For decades, human geneticists had envied geneticists working on model organ isms where high-resolution classical genetic maps could be established readily. Such maps were based on mutant genes: by crossing mutants, the inheritance of individual phenotypes could be tracked through generations. If two mutant phenotypes showed a tendency to be co-inherited, the underlying genes could be expected to be reasonably closely linked on the same chromosome. Recombination between linked loci could provide a measure of the physical distance separating the two genes.
For ethical and practical reasons, classical genetic mapping could never be contemplated in humans. The breakthrough that paved the way to mapping the human genome came from a simple insight: genetic maps do not have to be based on gene mutations that affect the phenotype. Mutation is essentially a random process, and the great majority of mutations do not change the phenotype (only 1.2% of our DNA is coding DNA, and other highly-conserved functional sequences account for just a few percent of our genome). So, general DNA polymorphic markers can be used instead of gene variants. Once assays were developed to track this general type of DNA polymorphism, maps based on DNA markers could be established.
The initial genetic maps based on polymorphic DNA markers provided a skeleton for each chromosome, upon which more detailed framework maps could be built, containing a high density of DNA markers including polymorphic markers and numerous additional nonpolymorphic markers. The latter were simply chosen because they had a unique sequence that could be assayed by polymerase chain reaction (PCR) and mapped to specific subchromosomal locations using different methods, as described below.
Once suitably high-density marker–marker framework maps were developed, it was possible to build framework maps based on DNA clones. As described in the next section, DNA clone maps involve identifying and arranging DNA clones in a linear order that corresponds to the original linear chromosomal order of the inserts of the cloned DNA sequences. Comprehensive clone maps for each chromosome provided the final substrate for genome sequencing that delivered the ultimate physical map at 1 bp resolution.
