Initially, analysis of the human genome sequence suggested that SNPs, which occurred on average in 1 of 300 nucleotides, were believed to be the main source of genetic and phenotypic individual variation. However, the creation of genome-wide scanning technologies and comparative genomic-sequence analyses revealed the large extent of DNA variation involving DNA segments smaller than those recognizable microscopically, but larger that those detected by conventional sequence analysis. Estimates have suggested that as much as 5-7% of the human genome might be duplicated, but that may change as a more finished genomic sequence is obtained because identification of repeat-rich regions is technically challenging and their misidentification is likely to underestimate such architectural features.89
The concept of "genomic disorders'' refers to disorders that result from DNA rearrangements of regional genomic architecture.89 These rearrangements usually consist of blocks of DNA that span from about 400 kilobases up to 3 megabases of genomic DNA with at least 97% identity, and provide substrates for homologous recombination. They may comprise deletions, duplications, inversions, gene fragments, pseudogenes, endogenous retroviral sequences, intrachromoso-mal rearrangements, and large-scale copy number variants of entire genes or fragments of genes. In a broader sense they can be regarded as all genomic changes that are not single-base pair substitutions.90 In some regions, such rearrangements have no apparent effect, but in other regions they may alter gene dosages to cause disease either alone or in combination with other genetic or environmental factors. Such variants are collectively referred to as copy number variants (CNVs) or copy number polymorphisms (CNPs).
Although a large number of Mendelian disorders have been shown to result from genomic rearrangements,89,91,92 there has been no systematic search for the polymorphic duplication of genes. Several polymorphic duplications of phar-macogenetic interest have been found by chance as summarized in Table 11.3. Some of these duplications have been, or may be, associated with specific phe-notypes. A few other duplications that may also express a functional phenotypic effect are also listed there.
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