The α-subunit of the skeletal muscle sodium channel is encoded proximal to Tk-1 on mouse Chromosome 11

Recent evidence suggests that the human neuromuscular disorders, hyperkalemic periodic paralysis and paramyotonia congenita, are both caused by genetic defects in the -subunit of the adult skeletal muscle sodium channel, which maps near the growth hormone cluster (GH) on Chromosome (Chr) 17q. In view of the extensive homology between this human chromosome and mouse Chr 11, we typed an interspecies backcross to determine whether the murine homolog (Scn4a) of this sodium channel gene mapped within the conserved chromosomal segment. The cytosolic thymidine kinase gene, Tk-1, was also positioned on the genetic map of Chr 11. Both Scn4a and Tk-1 showed clear linkage to mouse Chr 11 loci previously typed in this backcross, yielding the map order: Tr ^J-(Re, Hox-2, Krt-1)-Scn4a-Tk-1. No mouse mutant that could be considered a model of either hyperkalemic periodic paralysis or paramyotonia congenita has been mapped to the appropriate region of mouse Chr 11. These data incorporate an additional locus into the already considerable degree of homology observed for these human and mouse chromosomes. These data are also consistent with the view that the conserved segment region may extend to the telomere on mouse Chr 11 and on human 17q.     

Genetic and physical mapping of the natural resistance-associated macrophage protein 1 (NRAMP1) in chicken

The chicken natural resistance-associated macrophage protein 1 (NRAMP1) gene has been mapped by linkage analysis by use of a reference panel to develop the chicken molecular genetic linkage map and by fluorescence in situ hybridization. The chicken homolog of the murine Nramp1 gene was mapped to a linkage group located on Chromosome (Chr) 7q13, which includes three genes (CD28, NDUSF1, and EF1B) that have previously been mapped either to mouse Chr 1 or to human Chr 2q. Physical mapping by pulsed-field gel electrophoresis revealed that NRAMP1 is tightly linked to the villin gene and that the genomic organization (gene order and presence of CpG islands) of the chromosomal region carrying NRAMP1 is well conserved between the chicken and mammalian genomes. The regions on mouse Chr 1, human Chr 2q, and chicken Chr 7q that encompass NRAMP1 represent large conserved chromosomal segments between the mammalian and avian genomes. The chromosome mapping of the chicken NRAMP1 gene is a first step in determining its possible role in differential susceptibility to salmonellosis in this species.     

The Myb and Ahi-1 genes are physically very closely linked on mouse Chromosome 10

Ahi-1 has previously been identified as a common helper provirus integration site on mouse Chromosome (Chr) 10 in 16% of Abelson pre-B-cell lymphomas and shown to be closely linked to the Myb protooncogene. By using long-range restriction mapping, we have mapped the Myb and Ahi-1 regions within a 120-kbp DNA fragment. The Ahi-1 region is located approximately 35 kbp downstream of the Myb gene. A further comfirmation of this finding was obtained by screening a mouse YAC library. The three positive clones obtained contained both the Myb and Ahi-1 gene sequences. To test whether provirus integration in the Ahi-1 region enhances the expression of Myb by a cis-acting mechanism, we have also examined Myb gene expression in A-MuLV-induced pre-B-lymphomas. Our data have revealed that there is no clear evidence for such activation in the tumors we have tested, indicating that provirus insertion in the Ahi-1 region is activating a novel gene, apparently involved in tumor formation.     

Comparative mapping of mouse Chromosome 4 and human Chromosome 9: Lv,Orm, and Hxb are closely linked on mouse Chromosome 4

The genes for orosomucoid (ORM-1 and ORM-2), delta-aminolevulinate dehydratase (ALAD), and hexabrachion or tenascin (HXB) all map to the q31-qter region of human Chromosome (Chr) 9. The mouse homolog of each of these genes has been mapped to Chr 4, but hexabrachion has not previously been mapped by linkage analysis. We have now ordered Orm-1, Lv (the mouse homolog of ALAD), and Hxb in an interspecific backcross panel, by use of tyrosinase related protein-1, Tyrp-1, whose human homolog maps to 9p13-pter (Abbott et al., Genomics 1991) as a reference locus. No recombinants were identified in 124 animals between Lv and Orm-1. Hxb was found to be 1.6 cM distal to Lv and Orm-1, and 4.8 cM proximal to Tyrp-1, or b. These data therefore contribute to our knowledge of the conserved synteny between HSA 9q and MMU 4.     

Localization of two mouse genes encoding the protein tyrosine kinase receptor-related protein RYK

We have mapped the gene encoding the murine RYK growth factor receptor protein tyrosine kinase by genetic linkage analysis with recombinant inbred strains of mouse. Two distinct Ryk loci (Ryk-1 and Ryk-2) were identified. Ryk-1 mapped to Chromosome (Chr) 9, whereas Ryk-2 mapped to Chr 12. A similar arrangement of RYK-related loci was previously determined in the human. Synteny has already been established between murine Chr 9 in the region of Ryk-1, and human chromosome 3q11–12, the location of the human RYK-1 gene. However, the Ryk-2/RYK-2 loci on murine Chr 12 and human chr 17p13.3 define a new region of synteny.     

Gene homologs on human chromosome 15q21-q26 and a chicken microchromosome identify a new conserved segment

The genes for insulin-like growth factor 1 receptor (IGF1R), aggrecan (AGC1), β₂-microglobulin (B2M), and an H6-related gene have been mapped to a single chicken microchromosome by genetic linkage analysis. In addition, a second H6-related gene was mapped to chicken macrochromosome 3. The Igf1r and Agc1 loci are syntenic on mouse Chr 7, together with Hmx3, an H6-like locus. This suggests that the H6-related locus, which maps to the chicken microchromosome in this study, is the homolog of mouse Hmx3. The IGF1R, AGC1, and B2M loci are located on human Chr 15, probably in the same order as found for this chicken microchromosome. This conserved segment, however, is not entirely conserved in the mouse and is split between Chr 7 (Igf1r-Agc) and 2 (B2m). This comparison also predicts that the HMX3 locus may map to the short arm of human Chr 15. The conserved segment defined by the IGF1R–AGC1–HMX3—B2M loci is approximately 21–35 Mb in length and probably covers the entire chicken microchromosome. These results suggest that a segment of human Chr 15 has been conserved as a chicken microchromosome. The significance of this result is discussed with reference to the evolution of the avian and mammalian genomes. Received: 7 December 1996 / Accepted: 7 February 1997     

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     

Genomic structure and chromosomal localization of the mouse gene Punc

The mouse gene Punc encodes a member of the immunoglobulin superfamily of cell surface proteins. It is highly expressed in the developing embryo in nervous system and limb buds. At mid-gestation, however, expression levels of Punc decrease sharply. To allow investigation of such a regulatory mechanism, the genomic locus encompassing the Punc gene was cloned, characterized, and mapped. Fluorescent in situ hybridization was used to determine the chromosomal location of the Punc gene of mouse and human. Mouse Punc maps to Chromosome (Chr) 9 in the region D-E1, whereas the human PUNC gene is localized to Chr 15 at 15q22.3-23, a region known to be syntenic to mouse 9D-E1. The human PUNC gene therefore maps close to a genetic locus that is linked to Bardet-Biedl Syndrome, an autosomal recessive human disorder. Confirmation for the location of human PUNC was obtained through sequence relationships between mouse Punc cDNA, human PUNC cDNA, genomic sequence upstream of the murine Punc gene, and human STS markers that had been previously mapped on Chr 15. The STS sequence WI-14920 is in fact derived from the 3′-untranslated region of the human PUNC gene. WI-14920 had been placed at 228cR from the top of the Chr 15 linkage group, which provided positional information for the human PUNC gene at high resolution. Thus, this study identifies PUNC as the gene corresponding to a previously anonymous marker and serves as a basis to investigate its role in genetic disorders. Received: 8 July 1998 / Accepted: 14 October 1998     

Murine Stim1 maps to distal Chromosome 7 and is not imprinted

STIM1 (GOK) maps to a region of human Chromosome (Chr) 11p15.5 that is implicated in several embryonal tumors, and some evidence indicates that STIM1 may have a growth suppressor role in rhabdomyosarcoma. In this study we have mapped the murine homolog, Stim1, to the same position as Hbb on distal mouse Chr 7. This region is separated by 20 cM from the region of distal Chr 7 that contains Igf2, H19, and other imprinted genes. Using strain-specific polymorphisms, we have shown that Stim1 is expressed from both parental alleles in fetal and neonatal mouse tissues. Similar analyses of human Wilms' tumor and normal kidney tissues demonstrated biallelic expression of STIM1 in the majority of samples. These data demonstrate that Stim1 expression is not regulated by genomic imprinting in either mouse or human tissues. Thus, if STIM1 is a tumor suppressor at 11p15.5, loss of expression is not due to imprinting effects. Received: 23 January 1998 / Accepted: 10 April 1998     

Cloning and chromosomal mapping of the human p53-related KET gene to Chromosome 3q27 and its murine homolog Ket to mouse Chromosome 16

KET is a member of the newly discovered family of proteins that is related to the tumor suppressor p53. Here we describe the molecular cloning of a human cDNA of 4846 bp encoding a protein of 680 amino acids. The human KET protein shares 98% identity with the previously characterized rat homolog. The remarkably high degree of conservation lends support to the notion that KET proteins have important basic functions in development and differentiation. Using the GeneBridge 4 radiation hybrid panel, we have mapped KET to human Chromosome (Chr) 3q27. KET is located between the somatostatin gene SST (proximal) and the apolipoprotein D gene APOD (distal) in a region of conserved synteny to mouse Chr 16. This chromosomal region is deleted in early stages of tumorigenesis of mouse islet cell carcinomas and contains the hitherto unidentified Loh2 gene, a putative suppressor of angiogenesis. The murine homolog Ket was mapped in an interspecific backcross panel and falls into this region of loss of heterozygosity. From our mapping data we infer that KET might act as a tumor suppressor and is considered as a candidate for Loh2. Received: 30 April 1998 / Accepted: 17 July 1998     

Mouse genes encoding DNA topoisomerase I

We have initiated a genetic analysis of the physiologically important enzyme type I DNA topoisomerase in mouse. The exon-intron structures of the 5 part and the 3 part of the active gene, Top-1, were determined and shown to be quite similar to those of the previously determined human gene TOP1. The active mouse gene was mapped to the distal Chromosome (Chr) 2. In addition, the mouse genome contains one truncated processed topoisomerase-I-related pseudogene (retroposon), Top-1ps, on Chr 16. The Top-1ps locus, together with the immunoglobulin-lambda-light-chain locus, defines and additional conserved linkage group common to murine Chr 16 and human Chr 22, the site of the human pseudogene TOP1P2. The mapping data suggest that the pseudogene was established before mammalian radiation. Structural features, shared by the mouse and the human pseudogene, support this possibility.     

An autoimmune diabetes locus (Idd21) on mouse Chromosome 18

Twenty-four named Idd loci that contribute to the development of autoimmune diabetes in the nonobese diabetic (NOD) mouse have been mapped by linkage and congenic analysis. Previously, meta-analysis of genome-wide linkage scans supported the existence of a locus for susceptibility to autoimmune phenotypes on rodent Chromosome (Chr) 18, in a position orthologous to the human type 1 diabetes susceptibility locus IDDM6 (human Chr 18q12-q23). However, an autoimmune diabetes susceptibility locus has not previously been reported on mouse Chr 18. In this study, we demonstrate linkage of the majority of mouse Chr 18 to diabetes in a (ABH × NOD)F₁ × NOD backcross. Congenic analysis, introgressing at least 92% of Biozzi ABH Chr 18 onto the NOD background, confirmed the presence of a diabetes locus. The chromosome substitution strain (NOD.ABH-Chr18) had reduced diabetes incidence compared with NOD mice (P < 0.0001). We have named the Chr 18 diabetes locus Idd21.     

Linkage,but not gene order,of homologous loci,including α-L-iduronidase (Idua), is conserved in the Huntington disease region of the mouse and human genomes

-L-iduronidase (IDUA), which when deficient causes mucopolysaccharidosis type I, is located near the Huntington disease locus (HD) on human Chromosome (Chr) 4p16.3, approximately 10⁶ base pairs (bp) from the telomere. As part of our continuing efforts to define a detailed comparative map for this chromosomal segment in mice and humans, we have used an interspecific backcross between C57BL/6J and an inbred strain derived from Mus spretus to map Idua, the mouse homolog of IDUA. We also mapped the mouse homolog of D4S115, an anonymous locus approximately 250 kb proximal to IDUA. As expected, both Idua and D4S115h are located on the proximal portion of mouse Chr5 near homologs for other loci on human Chr 4p. Comparison of gene order in mice and humans demonstrates, however, that a chromosomal rearrangement within this conserved synteny has occurred since divergence of lineages leading to mice and humans.     

Chromosomal Mapping of Mouse Genes Expressed Selectively within the Central Nervous System

We have used RFLP analysis on DNA from a panel of interspecific (C57BL/6J × Mus spretus) F₁ × M. spretus backcross offspring to assign the genes encoding 10 neuron-specific mRNAs and 2 loci corresponding to cyclophilin 2-related sequences to the mouse chromosomal map. The Pss1 locus encoding the forebrain-enriched protein kinase C substrate RC3, a component of dendritic spines, mapped to proximal Chr 9. The Camkl locus encoding the calmodulin-binding protein kinase-like vesicle protein 1G5 mapped to distal Chr 9. The Gng7 locus encoding the γ7 G-protein subunit, highly enriched in the striatum and presumptively coupled to dopamine receptors, mapped to mid-Chr 10. The Htr1f, Htr5a, Htr5b, and Htr7 loci, encoding four serotonin receptors, mapped to Chr 16.5, 1, and 19, respectively. The Peplb locus, encoding a CD26 ectopeptidase-like neuronal membrane protein activated by kainate and long-term potentiation, mapped to Chr 5. The D2Sut1e and Cpu3 loci, encoding neural proteins of unknown functions, mapped to Chrs 2 and 9, respectively. Two cyclophilin 2-related loci, Cphn2-r1 and Cphn2-r2, mapped to different regions of Chr 9. Comparison of these 12 newly mapped loci with the existing mouse map and known regions of syntenic homology with the human map, along with the known features and expression profiles of the products of these genes, suggests a few candidates for mouse mutations and human neurological and immunological deficits, including the Tourette syndrome and Bloom syndrome genes.     

Molecular cloning, chromosomal assignment, and nucleotide sequence of the feline homeobox HOX3A.

The feline homolog to the mammalian homeobox locus, HOX3A, was isolated by screening a domestic cat genomic library with the murine Hox-3.1 probe. The nucleotide sequence similarity of the feline homeobox was 96% to human HOX3A, 94% to mouse Hox-3.1, and 94% to rat R4. The deduced amino acid sequence (homeodomain) of this feline homeobox was identical to all homeodomains of these cognate genes. Using a panel of feline x rodent somatic cell hybrids, the HOX3A locus was assigned to feline chromosome B4. Human HOX3A and mouse Hox-3.1 have been mapped previously to human chromosome 12 and mouse chromosome 15, respectively, both of which share syntenic homology to feline chromosome B4. These data demonstrate evolutionary conservation of both HOX3A gene sequences and chromosomal location during mammalian evolution.     

Identification and genetic mapping of the murine gene and 20 related sequences encoding chromosomal protein HMG-17

HMG-17 is an abundant, nonhistone chromosomal protein that binds preferentially to nucleosomal core particles of mammalian chromatin. The human gene for HMG-17 has been localized to Chromosome (Chr) 1p, but the murine gene has not been previously mapped. Here we identify the murine functional gene, Hmg17, from among more than 25 related sequences (probably processed pseudogenes) and show that it is located on mouse Chr 4, in a region known to have conserved linkage relationships with human Chr 1p. We also report the map locations of 20 additional Hmg17-related sequences on mouse Chrs 1, 2, 3, 5, 7, 8, 9, 13, 15, 16, 17, 18, and X. The multiple, dispersed members of the Hmg17 multigene family can be detected efficiently with a single cDNA probe and provide useful markers for genetic mapping studies in mice.     

Cardiac and skeletal muscle troponin I isoforms are encoded by a dispersed gene family on mouse Chromosomes 1 and 7

We mapped the locations of the genes encoding the slow skeletal muscle, fast skeletal muscle, and cardiac isoforms of troponin I (Tnni) in the mouse genome by interspecific hybrid backcross analysis of species-specific (C57BL/6 vs Mus spretus) restriction fragment length polymorphisms (RFLPs). The slow skeletal muscle troponin I locus (Tnni1) mapped to Chromosome (Chr) 1. The fast skeletal muscle troponin I locus (Tnni2), mapped to Chr 7, approximately 70 cM from the centromere. The cardiac troponin I locus (Tnni3) also mapped to Chr 7, approximately 5–10 cM from the centromere and unlinked to the fast skeletal muscle troponin I locus. Thus, the troponin I gene family is dispersed in the mouse genome. Received: 10 May 1995 / Accepted: 1 September 1995     

Linkage of phosphoribosylpyrophosphate synthetases 1 and 2, Prps1 and Prps2, on the mouse X Chromosome

The X Chromosome (Chr) genes for phosphoribosylpyrophosphate synthetases 1 and 2, Prps1 and Prps2, were mapped on the mouse X Chr with interspecific backcrosses between C57BL/6 (B6) and M. spretus (S). Southern analysis showed that Prps1 mapped between Plp and DXWas31, a mouse X Chr region that is homologous to Xq21-24 on the human X Chr while Prps2 mapped between DXWas31 and Amg, a region that is homologous to the map position of PRPS2 on Xp22 of the human X Chr. Additionally, other restriction fragments highlighted by PRS II showed autosomal segregation. In situ hybridization and FISH analysis of metaphase chromosome spreads prepared from lymphocytes of B6 or S male mice confirmed that there were in fact two different locations on the X Chr, X F1-2 and X F2-3 for Prps1 and 2 respectively, as well as two autosomal sites for Prps-like genes.     

Rbt (rabo torcido), a new mouse skeletal mutation involved in anteroposterior patterning of the axial skeleton,maps close to the ts (tail-short) locus and distal to the sox9 locus on chromosome 11

Rbt (Rabo torcido) is a new semidominant mouse mutant with a variety of skeletal abnormalities. Heterozygous Rbt mutants display homeotic anteroposterior patterning problems along the axial skeleton that resemble Polycomb group and trithorax gene mutations. In addition, the Rbt mutant displays strong similarities to the phenotype observed in Ts (Tail-short), indicating also a homeotically transformed phenotype in these mice. We have mapped the Rbt locus to an interval of approximately 6 cM on mouse Chromosome (Chr) 11 between microsatellite markers D11Mit128 and D11Mit103. The Ts locus was mapped within a shorter interval of approximately 3 cM between D11Mit128 and D11Mit203. This indicates that Rbt and Ts may be allelic mutations. Sox9, the human homolog of which is responsible for the skeletal malformation syndrome campomelic dysplasia, was mapped proximal to D11Mit128. It is, therefore, unlikely that Ts and Rbt are mouse models for this human skeletal disorder. Received: 14 April 1996 / Accepted: 22 July 1996