A full set of instructions on how to approach, research, write, and complete your Senior Integrative Exercise are provided on the Biology Department website. Please refer to these instructions.

A survey to help you choose your comps question will be distributed soon. Please fill out this survey as soon as you receive it, no matter which term you start your comps. Please choose your preferred questions (you will rank your three choices) based on your course background. Insufficient course preparation has been one of the most common sources of trouble during comps. The Biology faculty will assign you a comps question based on the survey

1. Tracking viral pathogen evolution with genomics approaches (Anderson)

Rapid genomic sequencing of the SARS-CoV-2 virus has enabled scientists to track the introduction and spread of COVID-19 across the world. By creating phylogenetic trees based on single nucleotide polymorphisms (SNPs) accumulated in a viral genome, it is possible to identify multiple introductions into new regions, track community spread, and estimate the approximate time at which new variants were introduced into different geographic regions. These genomic analyses can also provide insights into which mutations are associated with increased transmissibility or lethality. Conduct a literature review examining how genomic data has been used to infer the epidemic history of a viral pathogen like SARS-CoV2 or influenza, as well as the limitations and weaknesses involved with such inferences.

Recommended courses: Genomics and Bioinformatics and/or Genetics and/or Evolution

Deng et al., 2020. Genomic surveillance reveals multiple introductions of SARS-CoV-2 into Northern California. Science, eabb9263. https://science.sciencemag.org/content/early/2020/06/05/science.abb9263

Gonzalez-Reiche et al., 2020. Introductions and early spread of SARS-CoV-2 in the New York City area. Science 369, 297-301. https://science.sciencemag.org/content/369/6501/297

Hadfield et al., 2018. Nextstrain: real-time tracking of pathogen evolution. Bioinformatics 34, 4121-4123. https://academic.oup.com/bioinformatics/article/34/23/4121/5001388

Rambaut et al., 2008. The genomic and epidemiological dynamics of human influenzaA virus. Nature 453, 615-619. https://www.nature.com/articles/nature06945

2. Color in Biological Systems (Hougen-Eitzman)

Color provides us with beauty in landscapes, but its presence in biological systems often has more practical aspects. For example, color can be important for pollination, predation, camouflage, protection from predation and UV radiation, mate choice, and heat transfer, with strong effects both within and among species. In the system of your choice, review the ecological or evolutionary role and importance of color.

Cuthill, I.C., W. L. Allen, K. Arbuckle, B. Caspers, G Chaplin, et. al. 2017. The biology of color. Science 357:eaan0221.

Caro, T., and T. Ruxton. 2019. Aposematism: unpacking the defences. Trends in Ecology and Evolution 34: 595-604.

Dale, J., Dey, C. J., Delhey, K., Kempenaers, B. & Valcu, M. 2015. The effects of life history and sexual selection on male and female plumage colouration. Nature 527:367– 370.

Hughes, A., E. Liggins, and M. Stevens. 2019. Imperfect camouflage: how to hide in a variable world? Proceedings of the Royal Society B-Biological Sciences 286:

Maria Gabriela Gutierrez de Camargo, M., K. Lunau, M Batalha, S. Brings, V. Garcia de Brito, and L. Morellato. 2018. How flower colour signals allure bees and hummingbirds: a community-level test of the bee avoidance hypothesis. New Phytologist 222:1112- 1122.

Nicolai, M., M. Shawkey, S. Porchetta, R. Claus, and L. D’Alba. 2020. Exposure to UV radiance predicts repeated evolution of concealed black skin in birds. Nature Communications 11:2414.

Tan, E. J., B. D. Wilts, and B.T. Tan. 2020. What’s in a band? The function of the color and banding pattern of the Banded Swallowtail. Ecology and Evolution 10:2021-2029.

3.  The role of glia in learning and memory (Jaramillo)

For the last few decades, study of the cellular and molecular basis of learning and memory has focused on synaptic plasticity, broadly understood as activity-dependent changes in synaptic efficacy. This approach focused almost exclusively on the neuron’s pre- and postsynaptic terminals, largely ignoring the potential roles of glia. This outlook is no longer tenable. Indeed, recent work has started to unveil the key contributions that glial cells play in learning and memory. Two areas have attracted especial attention: First, the role of astrocytes in regulating synaptic function, leading to the concept of a “tripartite synapse”. Second, proper myelination may be essential for plasticity, learning, and memory.

Review our current understanding of the role of astrocytes and oligodendrocytes  in synaptic plasticity.

Recommended courses: Neurobiology

Huang, A. Y. et al. (2020) Region-Specific Transcriptional Control of Astrocyte Function Oversees Local Circuit Activities, Neuron, 106 (6), 992-100.

Khakh, B.S. (2019) Astrocyte-neuron interactions in the striatum: insights on identity, form, and function. Trends Neurosci. 42, 617–630.

Fields, R. D. (2015) A new mechanism of nervous system plasticity: activity-dependent myelination. Nat Rev Neurosci. 16(12):756-67.

Steadman, P. E. et al. (2020) Disruption of Oligodendrogenesis Impairs Memory Consolidation in Adult Mice. Neuron, 105(1):150-164

Pan, S., Mayoral, S.R., Choi, H.S. et al. (2020) Preservation of a remote fear memory requires new myelin formation. Nat Neurosci 23, 487–499.

4.  Novel Pathogens (McKone)

Novel pathogens can have particularly devastating consequences. Explore how novel pathogens impact populations, potentially including evolutionary responses or effects on broader ecological communities. Novelty could arise through mutation, hybridization, host shifts, or introduction to a new location (either accidentally or intentionally for biological control).

Recommended courses: Evolution, Genetics, or Population Ecology

Alves, J. M., Carneiro, M., Cheng, J. Y., de Matos, A. L., Rahman, M. M., Loog, L., … Jiggins, F. M. 2019. Parallel adaptation of rabbit populations to myxoma virus. Science 363:1319–1326. doi: 10.1126/science.aau7285

Hessenauer, P., Fijarczyk, A., Martin, H., Prunier, J., Charron, G., Chapuis, J., … Landry, C. R. 2020. Hybridization and introgression drive genome evolution of Dutch elm disease pathogens. Nature Ecology and Evolution 4:626–638. doi: 10.1038/s41559-020-1133-6

Koch, A., Brierley, C., Maslin, M. M., & Lewis, S. L. 2019. Earth system impacts of the European arrival and Great Dying in the Americas after 1492. Quaternary Science Reviews 207:13–36. doi: 10.1016/j.quascirev.2018.12.004

Scheele, B. C., Pasmans, F., Skerratt, L. F., Berger, L., Martel, A., Beukema, W., … Canessa, S. 2020. Amphibian fungal panzootic causes catastrophic and ongoing loss of biodiversity. Science 367:1459–1463. doi: 10.1126/science.aay2905

5.  Host targets of microbial pathogens (Mitra)

Microbial pathogens excel at co-opting and interfering with host proteins and processes. In order to cause disease, viruses, bacteria and eukaryotic microbes have evolved a variety of molecular resources in order to target the host. For example, coronaviruses, such as SARS-CoV-2, use the viral Spike protein to bind human Angiotensin-converting enyme 2, a membrane receptor expressed on the surface of airway epithelial cells, and facilitate host cell entry. Bacterial pathogens, such as Salmonella, E. coli and Ralstonia use a type III secretion system to inject proteins directly into host cells to aid infection or interfere with host defenses.

Choose a host pathway that is targeted by a microbial pathogen, describe the role of this pathway uninfected hosts, and explain how the microbial pathogen co-opts this pathway in order to cause disease. Focus on the cellular, molecular and biochemical level, and highlight open questions in this area.

Recommended courses: Biochemistry, Cell Biology, Immunology, or Microbiology

Haqshenas, G., and Doerig, C. (2019). Targeting of host cell receptor tyrosine kinases by intracellular pathogens. Sci Signal 12.

Ireton, K., Van Ngo, H., and Bhalla, M. (2018). Interaction of microbial pathogens with host exocytic pathways. Cell Microbiol 20, e12861.

Kubori, T., Kitao, T., and Nagai, H. (2019). Emerging insights into bacterial deubiquitinases. Curr Opin Microbiol 47, 14-19.

Ribet, D., and Cossart, P. (2018). Ubiquitin, SUMO, and NEDD8: Key Targets of Bacterial Pathogens. Trends Cell Biol 28, 926-940.

Tuli, A., and Sharma, M. (2019). How to do business with lysosomes: Salmonella leads the way. Curr Opin Microbiol 47, 1-7.

6.  Droplet spread and pathogen transmission (Nishizaki)

For many viral pathogens, transmission is linked to the spray of respiratory droplets during exhalation, conversation, or coughing. Large droplets may be deposited on nearby surfaces, whereas smaller aerosols remain airborne posing, “risk of exposure at distances beyond 1 to 2 meters from an infected individual” (Morawska & Milton 2020). A number of questions remain concerning the mechanisms of droplet generation, transport, and/or deposition under different environmental conditions. Similarly, the viability of pathogens involved with these modes of transmission may be modulated by

external factors such as temperature, light, and relative humidity. In general terms, potential responses should focus on linkages between the environment and pathogen transmission with an eye towards the efficacy of prevention measures (e.g., social distancing, masking, air filtration).

Recommended courses: Ecological Physiology and/or Ecomechanics and/or Animal Physiology

*Morawska, L., & Milton, D. K. 2020. It is time to address airborne transmission of covid-19 Clinical Infectious Diseases doi: 10.1093/cid/ciaa939

Bhardwaj, R., & Agrawal, A. 2020. Likelihood of survival of coronavirus in a respiratory droplet deposited on a solid surface. Physics of Fluids, 32(6): 061704. doi: 10.1063/5.0012009

Drossinos, Y., & Stilianakis, N. I. 2020. What aerosol physics tells us about airborne pathogen transmission. Aerosol Science and Technology 54:6. doi: 10.1080/02786826.2020.1751055

Han, Z., To, G. N. S., Fu, S. C., Chao, C. Y. H., Weng, W., & Huang, Q. 2014. Effect of human movement on airborne disease transmission in an airplane cabin: study using numerical modeling and quantitative risk analysis. BMC infectious diseases, 14(1), 1-19.

Jayaweera, M., Perera, H., Gunawardana, B., & Manatunge, J. 2020. Transmission of COVID-19 virus by droplets and aerosols: A critical review on the unresolved dichotomy. Environmental Research 109819. doi: 10.1016/j.envres.2020.109819.

Joob, B., & Wiwanitkit, V. 2020. Spray coverage of droplets: a medical biomechanics analysis and implication in COVID-19 prevention. International Journal of Preventive Medicine 11(1): 89. doi: 10.4103/ijpvm.IJPVM_186_20.

Mittal, R., Ni, R., & Seo, J. H. 2020. The flow physics of COVID-19. Journal of Fluid Mechanics 894. doi: 10.1017/jfm.2020.330

Pica, N., & Bouvier, N. M. 2012. Environmental factors affecting the transmission of respiratory viruses. Curr Opin Virol 2(1): 90-95. doi: 10.1016/j.coviro.2011.12.003

Zhou, J., Wei, J., Choy, K. T., Sia, S. F., Rowlands, D. K., Yu, D., … & Peiris, M. 2018.

Defining the sizes of airborne particles that mediate influenza transmission in ferrets. PNAS 115(10): E2386-E2392. doi: 10.1073/pnas.1716771115

7. The relationship between bat biology and their viral reservoir (Rand)

Bats are unique among mammals in their ability to fly, generate an extremely high metabolic rate during flight, possess unusual longevity given their small body size, and develop an apparent tolerance of a high viral load. It has been suggested that some of the biochemical and physiological traits associated with a high metabolic rate provide a portion of the protection from the pathological effects of viral infection. In addition, studies suggest that bats have unique defense mechanisms that allow them to be persistently and/or latently infected with viruses. Choose and review one or more of the biochemical, cellular, and/or physiological mechanisms that play a role in facilitating this unusual bat-virus relationship.

Recommended courses: Biochemistry, Cell Biology, Physiology or Immunology

Cui, J., F. Li, and Z. Shi (2019) Origin and evolution of pathogenic coronaviruses. Nature Reviews: Microbiology 17:181-192. https://www.nature.com/articles/s41579- 018-0118-9.

Hu, X.,:W. Li1, Z. He2, and F. Zhang (2020) Identification Sus scrofa and Mus musculus as potential hosts of SARS-CoV-2 via phylogenetic and homologous recombination analysis. [Not yet published; in version 2; awaiting second peer review]

Kacprzyk, J. et al. (2017) A potent anti-inflammatory response in bat macrophages may be linked to extended longevity and viral tolerance. Acta Chiropterologica, 19: 219-228. https://www.ingentaconnect.com/content/miiz/actac/2017/00000019/00000002/art00001

O’Shea,T.J. et al. (2014) Bat Flight and Zoonotic Viruses. Emerg Infect Dis. 20: 741– 745. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012789/

Subudhi, S., N. Rapin, V. Misra (2019) Immune System Modulation and Viral Persistence in Bats: Understanding Viral Spillover. Viruses,11:192 https://pubmed.ncbi.nlm.nih.gov/30813403/

Tuttle, M.D. (2020) A Viral Witch Hunt. Issues in Science and Technology, Mar. 27, 2020. https://www.merlintuttle.org/wp-content/uploads/2020/04/A-Viral-Witch- Hunt_Header-Logos.pdf

Tuttle, M.D. (2013) Threats to Bats and Educational Challenges. In: Adams R., Pedersen S. (eds) Bat Evolution, Ecology, and Conservation. Springer, New York, NY. https://link.springer.com/chapter/10.1007/978-1-4614-7397-8_18

8.  Exhausted T cells in viral infections and cancer (Walser-Kuntz)

**Fall/Winter Only**

Protection against a subsequent reinfection with SARS-CoV-2 will require the development of a robust and long-term memory response. T cells activated by antigen typically differentiate into memory or effector cells, however chronic exposure to persistent antigen (such as occurs during HIV infection or cancer) can alter this differentiation pathway, causing the responding cells to become exhausted. Exhaustion is marked by an increase in the expression of inhibitory receptors, alterations in metabolism, and reduced effector function. An increase in exhausted T cells has been reported in some patients diagnosed with COVID-19. Explore the T cell differentiation pathways leading to memory, effector, and exhausted T cells in response to a virus, such as SARS-CoV-2 or HIV, or in response to persistent antigen in the form of cancer cells. Your response should focus on the mechanisms involved in the development of exhaustion including signaling, transcription factor activation, and/or metabolic changes within the T cells.

Recommended courses: Immunology (Bio 310) or Virology (Bio 370)

Blank, C.U., Haining, W.N., Held, W. et al. (2019). Defining ‘T cell exhaustion’. Nature Reviews in Immunology, 19, 665–674.

De Biasi, S. et al. (2020). Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia. Nature Communications, 11, 1-17.

Diao B. et al. (2020). Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease (COVID-19). Frontiers in Immunology, 11, 827.

McLane, L., Abdel-Hakeem, M., & Wherry, E.J. (2019). CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annual Review of Immunology, 37, 457-495.

Philip, M. & Schietinger, A. (2019). Heterogeneity and fate choice: T cell exhaustion in cancer and chronic infections. Current Opinion in Immunology, 58, 98-103.

Wherry, E. J., & Kurachi, M. (2015). Molecular and cellular insights into T cell exhaustion. Nature Reviews Immunology, 15, 486–499.

9.  Trinucleotide Repeat Expansion (Zweifel)

Trinucleotide repeat (TNR) disorders are a group of over 30 inherited neuromuscular diseases that include Huntington’s disease, myotonic dystrophy type 1, and fragile X syndrome. These disorders are caused by the expansion of a triplet repeat sequence and exhibit a negative correlation between the repeat length and the onset of the disease. TNRs located in open reading frames are believed to produce gain-of-function proteins through translation of stretches of poly amino acids. In contrast, TNRs located in untranslated regions of a gene may cause disease pathology through toxic RNAs or by deregulated gene expression. In addition to these gain-of- function mechanisms, loss-of-function TNR diseases are believed to result from insertion of TNRs in either the 5’UTRs or introns of genes. Recent work in model organisms has provided insight into the molecular mechanisms involved in TNR expansion, and efforts to treat these diseases by targeting the expansion may soon reach the clinical stage.

Drawing on both model systems and human genetics results, examine the following topics as they relate to TNR variation: (1) the molecular mechanisms responsible for repeat sequence contraction and expansion, (2) the causes of TNR disease pathology, and (3) the current molecular interventions being used as potential therapies.

Recommended course: Genetics (Bio 240) or Cell Biology (Bio 280)

Mosbach, V., Poggi, L., and Richard, G.F. (2019). Trinucleotide repeat instability during double-strand break repair: from mechanisms to gene therapy. Current Genetics 65: 17-28.

Murman, A.E., Yu, J., Opal, P., and Peter, M.E. (2018). Trinucleotide repeat expansion diseases, RNAi and cancer. Trends Cancer 4(10): 684-700.

Neil, A.J., Kim J.C., and Mirkin, S.M. (2017). Precarious maintenance of simple DNA repeats in eukaryotes. Bioessays 39: 1700077.

10. Mycorrhizal mutualisms and global change (student submission)

Most land plants support mutualistic mycorrhizal fungi, and this association can have a large impact on plant ecological characteristics.  Review how mycorrhizal symbioses are predicted to affect the response of plants to rapid global change in the Anthropocene. 

Recommended courses: Ecosystem Ecology, Population Ecology, or Ecological Physiology

Jo, I., S. Fei, C. M. Oswalt, G.M. Domke, and R.P. Phillips.  2019.  Shifts in dominant tree mycorrhizal associations in response to anthropogenic impacts.  Science Advances 2019:eaav6358

Moyano, J., M. A. Rodriguez-Cabal, & M. A. Nuñez.  2020.  Highly invasive tree species are more dependent on mutualisms. Ecology 101:e02997.

Tedersoo, L., M. Bahram, & M. Zobel.  2020.  How mycorrhizal associations drive plant population and community biology.   Science 367: eaba1223.