Chapter 062. Principles of Human Genetics (Part 14)

Transmission of Genetic DiseaseOrigins and Types of Mutations A mutation can be defined as any change in the primary nucleotide sequence of DNA regardless of its functional consequences. Some mutations may be lethal, others are less deleterious, and some may confer an evolutionary advantage. Mutations can occur in the germline (sperm or oocytes); these can be transmitted to progeny. Alternatively, mutations can occur during embryogenesis or in somatic tissues. Mutations that occur during development lead to mosaicism, a situation in which tissues are composed of cells with different genetic constitutions. If the germline is mosaic, a mutation can be...
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Chapter 062. Principles of Human Genetics (Part 14) Chapter 062. Principles of Human Genetics (Part 14) Transmission of Genetic Disease Origins and Types of Mutations A mutation can be defined as any change in the primary nucleotidesequence of DNA regardless of its functional consequences. Some mutations maybe lethal, others are less deleterious, and some may confer an evolutionaryadvantage. Mutations can occur in the germline (sperm or oocytes); these can betransmitted to progeny. Alternatively, mutations can occur during embryogenesisor in somatic tissues. Mutations that occur during development lead to mosaicism,a situation in which tissues are composed of cells with different geneticconstitutions. If the germline is mosaic, a mutation can be transmitted to someprogeny but not others, which sometimes leads to confusion in assessing thepattern of inheritance. Somatic mutations that do not affect cell survival cansometimes be detected because of variable phenotypic effects in tissues (e.g.,pigmented lesions in McCune-Albright syndrome). Other somatic mutations areassociated with neoplasia because they confer a growth advantage to cells.Epigenetic events, heritable changes that do not involve changes in gene sequence(e.g., altered DNA methylation), may influence gene expression or facilitategenetic damage. With the exception of triplet nucleotide repeats, which canexpand (see below), mutations are usually stable. Mutations are structurally diverse—they can involve the entire genome, asin triploidy (one extra set of chromosomes), or gross numerical or structuralalterations in chromosomes or individual genes (Chap. 63). Large deletions mayaffect a portion of a gene or an entire gene, or, if several genes are involved, theymay lead to a contiguous gene syndrome. Unequal crossing-over betweenhomologous genes can result in fusion gene mutations, as illustrated by colorblindness (Chap. 29). Mutations involving single nucleotides are referred to aspoint mutations (Fig. 62-5). Substitutions are called transitions if a purine isreplaced by another purine base (A ↔G) or if a pyrimidine is replaced by anotherpyrimidine (C ↔T). Changes from a purine to a pyrimidine, or vice versa, arereferred to as transversions. If the DNA sequence change occurs in a codingregion and alters an amino acid, it is called a missense mutation. Depending on thefunctional consequences of such a missense mutation, amino acid substitutions indifferent regions of the protein can lead to distinct phenotypes. Polymorphisms aresequence variations that have a frequency of at least 1%. Usually, they do notresult in a perceptible phenotype. Often they consist of single base-pairsubstitutions that do not alter the protein coding sequence because of thedegenerate nature of the genetic code (synonymous polymorphism), although it ispossible that some might alter mRNA stability, translation, or the amino acidsequence (non-synonymous polymorphism) (Fig. 62-7). These types of basesubstitutions are encountered frequently during genetic testing and must bedistinguished from true mutations that alter protein expression or function. Smallnucleotide deletions or insertions cause a shift of the codon reading frame(frameshift). Most commonly, reading frame alterations result in an abnormalprotein segment of variable length before termination of translation occurs at astop codon (nonsense mutation) (Fig. 62-5). Mutations in intronic sequences or inexon junctions may destroy or create splice donor or splice acceptor sites.Mutations may also be found in the regulatory sequences of genes, resulting inreduced gene transcription. Mutation Rates As noted before, mutations represent an important cause of geneticdiversity as well as disease. Mutation rates are difficult to determine in humansbecause many mutations are silent and because testing is often not adequate todetect the phenotypic consequences. Mutation rates vary in different genes but areestimated to occur at a rate of ~10–10/bp per cell division. Germline mutation rates(as opposed to somatic mutations) are relevant in the transmission of geneticdisease. Because the population of oocytes is established very early indevelopment, only ~20 cell divisions are required for completed oogenesis,whereas spermatogenesis involves ~30 divisions by the time of puberty and 20 celldivisions each year thereafter. Consequently, the probability of acquiring newpoint mutations is much greater in the male germline than the female germline, inwhich rates of aneuploidy are increased (Chap. 63). Thus, the incidence of newpoint mutations in spermatogonia increases with paternal age (e.g.,achondrodysplasia, Marfan syndrome, neurofibromatosis). I ...