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 replication

Many mechanisms that help cells avoid mutations have evolved Evolution connection: DNA replication Base-pairing specificity

Evolution connection: DNA replication Base-pairing specificity DNA polymerase proofreading Many mechanisms that help cells avoid mutations have evolved

Evolution connection: DNA replication Many mechanisms that help cells avoid mutations have evolved Base-pairing specificity DNA polymerase proofreading Mismatch repair

Evolution 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

Evolution connection: DNA replication On average, mutations decrease fitness... but there are exceptions. Mutations maintain genetic variation in populations.

Evolution connection: DNA replication What happens when proof-reading and repair mechanisms are missing?

Evolution 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

Evolution connection: DNA replication The evolutionary trade-off of high-fidelity copying

Evolution 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, , copyright (2008) HIV evades our immune system HIV evolves resistance to our antiviral drugs High level of genetic variation challenges vaccine development

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: 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: Evolution connection: DNA replication