T

c spontaneously at any given site on the chromosome ranges from about iir6 to 10 11 per round of DNA replication, with some sites on the chromosome being "hotspots" where mutations arise at high frequency and other sites undergoing alterations at a comparatively low frequency.

One kind of sequence that is particularly prone to mutation merits special comment because of its importance in human genetics and disease. These mutation-prone sequences are repeats of simple di-. tri- or tctranucleotide sequences, which are known as DNA microsatellites. One well-known example involves repeats of the dinur.leotide sequence CA. Stretches of OA repeats are found at many widely scattered sites in Ihe chromosomes of humans and some other eukaryotes. The replication machinery has difficulty copying such repeats accurately, frequently undergoing "slippage." This slippage increases or reduces the number of copies of the repeated sequence. As a result, the CA repeat length at a particular site on the chromosome is often highly polymorphic in the population. This polymorphism provides a convenient physical marker for mapping inherited mutations, such as mutations that increase the propensity to certain diseases in humans (see Box 9-1, Expansion of Triple Repeals Causes Disease).

Some Replication Errors Escape Proofreading

As we have seen, the replication machinery achieves a remarkably high degree of accuracy using a proofreading mechanism, the 3' ā€”* 5' exonu-clease component of the replisome, which removes wrongly incorporated nucleotides (as we discussed in Chapter 8). Proofreading improves the fidelity of DNA replication by a factor of about 100- The proofreading exonuclease is not, however, foolproof. Some misincorporated nucleotides escape detection and become a mismatch between the newly synthesized strand and the template strand. Three different nucleotides can be misincorporated opposite each of the four kinds of nucleotides in the template strand (for example, T, G, or C opposite a T in the template) for a total of 12 possible mismatches (T:T, TiG, T:Cā€ž and so forth). If the misincorporated nucleotide is not subsequently detected

Box 9-1 Expansion of Triple Repeats Causes Disease

Another well-known example of etror-pione sequences is repeats of the triplet nudeotde sequences CGC and CAC in certain genes. In humans such triplet repeats are often found to undergo expansion from one generation to the next, resulting in diseases that are progressively more severe in the children and grandchildren of afflicted individuals. Examples of diseases that are caused by triplet expansion are adult muscular (myotonic) dystrophy, fragile X syndrome, which causes mental retardation; and Huntington's disease, which causes neurodegeneratbn CAG is the codon for glutamine, and its expansion in the coding sequence for the Huntingtm protein results in an extended stretch of glutamine residues in the mutant protein in patients with Huntington's disease. Recent research indicates that this polyglulamtne stretch interferes with the normal interaction between a glutamine rich patch in a transcription factor called Spl and a corresponding glutarnine-rich patch in 'Will30," a subunit of a component of the transcription machinery called TFIID (see Chapter ?2). This interference impairs transcription in neurons of the brain, including the transcription of the gene for the receptor of a neurotransmitter. Similar pdyglutamme stretches from CAG expansions in other genes may also exert their effects by disrupting interactions between transcription factors and TAFli 130.

FIGURE 9-2 A mutation can be permanently incorporated by replication.

A mutation may be introduced by mistncorpora-tion of a base in the first round of replication In the second round of replication, the mutation becomes permanently incorporated in the DNA sequence.

FIGURE 9-2 A mutation can be permanently incorporated by replication.

A mutation may be introduced by mistncorpora-tion of a base in the first round of replication In the second round of replication, the mutation becomes permanently incorporated in the DNA sequence.

c t c first round replication {mis-incorporatiofi)

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