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.     

Mapping of the SWAP70 gene to mouse Chromosome 7 and human Chromosome 11p15

 The protein SWAP-70 was isolated as part of a DNA recombination complex in B lymphocytes, where it is predominantly expressed. In resting B cells, SWAP-70 is found in the cytoplasm; upon B-cell activation, it is transported both into the nucleus and to the cell membrane, where it is associated with the B-cell receptor complex and may play a role in signal transduction. In the nucleus, its involvement in heavy-chain class switch recombination has been suggested. In this report, using restriction fragment length polymorphism, simple sequence length polymorphism, and fluorescence in situ hybridization, we map the chromosomal localization of the mouse and the human genes to syntenic regions of mouse mid Chromosome (Chr) 7 and human Chr 11p15. Received: 1 July 1999 / Revised: 28 July 1999     

Evolutionary History of the 11p15 Human Mucin Gene Family

The four human mucin genes MUC6, MUC2, MUC5AC, and MUC5B are located at chromosome 11p15.5. It has been demonstrated that the three mucins MUC2, MUC5AC, and MUC5B contain several Cys-subdomains of 108 amino acid residues. In contrast, little information is available concerning MUC6. These Cys-subdomains contain 10 cysteine residues that have a highly conserved position. We present here a coherent probable evolutionary history of this human gene family after comparison of the nucleotide sequences of these Cys-subdomains. The three MUC loci MUC2, MUC5AC, and MUC5B may have evolved from a common ancestral gene by two successive duplications. Moreover, we can postulate that MUC5AC and MUC5B have evolved in a concerted manner, while MUC2 has evolved separately. Received: 30 January 1997 / Accepted: 17 April 1997     

Linkage of a Gene Causing High Bone Mass to Human Chromosome 11 (11q12-13)

The purpose of this paper is to report the linkage of a genetic locus (designated "HBM") in the human genome to a phenotype of very high spinal bone density, using a single extended pedigree. We measured spinal bone-mineral density, spinal Z(BMD), and collected blood from 22 members of this kindred. DNA was genotyped on an Applied Biosystems model 377 (ABI PRISM Linkage Mapping Sets; Perkin Elmer Applied Biosystems), by use of fluorescence-based marker sets that included 345 markers. Both two-point and multipoint linkage analyses were performed, by use of affected/unaffected and quantitative-trait models. Spinal Z(BMD) for affected individuals (N = 12) of the kindred was 5.54 +/- 1.40; and for unaffected individuals (N = 16) it was 0.41 +/- 0.81. The trait was present in affected individuals 18-86 years of age, suggesting that HBM influences peak bone mass. The only region of linkage was to a series of markers on chromosome 11 (11q12-13). The highest LOD score (5.21) obtained in two-point analysis, when a quantitative-trait model was used, was at D11S987. Multipoint analysis using a quantitative-trait model confirmed the linkage, with a LOD score of 5.74 near marker D11S987. HBM demonstrates the utility of spinal Z(BMD) as a quantitative bone phenotype that can be used for linkage analysis. Osteoporosis pseudoglioma syndrome also has been mapped to this region of chromosome 11. Identification of the causal gene for both traits will be required for determination of whether a single gene with different alleles that determine a wide range of peak bone densities exists in this region.     

Cloning of cDNA Encoding Human Rapsyn and Mapping of the RAPSN Gene Locus to Chromosome 11p11.2–p11.1

We have isolated and sequenced cDNA clones for the human 43-kDa acetylcholine receptor-associated protein rapsyn. The cDNA encodes a 412-amino-acid protein that has a predicted molecular mass of 46,330 Da and shows 96% sequence identity with mouse rapsyn. Analysis of PCR amplifications, first from somatic cell hybrids and subsequently from radiation hybrids, localizes the human RAPSN gene locus to chromosome 11p11.2–p11.1 in close proximity to ACP2.     

Genomic Organization of the Human SPOCK Gene and Its Chromosomal Localization to 5q31

SPOCK, previously identified as testican, is a modular proteoglycan that carries both chondroitin and heparan sulfate glycosaminoglycan side chains. The overall genomic organization has been established. The SPOCK gene spans at least 70 kb and is composed of 11 exons: the first half of the gene is dramatically expanded, but the second half is more compact.In situhybridization and YAC mapping independently linked the SPOCK gene to 5q31, a region containing an impressive number of genes encoding growth factors, cytokines, and neurotransmitter and hormone receptors. The gene is located between the IL9 and the EGR1 genes, bordering the smallest commonly deleted region of chromosome 5.     

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.     

Cloning and Gene Mapping of the Chromosome 13q14 Region Deleted in Chronic Lymphocytic Leukemia

Frequent deletions and loss of heterozygosity in a segment of chromosome 13 (13q14) in cases of B-cell chronic lymphocytic leukemia (CLL) have suggested that this malignancy is caused by inactivation of an unknown tumor suppressor gene located in this region. Toward the identification of the putative CLL tumor suppressor, we have constructed a high-resolution physical map of YAC, PAC, and cosmid contigs covering 600 kb of the 13q14 genomic region. In addition to densely positioned genetic markers and STSs, this map was further annotated by localization of 32 transcribed sequences (ESTs) using a combination of exon trapping, direct cDNA selection, sample sequencing of cosmids and PACs, and homology searches. On the basis of these mapping data, allelic loss analyses at 13q14 using CLL tumor samples allowed narrowing of the genomic segment encompassing the putative CLL gene to <300 kb. Twenty-three ESTs located within this minimally deleted region are candidate exons for the CLL-associated tumor suppressor gene.     

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.     

Human Rod Monochromacy: Linkage Analysis and Mapping of a Cone Photoreceptor Expressed Candidate Gene on Chromosome 2q11

We have performed linkage analysis in eight families with rod monochromacy, an autosomal recessively inherited condition with complete color blindness. Significant linkage was found with markers located at the pericentromeric region of chromosome 2. A maximum lod score of 5.36 was obtained for marker D2S2333 at θ = 0.00. Mapping of meiotic breakpoints localized the disease gene between markers D2S2187 and D2S2229. Homozygosity for a number of subsequent markers indicating identity by descent was found in two families and provides evidence for a further refinement of the locus proximal to D2S373. This defines an interval of ≈3 cM covering theACHM2locus for rod monochromacy. Radiation hybrid mapping of theCNGA3gene encoding the α-subunit of the cGMP gated cation channel in human cone photoreceptors resulted in a maximum lod score of 16.1 with marker D2S2311 combined with a calculated physical distance of 6.19cR_10,000. Screening of the CEPH YAC library and subsequent STS mapping indicated the physical order cen–D2S2222–D2S2175–(D2S2187/D2S2311)–qtel ofmarkers on 2q11 and showed that theCNGA3gene maps most closely to D2S2187 and D2S2311. These data indicate that theCNGA3gene maps within the critical interval of theACHM2locus for rod monochromacy and thus is a candidate gene for this disease.     

Admixture Mapping of Quantitative Trait Loci for BMI in African Americans: Evidence for Loci on Chromosomes 3q, 5q,and 15q

Obesity is a heritable trait and a major risk factor for highly prevalent common diseases such as hypertension and type 2 diabetes. Previously we showed that BMI was positively correlated with African ancestry among the African Americans (AAs) in the US National Heart, Lung, and Blood Institute's Family Blood Pressure Program (FBPP). In a set of 1,344 unrelated AAs, using Individual Ancestry (IA) estimates at 284 marker locations across the genome, we now present a quantitative admixture mapping analysis of BMI. We used a set of unrelated individuals from Nigeria to represent the African ancestral population and the European American (EA) in the FBPP as the European ancestral population. The analysis was based on a common set of 284 microsatellite markers genotyped in all three groups. We considered the quantitative trait, BMI, as the response variable in a regression analysis with the marker location specific excess European ancestry as the explanatory variable. After suitably adjusting for different covariates such as sex, age, and network, we found strong evidence for a positive association with European ancestry at chromosome locations 3q29 and 5q14 and a negative association on chromosome 15q26. To our knowledge, this is the largest quantitative admixture mapping effort in terms of sample size and marker locus involvement for the trait. These results suggest that these regions may harbor genes influencing BMI in the AA population.     

用放射杂交板定位鸡的MC4R基因以及其在鸡和人染色体上同源区的比较分析

黑素皮质素受体(melanocortin-4 receptor,MC4R)基因的突变与猪、鼠和人等的食欲、肥胖和生长有关联性,然而对鸡的MC4R基因的功能却知之甚少。为了确定鸡的MC4R基因在染色体上的位置,使用鸡-仓鼠杂交板(ChickRH6)做了该基因的定位工作。通过扩增ChickRH6杂交板上的93个样品,然后经整合分析将mC4R基因定位在2号染色体上的标记MCW0062、BCL2和OVY附近,即2q12。这个连锁图上的5个标记基于两点分析与MC4R的LOD值都大于5。同时,以MC4R基因为标记做了鸡和人的染色体比较分析。结果显示鸡的2号染色体(GGA2)和人的18号染色体(HSA18)存在同源区,且基因BCL2和肥胖基因(obesity)位于MC4R基因附近。推测鸡的MC4R基因与人的MC4R基因可能具有相似的功能。该研究揭示了鸡和人MC4R基因的染色体分布,并用杂交放射板将鸡的MC4R基因定位在2号染色体的12区带。     

Mapping of the Human Cysteine-Rich Intestinal Protein GeneCRIP1to the Human Chromosomal Segment 7q11.23

We report here on the mapping of a cDNA encoding for human cysteine-rich heart protein (HCRHP), a counterpart of the murine cysteine-rich intestinal protein CRIP. By somatic cell hybrid analysis and radiation hybrid mapping, we have located the geneCRIP1(HGMW-approved symbol) on the subcentromeric region of the q arm of human chromosome 7, flanking a deletion associated with Williams syndrome.     

Molecular Characterization of Human Neogenin, a DCC-Related Protein, and the Mapping of Its Gene (NEO1) to Chromosomal Position 15q22.3–q23

Neogenin was first identified in the chick embryo, and like a number of cell surface proteins of the immunoglobulin (Ig) superfamily, including N-CAM and L1 (generally called cell adhesion molecules or CAMs), it is expressed on growing nerve cells in the developing nervous system of vertebrate embryos. Neogenin is also expressed in other embryonic tissues, suggesting a more general role in developmental processes such as tissue growth regulation, cell–cell recognition, and cell migration. Neogenin, unlike the CAMs, is closely related to a unique tumor suppressor candidate molecule, deleted in colorectal carcinoma (DCC). Like DCC, the neogenin protein consists of four immunoglobulin-like (Ig-like) domains followed by six fibronectin type III domains, a transmembrane domain, and an intracellular domain. We now report the cloning and sequencing of cDNA clones coding for the human neogenin protein. Human neogenin shares 87% identity with its chicken homolog, and like its chicken counterpart it is expressed in at least two different isoforms derived from alternative splicing in the intracellular domain. Northern blot analysis revealed two mRNA species of about 5 and 7 kb. The chromosomal location of the human neogenin gene (HGMW-approved symbol NEO1) was determined as 15q22.3–q23, using fluorescencein situhybridization. The gene therefore maps in the vicinity of a locus associated with Bardet–Biedl syndrome. The identification of human neogenin and its chromosomal location provides a basis for studying its involvement in genetic disorders or diseases.