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Allelic heterozygosity most often results when different alleles are inherited from the egg and the sperm, but it also occurs as a consequence of spontaneous alteration in nucleotide sequence (mutation). Genetic change occurring during formation of an egg or a sperm is called a germinal mutation. When the change occurs after conception—from the earliest stages of embryogenesis to dividing cells in the body of the oldest adult—it is termed a somatic mutation. As is discussed below, the role of somatic mutation in the etiology of human disease is now increasingly recognized.

The coarsest type of mutation is alteration in the number or physical structure of chromosomes. For example, nondisjunction (failure of chromosome pairs to separate) during meiosis—the reduction division that leads to production of mature ova and sperms—causes the embryo to have too many (eg, three copies of chromosome 21 in the Down syndrome) or too few (eg, only one sex chromosome, the X, in Turner syndrome) chromosomes, a situation called aneuploidy. Rearrangement of chromosome arms, such as occurs in translocation or inversion, is a mutation even if breakage and reunion do not disrupt any coding sequence. Thus, the phenotypic effect of gross chromosomal mutations can range from profound (as in aneuploidy) to nil.

A bit less coarse, but still detectable cytologically, are deletions of part of a chromosome. Such mutations almost always alter phenotype because a number of genes are lost; however, a deletion may involve only a single nucleotide, whereas about 1–2 million nucleotides (1–2 megabases) must be lost before the defect can be visualized by the most sensitive cytogenetic methods short of in situ hybridization or array analysis. Deletions and duplications of substantial regions of nucleotide sequence are remarkably common among humans. Many are apparently harmless and are passed from parent to child in an autosomal dominant pattern of inheritance. Others involve one or more genes that can have subtle or profound clinical consequences. The latter are often de novo, meaning that neither parent has the copy number variation, which must have arisen during meiosis of one of the gametes.

Mutations of one or a few nucleotides in exons have several potential consequences. Changes in one nucleotide can alter which amino acid is encoded; if the amino acid is in a critical region of the protein, function might in this way be severely disturbed (eg, sickle cell disease). On the other hand, some amino acid substitutions have no detectable effect on function, and the phenotype is therefore unaltered by the mutation. Similarly, because the genetic code is degenerate (two or more different three-nucleotide sequences, called codons, encode the same amino acids), nucleotide substitution does not necessarily alter the amino acid sequence of the protein. Three specific codons signal termination of translation; thus, a nucleotide substitution in an exon that inappropriately generates one of the stop codons usually causes a truncated protein, which is nearly always dysfunctional. Other nucleotide substitutions ...

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