International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

D10 Development of a Genetic and Physical Map of the Region of Mouse Chromosome 8 Homologous to the Facioscapulohumeral Muscular Dystrophy Locus on Human Chromosome 4q35: Cloning of an Evolutionary Chromosomal Breakpoint

D. J. Bolland1, P. K. Grewal1, M. van Geel2, R. R. Frants3, P. J. de Jong3, J. E. Hewitt1,2. 1Institute of Genetics, Queen's Medical School, Nottingham University, Nottingham, UK; 2Dept. of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY; 3Leiden University Medical Centre, MGC-Dept. of Human Genetics, Leiden, The Netherlands

The central region of mouse chromosome 8 shows homology to human chromosome 4q35, which contains the locus for the dominant neuromuscular disorder facioscapulohumeral muscular dystrophy (FSHD). The causal mutation in FSHD is the deletion of integral copies of a 3.3kb repeat from within a tandem repeat locus. However, this does not appear to directly disrupt a gene and no transcribed sequences appear to be present at this locus. As a result a position effect hypothesis has been suggested to explain how the mutation causes the disease. The most distal gene on human 4q is FRG1 (FSHD Region Gene 1), which maps 100kb proximal to the repeats. This gene has been excluded as a candidate for FSHD as mRNA levels are not altered in patient tissues. The mouse homologue of FRG1 has been cloned and maps to mouse chromosome 8. Therefore, this gene was used as the starting point for development of a comparative mouse map by genetic mapping (using the European Collaborative Interspecific Backcross) and physical mapping with YAC and PAC clones. These maps will aid the search for the FSHD gene and will be an important step towards producing a mouse model of the disease.

Using gene-based polymorphic markers we have shown that on mouse chromosome 8 the block of distal 4q homology is flanked by genes with homologues on human 8p. Genetic and physical mapping showed Frg1 to mark the centromeric boundary of the 4q homology. The mouse acid ceramidase (Ac) and pericentriolar material 1 (Pcm1) genes are adjacent to Frg1 and all three genes map within a single PAC clone (RPC21-44K14), with the gene order Frg1-Ac-Pcm1. As the human homologues of Ac and Pcm1 are on human chromosome 8p22, this defines the 4q35/8p22 homology breakpoint. Comparison of DNA sequence of both the Fugu and mouse Frg1-Ac intervals with the genomic sequence containing the human FRG1 and AC genes has refined this breakpoint to within 20kb. The construction of physical contigs demonstrated that the FRG1-AC-PCM1 linkage group is conserved in Fugu, pig, cow and dog, suggesting this represents the ancestral gene order.

 


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