TAILIEUCHUNG - Chapter 062. Principles of Human Genetics (Part 16)

Dipyrimidine and CPG Sequences Certain DNA sequences are particularly susceptible to mutagenesis. Successive pyrimidine residues (., 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. | Chapter 062. Principles of Human Genetics Part 16 Dipyrimidine and CPG Sequences Certain DNA sequences are particularly susceptible to mutagenesis. Successive pyrimidine residues . 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 at least one-third of point mutations associated with polymorphisms and mutations. Many of the MSH2 mutations in HNPCC for example involve CpG sequences. In addition to the fact that certain types of mutations C T or G A are relatively common the nature of the genetic code also results in overrepresentation of certain amino acid substitutions. Unstable DNA Sequences Trinucleotide repeats may be unstable and expand beyond a critical number. Mechanistically the expansion is thought to be caused by unequal recombination and slipped mispairing. A premutation represents a small increase in trinucleotide copy number. In subsequent generations the expanded repeat may increase further in length and result in an increasingly severe phenotype a process called dynamic mutation see below for discussion of anticipation . Trinucleotide expansion was first recognized as a cause of the fragile X syndrome one of the most common causes of mental retardation. Other disorders arising from a similar mechanism include Huntington disease Chap. 365 X-linked spinobulbar muscular atrophy Chap. 369 and myotonic dystrophy Chap. 382 . Malignant cells are also characterized by genetic instability indicating a breakdown in mechanisms that regulate DNA repair and the cell cycle. Functional Consequences of Mutations .

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