15.4 Single-Gene Mutations Cause a Wide Range of Human Diseases. Copyright 2009 Pearson Education, Inc.

Transcription

1 15.4 Single-Gene Mutations Cause a Wide Range of Human Diseases 1

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3 Muscular dystrophy results from mutation in the gene encoding dystrophin. The more severe Duchenne muscular dystrophy (DMD) is typically the result from a frameshift mutation in the dystrophin gene. This leads to a nonfunctional truncated protein. The less severe Becker muscular dystrophy (BMD) is primarily due to alteration of the protein sequence. 3

4 Trinucleotide repeat sequences are responsible for: Fragile X syndrome Huntington disease (HD) Myotonic dystrophy (MD) Spinobulbar muscular atrophy The greater the number of repeats, the earlier disease onset occurs. In affected individuals, the number of repeats may increase in each subsequent generation, a phenomenon known as genetic anticipation. 4

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6 15.5 Organisms Use DNA Repair Systems to Counteract Mutations Bacterial DNA polymerase III is able to recognize and correct errors in replication, a process called proofreading. Mismatch repair corrects errors that remain after proofreading. The correct DNA strand is recognized based on DNA methylation of the parental strand. Postreplication repair occurs when DNA replication skips over a lesion and requires homologous recombination mediated by the RecA protein. 6

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8 The SOS repair system allows DNA synthesis to become error-prone. SOS Response Although SOS repair is itself mutagenic, it may allow the cell to survive DNA damage that might otherwise kill it. SOS response in bacteria 8

9 Photoreactivation repair removes thymine dimers caused by UV light. The process depends on the activity of a protein called photoreactivation enzyme (PRE). 9

10 Excision repair involves three steps: removal of the mutation by a nuclease gap filling by DNA polymerase sealing of the nick by DNA ligase Base excision repair (BER) involves: recognition of the erroneous base cutting of the DNA 10

11 Nucleotide excision repair (NER) repairs bulky lesions and involves the uvr genes. 11

12 Individuals with xeroderma pigmentosum (XP) have lost the ability to undergo nucleotide excision repair. Pol eta is the key enzyme that replicates through UV irradiation-induced DNA damage. Genetic defects in pol eta result in Xeroderma Pigmentosum Variant (XP-V). 12

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14 DNA double-strand break (DSB) repair is activated when both DNA strands are cleaved. It is responsible for reannealing the two strands. Homologous recombinational repair fixes a double-strand DNA break by digesting back the 5' ends of the broken helix to leave overhanging 3' ends that interact with a region of an undamaged sister chromatid to allow DNA polymerase to copy the undamaged DNA sequence into the damaged strand. 14

15 There are other pathways for DSB repair via homologous recombination. This type of repair is accurate, and is prominent in late S/G2.

16 DSBs can also be repaired via nonhomologous endjoining, which is error-prone and is prominent during G1. End joining repairs double-stranded breaks but does not require a homologous region of DNA during repair. 16

17 15.6 The Ames Test Is Used to Assess the Mutagenicity of Compounds The Ames test uses any of a dozen strains of Salmonella typhimurium selected for their increased sensitivity to mutagens and their ability to reveal the presence of specific types of mutations. 17

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19 15.7 Geneticists Use Mutations to Identify Genes and Study Gene Function In order to identify the genes and processes that regulate biological functions, geneticists often induce mutations in model organisms. 19

20 15.8 Transposable Elements Move within the Genome and May Create Mutations 20

21 Insertion Sequences 21

22 Barbara McClintock Nobel Prize 1983 Transposons: The Ac Ds System in Maize 22

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25 Copia Elements in Drosophila P Element Transposons in Drosophila 25

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27 Transposons Create Mutations and Provide Raw Material for Evolution 27

28 Homologous recombination between transposable elements can result in deletions, duplications, and inversions 28

29 Creation of target site duplication in host chromosome DNA during transposition 29

30 Transposons Use Two Different Methods to Move Within Genomes: Nonreplicative and replicative methods of DNA transposition 30

31 Structural features of retroviruses and retrotransposons 31

32 Transposition by an LTR-containing retrotransposon, copia 32

33 Electron microscopic images of virus-like particles in yeast cells that contain the retrotransposonty 33