Human homologs of two testes-expressed loci on mouse chromosome 17 map to opposite arms of chromosome 6

Our laboratory has recently cloned and characterized two testes-expressed loci--the Tcp-10 gene family cluster and the D17Si11 gene--that map to the proximal portion of mouse chromosome 17. Human homologs of both loci have been identified and cloned. Somatic cell hybrid lines have been used to map the human homolog of D17Si11 to the short arm of chromosome 6 (p11-p21.1) along with homologs of other genes from the (Pim-1)-(Pgk-2) region of the mouse chromosome. The human TCP 10 locus maps to the long arm of chromosome 6 (q21-qter) along with homologs of other genes from the mouse chromosome 17 region between the centromere and Pim-1. The mapping of large portions of the mouse t haplotype to unlinked regions on human chromosome 6 rules out the possibility that a t-haplotype-like chromosome could exist in humans.     

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.     

Glial fibrillary acid protein, an astrocytic-specific marker, maps to human chromosome 17.

The murine glial fibrillary acid protein (GFAP) gene is located on chromosome 11 in close proximity to the genes encoding transforming protein p53 (Trp53) and myeloperoxidase (Mpo). Both Trp53 and Mpo have been mapped to human chromosome 17, but the chromosomal assignment of human GFAP has not been previously determined. In this report, we have amplified a cDNA fragment encoding a portion of GFAP from human brain and have used this probe to screen a mouse x human somatic cell hybrid panel. The results show that a human-specific GFAP species of approx 3.7 kb maps to one of these lines, TMS5, which contains chromosome 17 as its only human chromosome. On the basis of these data we speculate that there may be evolutionary relatedness between GFAP and other genes that map to both murine chromosome 11 and human chromosome 17.     

Chromosomal localization of two human zinc finger protein genes, ZNF24 (KOX17) and ZNF29 (KOX26), to 18q12 and 17p13-p12, respectively

Two members of the zinc finger Krüppel family, ZNF24 (KOX17) and ZNF29 (KOX26), have been localized by somatic cell hybrid analysis and in situ chromosomal hybridization to human chromosomes 18q12 and 17p13-p12, respectively. The mapping of ZNF29 together with the previously reported localization of ZFP3 suggests that a zinc finger gene complex is located on human chromosome 17p. ZNF29 maps centromeric to the human p53 tumor antigen gene (TP53). In the analogous murine position, the two mouse zinc finger genes Zfp2 and Zfp3 have recently been assigned to the distal region of mouse chromosome 11, the murine homolog of human chromosome 17. Both human zinc finger genes ZNF24 and ZNF29 are in chromosomal regions that have been noted to be deleted in neoplasms of the lung and of the central nervous system at chromosome 17p and in colorectal neoplasia at chromosomes 17p and 18q.     

The murine homolog of the human breast and ovarian cancer susceptibility geneBrca1 maps to mouse chromosome 11D

The recently cloned human breast and ovarian cancer suseptibility gene,BRCA1, is located on human chromosome 17q21. We have isolated murine genomic clones containingBrca1 as a first step in generating a mouse model for the loss ofBRCA1 function. A mouse genomic library was screened using probes corresponding to exon 11 of the humanBRCA1 gene. Two overlapping mouse clones were identified that hybridized to humanBRCA1 exons 9–12. Sequence analysis of 1.4 kb of the region of these clones corresponding to part of human exon 11 revealed 72% nucleic acid identity but only 50% amino acid identity with the human gene. The longest of the mouseBrca1 genomic clones maps to chromosome 11D, as determined by two-color fluorescence in situ hybridization. The synteny to human chromosome 17 was confirmed by cohybridization with the mouse probe for the NF1-gene. This comparative study confirms that the relative location of theBRCA1 gene has been conserved between mice and humans.     

Evolutionary aspects of the genomic organization of rat chromosome 10

Using FISH and RH mapping a chromosomal map of rat chromosome 10 (RNO10) was constructed. Our mapping data were complemented by other published data and the final map was compared to maps of mouse and human chromosomes. RNO10 contained segments homologous to mouse chromosomes (MMU) 11, 16 and 17, with evolutionary breakpoints between the three segments situated in the proximal part of RNO10. Near one of these breakpoints (between MMU17 and 11) we found evidence for an inversion ancestral to the mouse that was not ancestral to the condition in the rat. Within each of the chromosome segments identified, the gene order appeared to be largely conserved. This conservation was particularly clear in the long MMU11-homologous segment. RNO10 also contained segments homologous to three human chromosomes (HSA5, 16, 17). However, within each segment of conserved synteny were signs of more extensive rearrangements. At least 13 different evolutionary breakpoints were indicated in the rat-human comparison. In contrast to what was found between rat and mouse, the rat-human evolutionary breaks were distributed along the entire length of RNO10.     

A Comprehensive Genetic Map of Murine Chromosome 11 Reveals Extensive Linkage Conservation between Mouse and Human

Interspecific backcross animals from a cross between C57BL/6J and Mus spretus mice were used to generate a comprehensive linkage map of mouse chromosome 11. The relative map positions of genes previously assigned to mouse chromosome 11 by somatic cell hybrid or genetic backcross analysis were determined (Erbb, Rel, 11-3, Csfgm, Trp53-1, Evi-2, Erba, Erbb-2, Csfg, Myhs, Cola-1, Myla, Hox-2 and Pkca). We also analyzed genes that we suspected would map to chromosome 11 by virtue of their location in human chromosomes and the known linkage homologies that exist between murine chromosome 11 and human chromosomes (Mpo, Ngfr, Pdgfr and Fms). Two of the latter genes, Mpo and Ngfr, mapped to mouse chromosome 11. Both genes also mapped to human chromosome 17, extending the degree of linkage conservation observed between human chromosome 17 and mouse chromosome 11. Pdgfr and Fms, which are closely linked to II-3 and Csfgm in humans on chromosome 5, mapped to mouse chromosome 18 rather than mouse chromosome 11, thereby defining yet another conserved linkage group between human and mouse chromosomes. The mouse chromosome 11 linkage map generated in these studies substantially extends the framework for identifying homologous genes in the mouse that are involved in human disease, for elucidating the genes responsible for several mouse mutations, and for gaining insights into chromosome evolution and genome organization.     

Assignment of the human homologue of the mouse t-complex gene TCTE3 to human chromosome 6q27.

The gene TCTE3 from the mouse t-complex region is expressed specifically in testicular germ cells. It maps in the central subregion of the t-complex on mouse chromosome 17 containing loci involved in transmission ratio distortion and male sterility. In this study, somatic cell hybrid lines have been used to map the human homologue, TCTE3, to the long arm of chromosome 6. CISS hybridization with the human lambda clone h117 refined this chromosome assignment to the very distal position of chromosome 6q27, thus providing further evidence that loci from the t-complex of mouse chromosome 17 can map to opposite arms of human chromosome 6.     

A physical map of the mouse shaker-2 region contains many of the genes commonly deleted in Smith-Magenis syndrome (del17p11.2p11.2)

We report the construction of a physical map of the region of mouse chromosome 11 that encompasses shaker-2 (sh2), a model for the human nonsyndromic deafness DFNB3. DFNB3 maps within the common deletion region of Smith-Magenis syndrome (SMS), del(17)(p11.2p11.2). Eleven of the genes mapping within the SMS common deletion region have murine homologs on the sh2 physical map. The gene order in this region is not perfectly conserved between mouse and human, a finding to be considered as we engineer a mouse model of Smith-Magenis syndrome.     

Assignment of 204 genes localized on HSA17 to a porcine RH (IMpRH) map to generate a dense comparative map between pig and human/mouse

Bi- and uni-directional chromosome painting (ZOO-FISH) and gene mapping have revealed correspondences between human chromosome (HSA) 17 and porcine chromosome (SSC) 12 harboring economically important quantitative trait loci. In the present study, we have assigned 204 genes localized on HSA17 to SSC12 to generate a comprehensive comparative map between HSA17 and SSC12. Two hundred fifty-five primer pairs were designed using porcine sequences orthologous with human genes. Of the 255 primer pairs, 208 (81.6%) were used to assign the corresponding genes to porcine chromosomes using the INRA-Minnesota 7000-rad porcine x Chinese hamster whole genome radiation hybrid (IMpRH) panel. Two hundred three genes were integrated into the SSC12 IMpRH linkage maps; and one gene, PPARBP, was found to link to THRA1 located in SSC12 but not incorporated into the linkage maps. Three genes (GIT1, SLC25A11, and HT008) were suggested to link to SSC12 markers, and the remaining gene (RPL26) did not link to any genes/expressed sequence tags/markers registered, including those in the present study. A comparison of the gene orders among SSC12, HSA17, and mouse chromosome 11 indicates that intra-chromosomal rearrangements occurred frequently in this ancestral mammalian chromosome during speciation.     

Comparative mapping of cattle chromosome 19: cytogenetic localization of 19 BAC clones

Here we present the results of fluorescent in situ hybridization (FISH) mapping of a set of cattle BAC clones preselected for assignment on cattle chromosome 19 (BTA19). The BAC clones were anchored to human chromosome 17 (HSA17) sequences by BLASTn similarity search of cattle BAC-ends against the human genome sequence (NCBI build 33). Five blocks of homologous synteny were defined in the comparative map of BTA19 and HSA17 built with FISH data and the human genome coordinates. The positions for four evolutionary breakpoints in the bovine and human chromosomes were identified. Comparison of the FISH comparative map with previously published comparative RH, physical, and cytogenetic maps of BTA19 did not reveal major conflicts and allowed for the extension of the boundaries of homology between BTA19 and HSA17. Comparative analysis of HSA17, BTA19, and mouse chromosome 11 (MMU11) demonstrates that most likely mice retain the ancestral organization of the synteny group, and both cattle and human chromosomes underwent several major internal rearrangements after the divergence of Primates, Rodentia, and Cetartiodactyla.     

BAC contig from a 3-cM region of mouse chromosome 11 surrounding Brca1

Even with the completion of a draft version of the human genome sequence only a fraction of the genes identified from this sequence have known functions. Chromosomal engineering in mouse cells, in concert with gene replacement assays to prove the functional significance of a given genomic region or gene, represents a rapid and productive means for understanding the role of a given set of genes. Both techniques rely heavily on detailed maps of chromosomal regions, initially to understand the scope of the regions being modified and finally to provide the cloned resources necessary to allow both finished sequencing and large insert complementation. This report describes the creation of a BAC clone contig on mouse chromosome 11 in a region showing conservation of synteny with sequences on human chromosome 17. We have created a detailed map of an approximately 3-cM region containing at least 33 genes through the use of multiple BAC mapping strategies, including chromosome walking and multiplex oligonucleotide hybridization and gap filling. The region described is one of the targets of a large effort to create a series of mice with regional deletions on mouse chromosome 11 (33-80 cM) that can subsequently be subjected to further mutagenesis.     

Chromosomal Localization and Genomic Organization of Genes Encoding Guanylyl Cyclase Receptors Expressed in Olfactory Sensory Neurons and Retina

We recently cloned three membrane guanylyl cyclases, designated GC-D, GC-E, and GC-F, from rat olfactory tissue and eye. Amino acid sequence homology suggests that they may compose a new gene subfamily of guanylyl cyclase receptors specifically expressed in sensory tissues. Their chromosomal localization was determined by mouse interspecific backcross analysis. The GC-D, GC-E, and GC-F genes (Gucy2d, Gucy2e,andGucy2f) are dispersed through the mouse genome in that they map to chromosomes 7, 11, and X, respectively. Close proximity of the mouse GC-D gene toOmp(olfactory marker protein) andHbb(hemoglobin β-chain complex) suggests that the human homolog gene maps to 11p15.4 or 11q13.4–q14.1. The human GC-F gene was localized to the long arm of chromosome Xq22 by fluorescencein situhybridization. The genomic organization of the mouse GC-E gene was determined and compared to other guanylyl cyclase genes. The mouse GC-D, GC-E, and GC-F genomic clones contain identical exon–intron boundaries within their extracellular and cytoplasmic domains, demonstrating the conservation of the gene structures. With respect to human genetic diseases, GC-E mapped to mouse chromosome 11 within a syntenic region on human chromosome 17p13 that has been linked with loci for autosomal dominant retinitis pigmentosa and Leber congenital amaurosis. No apparent disease loci have been yet linked to the locations of the GC-D or GC-F genes.     

Isolation and preliminary characterization of the human and mouse homologues of the bacterial cell cycle gene era

Era is an essential GTPase that is required for proper cell cycle progression and cell division in Escherichia coli and is found in nearly all bacteria sequenced to date. To determine whether Era is also present in eukaryotic organisms, we searched the dbEST database and found EST clones coding for proteins that were similar to Era. Full sequencing of these ESTs from human and mouse identified a conserved homologue, ERAL1 (Era-like 1). ERAL1 maps to 17q11.2 in human and is located in the syntenic region of mouse chromosome 11. ERAL1 may be an attractive candidate for a tumor suppressor gene since ERAL1 is located in a chromosomal region where loss of heterozygosity is often associated with various types of cancer.     

Chromosomal localization of zinc finger protein genes in man and mouse

We have determined the mouse and human chromosomal location of a gene (Zfp-3) that codes for a protein that contains potential DNA zinc-binding fingers. An analysis of the segregation of restriction fragment length polymorphisms in recombinant inbred strains and in an interspecific backcross demonstrated that Zfp-3 is located on mouse chromosome 11. Zfp-3 is very closely linked to the Trp53-1 locus but unlinked to another finger protein gene Zfp-4 located on mouse chromosome 8. In humans ZFP3 has been localized to chromosome 17p12-17pter and thus is part of the conserved linkage group between this chromosome and the distal half of mouse chromosome 11.     

Detailed four-way comparative mapping and gene order analysis of the canine ctvm locus reveals evolutionary chromosome rearrangements

Canine tricuspid valve malformation (CTVM) maps to canine chromosome 9 (CFA9), in a region syntenic with gene-dense human chromosome 17q. To define synteny blocks, we analyzed 148 markers on CFA9 using radiation hybrid mapping and established a four-way comparative map for human, mouse, rat, and dog. We identified a large number of rearrangements, allowing us to reconstruct the evolutionary history of individual synteny blocks and large chromosomal segments. A most parsimonious rearrangement scenario for all four species reveals that human chromosome 17q differs from CFA9 and the syntenic rodent chromosomes through two macroreversals of 9.2 and 23 Mb. Compared to a recovered ancestral gene order, CFA9 has undergone 11 reversals of <3 Mb and 2 reversals of >3 Mb. Interspecies reuse of breakpoints for micro- and macrorearrangements was observed. Gene order and content of the ctvm interval are best extrapolated from murine data, showing that multispecies genome rearrangement scenarios contribute to identifying gene content in canine mapping studies.     

Human tyrosinase gene, mapped to chromosome 11 (q14----q21), defines second region of homology with mouse chromosome 7

The enzyme tyrosinase (monophenol,L-dopa:oxygen oxidoreductase; EC 1.14.18.1) catalyzes the first two steps in the conversion of tyrosine to melanin, the major pigment found in melanocytes. Some forms of oculocutaneous albinism, characterized by the absence of melanin in skin and eyes and by a deficiency of tyrosinase activity, may result from mutations in the tyrosinase structural gene. A recently isolated human tyrosinase cDNA was used to map the human tyrosinase locus (TYR) to chromosome 11, region q14----q21, by Southern blot analysis of somatic cell hybrid DNA and by in situ chromosomal hybridization. A second site of tyrosinase-related sequences was detected on the short arm of chromosome 11 near the centromere (p11.2----cen). Furthermore, we have confirmed the localization of the tyrosinase gene in the mouse at or near the c locus on chromosome 7. Comparison of the genetic maps of human chromosome 11 and mouse chromosome 7 leads to hypotheses regarding the evolution of human chromosome 11.     

A Physical Map of the Mouseshaker-2Region Contains Many of the Genes Commonly Deleted in Smith–Magenis Syndrome (del17p11.2p11.2)

We report the construction of a physical map of the region of mouse chromosome 11 that encompassesshaker-2(sh2), a model for the human nonsyndromic deafnessDFNB3. DFNB3maps within the common deletion region of Smith–Magenis syndrome (SMS), del(17)(p11.2p11.2). Eleven of the genes mapping within the SMS common deletion region have murine homologs on thesh2physical map. The gene order in this region is not perfectly conserved between mouse and human, a finding to be considered as we engineer a mouse model of Smith–Magenis syndrome.