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Evolutionconnection replication
Evolutionconnection replication
Evolutionconnection replication
Evolutionconnection replication
Evolutionconnection replication
Evolutionconnection replication
Evolutionconnection replication
Evolutionconnection replication
Evolutionconnection replication
Evolutionconnection replication
Evolutionconnection replication
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Evolutionconnection replication

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  • We’ve just studied how DNA is copied and some of the different ways the system guards against errors (mutations). The specificity of the genetic code is an important first step in maintaining the fidelity of the sequence; however, as we’ve learned, many additional mechanisms have evolved…
  • DNA polymerase compares each newly added base against the template, in a sense, proofreading its own work. If a mistake is found, it is corrected before moving on.
    This image shows the replication fork with DNA polymerase attached.
  • Mismatch repair can catch mistakes shortly after replication by recognizing which strand was used as the template and fixing mismatched bases on the newly synthesized strand.
  • In excision repair, a section of the DNA surrounding damaged bases or damaged nucleotides are cut out and replaced, based on the non-damaged strand.
    Other cellular mechanisms, such as double-strand break repair, have also evolved and repair different sorts of damage.
    Cells go to extreme lengths to make sure that their DNA is copied accurately and that the DNA sequence is maintained with fidelity after that. The end result of this is impressive. (CLICK) Recent estimates suggests that, in humans, mistakes slip by only once in every 30 million base pairs or so.
  • DNA proofreading and repair mechanisms evolved because, on average, mutations decrease the fitness of the individual carrying them. Most mutations are neutral or deleterious. But there are exceptions. Sometimes, mutations are advantageous, as in the case of antibiotic resistant bacteria (CLICK) or the peppered moth (CLICK), where a mutation that caused dark body color allowed moths to survive better in their polluted environment.
    (CLICK) Mutation generates genetic variation in populations, and natural selection acts on this variation, weeding out the deleterious mutations and increasing the frequency of the advantageous ones. Genetic variation is the raw material of evolution.
  • What happens when some of these repair mechanisms are missing? Retroviruses (like HIV, shown here) are a case in point. They have single-stranded RNA (not DNA) as their genetic material. In order to make copies of themselves, they use an enzyme called reverse transcriptase. This enzyme makes a DNA copy of RNA. But unlike DNA polymerase, reverse transcriptase cannot proof-read.
    (Note to instructor: If you wish, this is an opportunity to go into greater depth on how HIV reproduces by invading a cell and using reverse transcriptase to make a DNA copy of their RNA. This DNA is then integrated into the host’s genome in that cell and directs the host’s cellular machinery to produce copies of the virus.)
  • What happens without proofreading? Each time reverse transcriptase copies HIV’s genome, it makes many mistakes—as many as one mistake per thousand base pairs copied. This high mutation rate (combined with the virus’s rapid rate of reproduction) means that HIV evolves at lightning fast speeds.
    Organisms that use proof-reading DNA polymerase (which only makes a mistake once every billion base pairs or so in eukaryotic cells) have much lower mutation rates and evolve much more slowly.
    What does this mean in terms of our evolution?
  • It’s a tradeoff. For high fidelity copiers (like humans), very few of our offspring carry damaging mutations. On the other hand, little new variation is generated each generation to contribute to our future evolution. Retroviruses, on the other hand, produce a lot of offspring with deleterious mutations—but they are also evolutionarily nimble. They have lots of standing genetic variation and can evolve quickly when faced with new environmental conditions.
    This has direct implications for human health.
  • HIV-1 genomes evolve about a million times as quickly eukaryotic DNA genomes do. This phylogeny tracks the evolutionary history of an HIV infection within a single patient over the course of 10 years. This rapid pace of HIV evolution has enormous implications for our ability to fight the virus:
    HIV evolves to evade the antibodies our immune systems produce to attack it.
    HIV evolves resistance to the drugs we develop against it. This puts medical researchers in an arms race against the virus. New drugs must be constantly developed, and patients often need to take cocktails of drugs to slow the evolution of resistance and keep viral loads low.
    Finally, because the virus is so genetically variable and changes so quickly, researchers have not yet managed to develop a vaccine that works against the virus consistently.
    In this case, small differences at the molecular level (like using reverse transcriptase instead of DNA polymerase to copy one’s genetic material) have a big impact on evolution and on human health. The evolutionary trade-off of sloppy copying is worth it for HIV and means that it can evolve remarkably quickly—and this rapid evolution is what makes the virus so difficult for us to fight.
  • Transcript

    • 1. Learning goals: Students will understand that 1) molecular mechanisms that preserve the fidelity of the genetic sequence have been favored by natural selection, 2) some entities, such as HIV, lack some of these mechanisms and so have a higher rate of mutation and evolution, and 3) many challenges posed to medical science by HIV can be attributed to the virus’s rapid evolution. For the instructor: This short slide set explains molecular features of DNA replication, such as the proof-reading ability of DNA polymerase, using evolutionary theory and explores an alternate evolutionary scenario (with implications for human health) in which mutation rates are higher. To integrate it best, use this slide set immediately after you’ve discussed DNA replication. Alternatively, you may wish to incorporate this material after you’ve covered the topic of mutation. To save time, you may wish to condense the material on slides two through five by simply listing the mechanisms and selecting one image to include. Each of the following slides comes with a sample script for the instructor. To review this script, download the PowerPoint file and view the Notes associated with each slide. Evolution Connection slideshows are provided by Understanding Evolution (understandingevolution.org) and are copyright 2011 by The University of California Museum of Paleontology, Berkeley, and the Regents of the University of California. Feel free to use and modify this presentation for educational purposes. Evolution connection: DNA replicationEvolution connection: DNA replication
    • 2. Many mechanisms that help cells avoid mutations have evolved Evolution connection: DNA replicationEvolution connection: DNA replication • Base-pairing specificity
    • 3. Evolution connection: DNA replicationEvolution connection: DNA replication • Base-pairing specificity • DNA polymerase proofreading Many mechanisms that help cells avoid mutations have evolved
    • 4. Evolution connection: DNA replicationEvolution connection: DNA replication Many mechanisms that help cells avoid mutations have evolved • Base-pairing specificity • DNA polymerase proofreading • Mismatch repair
    • 5. Evolution connection: DNA replicationEvolution connection: DNA replication Many mechanisms that help cells avoid mutations have evolved After all these corrections, mistakes are rare: 1 in 30 million base pairs. • Base-pairing specificity • DNA polymerase proofreading • Mismatch repair • Excision repair and more
    • 6. Evolution connection: DNA replicationEvolution connection: DNA replication On average, mutations decrease fitness . . . but there are exceptions. Mutations maintain genetic variation in populations.
    • 7. Evolution connection: DNA replicationEvolution connection: DNA replication What happens when proof-reading and repair mechanisms are missing?
    • 8. Evolution connection: DNA replicationEvolution connection: DNA replication What happens when proof-reading and repair mechanisms are missing? Reverse transcriptase: sloppy copying (one mistake per thousand base pairs)  high mutation rate  quick evolution DNA polymerase: accurate copying (one mistake per billion base pairs)  low mutation rate  slow evolution Molecule images © 2012 David Goodsell & RCSB Protein Data Bank
    • 9. Evolution connection: DNA replicationEvolution connection: DNA replication The evolutionary trade-off of high-fidelity copying
    • 10. Evolution connection: DNA replicationEvolution connection: DNA replication HIV evolves quickly Reprinted by permission from Macmillan Publishers Ltd: Wagner, A. Neutralism and selectionism: a network-based reconciliation. Nature Reviews Genetics 9, 965-974, copyright (2008) • HIV evades our immune system • HIV evolves resistance to our antiviral drugs • High level of genetic variation challenges vaccine development
    • 11. Nowak, M. (1990). HIV mutation rate. Nature. 347:522. Shankarappa, R. Margolick, J. B., Gange, S. J., Rodrigo, A. G., Upchurch, D., . . . Mullins, J. I. (1999). Consistent viral evolutionary changes associated with the progression of Human Immunodeficiency Virus Type 1 infection. Journal of Virology. 73: 10489-10502. Xue, Y., Wang, Q., Long, Q., Ng, B. L., Swedlow, H., Burton, J. . . . Tyler-Smith, C. (2009). Human Y chromosome base-substitution mutation rate measured by direct sequencing in a deep-rooting pedigree. Current Biology. 19: 1453-1457. Evolution connection: DNA replicationEvolution connection: DNA replication

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