Four human Chromosome 3q and four human Chromosome 21 loci map onto sheep Chromosome 1q

Eight new loci have been assigned to sheep Chromosome (Chr) 1q by use of a chromosomally characterized minipanel of sheep x hamster cell hybrids. Four loci, which have been mapped to the distal region of human Chr 3q, are ceruloplasmin (CP), sucrase isomaltase (SI), glucose transporter 2 (GLUT2), and ectopic viral integration site 1 (EVI1). The other four loci, on human Chr 21, include interferon alpha receptor (IFNAR); interferon inducible protein p78, murine (MX1); collagen type VI, alpha 1 (COL6A1); and S100 protein, beta polypeptide (S100B). All of these loci, except GLUT2 and MX1, have been mapped onto bovine Chr 1 or are syntenic with loci on this chromosome. The in situ localization of transferrin (TF) to sheep Chr 1q42-q45 confirms our previous assignment of this locus and independently anchors the eight new syntenic loci to sheep Chr 1q.     

Assignment of the CD45-AP Gene to the Centromeric End of Mouse Chromosome 19 and Human Chromosome 11q13.1–q13.3

CD45-AP is a recently identified phosphorylated protein that specifically associates with the leukocyte-specific transmembrane glycoprotein CD45. The gene for CD45-AP,Ptprcap(protein tyrosine phosphatase, receptor type c polypeptide associated protein), was mapped in mouse by typing the progeny of two multilocus crosses using the mouse CD45-AP cDNA as a Southern hybridization probe. The CD45-AP gene mapped to the centromeric region of Chr 19 proximal to the genesFth, Cd5,andPcna-rs.The gene for the human CD45-AP homologue,PTPRCAP,was localized to chromosome band 11q13.1–q13.3 by fluorescencein situhybridization using human genomic CD45-AP DNA as a hybridization probe. The genetic mapping of thePtprcap/PTPRCAPgenes extends the previously defined synteny conservation of various genes that have been assigned to these regions of the mouse and the human chromosomes.     

Genetic Linkage of the Muckle-Wells Syndrome to Chromosome 1q44

The Muckle-Wells syndrome (MWS) is a hereditary inflammatory disorder characterized by acute febrile inflammatory episodes comprising abdominal pain, arthritis, and urticaria. Progressive nerve deafness develops subsequently, and, after several years, the disease is complicated by multiorgan AA-type amyloidosis (i.e., amyloidosis derived from the inflammatory serum amyloid-associated protein) (MIM 191900) with renal involvement and end-stage renal failure. The mode of inheritance is autosomal dominant, but some sporadic cases have also been described. No specific laboratory findings have been reported. The genetic basis of MWS is unknown. Using a genomewide search strategy in three families, we identified the locus responsible for MWS, at chromosome 1q44. Our results indicate that the gene is located within a 13.9-cM region between markers D1S2811 and D1S2882, with a maximum two-point LOD score of 4. 66 (recombination fraction.00) at D1S2836 when full penetrance is assumed. Further identification of the specific gene that is responsible for MWS will therefore provide the first biological element for characterizing MWS, other than doing so on the basis of its variable clinical expression.     

Localization of the -Glutamine Synthetase Gene to Chromosome 1q23

Glutamine synthetase (E.C. 6.3.1.2) is expressed throughout the body and plays an important role in controlling body pH and in removing ammonia from the circulation. The enzyme clears -glutamate, the major neurotransmitter in the central nervous system, from neuronal synapses. The enzyme is a very sensitive marker of many disease and aging processes, especially those involving reactive oxygen species. This report describes the localization of the enzyme to chromosome 1 by PCR analysis of a human/rodent somatic cell hybrid panel. We also describe the localization of a recently described pseudogene to chromosome 9. Further localization of the glutamine synthetase gene locus to 1q23 was accomplished by fluorescencein situhybridization. The glutamine synthetase gene was mapped to five CEPH megaYACs between the polymorphic PCR markers D1S117 and D1S466 by analysis of the Whitehead Institute's recently described chromosome 1 contig map.     

A radiation hybrid panel for human Chromosome 6q

A panel of 63 radiation-reduced hybrids has been derived from a mouse cell line containing a neo-marked human Chromosome (Chr) 6, primarily to provide a resource for higher resolution localization of new markers. Hybrids were generated with radiation doses of 40–400 Gy, selected in G418, and were shown by PCR to contain the neo gene. PCR was also used to score the retention of 15 loci that map from 6q13 to q25.2 of the current consensus map plus six other loci assigned to 6q26-q27. An average retention frequency of 27.8% was observed, with the highest frequencies at D6S313 and D6S280 (63.5%) located near the centromere at 6q13, and at D6S283 (68.5%) at 6q16.3-q21, presumably close to the neo integration site. Lowest frequencies (4.8%) were observed for telomeric markers. All markers segregated independently except D6S297 and D6S193. Agreement and some improvement to the current consensus map of 6q was made by mapping 12 loci by the non-parametric statistical method of Falk. In addition, deletion mapping with informative hybrids allowed the ordering of six loci from 6q26 to q27 and permitted some integration of maps of this region.     

Linkage of Familial Schizophrenia to Chromosome 13q32

Over the past 4 years, a number of investigators have reported findings suggestive of linkage to schizophrenia, with markers on chromosomes 13q32 and 8p21, with one recent study by Blouin et al. reporting significant linkage to these regions. As part of an ongoing genome scan, we evaluated microsatellite markers spanning chromosomes 8 and 13, for linkage to schizophrenia, in 21 extended Canadian families. Families were analyzed under autosomal dominant and recessive models, with broad and narrow definitions of schizophrenia. All models produced positive LOD scores with markers on 13q, with higher scores under the recessive models. The maximum three-point LOD scores were obtained under the recessive-broad model: 3.92 at recombination fraction (theta).1 with D13S793, under homogeneity, and 4.42 with alpha=.65 and straight theta=0 with D13S793, under heterogeneity. Positive LOD scores were also obtained, under all models, for markers on 8p. Although a maximum two-point LOD score of 3.49 was obtained under the dominant-narrow model with D8S136 at straight theta=0.1, multipoint analysis with closely flanking markers reduced the maximum LOD score in this region to 2. 13. These results provide independent significant evidence of linkage of a schizophrenia-susceptibility locus to markers on 13q32 and support the presence of a second susceptibility locus on 8p21.     

Genetic Mapping of the BRCA1 Region on Chromosome 17q21

Chromosome 17q21 harbors a gene (BRCA1) associated with a hereditary form of breast cancer. As a step toward identification of this gene itself we developed a number of simple-sequence-repeat (SSR) markers for chromosome 17 and constructed a high-resolution genetic map of a 40-cM region around 17q21. As part of this effort we captured genotypes from five of the markers by using an ABI sequencing instrument and stored them in a locally developed database, as a step toward automated genotyping. In addition, YACs that physically link some of the SSR markers were identified. The results provided by this study should facilitate physical mapping of the BRCA1 region and isolation of the BRCA1 gene.     

Genetic Polymorphism and Recombination in the Subtelomeric Region of Chromosome 14q

Subtelomeric regions of human chromosomes are the sites of increased meiotic recombination and have a male-to-female recombination ratio that is higher than elsewhere in the genome. We isolated two novel, polymorphic CA repeat markers from the distal part of the immunoglobulin heavy chain gene cluster, approximately 90 and 200 kb from the telomere of chromosome 14q. The 14q telomere was unambiguously located by physical mapping of telomeric YACs andBal31 exonuclease digestion of genomic DNA. We then constructed haplotypes using genotype data from these markers and data from sCAW1 (D14S826) for use as a highly polymorphic genetic marker. Linkage analysis using the 40 pedigree CEPH reference panel and genotype data from these and other loci physically mapped to the terminal 1.5 Mb of chromosome 14q revealed an apparent increase in meiotic recombination within this region, relative to the average rate for the genome. Further, we found that recombination was higher in females than in males, indicating that the subtelomeric region of 14q differs from other human subtelomeric regions.     

Chromosome 3q (22-ter) encodes the human transferrin receptor

The human transferrin receptor is an integral membrane glycoprotein of 180,000 molecular weight (mol. wt.) formed from two subunits of 90,000 mol. wt. A clone panel of Chinese hamster-human somatic cell hybrids was screened using a single cell plating cytotoxicity assay and rabbit antiserum raised to purified human transferrin receptor. Chromosome 3 displayed the highest rate of concordance with the presence of human transferrin receptor, as assayed by cytotoxicity. Antitransferrin receptor serum-resistant segregants of chromosome 3 positive, receptor-positive hybrids were selected, using antiserum and complement. The segregants consistently lost chromosome 3. 125I human transferrin binding studies confirmed synteny between the functional human transferrin receptor and chromosome 3. Examination of hybrids with either translocated or deleted chromosome 3's allows regional mapping to 3q(22-ter).     

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.     

Chromosome 4q;10q translocations; Comparison with different ethnic populations and FSHD patients

Background  

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by the weakness of facial, shoulder-girdle and upper arm muscles. Most patients with FSHD have fewer numbers of tandem repeated 3.3-kb KpnI units on chromosome 4q35. Chromosome 10q26 contains highly homologous KpnI repeats, and inter-chromosomal translocation has been reported.     

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.     

A High-Resolution Interval Map of the q21 Region of the Human X Chromosome

In a previous study, we have developed a panel of chromosomal rearrangements for the physical mapping of the q13-q21 region of the human X chromosome (Philippe et al., Genomics 17: 147-152, 1993). Here, we report the physical localization of 36 additional polymorphic markers by polymerase chain reaction analysis. The high density of chromosomal breakpoints in Xq21 allows us to map 58 DNA loci in 22 intervals. As a result, this segment of the X chromosome is saturated with approximately three sequence tagged sites per megabase of DNA, which will facilitate the construction of a YAC contig of this region.     

Fine Mapping of the Body Fat QTL on Human Chromosome 1q43

IntroductionEvidence for linkage and association of obesity-related quantitative traits to chromosome 1q43 has been reported in the Quebec Family Study (QFS) and in populations of Caribbean Hispanic ancestries yet no specific candidate locus has been replicated to date.MethodsUsing a set of 1,902 single nucleotide polymorphisms (SNPs) genotyped in 525 African American (AA) and 391 European American (EA) women enrolled in the NIEHS uterine fibroid study (NIEHS-UFS), we generated a fine association map for the body mass index (BMI) across a 2.3 megabase-long interval delimited by RGS7 (regulator of G-protein signaling 7) and PLD5 (Phospholipase D, member 5). Multivariable-adjusted linear regression models were fitted to the data to evaluate the association in race-stratified analyses and meta-analysis.ResultsThe strongest associations were observed in a recessive genetic model and peaked in the 3’ end of RGS7 at intronic rs261802 variant in the AA group (p = 1.0 x 10⁻⁴) and in meta-analysis of AA and EA samples (p = 9.0 x 10⁻⁵). In the EA group, moderate associations peaked at rs6429264 (p = 2.0 x 10⁻³) in the 2 Kb upstream sequence of RGS7. In the reference populations for the European ancestry in the 1,000 genomes project, rs6429264 occurs in strong linkage disequilibrium (D’ = 0.94) with rs1341467, the strongest candidate SNP for total body fat in QFS that failed genotyping in the present study. Additionally we report moderate associations at the 3’ end of PLD5 in meta-analysis (3.2 x 10⁻⁴ ≤ p ≤ 5.8 x 10⁻⁴).ConclusionWe report replication data suggesting that RGS7, a gene abundantly expressed in the brain, might be a putative body fat QTL on human chromosome 1q43. Future genetic and functional studies are required to substantiate our observations and to potentially link them to the neurobehavioral phenotypes associated with the RGS7 region.