Our journey begins with the example of sickle cell disease, a common clinically important genetic disorder (Box 1.2) (Ingram 2004; Frenette and Atweh 2007). Research into sickle cell disease was pivotal in demonstrating a molecular basis for disease, illustrating how DNA sequence variation (the genotype) can have profound functional consequences, in this case at a structural level in the encoded protein, resulting in a specific disease (the observed phenotype) (Box 1.3).
Research into the molecular basis of sickle cell disease was however unusual in some respects, as in this disease it was observed variation in a specific protein that allowed the underlying variation at the DNA level to be defined. This contrasts with the majority of inherited diseases in which a phenotype was mapped to a genetic locus on a chromosome (Box 1.4), and the particular genes (Box 1.5) and causative mutations within them identified without knowledge of the encoded protein (linkage and positional cloning are described in detail in Chapter 2).
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