The gene map of the Norway rat (Rattus norvegicus) and comparative mapping with mouse and man

The current status of the rat gene map is presented. Mapping information is now available for a total of 214 loci and the number of mapped genes is increasing steadily. The corresponding number of loci quoted at HGM10 was 128. Genes have been assigned to 20 of the 22 chromosomes in the rat. Some aspects of comparative mapping with mouse and man are also discussed. It was found that there is a good correlation between the morphological homologies detectable in rat and mouse chromosomes, on the one hand, and homology at the gene level on the other. For 10 rat synteny groups all the genes so far mapped are syntenic also in the mouse. For the remaining rat synteny groups it appears that the majority of the genes will be syntenic on specific (homologous) mouse chromosomes, with only a few genes dispersed to other members of the mouse karyotype. Furthermore, the data indicate that mouse chromosome 1 genetically corresponds to two rat chromosomes, viz., 9 and 13, equalizing the difference in chromosome number between the two species. Further mappings will show whether the genetic homology will prove to be as extensive as these preliminary results indicate. As might be expected from evolutionary considerations, rat synteny groups are much more dispersed in the human genome. It is clear, however, that many groups of genes have remained syntenic during the period since man and rat shared a common ancestor. One further point was noted. In two cases groups of genes were syntenic in the mouse but dispersed to two chromosomes in rat and man, whereas in a third case a group of genes was syntenic in the rat but dispersed to two chromosomes in mouse and man. This finding argues in favor of the notion that the original gene groups were on separate ancestral chromosomes, which have fused in one rodent species but remained separate in the other and in man.     

Structure and mapping of the gene encoding mouse high affinity Fc gamma RI and chromosomal location of the human Fc gamma RI gene.

We describe the isolation and characterization of the gene encoding the mouse high affinity Fc receptor Fc gamma RI. Using a mouse cDNA Fc gamma RI probe four unique overlapping genomic clones were isolated and were found to encode the entire 9 kb of the mouse Fc gamma RI gene. Sequence analysis of the gene showed that six exons account for the entire Fc gamma RI cDNA sequences including the 5'- and 3'-untranslated sequences. The first and second exons encode the signal peptide; exons 3, 4, and 5 encode the extracellular Ig binding domains; and exon 6 encodes the transmembrane domain, the cytoplasmic region, and the entire 3'-untranslated sequence. This exon pattern is similar to Fc gamma RIII and Fc epsilon RI but differs from the related Fc gamma RII gene which contains 10 exons and encodes the b1 and b2 Fc gamma RII. Southern blot analysis had shown that the mouse Fc gamma RI gene is a single copy gene with no RFLP in inbred strains of mice, but analysis of an intersubspecies backcross of mice showed that unlike other mouse FcR genes which are on mouse chromosome 1 the locus encoding Fc gamma RI, termed Fcg1, is located on chromosome 3. Interestingly, the Fcg1 locus is located near the end of a region with known linkage homology to human chromosome 1. Analysis of human x rodent somatic cell hybrid cell lines indicates that the human FCG1 locus encoding the human Fc gamma RI maps to chromosome I and therefore possibly linked to other FcR genes on this chromosome. These results suggest that the linkage relationships among these genes in the human genome are not preserved in the mouse.     

The human and mouse replication-dependent histone genes

The multigene family encoding the five classes of replication-dependent histones has been identified from the human and mouse genome sequence. The large cluster of histone genes, HIST1, on human chromosome 6 (6p21-p22) contains 55 histone genes, and Hist1 on mouse chromosome 13 contains 51 histone genes. There are two smaller clusters on human chromosome 1: HIST2 (at 1q21), which contains six genes, and HIST3 (at 1q42), which contains three histone genes. Orthologous Hist2 and Hist3 clusters are present on mouse chromosomes 3 and 11, respectively. The organization of the human and mouse histone genes in the HIST1 cluster is essentially identical. All of the histone H1 genes are in HIST1, which is spread over about 2 Mb. There are two large gaps (>250 kb each) within this cluster where there are no histone genes, but many other genes. Each of the histone genes encodes an mRNA that ends in a stemloop followed by a purine-rich region that is complementary to the 5' end of U7 snRNA. In addition to the histone genes on these clusters, only two other genes containing the stem-loop sequence were identified, a histone H4 gene on human chromosome 12 (mouse chromosome 6) and the previously described H2a.X gene located on human chromosome 11. Each of the 14 histone H4 genes encodes the same protein, and there are only three histone H3 proteins encoded by the 12 histone H3 genes in each species. In contrast, both the mouse and human H2a and H2b proteins consist of at least 10 non-allelic variants, making the complexity of the histone protein complement significantly greater than previously thought.     

The genes coding for the muscle contractile proteins, myosin heavy chain, myosin light chain 2, and skeletal muscle actin are located on three different mouse chromosomes.

The chromosomal distribution of murine genes expressed during differentiation of skeletal muscle cells was determined by Southern blot analysis of DNA from mouse-Chinese hamster hybrid cell lines containing incomplete subsets of mouse chromosomes. All detectable myosin heavy chain genes are located on chromosome 11. The gene for the myosin light chain 2 is located on chromosome 7. The skeletal muscle alpha-actin gene and several other actin genes, or pseudogenes, are located on chromosome 3. Additional actin DNA sequences are distributed on other mouse chromosomes.     

Genomic organization and expression profile of the small GTPases of the RhoBTB family in human and mouse

Members of the RhoBTB subfamily of Rho GTPases are present in vertebrates, Drosophila and Dictyostelium. RhoBTB proteins are characterized by a modular organization, consisting of a GTPase (guanosine triphosphatase) domain, a proline rich region, a tandem of two BTB (Broad-Complex, Tramtrack, and Bric à brac) domains and a C-terminal region of unknown function and might act as docking points for multiple components participating in signal transduction cascades. We have determined the genomic organization and the expression pattern of the three RHOBTB genes of human and mouse. The exon-intron organization of each gene is conserved in three vertebrate species (human, mouse and Fugu). RHOBTB1 and RHOBTB2 have a similar exon-intron organization and are closely related to the single gene encoding the RhoBTB orthologs of two insect species. By contrast, the exon-intron organization of RHOBTB3 differed substantially from that of the two other genes, indicating that this gene arose by a duplication event independent of the one that gave rise to RHOBTB1 and RHOBTB2. RHOBTB1 (located on chromosome 10) and RHOBTB3 (located on chromosome 5) appear ubiquitously expressed. However, they display a differential pattern of expression: RHOBTB1 showed high levels in stomach, skeletal muscle, placenta, kidney and testis, whereas RHOBTB3 was highly expressed in neural and cardiac tissues, pancreas, placenta and testis. RHOBTB2 (located on chromosome 8) showed much lower levels of expression than the other two human RHOBTB genes and it was most abundant in neural tissues. The expression patterns of the human and mouse genes were roughly comparable. All three genes were also detected in fetal tissues, and in a number of cell lines RHOBTB3 predominates. RHOBTB genes are upregulated in some cancer cell lines, suggesting that these proteins might participate in tumorigenesis.     

The genes coding for the cardiac muscle actin, the skeletal muscle actin and the cytoplasmic beta-actin are located on three different mouse chromosomes.

The actins are a group of highly conserved proteins encoded by a multigene family. We have previously reported that the skeletal muscle actin gene is located on mouse chromosome 3, together with several other unidentified actin DNA sequences. We show here that the gene coding for the cardiac muscle actin, which is closely related to the skeletal muscle actin (1.1% amino acid replacements), is located on mouse chromosome 17. The gene coding for the cytoplasmic beta-actin is located on mouse chromosome 5. Thus, these three actin genes are located on three different chromosomes.     

The LIM proteins FHL1 and FHL3 are expressed differently in skeletal muscle

We have determined the complete mRNA sequence of FHL3 (formerly SLIM2). We have confirmed that it is a member of the family of LIM proteins that share a similar secondary protein structure, renamed as Four-and-a-Half-LIM domain (or FHL) proteins in accordance with this structure. The "half-LIM" domain is a single zinc finger domain that may represent a subfamily of LIM domains and defines this particular family of LIM proteins. The distribution of FHL mRNA expression within a variety of murine tissues is complex. Both FHL1 and FHL3 were expressed in a number of skeletal muscles while FHL2 was expressed at high levels in cardiac muscle. Localisation of FHL3 to human chromosome 1 placed this gene in the proximity of, but not overlapping with, alleles associated with muscle diseases. FHL1 and FHL3 mRNAs were reciprocally expressed in the murine C2C12 skeletal muscle cell line and this suggested that the pattern of expression was linked to key events in myogenesis.     

Mechanism of imprinting on mouse distal chromosome 7

Genomic imprinting is an epigenetic mode of gene regulation that results in expression of the autosomal 'imprinted' genes from only a single allele, determined exclusively by parental origin. To date over 20 imprinted genes have been identified in mouse and man and these appear to lie in clusters in restricted regions on a subset of chromosomes. This may be a critical feature of imprinting suggesting a domain-type mode of regulation. Imprinted domains are replicated asynchronously, show sex-specific meiotic recombination frequencies and have CpG-rich regions that are differentially methylated, often associated with the imprinted genes themselves. Mouse distal chromosome 7 is one such domain, containing at least nine imprinted genes spanning over 1 Mb of DNA. For the maternally expressed p57Kip2 gene, passage through the female germline is essential to generate the active state, whereas passage through the male germline is needed to force the maternally expressed H19 gene into an inactive state. It is therefore possible that the mouse distal chromosome 7 imprinted domain is actually composed of two or more independently regulated subdomains.     

Mapping polypeptide hormone genes in the mouse: somatostatin, glucagon, calcitonin, and parathyroid hormone

Mouse-Chinese hamster hybrids segregating mouse chromosomes were analyzed by Southern hybridization techniques to map the genes for somatostatin (Smst), glucagon (Gcg), calcitonin (Calc), and parathyroid hormone (Pth). The mouse gene for somatostatin, detected on a 20-kb EcoRI fragment, is located on mouse chromosome 16. Glucagon cDNA hybridized to a 14-kb EcoRI fragment residing on chromosome 2. Calcitonin and parathyroid hormone genes, detected on 7.8-kb HindIII and 6.0-kb BamHI fragments, respectively, were on mouse chromosome 7. The calcitonin and parathyroid hormone genes appear to be part of a larger linkage group which has been conserved in mouse and man.     

The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea

Human LRIG1 (formerly LIG1), human LRIG2, and mouse Lrig1 (also known as Lig-1) encode integral membrane proteins. The human genes are located at chromosomes 3p14 and 1p13, which are regions frequently deleted in human cancers. We have searched for additional members of the LRIG family and by molecular cloning identified human LRIG3 and its mouse ortholog Lrig3. Human LRIG3 is located at chromosome 12q13. In silico analysis of public databases revealed a mouse Lrig2 mRNA, three LRIG homologs in the puffer fish Fugu rubripes, and one LRIG homolog in the ascidian tunicate Ciona intestinalis. The human and mouse LRIG polypeptides have the same predicted domain organization: a signal peptide, 15 tandem leucine-rich repeats with cysteine-rich N- and C-flanking domains, three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail. The extracellular part--especially the IgC2.2 domain, the transmembrane domain, and the membrane-proximal part of the cytoplasmic tail--are the most conserved regions. Northern blot analysis and real-time RT-PCR revealed that the three LRIG paralogs are widely expressed in human and mouse tissues. In conclusion, the LRIG gene family was found to have three widely expressed mammalian paralogs, corresponding orthologs in fish, and a homolog in Ascidiacea.