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In all genes, information is contained in parcels called exons, which are interspersed with stretches of DNA called introns that do not encode any information about the protein sequence. However, introns may contain genetic regulatory sequences, and some introns are so large that they encode an entirely distinct gene.

The exact location of a gene on a chromosome is its locus, and the array of loci constitutes the human gene map. A variation of this map, identifying selected loci known to be involved in human disease, is shown in eFigure 40–2. The difference in the higher resolution of the ordering of genes achievable by molecular techniques (such as linkage analysis) compared to cytogenetic techniques (such as visualization of small defects) is substantial, though the gap is narrowing. The chromosomes in the “standard” karyotype shown in eFigure 40–1 have about 450 visible bands; under the best of cytologic and microscopic conditions, a total of about 1600 bands can be seen. But even in this extended configuration, each band contains dozens—sometimes hundreds—of individual genes. Thus, loss (deletion) of a small band will involve loss of many coding sequences and will have diverse effects on the phenotype. Routine cytogenetic techniques of visualizing chromosomes are largely being supplanted by array-based approaches.

eFigure 40–2

A partial “morbid map” of the human genome. Shown next to the ideogram of the human X and Y chromosomes are representative mendelian disorders caused by mutations at that locus. Over 460 phenotypes have been mapped to the X chromosome and 8 to the Y chromosome. (From V. McKusick and J. Strayer.)

The number and arrangement of genes on homologous chromosomes are identical even though the actual coding sequences of homologous genes, or the number of copies of those genes, may not be. Homologous copies of a gene are termed alleles. In comparing alleles, it must be specified at what level of analysis the comparison is being made. When alleles are truly identical—in that their coding sequences and the number of copies are invariant—the individual is homozygous at that locus. At a coarser level, the alleles may be functionally identical despite subtle variations in nucleotide sequence—with the result either that the proteins produced from the two alleles are identical or that whatever differences there may be in amino acid sequence will have no bearing on the function of the protein. If the individual is being analyzed at the level of the protein phenotype, allelic homozygosity would again be an apt descriptor. However, if the analysis were at the level of the DNA—as occurs in nucleotide sequencing—then, despite functional identity, the alleles would be viewed as different and the individual would be heterozygous for that locus. Heterozygosity based on differences in the protein products of alleles has been detectable for decades, for example by electrophoresis, and was the first hard evidence concerning the high degree ...

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