Appendix A: 

 Primer on Molecular 

 Genetics 



Meiotic recombination, a relatively rare event, produces DNA strand breakage and 

 rejoining; the result is separation of two markers originally on the same chromosome. 

 The frequency of occurrence of these rare events provides an estimate of the distance 

 between two markers. The closer they are. the less likely that a recombination event 

 will fall between them and separate them. 



The power of the genetic map is that an inherited disease can be located on the map, 

 even though the molecular basis of the disease is not yet understood and the gene for 

 the disea.se is not yet identified. Thus, genetic maps can be used to locate the 

 neighborhood of important disease genes. The current resolution of the human genetic 

 map is 10 million base pairs, about the same as the chromosome map. 



Physical maps 



Physical maps are ordered sets of DNA fragments made from restriction enzyme 

 fragments. This mapping is done by either the top-down or the bottom-up approach 

 (Fig. 12). Both of these approaches require purifying and analyzing large numbers of 

 DNA fragments. 



Top-down mapping. In top-down mapping, a single chromosome is cut into large 

 pieces, which are then ordered, subdivided, and mapped further. DNA pieces can be 

 located in regions about 100.000 to I million base pairs in size. 



Bottom-up mapping. In bottom-up mapping, the chromosome is cut into small pieces. 

 These pieces — the resulting clones — are then placed in order according to structural 



Fig. 12. Two physical mapping 

 strategies. The top-down strategy 

 gives low resolution but high 

 connectivity. The bottom-up 

 strategy has low connectivity 

 because not enough clones can be 

 mapped to give neighboring 

 contigs. 



Top-Down Strategy 



chromosome 



fragments 



single fragment 

 digest 



Results: Macro-restriction map: complete but low resolution 

 Bottom-Up Strategy 

 fragments ^^^^^^^^^^>» ^^^^^^— ^^^— 



contigs 



z"/"z /-\ -r\ 



YAC or cosmld clones 

 Results: Map based linked library: detailed but incomplete 



132 



