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Ch. 15 - Gene Mutation, DNA Repair, and Transposition
Klug - Concepts of Genetics  12th Edition
Klug12th EditionConcepts of Genetics ISBN: 9780135564776Not the one you use?Change textbook
Chapter 15, Problem 27

What evidence indicates that mutations in human DNA mismatch repair genes are related to certain forms of cancer?

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1
Understand the role of DNA mismatch repair (MMR) genes: These genes encode proteins responsible for correcting errors that occur during DNA replication, such as base-base mismatches or insertion-deletion loops.
Recognize that mutations in MMR genes can lead to a failure in correcting replication errors, resulting in an accumulation of mutations throughout the genome, a condition known as microsatellite instability (MSI).
Examine clinical and genetic studies showing that individuals with inherited mutations in MMR genes, such as MLH1, MSH2, MSH6, and PMS2, have a higher risk of developing certain cancers, particularly Lynch syndrome-associated colorectal and endometrial cancers.
Review molecular evidence from tumor samples demonstrating high levels of MSI and loss of MMR protein expression, which correlates with mutations in MMR genes and supports their role in tumor development.
Consider experimental data where restoring normal MMR gene function in cancer cells reduces mutation rates and tumorigenic potential, further confirming the causal relationship between MMR gene mutations and cancer.

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Key Concepts

Here are the essential concepts you must grasp in order to answer the question correctly.

DNA Mismatch Repair Mechanism

DNA mismatch repair (MMR) is a cellular process that corrects errors introduced during DNA replication, such as base-base mismatches and insertion-deletion loops. Proper functioning of MMR maintains genomic stability by preventing mutations from accumulating. Defects in MMR genes impair this correction, leading to increased mutation rates.
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Mutations in MMR Genes and Cancer

Mutations in human MMR genes, such as MLH1, MSH2, MSH6, and PMS2, disrupt the repair process, causing microsatellite instability and accumulation of mutations. This genomic instability is strongly linked to the development of certain cancers, notably hereditary nonpolyposis colorectal cancer (Lynch syndrome), demonstrating a direct connection between MMR gene defects and cancer risk.
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Evidence from Genetic and Clinical Studies

Genetic analyses of cancer patients reveal germline mutations in MMR genes associated with familial cancer syndromes. Tumor samples often show microsatellite instability and loss of MMR protein expression. Clinical studies correlate these molecular findings with increased cancer incidence, providing strong evidence that MMR gene mutations contribute to cancer development.
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Related Practice
Textbook Question

Presented here are hypothetical findings from studies of heterokaryons formed from seven human xeroderma pigmentosum cell strains:

These data are measurements of the occurrence or nonoccurrence of unscheduled DNA synthesis in the fused heterokaryon. None of the strains alone shows any unscheduled DNA synthesis. Which strains fall into the same complementation groups? How many different groups are revealed based on these data? What can we conclude about the genetic basis of XP from these data?

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Textbook Question
Imagine yourself as one of the team of geneticists who launches a study of the genetic effects of high-energy radiation on the surviving Japanese population immediately following the atom bomb attacks at Hiroshima and Nagasaki in 1945. Demonstrate your insights into both chromosomal and gene mutation by outlining a short-term and long-term study that addresses these radiation effects. Be sure to include strategies for considering the effects on both somatic and germ-line tissues.
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Textbook Question
With the knowledge that radiation causes mutations, many assume that human-made forms of radiation are the major contributors to the mutational load in humans. What evidence suggests otherwise?
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Textbook Question

Among Betazoids in the world of Star Trek®, the ability to read minds is under the control of a gene called mindreader (abbreviated mr). Most Betazoids can read minds, but rare recessive mutations in the mr gene result in two alternative phenotypes: delayed-receivers and insensitives. Delayed-receivers have some mind-reading ability but perform the task much more slowly than normal Betazoids. Insensitives cannot read minds at all. Betazoid genes do not have introns, so the gene only contains coding DNA. It is 3332 nucleotides in length, and Betazoids use a four-letter genetic code.

The following table shows some data from five unrelated mr mutations.

For each mutation, provide a plausible explanation for why it gives rise to its associated phenotype and not to the other phenotype. For example, hypothesize why the mr-1 nonsense mutation in codon 829 gives rise to the milder delayed-receiver phenotype rather than the more severe insensitive phenotype. Then repeat this type of analysis for the other mutations. (More than one explanation is possible, so be creative within plausible bounds!)

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Textbook Question

Skin cancer carries a lifetime risk nearly equal to that of all other cancers combined. Following is a graph [modified from K. H. Kraemer (1997). Proc. Natl. Acad. Sci. (USA) 94:11 14] depicting the age of onset of skin cancers in patients with or without XP, where the cumulative percentage of skin cancer is plotted against age. The non-XP curve is based on 29,757 cancers surveyed by the National Cancer Institute, and the curve representing those with XP is based on 63 skin cancers from the Xeroderma Pigmentosum Registry.

Provide an overview of the information contained in the graph. 

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Textbook Question

Skin cancer carries a lifetime risk nearly equal to that of all other cancers combined. Following is a graph [modified from K. H. Kraemer (1997). Proc. Natl. Acad. Sci. (USA) 94:11 14] depicting the age of onset of skin cancers in patients with or without XP, where the cumulative percentage of skin cancer is plotted against age. The non-XP curve is based on 29,757 cancers surveyed by the National Cancer Institute, and the curve representing those with XP is based on 63 skin cancers from the Xeroderma Pigmentosum Registry.

Explain why individuals with XP show such an early age of onset.

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