Course description: This seminar will focus on 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(s) for each disorder were identified; 2) the biology of the disease at the organism, tissue, cell, and molecular level; and 3) strategies to treat each disease 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 human genetic disorders, you will understand the experimental approaches that are appropriate under different conditions, and you will learn to think critically about experimental design. You will devise and propose hypothetical experiments to address unanswered questions in human genetics. You will appreciate 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.
Prerequisite: Bio301 (Genetics). I expect that you have good background knowledge of basic principles of classical and molecular genetics. It is your responsibility to review appropriate materials as necessary.
Textbooks: Our primary readings will consist of research papers and review papers from the literature, as well as selections on the web.
Required book: Decoding Darkness: the Search for the Genetic Causes of Alzheimer Disease by Tanzi and Parson (Perseus, 2001).
Optional resource textbook: Human Molecular Genetics, 3rd edition by Strachan and Read (Garland Science, 2004). It is feasible for students to share this book or for students to borrow my copy and read it in the Biocenter, Dana 211.
Optional writing resource: A Short Guide to Writing
about Biology by J. Pechenik (Addison-Wesley; any recent edition will do).
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
assistant (on two occasions) |
One formal in-class presentation |
Research paper/ mock grant proposal |
Two written critiques
of other students' mock grant proposals |
Quality of your contributions to the community technique catalog |
Final exam (written summary
evaluation of a research paper) |
General Participation |
|
20% (10% each) |
15% |
25% |
10% (5% each) |
5% |
15% |
10% |
Reading assignments: Since we meet only once a week, it's crucial to pace yourself and spread your reading across many days. Papers are available
as PDFs in my public folder at Biology\Hales\Bio363Spring2011. Some are also
available online. Bring printed copies to class of all papers designated "background," "main," and "supplementary," unless otherwise noted. To avoid printing difficulties, download files to your local computer before sending to the printer. Since some papers have color figures in which the color is essential to the meaning, you should view these on a computer and/or obtain color printouts.
*Three important notes:
1) Background reading and papers designated as "main" papers should be read very carefully before class. As you read, write detailed notes directly on your copies of the papers, particularly to annotate the figures, so that you can quickly recall the meaning. I will provide study questions (hyperlinked in the schedule below) to guide your reading. Come to class prepared
to explain to the class anything covered in the reading.
2) If you don't understand something in the reading, be proactive and
look up the concept in a textbook and/or on the web.
3) For papers designated as "supplementary," read the introduction and conclusions carefully, and skim the results section (UNLESS you are a discussion assistant for that week, in which case you should read and understand the data carefully, make a list of study questions, and be ready to help others work through the paper).
Weekly class routine: We will break the class time into three portions each week, with short breaks in between.
First portion: Discuss background information on the disorder in question. Start main paper.
Second portion: Dissect main paper, sometimes in smaller groups. Discussion assistants then lead class as we explore the supplementary paper.
Third portion:
Student presentation. (Student can alternatively choose to present at the beginning of class).
Laptop computer: If you have a laptop with wireless capability, bring it to class to facilitate in-class searches on questions that come up
Roles of discussion assistants: Twice during the semester, you and a partner will be designated as discussion assistants. Your jobs are as follows:
--Read the supplementary paper carefully ahead of time.
--Be prepared to stand up in front of the class to explain the main point of the paper and to lead the class (interactively) through the most important data figure(s).
--Compose and add entries to the Community Technique Catalog by the Monday after class. First, make sure the names of all molecular techniques from that week's main and supplementary papers are listed (by name and reference only) in the catalog. Then pick the two to four most important techniques from that week's papers that have not already been covered, and explain them in detail. If necessary, fill in entries from previous weeks.
Community technique catalog: As a class, we will construct an Excel spreadsheet with a running list of experimental techniques we encounter in our assigned research papers. When you are discussion assistant, it is your job to add appropriate entries to the technique catalog from the papers assigned for that week. For each entry in the catalog, summarize briefly what the technique allows you to assess, and how it is performed. Cross-reference the catalog to paper(s) we read. Use your textbook and the WWW for background information. The file is in the public folders at Biology\Hales\Bio363Spring2011. Whenever you update the technique catalog, you MUST save a copy in the public folder as well as in a backup location, such as your email or a flash drive.
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 March 9th, which is the day when we will focus on Alzheimer's disease. Take notes as you read to help you remember the important points. On the schedule below are intermediate deadlines for reading particular chapters.
Formal presentation: You will give one 20 minute formal presentation during the semester on a genetic disorder of your choice; it must be one that we do not otherwise cover. No two students can choose the same topic, so clear your topic with me early to get first dibs on it. 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. I must approve your research paper choice and you must have it in hand at least seven days before your presentation. Don't try to explain the entire paper--instead, pick the most crucial two or three figures and explain those in detail. You must prepare a handout with an outline and any important images to distribute to the class. During your preparation, I encourage you to take advantage of the Speaking Center, a campus resource to help you develop a comfortable and effective public speaking style. The grading rubric is as follows: background section, 50 points; explanation of research paper, 50 points; fielding questions from audience, 20 points; handout, 10 points; effectiveness of presentation method (powerpoint, etc.), 10 points; public speaking presence (voice, posture, enunciation),10 points.
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 (one that we are not covering in class) and then propose the next research questions to address, explaining the experiments you would perform to answer those questions. Most students choose to expand upon the topic covered in the formal presentation. The mock grant proposal will include the following sections:
abstract, specific aims, background and significance, experimental design and
methods, conclusion, and references. Refer to Pechenik's A Short Guide to Writing about Biology
for basic strategies. Go to this NIH page to download sample grant proposals; note that for you, the three relevant sections are Specific Aims, Background and Significance, and Research Plan. The mock grant proposal should be at least 2500 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.
A topic proposal & bibliography is due Friday February 11th at 4 PM by email. You must put significant effort into acquiring and reading references before writing the topic proposal. It should be at least 250 words, including a few sentences of background on the disease, a few sentences on recent research, and a few sentences on the types of experiments you will propose. Use proper citation format as described here: Davidson Department of Biology statement on plagiarism. The title of the file you email must begin with your last name.
The actual mock grant proposal is due Monday April 4th at 10AM;
email the file to me and to your peer reviewers, who are the two people listed after you on the class roster at the top of the schedule below. 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 500-700 word critique for EACH of the two proposals that you read. These critiques are due to me as email attachments by the date indicated on the schedule below. Also send your critique to the original author of each paper.
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.
|
Schedule |
||||
Date |
Main
Topic (links to study sheets will become active about a week before each class) |
Discussion
assistants &
|
Reading
|
Decoding
Darkness reading |
| W 1/12 |
Class introduction and presentation scheduling. How to find papers in the literature.
Main topic: |
Class roster for presentation scheduling (will be determined the first day): |
Townes, M.C. 2008. Gene replacement therapy for sickle cell disease and other blood disorders Hematology (Am Soc Hematol Educ Program) 2008:193-196. PDF online. Main paper By next week: Pick your topic for your formal presentation and mock grant proposal. No two students can choose the same topic, so clear it with me early to get first priority. |
N/A |
| W 1/19 |
MARFAN SYNDROME
|
Discussion assistants: 3&7 | Background Read "Marfan Syndrome: a Silent Killer" from Sports Illustrated, February 17, 1986. PDF on the public server. Pictures of Flo Hyman are here, here, and here. Textbook reference material: Strachan and Read chapters 13 and 14. Ramirez and Dietz. 2007. Marfan syndrome: from molecular pathogenesis to clinical treatment. Curr Opin Genet Devel. 17: 252-258. on the public server. Main papers Dietz et al. 1991. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352: 337-339. Neptune et al. 2003. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Supplementary paper |
Chapters 1-3 |
| W 1/26 |
|
Background Explore Promenade 'round the Cochlea and The Cochlea of the Inner Ear to learn how the ear works. Dror and Avraham. 2009. Hearing loss: mechanisms revealed by genetics and cell biology. Annu. Rev. Genet. 43: 411-437. Main papers 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. Skim the abstract and focus mainly on Figure 4 of this paper, with a glance at Figure 3 as well. Supplementary paper Extra article to skim about the scientists who are trying to identify the mechanotransduction channel on the hair cells of the inner ear (don't need to bring this to class) |
Chapters 4-6 |
|
| W 2/2 |
DWARFISM |
Discussion assistants: 6&9
Formal presenter: 2 |
Background 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. 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. 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. Main paper Supplementary paper |
Chapters 7-8 |
| W 2/9 |
HUTCHINSON-GILFORD PROGERIA
Topic proposals and annotated bibliographies are due by email Friday Feb 11th at 4PM. |
Formal presenter: 3 |
Background Background reading on the web: Worman et al. 2009. Laminopathies and the long strange trip from basic cell biology to therapy. J Clin Invest. 119: 1825-1836. Main papers De Sandre-Giovannoli et al. 2003. Lamin A truncation in Hutchinson-Gilford progeria. Science 300: 2055. 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. (also see folder of supplementary figures and materials). Supplementary paper Also glance at the following paper to see how a conundrum was cleared up. Yang et al. 2011. Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin. Human Molecular Genetics published ahead of print December 2010. |
Chapter 9 |
| W 2/16 |
ATHEROSCLEROSIS
|
Formal presenter: 4
|
Background Oram J.F. 2002. Molecular basis of cholesterol homeostasis: lessons from Tangier disease and ABCA1. Trends Mol Med. 8: 168-73. Pajukanta P. 2004. Do DNA sequence variants in ABCA1 contribute to HDL cholesterol levels in the general population? J Clin Invest. 114: 1244-7. Main paper Supplementary paper |
Chapter 10
|
| W 2/23 |
CANCER AND GENOME INTEGRITY:
|
Background Background reading on the web: To help prepare for the Ellis paper, look up the following two phenomena and compare and contrast them. Chu, W. and I. Hickson. 2009. RecQ helicases: multifunctional genome caretakers. Nature Rev Cancer 9 : 644-654. Main paper Supplementary paper Extra paper only for the adventurous |
Chapters 11-12 | |
W |
SPRING BREAK | . |
Email me feedback on how the course is going so far. | |
| W 3/9 |
ALZHEIMER'S DISEASE
|
Discussion assistants: 2&9
Formal presenter: 6
|
Background Bertram et al. 2010. The genetics of Alzheimer disease: back to the future. Neuron 68: 270-281. 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. This paper is a little old but has useful figures. Main paper Supplementary paper |
Review whole book |
| W 3/16 |
TRINUCLEOTIDE REPEAT DISEASES: HUNTINGTON DISEASE
|
Discussion assistants: 3&4 Formal presenter: 7 |
Background Textbook reference material: Strachan and Read, Chapter 11 section 11.5.2 (pp. 337-339); also Chapter 16 section 16.5.4 (pp. 476-478). Gatchel J.R. and H.Y. Zoghbi. 2005. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet. 10: 743-55. Bates, G.P. 2005. The molecular genetics of Huntington disease--a history. Nat Rev Genet. 10: 766-773. Main paper Supplementary paper |
|
| W 3/23 |
NARCOLEPSY
|
Discussion assistants: 11&12 Formal presenter: 8 |
Background Crocker and Sehgal. 2010. Genetic analysis of sleep. Genes Dev 24: 1220-1235. Skim for an overview of the field; no need to bring this to class. Chabas et al. 2003. The genetics of narcolepsy. Annu Rev Genomics Hum Genet 4: 459-483. Main papers Hallmeyer et al. 2009. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nature Genetics 41: 708-712. Supplementary paper |
|
| W 3/30 |
NO CLASS | Finish your mock grant proposals. They are due by email attachment on Monday April 4th at 10 AM. Also email a copy to your peer reviewers, who are the two people after you on the class roster at the top of this schedule chart. (Bottom of list wraps around to top.) | ||
| W 4/6 |
CHROMOSOMAL ABNORMALITIES:
|
Formal presenter: 9 |
Background National Down Syndrome Society general information (follow links on this page) Antonarakis et al. 2004. Chromosome 21 and down syndrome: from genomics to pathophysiology. Nat Rev Genet 5: 725-38. Main papers 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. Supplementary paper |
|
| W 4/13 |
EPIGENETICS:
|
Formal presenter: 10
|
Background Background browsing on the web: Robertson, K. 2005. DNA methylation and human disease. Nature Reviews Genetics 6:597-610. Choufani et al. 2010. Beckwith-Wiedmann syndrome. American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 154C: 343–354. Main papers Correspondence (2 pdfs) between the authors of the Sparago et al. and Prawitt et al. papers, from Nature Genetics 37: 785-787. Supplementary paper |
|
| W 4/20 |
NON-CLASSICAL INHERITANCE: UNIPARENTAL DISOMY AND MOSAICISM Peer reviews of grant proposals due as email attachments by Friday April 22nd at 4PM. Also email your reviews to the original authors. |
Background Textbook reference material: Strachan and Read pp. 109-110, section 4.3.6 Robinson, W.P. 2000. Mechanisms leading to uniparental disomy and their clinical consequences. Bioessays 22: 452-459. Youssoufian H, Pyeritz R.E. 2002. Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet. 3: 748-58. Main paper Supplementary paper |
|
|
| W 4/27 |
Wrap up; we may also explore one or two areas in which significant human genetics advances have occurred this semester. Course evaluations |
|
Dietz. 2010. New therapeutic approaches to Mendelian disorders. New England J Med 363: 853-862. More TBA Also, for Easter: Peep research |
|
| W 5/4 |
Picnic or food outing TBA. |
|
||
| 5/4 to 5/9 | Take home final exam | . |
The final exam assignment is now available! This year's exam will be due at 10 AM on Monday May 9th as an email attachment. Please include your last name at the beginning of the title of the file. |
|
|
|