Chapter 062. Principles of Human Genetics (Part 16)

Dipyrimidine and CPG SequencesCertain DNA sequences are particularly susceptible to mutagenesis. Successive pyrimidine residues (e.g., T-T or C-C) are subject to the formation of ultraviolet light–induced photoadducts. If these pyrimidine dimers are not repaired by the nucleotide excision repair pathway, mutations will be introduced after DNA synthesis. The dinucleotide C-G, or CpG, is also a hot spot for a specific type of mutation. In this case, methylation of the cytosine is associated with an enhanced rate of deamination to uracil, which is then replaced with thymine. This C →T transition (or G →A on the opposite strand) accounts for...
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Chapter 062. Principles of Human Genetics (Part 16) Chapter 062. Principles of Human Genetics (Part 16) Dipyrimidine and CPG Sequences Certain DNA sequences are particularly susceptible to mutagenesis.Successive pyrimidine residues (e.g., T-T or C-C) are subject to the formation ofultraviolet light–induced photoadducts. If these pyrimidine dimers are not repairedby the nucleotide excision repair pathway, mutations will be introduced after DNAsynthesis. The dinucleotide C-G, or CpG, is also a hot spot for a specific type ofmutation. In this case, methylation of the cytosine is associated with an enhancedrate of deamination to uracil, which is then replaced with thymine. This C →Ttransition (or G →A on the opposite strand) accounts for at least one-third of pointmutations associated with polymorphisms and mutations. Many of the MSH2mutations in HNPCC, for example, involve CpG sequences. In addition to the factthat certain types of mutations (C →T or G →A) are relatively common, thenature of the genetic code also results in overrepresentation of certain amino acidsubstitutions. Unstable DNA Sequences Trinucleotide repeats may be unstable and expand beyond a criticalnumber. Mechanistically, the expansion is thought to be caused by unequalrecombination and slipped mispairing. A premutation represents a small increasein trinucleotide copy number. In subsequent generations, the expanded repeat mayincrease further in length and result in an increasingly severe phenotype, a processcalled dynamic mutation (see below for discussion of anticipation). Trinucleotideexpansion was first recognized as a cause of the fragile X syndrome, one of themost common causes of mental retardation. Other disorders arising from a similarmechanism include Huntington disease (Chap. 365), X-linked spinobulbarmuscular atrophy (Chap. 369), and myotonic dystrophy (Chap. 382). Malignantcells are also characterized by genetic instability, indicating a breakdown inmechanisms that regulate DNA repair and the cell cycle. Functional Consequences of Mutations Functionally, mutations can be broadly classified as gain-of-function andloss-of-function mutations. Gain-of-function mutations are typically dominant,i.e., they result in phenotypic alterations when a single allele is affected.Inactivating mutations are usually recessive, and an affected individual ishomozygous or compound heterozygous (e.g., carrying two different mutantalleles of the same gene) for the disease-causing mutations. Alternatively,mutation in a single allele can result in haploinsufficiency, a situation in which onenormal allele is not sufficient to maintain a normal phenotype. Haploinsufficiencyis a commonly observed mechanism in diseases associated with mutations intranscription factors (Table 62-2). Remarkably, the clinical features amongpatients with an identical mutation in a transcription factor often varysignificantly. One mechanism underlying this variability consists in the influenceof modifying genes. Haploinsufficiency can also affect the expression of rate-limiting enzymes. For example, haploinsufficiency in enzymes involved in hemesynthesis can cause porphyrias (Chap. 352). An increase in dosage of a gene product may also result in disease, asillustrated by the duplication of the DAX1 gene in dosage-sensitive sex-reversal(Chap. 343). Mutation in a single allele can also result in loss of function due to adominant-negative effect. In this case, the mutated allele interferes with thefunction of the normal gene product by one of several different mechanisms: (1) amutant protein may interfere with the function of a multimeric protein complex, asillustrated by mutations in type 1 collagen (COL1A1, COL1A2) genes inosteogenesis imperfecta (Chap. 357); (2) a mutant protein may occupy bindingsites on proteins or promoter response elements, as illustrated by thyroid hormoneresistance, a disorder in which inactivated thyroid hormone receptor binds to targetgenes and functions as an antagonist of normal receptors (Chap. 335); or (3) amutant protein can be cytotoxic as in α1 antitrypsin deficiency (Chap. 254) orautosomal dominant neurohypophyseal diabetes insipidus (Chap. 334), in whichthe abnormally folded proteins are trapped within the endoplasmic reticulum andultimately cause cellular damage.[newpage] Genotype and Phenotype Alleles, Genotypes, and Haplotypes An observed trait is referred to as a phenotype ; the genetic informationdefining the phenotype is called the genotype . Alternative forms of a gene or agenetic marker are referred to as alleles. Alleles may be polymorphic variants ofnucleic acids that have no apparent effect on gene expression or function. In othe ...