Comparative Mapping
The genomes of model organisms provide data complementary to that derived from the human genome. There is an approximate 1:1 correlation between human genes and those of most vertebrates, and extensive syntenic relationships have been established between several mammalian species. Mapping and sequencing can often be performed more quickly or at higher resolution in model organisms, and some phenotypes can be assayed, and therefore mapped, in other species when they cannot be studied in man. These points were demonstrated by presentations at this workshop on the genetic control of Wallerian degeneration in the mouse and on the analysis of TAL1 promoter sequences conserved between Fugu, chicken, mouse and man. Other recent publications described below have mapped genes for tumour susceptibility, diabetes and obesity to regions of the mouse genome homologous to human chromosome 1.
Wallerian degeneration is the degeneration of an axon distal to a site of injury. A similar process, Wallerian-like degeneration, is a common endpoint of many forms of axonal pathology in the central and peripheral nervous system. The C57BL/WldS mouse has a neuroprotective dominant mutation in distal mouse chromosome 4 that results in abnormally slow Wallerian degeneration (Lunn et al., 1989; Lyon et al., 1993). This location is homologous to that of the human peripheral neuropathy CMT2A (1p36), raising the possibility that the two phenotypes are caused by mutations in the respective mouse and human homologues (Ben-Othmane, et al., 1993). Coleman and colleagues (1998) reported the identification of a tandem triplication within the candidate genetic interval in the C57BL/WldS mouse. This suggests that delayed Wallerian degeneration could be caused by increased gene dosage or by gene disruption. Genes lying in or around the triplication in the mouse will be candidates for WldS as well as for CMT2A.
Gottgens and colleagues (workshop abstract) studied the promoter of the gene TAL1 (SCL) by looking for non-coding regions that are conserved between species as divergent as Fugu, chicken, mouse and human. TAL1, mapping to 1p32, is an important gene in development because it is a master regulator of haemopoiesis. When the Fugu sequences were included in the analysis, very few non-coding sequences were conserved between all four species, and were limited to the promoter. Gottgens was also able to demonstrate functional conservation of these promoter sequences between chicken and mouse.
Many malignancies have deletions and rearrangements of 1p36. Therefore, it is of interest to note several recent reports of genes controlling tumour susceptibility mapping in the homologous region in the mouse (distal mouse chromosome 4). Cormier and co-workers (1997) report resistance to intestinal neoplasia in transgenic mice over expressing the gene Pla2g2a; Mock and colleagues (1997) report the mapping of one or more loci conferring susceptibility to plasmacytoma; and Radany and co-workers (1997) report loss of heterozygosity in distal mouse chromosome 4 in mammary carcinoma.
Mapping in the mouse is also contributing to the identification of chromosome 1genes controlling diabetes and obesity. Diabetes susceptibility loci have been mapped in regions of conserved synteny with human 1p36 (Idd9 ; McAleer et al., 1995) and 1p13 (Idd10 and Idd18; Podolin et al., 1998). The region 1p32-p22 has been linked to obesity and insulin levels (Chagnon et al., 1997) following mapping of obesity and diabetes to the homologous regions in rodents. Finally, a gene for hyperlipidaemia has been localized to distal mouse chromosome 3, a region homologous to human 1q21-q23 (Castellani et al., 1998).
For further reference, extensive comparative mapping data is available on the World Wide Web at the Jackson Laboratories (http://www.informatics.jax.org/homtools.html).