Mammalian Genome 10, 959 (1999). Incorporating Mouse Genome © Springer-Verlag New York Inc. 1999 Glenn L. Radice* Center for Research on Reproduction and Women’s Health, University of Pennsylvania School of Medicine, 1355 Biomedical Research Building, II, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6142 USA Submitted: 18 December 1998 Introduction The eighth mouse Chromosome 18 (Chr 18) Committee report positioning four neurological mutations within 1–2 cM of each includes 544 entries of genes, anonymous DNA markers, chromo- other. Two of these mutations, twirler and the transgene insertion, somal rearrangements, mutations or traits that have been mapped 9257, may be alleles of the same gene given the close similarity of to this chromosome (Table I). Since the last report, 49 new entries their phenotypes including circling behavior and inner ear defects. have been added including 23 recently mapped genes. The report Two other mutations, ataxia (ax) and the murine model of the nih includes 25 new expressed sequence tags (ESTs) mostly from the Niemann Pick Type C disorder (npc and sphingomyelinosis, ERATO Doi effort in Japan (D18Ertd markers), which is based on spm, alleles) also have similar neurological phenotypes. Comple- early embryonic (blastocyst) gene expression. Many of the new mentation analysis between the closely linked ax and npc1 muta- loci were mapped in the Jackson interspecies backcross, BSS. The tions demonstrated that these mutations do not represent alleles of construction of the composite map has been discussed in previous the same gene and most likely do not represent mutations in the reports; however, please keep in mind that marker order and ge- same genetic pathway. Recently, the mouse and human npc genes netic distances are not absolute. The consensus map has been were isolated and found to have homology to mediators of cho- generated by compiling data from a large number of individual lesterol homeostasis. The mouse model will provide an important mapping studies; therefore, many loci have never been mapped resource for studying the role of NPC1 in cholesterol homeostasis with respect to one another in the same genetic cross. and neurodegeneration. A new recessive mutation, lanceolate hair (lah), arose in a As indicated in Table I, mouse Chr 18 contains regions of mutagenesis experiment using ethylnitrosourea (ENU). The lah conserved homology with three human chromosomes: 5, 10, and mice develop generalize hair loss associated with breakage of ab- 18. Beginning at the most proximal end (0–2 cM), a small region normal hair shafts. The lah mouse may represent a model for the containing two genes, Tcf8 and Tpl2, is syntenic to human Chr human condition, Netherton’s syndrome. Mutational analysis of 10p11. The next interval (3–9 cM) contains 8 genes syntenic to the tumor suppressor gene, Apc, continues to provide important human Chr 18q11-q12, with the exception of Aqp4 which is syn- insight into the human disease, familial adenomatous polyposis tenic with human 18q22. However, recent mapping data using a (FAP). Recently, two candidate tumor suppressor genes, Madh2 larger probe for fluorescence in situ hybridization (FISH) localized and Madh4, were mapped to Chr 18. By generating cis-compound the human Aqp4 gene to human Chr 18q11-q12, which is more heterozygotes for mutations in the Apc and Madh4 (also known as likely based on the syntenic region of the mouse homolog. A large Dpc4 and Smad4) genes, it was shown that Madh4 plays an im- centrally located region (10–36 cM) contains 23 genes syntenic to portant role in the malignant progression of colorectal tumors. Null human Chr 5q21-q33. The remaining distal portion of Chr 18 mutations in Madh2 and Madh4 interfere with the TGFB signaling (37–56 cM) contains 10 genes syntenic to human Chr 18q11-q23. pathway leading to early embryonic lethality. Chimera analysis Comparison of the conserved homology regions between mouse demonstrated that both mutations affect the extraembryonic tissue, and human is an invaluable tool for deciphering the genetic basis visceral endoderm, which in turn influences the epiblast. The tran- of human diseases. scription factor, GATA6, was also shown to be required for differ- Acknowledgments. We thank Ken Johnson and Muriel Davisson for their entiation of the visceral endoderm of the early embryo. To date, contributions in generating the previous Mouse Chromosome 18 Commit- null mutations in seven genes on Chr 18 have resulted in embry- tee Reports on which the current consensus map is largely based. We are onic lethal phenotypes. grateful for the assistance of The Jackson Laboratory Informatics Group The genetic map of proximal Chr 18 has recently been refined, in providing relevant data and electronic references. We apologize for errors and omissions and welcome comments and corrections (Email: email@example.com). Support was provided by National Institutes * Committee Chair of Health grant HL57554.
Mammalian Genome – Springer Journals
Published: Oct 1, 1999
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