The Unifying Concept in Biology

1. EVOLUTION The Unifying Concept in Biology Dr. Carol Eunmi Lee University of Wisconsin, Madison

2. “Nothing in biology makes sense except in the light of evolution” Theodosius Dobzhansky (1900-1975)

3. Who am I? • BA, MA from Stanford University Anthropology (Human Evolution) • PhD, University of Washington Evolutionary Genetics • Postdoc, University of California, San Diego Evolutionary Physiology and Biochemistry • Professor, University of Wisconsin, Madison Center of Rapid Evolution, Zoology, Genetics

4. TA • Marijan Posavi: Ph.D. Animal Science, Ph.D. candidate in Zoology • Will lead optional discussion (times posted on website) • He has office hours and can help with understanding the course material, but, he is NOT a private tutor (not possible for ~100+ students) • Please contact me if you are having trouble with this course and need a tutor

5. Research in my Lab • Adaptation, Functional evolutionary genomics, Physiological Evolution • Rapid evolution of invasive species entering the Great Lakes (zebra mussels, quagga mussels, copepods) • Evolution of microbial species carried by these invaders

6. Course Website • https://mywebspace.wisc.edu/carollee/web/Lee/Evolution410.html

7. ***Background needed for this course • Some understanding of basic genetics (Hardy Weinberg Equilibrium, DNA, RNA, transcription, translation, allele, genotype)

8. Results from diagnostic quiz • N = 98 • Mean = 5.59 ± 2.00

9. Evolution of a Pathogen as an Example: I will now use an infectious disease to illustrate basic evolutionary concepts. The following example illustrates several evolutionary mechanisms I will explain these concepts in more detail over the next few lectures

10. HIV: Fastest evolving organism on Earth HIV infects macrophages, T-cells

11. AIDS Pandemic • AIDS is among the most deadly epidemics in Human History (1981-2012: ~36 million deaths) • ~34 million people living with AIDS (estimated 2010) • 90 million deaths predicted by 2020 #people living with HIV UNAIDS. 2008 Report on the Global AIDS Epidemic (http://www.unaids.org/en/KnowledgeCentre/HIVData/GlobalReport/2008/)

12. A global view of HIV infection 33 million people [30–36 million] living with HIV, 2007

13. Problem: • HIV has the fastest mutation rate of any virus or organism observed to date • HIV evolves more rapidly than humans, and more quickly than the ability of humans to produce new drugs • Implications: AIDS vaccines are unlikely to work on all strains of the virus… …and unlikely to work on a given strain in the long run • Our understanding of how to combat viruses had in general been poor, and the recent intensive research on HIV has greatly enhanced our understanding of how to combat viruses in general

14. Evolutionary History of HIV HIV evolved multiple times from SIV (Simian Immunodeficiency Virus) There are multiple strains of HIV of different evolutionary origins and with different properties (coat proteins are divergent) http://www.sciencemag.org/cgi/content/full/313/5786/462 Time

15. HIV HIV virion latches onto proteins on surface of host cell • Retrovirus with two single strand RNA genomes • Uses Reverse Transcriptase to replicate RNA --> DNA • Attacks host immune system: infects host macrophages and helper T cells (Review in textbook on HIV)

16. Evolutionary Forces operating during HIV infection • Genetic Drift(Lecture 6):Viruses and bacteria in general have huge population sizes, where genetic drift tends to be less important • Mutation(Lecture 7):Fastest mutation rate known. Lots of genetic variation is produced. Virus can respond very quickly to Natural Selection • Natural Selection(Lecture 10): • Selection is imposed by the host immune system • Very strong selection is imposed by drugs • Transmission rate selects on levels of Virulence (tendency to cause disease). When transmission of virus to new hosts is rapid, selection favors strains that are more harmful to host

17. Evolution in a Host-Parasite System(Coevolution) I will now discuss how NATURAL SELECTIONacts on HIV: (1) Drugs impose Selection on HIV: --> evolution of drug resistance (2)Transmission Rate imposes Selection on HIV: --> evolution of virulence (3) Host immune system also imposes selection on the virus HIV  talk more about this in lecture on Selection

18. (1) Selection in Response to Drugs Several Types of Drugs: • Reverse transcriptase (RT) inhibitors, interrupts early stage of virus replication. Example: AZT • Protease inhibitors, interrupts virus replication at a later step in its life cycle These drugs do not cure people of AIDS, they only retard the progress of the disease

19. AZT Why does AZT work initially but fail in the long run? • AZT (Azidothymidine) is a thymidine mimic which stops reverse transcription and impedes viral replication • Mutations in the viral reverse transcriptase gene of HIV arise, such that the enzyme can recognize AZT and cease to incorporate it • These mutations slow down viral genome replication (as the reverse transcriptase becomes more careful), but confer resistance to AZT (Tradeoff between speed vs. accuracy of reverse transcription) • These slow and careful mutants are favored by selection • Viral resistance to AZT evolves within human hosts… (takes about 6 months) • When AZT therapy stops, back mutations that restore the Amino Acid sequence to the original state are then favored by selection so that reverse transcription could speed up again(fast & sloppy are favored – because fast replicating mutants would outgrow the slower)

20. AZT (Azidothymidine) is a thymidine mimic which stops reverse transcription and impedes viral replication

21. In the presence of AZT, Selection favors mutants that are resistant to AZT • Resulting in a change in % in the population, toward a higher % of AZT resistant mutants

22. AZT Why does AZT work short term but fail in the long run? • The drug AZT imposes Selection on the virus. High levels of genetic variation (generated by high mutation rate) allows the virus to respond to selection and evolve drug resistance. • HIV has a high mutation rate because its reverse transcriptase is extremely error prone, causing mutations to often arise in the viral genome. • Occasionally a mutation can be favorable (as in the case of resistance to AZT), and would be favored by selection, leading to an increase in % of the new favorable mutant in the population of viruses

23. (2) Selection on Virulence of HIV • Need to keep host alive long enough to get passed on to the next host (Evolutionary tradeoff between fast population growth versus keeping the host alive) • High Transmission rate : High Virulence (Can grow fast and jump to the next host; ok if host dies; the genetic strain that grows faster will win) • Low Transmission Rate : Low Virulence (More virulent strains would die with the host and get selected out; less virulent strain that does not kill the host will win)

24. Selection on Virulence • High Transmission: High Virulence

25. High Transmission Rate If the virus is likely to move to a new host, the faster growing (and more virulent) strain is likely to overtake the slower strains and “win” It’s ok to kill the host, since the chances of jumping to a new host is high Natural selection will favor the MORE virulent strain

26. Selection on Virulence • Low Transmission: Low Virulence

27. Low Transmission Rate If the virus is not likely to move to a new host the slower growing (and less virulent) strain is likely to “win” It’s not ok to kill the host, since the chances of jumping to a new host are low. If the virus kills the host, it will kill itself Natural selection will favor the LESS virulent strain

28. Evolution in Host-Parasite System SELECTION ON THE HOST (Humans) • Some humans have resistance to some HIV strains. Likely that the proportion of people with resistant alleles will increase. • Gene Therapy? Could we win an arms race? But HIV evolves faster than we do and more quickly than our ability to produce new drugs

29. The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele Novembre et al 2005, PLOS Biology Frequency of CCR5 Δ32 allele (Figure 1.20 in Freeman & Herron)

30. Combating HIV • Must lower transmission rate of HIV so that less fatal strains evolve • Must understand evolutionary properties of a disease: • Evolutionary history • Mutation rate • Selective Forces • Evolutionary Tradeoffs • Evolution in response to drug AZT: slow & accurate vs. fast & sloppy replication • Evolution in response to transmission rate: slow growing & less virulent (keep host alive) vs. fast growing & more virulent

31. Sample Exam Question: (A) Because population growth rate of HIV is so high(B) Because mutation rate of HIV is so high(C) Because transmission rate of HIV is so Low(D) Because selection acting on HIV is so high 1: Why is it difficult for scientists to develop drugs that could cure patients of HIV? Pick the most correct answer.

32. Sample Exam Question: (A) Applying a greater diversity of antiviral drugs to the AIDS patient(B) The widespread use of contraceptives (such as condoms) that would reduce the probability of transmission to the next host(C) Increasing transmission rate of the virus such that a less virulent strain evolves(D) Reducing rate of mutation rate by using drugs that slow down reverse transcriptase, such as AZT 2: Which of the following would most likely reduce the virulence (lethality) of HIV, the virus that causes AIDS?

33. History of Evolutionary Thought Dr. Carol Eunmi Lee University of Wisconsin, Madison

34. Today’s OUTLINE: (1) Development of Darwin’s Thought (2) Lamarck vs. Darwin (3) The Contribution of Darwin (4) The Contribution of Mendel (5) Conflict between “Mendelism” and “Darwinism”  Next time, the “Evolutionary Synthesis” of Mendel and Darwin

35. Charles Darwin(1809-1882) Origin of Species is one of the most influential texts of this century

36. Charles Darwin (1809-1882) • His father was a doctor (Richard Darwin) and his grandfather was Erasmus Darwin, also a doctor and a prominent scholar who was already thinking about evolution • Initially he studied Medicine at the University of Edinburgh • He neglected his studies and could not stand the sight of surgery or the sight of blood (had nausea, fainted) • Sent by his father at Christ’s College, Cambridge University to become an Anglican priest • He still neglected his studies, but he did pursue a passionate interest in Natural History • He became close to botany professor Rev. John Henslow and met other leading naturalists who saw scientific work as religious natural theology (and viewed adaptation [i.e. evolution] as God acting through laws of nature)

37. Reverend John Stevens Henslow (1796–1861) “I fully believe a better man never walked this earth”Charles Darwin to J.D. Hooker, 1861 • Darwin’s Botany professor at Christ’s College (Divinity School), Cambridge University • Henslow encouraged students to make observations of their own, rather than being spoon-fed • After Darwin completed his final examination in 1831, Henslow persuaded him to begin studying geology, and made arrangements for him to take Adam Sedgwick’s geology course and a trip to map geological strata in North Wales • Shortly thereafter, in 1831, Henslow encouraged Darwin to join the Voyage of the Beagle as the ship’s naturalist More on Henslow: Darwin's Mentor: John Stevens Henslow 1796–1861 By Walters & Stow

38. Voyage of the Beagle HMS Beagle, a ship sent by British Navy to chart coastline of South America HMS Beagle off of South America

39. During the 5-year Voyage • Darwin was supposed to be primarily a geologist; He had some expertise in geology, beetle collecting and dissecting marine invertebrates • He made observations on geological formations as the ship was mapping the coastline • At Punta Alta in Patagonia he made a major find of fossil bones of huge extinct mammals in cliffs beside modern seashells, indicating recent extinction with no signs of change in climate or catastrophe (“extinctions happen”)

40. The Galapagos Islands Archipelago of volcanic islands distributed around the equator in the Pacific Ocean, 972 km (525 nmi) west of continental Ecuador

41. The Galapagos Islands Why were these islands so important in shaping Darwin’s thinking?

42. The Galapagos Islands • As an archipelago, there were many islands with different populations of a “species” on each island • The populations were related, but were slightly different on each island… (not clear boundaries) • This led Darwin to conclude that the populations descended from a common ancestor… and he ultimately concluded that they had evolved and were evolving… •  led Darwin to question the stability of the concept of a “species”

43. Darwin’s Mockingbirds

44. "My attention was first thoroughly aroused by comparing together the various specimens ... of the mocking-thrush" C. Darwin, The Voyage of the Beagle (1839) • On Sept 17 1835, Darwin disembarked from the Beagle in the Galápagos near Sappho Cove on Chatham Island (now known as Isla San Cristóbal), and was struck by the bold, terrestrial mockingbird. • The bird is known today as Mimus melanotis, the San Cristóbal Mockingbird. Over the next 6 weeks that Darwin spent in the Galápagos, he observed mockingbirds on three other islands. • Darwin noticed the mockingbirds differed between islands. Nicolas Lawson, acting Governor of Galápagos, told Darwin that the tortoises also differed from island to island. • Towards the end of the voyage, Darwin speculated that the distribution of the mockingbirds and the tortoises might "undermine the stability of Species”. Species might not be fixed entities, but are changing over time…

45. Galapagos IslandsDarwin’s Mockingbirds (he did not focus that much on the finches; they were studied more later by the Grants)Tortoises and other animals • Mockingbirds on different islands differed slightly in size, shape and coloration • And all shared some traits (homologous traits) • He concluded that these birds must have shared a common ancestor--and were not independently created

46. Significance of the HMS Beagle Voyage • Collections to study later • Exposed Darwin to geological formations, fossils embedded in strata – animals that no longer exist today and are clearly extinct – this was known, but Darwin got to see this himself • Exposure to animal diversity, related populations within species living in different habitats: • “Species” are not immutable fixed entities • Organisms are related by common ancestry (tree-like branching) • They are changing and branching in response to the environment

47. Return to England • Returned and discussed his geological and biological finding with other scholars, influenced by Malthus, etc. • Married the wealthy Emma Wedgewood • Did not have to work, and could study the samples he collected, perform experiments, make observations, think, and write books for the rest of his life

48. Historical Context: • By mid-1800s scientific context was in place for development of theory of Evolution • Developments in Geology: Discovery that earth is more than 6,000 years old Fossil Record showed change in species over time • http://www.ucmp.berkeley.edu/history/evotmline.html

49. Influences on Darwin • Geology: Darwin had Lyell’s Principles of Geology on board the HMS Beagle • Lamarck ’s (1744-1829): Concept of Adaptation, Inheritance of acquired characteristics • Malthus (1766-1834): Competition within species and struggle for survival

50. Influences on Darwin • Geology: Darwin had Lyell’s Principles of Geology on board the HMS Beagle, given to him by captain of the HMS Beagle (Robert FitzRoy) • Fossil record: • The earth is old • Many animals that once existed are now extinct • There are layers (strata) in the fossil record show a pattern of change