidates for involvement in DS-CHD. The DS-CHD candidate region has been suggested to span between PFKL and D21S3, which is the STS marker near the ETS2 loci. To identify gene(s) or a gene cluster on Chr 21 responsible for the downregulation of mlc2a and PEBP, we fragmented Chr 21 at the EST2 loci, by telomere-directed chromosome truncation in homologous recombination-proficient chicken DT40 cells. The modified Chr 21 was transferred to mouse ES cells by microcell-mediated chromosome transfer (MMCT), via CHO cells. We used ES cell lines retaining the Chr 21 truncated at the ETS2 locus (Chr 21E) to produce chimeric mice and compared overall protein expression patterns in hearts of the chimeras containing the intact and the fragmented Chr 21 by two-dimensional electrophoresis. While mouse mlc2a and PEBP expression was downregulated in the chimeras containing the intact Chr 21, the expression was not affected in the Chr 21E chimeras. Therefore, we suggest that Chr 21 gene(s) distal from the ETS2 locus reduce mouse mlc2a and PEBP expression in DS model mice and DS. Thus, this chromosome engineering technology is a useful tool for identification or mapping of genes that contribute to the DS phenotypes.     

Chromosomal localization of mouse and human neurotensin receptor genes

Neurotensin is a tridecapeptide that plays several neurotransmitter or neuromodulatory roles both in the central nervous system and in the periphery. These actions are mediated by a high-affinity receptor (Ntsr). Both rat and human cDNAs encoding high-affinity receptors have been recently cloned. The availability of Ntsr probes allowed us to localize the corresponding genes on the mouse and human chromosomes. The present data demonstrate that the Ntsr gene is assigned to the H region of the mouse Chromosome (Chr) 2 and to the long arm of the human Chr 20.     

Assignment of the gene coding for hepatocyte growth factor-like protein to mouse chromosome 9

The gene coding for hepatocyte growth factor-like protein has been localized to mouse chromosome 9 at a locus (Hgfl) distal to the Trf locus. The likely gene order in this region is centromere-Trf-Gnai-2-Hgfl-Cck. The region surrounding the Hgfl locus shows homology of syntenty to band p21 on human chromosome 3.     

Genomic structure, mapping, and expression analysis of the mammalian Lunatic, Manic, and Radical fringe genes

The three members of the mammalian fringe gene family, Manic fringe (Mfng), Radical fringe (Rfng), and Lunatic fringe (Lfng), were identified on the basis of their similarity to Drosophila fringe (fng) and their participation in the evolutionarily conserved Notch receptor signaling pathway. Fringe genes encode pioneer secretory proteins with weak similarity to glycosyltransferases. Both expression patterns and functional studies support an important role for Fringe genes in patterning during embryonic development and an association with cellular transformation. We have now further characterized the expression and determined the chromosomal localization and genomic structure of the mouse Mfng, Rfng, and Lfng genes; the genomic structure and conceptual open reading frame of the human RFNG gene; and the refined chromosomal localization of the three human fringe genes. The mouse Fringe genes are expressed in the embryo and in adult tissues. The mouse and human Fringe family members map to three different chromosomes in regions of conserved synteny: Mfng maps to mouse Chr 15, and MFNG maps to human Chr 22q13.1 in the region of two cancer-associated loci; Lfng maps to mouse Chr 5, and LFNG maps to human Chr 7p22; Rfng maps to mouse Chr 11, and RFNG maps to human Chr 17q25 in the minimal region for a familial psoriasis susceptibility locus. Characterization of the genomic loci of the Fringe gene family members reveals a conserved genomic organization of 8 exons. Comparative analysis of mammalian Fringe genomic organization suggests that the first exon is evolutionarily labile and that the Fringe genes have a genomic structure distinct from those of previously characterized glycosyltransferases. Received: 19 February 1999 / Accepted: 22 February 1999     

Genetic mapping of a new homeobox gene to mouse chromosome 7

A newly identified homeobox gene designated Dbx has been mapped to mouse Chromosome (Chr) 7. This gene is expressed in a restricted manner in developing mouse brain and spinal cord and has amino acid sequence similarities with members of the homeobox gene family such as Drosophila H2.0 and mouse Hlx. Using a fragment of the Dbx cDNA as a probe, a PstI restriction fragment length polymorphism was used to determine genotypes of 144 progeny from an interspecific backcross. Segregation analysis revealed linkage of Dbx with six prepositioned reference loci on mouse Chr 7. No recombination was observed between Dbx and Odc-rs6, indicating that Dbx lies approximately 25 cM distal to the Chr 7 centromere in a region that has conserved linkage relationships with regions of human Chrs 11 and 19.