Course description: This seminar will focus on a number of specific human genetic disorders, using a case-study format with primary research papers as our main resource. We will explore 1) the methods by which the associated gene for each disorder was/is being cloned; 2) the biology of the disease at the organism, tissue, cell, and molecular level; and 3) the strategies being developed to treat each disease both with gene therapy and conventional methods. We will also explore phenomena leading to non-classical patterns of inheritance .
Course objectives: This seminar is designed to refine and extend your fluency (both verbal and written) in genetic concepts and techniques. Through the dissection of research papers on many different human genetic disorders, you will gain an understanding of the types of experimental approaches that are appropriate under different conditions, and you will learn to think critically about experimental design. You will learn to devise and propose hypothetical experiments to address unanswered questions in human genetics. You will gain an appreciation of the peer review process through critiquing the mock grant proposals of other students and having your own proposal critiqued. You will attain a realistic view of the sociology, politics, and serendipity of science in the big leagues.
Prerequisite: Bio301 (Genetics). I will expect that you have good background knowledge of basic principles of classical and molecular genetics. It will be your responsibility to review appropriate materials if necessary.
Textbooks and other reading:
Our primary readings will consist of research papers from the literature (see
class schedule below).
Human Molecular Genetics, 3rd edition by Strachan and Read (Garland Science, 2004) is required.
Decoding Darkness: the Search for the Genetic Causes of Alzheimer Disease
by Tanzi and Parson (Perseus, 2001) is also required.
An optional resource for your writing assignments is A Short Guide to Writing
about Biology by J. Pechenik (Addison-Wesley; most recent edition is 6th ed. 2006, but any will do) .
Additional handouts and WWW reading to be announced.
Email: I will regularly send important announcements via email. You are responsible for any information/assignments/instructions I send by email, so check your messages each day.
Attendance and Participation: Since this seminar meets only once a week, your attendance is essential. An unexcused absence will result in a penalty of one +/- increment on your course grade. A second unexcused absence will result in a failing grade. Your participation grade will be based on the extent to which you ask questions and contribute to discussion.
Grading: Your final grade for the course will be calculated as follows:
|
Performance as discussion
leader (on two occasions) |
One formal in-class presentation |
Research paper/ mock grant proposal |
Two written critiques
of other students' mock grant proposals |
Written catalog
of experimental techniques encountered during the semester |
Final exam (written summary
evaluation of a research paper) |
General Participation |
|
20% (10% each) |
15% |
25% |
10% (5% each) |
5% |
15% |
10% |
Honor Code: Your signature on every assignment will affirm your respect for and compliance with the Davidson Honor Code. The full Honor Pledge reads as follows: "On my honor I have neither given nor received unauthorized information regarding this work, I have followed and will continue to observe all regulations regarding it, and I am unaware of any violation of the Honor Code by others." Plagiarism is an Honor Code violation and is defined as representing another person's words and ideas as one's own. Paraphrasing (taking another person's sentences and changing a few words here and there) is NOT equivalent to writing something in your own words, and it is considered plagiarism unless proper citation is made. Please see the Davidson Department of Biology statement on plagiarism for comprehensive information.
General format for each week: If you have a laptop with wireless capability, bring it to class to facilitate in-class searches on questions that come up. Each week the class will be broken into three portions with short breaks in between. We will focus on a single disorder or small set of related disorders each week. After background information, including a clinical description/history of the disease, we will discuss the research papers assigned for that week. Some of the discussion will be student-led. The papers will center on the disease of the week and might cover A) how the gene(s) associated with the condition were cloned; B) the pathophysiology of the disease; and/or C) gene therapy approaches. In some weeks, the last portion of class will be a formal student presentation.
Weekly assignments: For each week there
will be some background reading (review articles, WWW selections, and/or textbook
passages) as well as research papers to analyze. Most of the papers are available
as PDFs in my public folder (under Biology) on Louise. Some papers are also
available online.You are responsible for printing them out, making notes on
them as you read, and bringing them to class. To avoid printing difficulties, if you access papers in the public folders on Louise, copy the file to your local computer before sending to the printer. Occasionally, when PDFs are not
available, I will distribute paper copies ahead of time.
THREE IMPORTANT
NOTES:
1) I will provide study questions (hyperlinked in the schedule below) to guide your reading.
2) If you don't understand something in the reading, be proactive and
look up the concept in the text and/or on the web.
3) Come to class prepared
to explain anything covered in the reading, even when it's not your week to
lead discussion.
Decoding Darkness: This book is a personal account of attempts to elucidate the genetic causes of Alzheimers. You are expected to read the whole book by April 8th, which is the day when we will focus on Alzheimer's disease. On the schedule below are intermediate deadlines for reading particular chapters. On the indicated dates, you should turn in notes/outlines on the assigned chapters.
Leading discussion: Twice during the semester, you and a partner will lead discussion on one of the papers assigned for the week. You must send me study questions on that paper by 5 PM on the previous Friday night so that I can post the questions online.
Formal presentation: You will give one 20 minute formal presentation during the semester on a disorder of your choice; it must be one that we do not otherwise cover. Background information on the disease should take up about half of your presentation. Analysis of an original research paper should take up the other half. IMPORTANT: don't try to explain the entire paper-- instead, pick the two or three figures that are most crucial to the take home message of the paper, and explain those in detail. Come to me for suggestions and advice as you are choosing this paper. I must approve your research paper choice and you must have it in hand at least seven days before your presentation. You must prepare a handout with an outline and any important images to distribute to the class. Also, please email me any useful web links that you discover during the course of your research.You will have access to all audiovisual equipment in the room, including the computer and document camera. During your preparations for your presentation, I encourage you to take advantage of the Speaking Center, a campus resource to help you develop a comfortable and effective public speaking style.
Research paper/ mock
grant proposal: You will write a paper in the style of an NIH grant proposal. You will read original research papers on a human genetic disorder (that we are not covering in class) and then propose the next questions to address, explaining the experiments you would perform to answer those questions. It is fine to expand upon the topic that you cover
in your formal presentation. The paper will include the following sections:
abstract, specific aims, background and significance, experimental design and
methods, conclusion, and references. Refer to A Short Guide to Writing about Biology
by J. Pechenik for basic strategies. Go to this page to download sections of a sample grant proposal; note that for you, the relevant sections are #2 (specific aims), #3 (background and significance) and #5 (research plan). The paper should be roughly 2000-4000 words, not including references.
For information on proper citation of sources, refer to the Pechenik book and the Davidson Department of Biology statement on plagiarism.
Due date for topic proposal plus bibliography: Friday February 22nd at 4 PM. Email the file to me. You must include a couple sentences of background on the disease, a few sentences on recent research, and a few sentences on the experiments you will propose. Use proper citation format as described here: Davidson Department of Biology statement on plagiarism. The title of the file you send must begin with your last name.
Due date for mock grant proposal: Friday April 11th at 4 PM;
email the file to me and to your peer reviewers. The title of the file you send must begin with your last name.
Peer critiques: You will receive the grant proposals of two other students by email. For each one, your main tasks are to evaluate the clarity and completeness of the background and significance section, and to assess the plausibility, logic, and value of the proposed experiments. You are to write a 400-700 word critique for EACH of the two proposals that you read. These critiques are due to me as email attachments by 4 PM on Friday April 25th. Also send your critique to the original author of each paper.
Catalog of experimental techniques: In an Excel spreadsheet, keep an alphabetical running list of experimental techniques we encounter in the assigned research papers. For each entry in your catalog, summarize briefly what the technique allows one to assess, and how it is performed. Cross-reference your catalog to the specific figures from the paper(s) we read in which a given technique plays a crucial role. Use your textbook and the WWW as references. I strongly encourage you to keep your catalog up to date each week, in order to avoid despair at the end of the semester. The catalog is due by email on Friday May 2nd at 4 PM. The title of the file you send must begin with your last name.
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Schedule |
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Date |
Main
Topic (links to study sheets will become active by the Friday evening before each class) |
Discussion
leaders & 2008 roster |
Reading
|
Decoding
Darkness |
| T 1/15 |
Introduction and administrative details. How to find papers from the literature.
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Read the whole syllabus. You are responsible for knowing all the information/requirements detailed therein. Over the first week of the semester, read through Strachan and Read (textbook) Chapters 1 and 2, and also pp 102-111 of Chapter 4, for a refresher on some basic genetics. Read the following before class on 1/15: Read background information on sickle cell anemia at http://sickle.bwh.harvard.edu/menu_sickle.html ; follow the first eight links under "Overview." Use the study sheet to help focus on important points. Ingram, V.M. 2004. Sickle-cell anemia hemoglobin: the molecular biology of the first "molecular disease"--the crucial importance of serendipity. Genetics 167: 1-7. PDF online or on the Louise public folders in Biology\Hales\Human Genetics\1-12-05sicklecell. Walters, M.C. 2005. Stem cell therapy for sickle cell disease: transplantation and gene therapy. Hematology (Am Soc Hematol Educ Program) 2005:66-73. PDF online or on Louise. Imren, S., et al. 2004. High-level beta-globin expression and preferred intragenic integration after lentiviral transduction of human cord blood stem cells. J. Clin. Invest. 114: 953-62. PDF online or on Louise. See the study sheet for guidance on how to approach the paper. Use the Strachan and Read textbook as a reference to look up the techniques used. |
N/A |
|
| T 1/22 |
MARFAN SYNDROME
|
N/A |
Background reading on the web: National Marfan Foundation (follow the links under "About Marfan Syndrome," "Living with Marfan Syndrome," and "Related Disorders.") Read "Marfan Syndrome: a Silent Killer" from Sports Illustrated, February 17, 1986. PDF on Louise. Pictures of Flo Hyman are here, here, and here. Ramirez and Dietz. 2007. Marfan syndrome: from molecular pathogenesis to clinical treatment. Curr Opin Genet Devel. 17: 252-258. PDF on Louise. Strachan and Read: read through chapters 13 and 14 to review gene mapping and identification. Don't get bogged down in details. Kainulainen, K. et al. 1990. Location on chromosome 15 of the gene defect causing Marfan syndrome. New Engl. J. of Med. 323:935-939. (distributed on 1/15) Dietz et al. 1991. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352: 337-339. (distributed on 1/15) Byers, P.H. 2004. Determination of the molecular basis of Marfan syndrome: a growth industry. J. Clin. Invest. 114: 161-163. PDF on Louise. BRING THE FOLLOWING TWO PAPERS TO CLASS, BUT YOU DON'T NEED TO READ THEM AHEAD OF TIME: Judge et al. 2004. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J. Clin. Invest. 114: 172-181. PDF on Louise. |
Introduction, Chapter
1 |
| T 1/29 |
|
Discussion leaders: 4&9
Formal presenter: 1
|
Read Strachan and Read Chapter 16 through section 16.7, skipping section 16.6.4 and box 16.6 (we'll save those for later).
Background reading on the web: Petit et al. 2001. Molecular Genetics of Hearing Loss. Annu. Rev. Genet. 35:589-645. PDF is on Louise. Read ONLY through the middle of page 595, and then scan the rest of the paper to get a general sense of the categories of genes involved. Be sure to examine Fig 1 at the very end of the PDF. You don't need to print this or bring it to class. El Amraoui and Petit. 2005. Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells, J. Cell Sci. 118: 4593-4603. See study sheet for guidance on what to focus on in this paper. Bolz et al. 2001. Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nature Genetics 23: 108-112. PDF on Louise. *Di Palma et al. 2001. Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. Nature Genetics 23: 103-107. PDF on Louise Scott. D.A. et al. 1998. Connexin mutations and hearing loss. Nature 391:32. |
Chapter 2 |
| T 2/5 |
ATHEROSCLEROSIS |
Read through Strachan and Read, Chapter 20 for the general ideas; stop at the end of section 20.2.6. Lusis, AJ. 2000. Atherosclerosis. Nature 407: 233-241.Make an outline of the events underlying atherosclerosis, and bring your outline to class. Oram J.F. 2002. Molecular basis of cholesterol homeostasis: lessons from Tangier disease and ABCA1. Trends Mol Med. 8: 168-73. PDF on Louise. Pajukanta P. 2004. Do DNA sequence variants in ABCA1 contribute to HDL cholesterol levels in the general population? J Clin Invest. 114: 1244-7. PDF on Louise. Joyce et al. 2002. The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. *Timmins et al. 2005. Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I. J. Clin. Invest. 115: 1333-1342. PDF online or on Louise. |
Chapter 3 | |
| T 2/12 |
DWARFISM
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Discussion leaders: 6&8
Formal presenter: 3
|
Browse Little People of America Online Resources. Ornitz, D.M. and P.J. Marie. 2002. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes and Development 16: 1446-1465. PDF on Louise. Vajo et al. 2000. The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr Rev 21:23-39. PDF on Louise. NOTE: use this as a reference and to clarify any information from the Ornitz paper; don't read the whole thing. You do NOT need to print this or bring it to class. *Chen, L. et al. 1999. Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. J Clin Invest 104: 1517-1525. PDF online or on Louise. Please note that there is a major typo here- the image that should be with the figure 1 legend is next to the figure 2 legend and vice versa. Aikawa et al. 2001. Fibroblast growth factor inhibits chondrocytic growth through induction of p21 and subsequent inactivation of cyclin E-Cdk2. J. Biol Chem 276: 29347-52. PDF online or on Louise. |
Chapter 4 |
| T 2/19 |
BLOOM SYNDROME: Topic proposals and annotated bibliographies are due by email Friday Feb 22nd at 4PM. |
Discussion leaders: 1&9 Formal presenter: 4
|
Strachan and Read, Chapter 17. Focus on section 17.5 and skim the other parts of the chapter to refresh your memory about cancer genetics. Background reading on the web: To help prepare for the Ellis paper, compare and contrast the following two phenomena: Hickson, I. 2003. RecQ helicases: caretakers of the genome. Nature Rev Cancer 3: 169-178. on Louise. Ellis, NA et al. 1995. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83: 655-666. distributed on 2/8. *Luo, G. et al. 2000. Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nature Genetics 26: 424-429. on Louise. |
Chapter 5 |
| T 2/26 |
HUTCHINSON-GILFORD PROGERIA
|
Discussion leaders: 3&7 Formal presenter: 5
|
Strachan and Read, chapter 21. Background reading on the web: Mattout et al. 2006. Nuclear lamins, diseases, and aging. Curr Opin Cell Biology 18: 1-7. on Louise. Eriksson et al. 2003. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423: 293-8. on Louise. De Sandre-Giovannoli et al. 2003. Lamin A truncation in Hutchinson-Gilford progeria. Science 300: 2055. on Louise; also see PDF of supplementary data. Scaffidi, P. and T. Misteli. 2005. Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nature Medicine 11: 440-445. on Louise. *Yang et al. 2006. A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation. J Clin Invest. 116: 2115-21. |
Chapters 6-7 |
T |
SPRING BREAK | . |
. | |
| T 3/11 |
POLYCYSTIC KIDNEY DISEASE
|
Discussion leaders: 2&8
Formal presenter: 6 |
Email
me feedback on how the course is going so far.
Browse the PKD Foundation site and the NIH PKD info page. Hildebrandt, F. and E. Otto. 2005. Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nature Reviews Genetics 6: 928-940. on Louise. Delmas, P. 2004. Polycystins: from mechanosensation to gene regulation. Cell 118: 145-148. on Louise. Bhunia et al. 2002. PKD1 induces p21waf1 and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a precell requiring PKD2. Cell 109: 157-168. on Louise. *Chauvet et al. 2004. Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus. J Clin Invest 114: 1433-1443. on Louise. |
Chapter 8 |
| T 3/18 |
TRINUCLEOTIDE REPEAT DISEASES: HUNTINGTON DISEASE |
Discussion leaders: 1&4 Formal presenter: 7 |
Strachan and Read, Chapter 11 section 11.5.2 (pp. 337-339); also Chapter 16 section 16.5.4 (pp. 476-478). Bates, G.P. 2005. The molecular genetics of Huntington disease-- a history. Nat Rev Genet. 10: 766-773. on Louise. Gatchel J.R. and H.Y. Zoghbi. 2005. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet. 10:743-55. on Louise. Michalik A, and C. Van Broeckhoven. 2003. Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet 12: R173-86. PDF online or on Louise. Arrasate et al. 2004. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431: 805-10. on Louise. *DiFiglia et al. 2007. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. PNAS 104: 17204-17209. |
Chapters 9-10 |
| T 3/25 |
EASTER BREAK |
Peep research | ||
| T 4/1 |
CHROMOSOMAL ABNORMALITIES: |
Discussion leaders: 3&5 Formal presenter: 8
|
Strachan
and Read, pp. 51-58 and 480-483. Background reading on the web: Antonarakis et al. 2004. Chromosome 21 and down syndrome: from genomics to pathophysiology. Nat Rev Genet 5: 725-38. on Louise. Kahlem et al. 2004. Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of down syndrome. Genome Res 14: 1258-67. PDF online or on Louise. Lyle et al. 2004. Gene expression from the aneuploid chromosome in a trisomy mouse model of Down syndrome. Genome Res 14: 1268-74. PDF online or on Louise. *Altafaj et al. 2001. Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. Hum Mol Genet 10: 1915-1923. PDF online or on Louise. |
Chapters 11-12 |
| T 4/8 |
ALZHEIMER'S DISEASE Grant proposals are due as an email attachment on Friday April 11th at 4 PM. Also email a copy to your peer reviewers. |
Discussion leaders: 6&2 Formal presenter: 9
|
Background on the web: Anatomy of the brain; Cross section of normal and Alzheimers brain; Diagram of amyloid plaques and neurofibrillary tangles. Tanzi, R.E. and L. Bertram. 2005. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120: 545-555. on Louise. Hardy, J. and D.J. Selkoe. 2002. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297: 353-356. on Louise. *Lee et al. 2005. BACE overexpression alters the subcellular processing of APP and inhibits A-beta deposition in vivo. J. Cell Biol. 168: 291-302. on Louise. Jankowsky et al. 2005. Persistent amyloidosis following suppression of A-beta production in a transgenic model of Alzheimer disease. PLOS Medicine 2: 1318-1333. on Louise. |
Review whole book!
|
| T 4/15 |
NARCOLEPSY |
Background information on the web: Chabas et al. 2003. The genetics of narcolepsy. Annu Rev Genomics Hum Genet 4: 459-483. on Louise. Black, J.L. 3rd. 2005. Narcolepsy: A review of evidence for autoimmune diathesis. Int. Rev. Psychiatry 17 : 461-469. on Louise. Lin et al. 1999. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98: 365-376. on Louise. Chemelli et al. 1999. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98: 437-451. on Louise. Note that you should also look at the Hara et al. 2001 paper in the supplementary folder to contrast the approaches used in these two studies. Peyron et al. 2000. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Medicine 6: 991-997. on Louise. |
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| T 4/22 |
NON-CLASSICAL INHERITANCE I: EPIGENETICS AND DISEASE Peer reviews of grant proposals due as email attachments by Friday April 25th at 4PM. Also email your reviews to the original authors. |
Strachan and Read, pp 294-306, also p. 472 Box 16.6 Background browsing on the web: Robertson, K. 2005. DNA methylation and human disease. Nature Reviews Genetics 6:597-610. Weksberg et al. 2003. Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Molec Genet 12: R61-R68. on Louise. Sparago et al. 2004. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith Wiedmann syndrome. Nature Genetics 36: 958-960. on Louise. Prawitt et al. 2005. Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor. Proc Nat Acad Sci USA 102: 4085-4090. on Louise. Correspondence (2 pdfs) between the authors of the two BW syndrome papers above, from Nature Genetics 37: 785-787. on Louise. |
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| T 4/29 |
NON-CLASSICAL INHERITANCE II: MOSAICISM AND UNIPARENTAL DISOMY Technique catalog due at 4:00 PM on Friday May 2nd. |
Strachan and Read pp. 109-110, section 4.3.6
Youssoufian H, Pyeritz RE.. 2002. Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet. 3: 748-58. on Louise. Leuer et al. 2001. Somatic Mosaicism in Hemophilia A: A Fairly Common Event. Am. J. Hum. Genet., 69:75-87. on Louise. Robinson, W.P. 2000. Mechanisms leading to uniparental disomy and their clinical consequences. Bioessays 22: 452-459. on Louise Gelb et al. 1998. Paternal Uniparental Disomy for Chromosome 1 Revealed by Molecular Analysis of a Patient with Pycnodysostosis. Am. J. Hum. Genet. 62:848-854. on Louise. Smith et al. 2007. Severe presentation of Beckwith–Wiedemann syndrome associated with high levels of constitutional paternal uniparental disomy for chromosome 11p15. Am. J. Med. Genet.Part A 143A:3010-3015. Wilson et al. 2008. The clinical phenotype of mosaicism for genome-wide paternal uniparental disomy: two new reports. Am. J. Med. Genet.Part A 146A:137–148. |
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| T 5/6 |
End of the semester picnic. |
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Groups of two or three students will skim an assigned paper on a disorder for which the genetics are just beginning to emerge (e.g. Tourettes, schizophrenia, dyslexia, etc.) and give a brief informal report to the class over lunch. |
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| 5/9 to 5/12 |
Take home final exam | . |
For the final exam you will read an assigned research paper and write a summary and critique. It will be due at noon on Monday May 12th as an email attachment. Please include your last name at the beginning of the title of the file. The final exam assignment is available now! (See the exam assignments from previous years: 2001, 2002, 2003, 2005, 2006) |
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