A dual-color FISH gene map of the proximal region of rat Chromosome 4 and comparative analysis in human and mouse

The development and refinement of the rat genome map is a prerequisite for a continued qualified and fruitful use of this model system for the study o f complex traits. In two distinct rat cancer models, recurrent amplificatio n affecting the proximal region of rat Chr 4 was detected. To further chara cterize this region, we turned to the evolutionarily conserved chromosome s egments in human Chr 7 and mouse Chrs 5 and 6 to identify functional and po sitional candidate genes. By means of single- and dual-color FISH on metaph ase,, prometaphase, and interphase chromatin, 15 genes in rat Chr 4q11-q23 (Cdk5, Hgf, Dmtf1, Abcb1, Cyp51, Cdk6, Tac1, Asns, Cav1, Met, Wnt2, Cftr, S moh, Braf, Arhgef5) were mapped and aligned. In the course of this work, si x cancer-related rat genes were isolated de novo and partly sequenced. Ten loci were also mapped by FISH in the mouse. The map provides the framework for a more detailed genetic characterization of individual tumor amplicons, but may also be valuable for the analysis of this region in other rat mode ls of human complex disease. In addition, our data facilitate the analysis of events in mammalian chromosomal evolution affecting the region. In a com parison with human sequence data, we found that there is considerable conse rvation in this region both in gene order and in distances between genes. T here is a single evolutionary breakpoint between rat and mouse and two betw een rat and human. Since our analysis shows that the three breaks all occur red in different positions, they must be independent of one another. The da ta tend to support the notion that the genomic configuration, in rat Chr 4 is ancestral compared with that in humans and mice.