Biology 363: Human Genetics

Spring 2013, Davidson College

Wednesdays 1:30-4:20 PM in Chambers 1045
Dr. Karen Hales, Dana 201A, x2324

Weekly schedule
Jump to assignments for
Jan 16, 23, 30, Feb 6, 13, 20, 27,
Mar 13, 20, 27, Apr 10, 17, 24,
May 1

Course description: This seminar will focus on specific human genetic conditions, 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 condition were identified; 2) the biology at the organism, tissue, cell, and molecular level; and 3) gene therapy and other treatment methods.

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 conditions, you will understand the experimental approaches that are appropriate under different circumstances, 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: Bio201 (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).

Office hours: Please email me in advance to make an appointment for any mutually acceptable time; list three possible dates/times in your email and I'll get back to you. Or, stop by any time my door is open.

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
Final exam (written summary evaluation of a research paper)
Class preparation and general participation
20% (10% each)
10% (5% each)

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 online or through means I will describe in class. Bring printed copies to class of all papers designated "background" and "main" 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 online.
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 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 condition 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 to read the supplementary paper carefully ahead of time and then 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).

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 the day when we focus on Alzheimer's disease. Take notes as you read to help you remember the important points. On the schedule below are suggested 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. REMIND ME and I will send you a sample grant proposal from a previous year. I want to select one that does not focus on a disorder that any of you have chosen. 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 in Februrary (see schedule below) 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 in April (see schedule below); 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.

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Main Topic
(links to study sheets will become active about a week before each class)

Discussion assistants &
Student presenter

Find papers online for those with links (may require you to be on college's network to access articles via subscription).

Decoding Darkness reading

Class introduction and presentation scheduling.

How to find papers in the literature.

Brief review of essential concepts in genetics.

Main topic:
(First human genetic disorder characterized)

study sheet

Class roster for presentation scheduling:

1. Tim
2. Haley
3. Chris
4. Roshelle
5. Eric
6. Brit
7. Hanna
8. Bethany

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At; follow the first eight links under "Overview." Use the study sheet to help focus on important points.

Ingram, 2004. Sickle-cell anemia hemoglobin: the molecular biology of the first "molecular disease"--the crucial importance of serendipity. Genetics167: 1-7.

Townes, 2008. Gene replacement therapy for sickle cell disease and other blood disorders Hematology (Am Soc Hematol Educ Program) 2008:193-196.

Main paper
Chang et al., 2006. Correction of the sickle cell mutation in embryonic stem cells. Proc Natl Acad Sci U S A. 103: 1036-1040. See the study sheet for guidance on how to approach the paper. Take the initiative to look up information on techniques with which you are not familiar.

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.


(Traditional linkage analysis via lod scores)

study sheet



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 the public server. Pictures of Flo Hyman are here, here, and here.

Textbook reference material: Strachan and Read chapters 14 and 16.

Ramirez and Dietz. 2007. Marfan syndrome: from molecular pathogenesis to clinical treatment. Curr Opin Genet Devel. 17: 252-258.

Main papers
Kainulainen et al., 1990. Location on chromosome 15 of the gene defect causing Marfan syndrome. New Engl. J. of Med. 323:935-939.

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.
Nat Genet. 33(3):407-11.

Supplementary paper
Judge et al. 2004. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J. Clin. Invest. 114: 172-181.


(Genomic methods for dissecting chromosomal disorders)

study sheet

Discussion assistants: 3&6


Formal presenter: 1


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Review (in Strachan and Read or in your old genetics textbook) errors of chromosome number and structure.

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
Prandini et al., 2007. Natural gene expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. Amer. J. Hum. Genet. 81: 252-263.

Korbel et al., 2009. The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. PNAS 106: 12031-12036.

Supplementary papers
For reference: Haydar and Reeves, 2011. Trisomy 21 and early brain development. Trends Neurosci. 35: 81-91
For data to present: Yabut et al., 2010. Dyrk1A overexpression inhibits proliferation and induces premature neuronal differentiation of neural progenitor cells. J. Neurosci. 30: 4004-4014.

Chapters 1-3

(Genome wide association studies [GWAS] and now whole-exome or whole- genome sequencing)

study sheet

Discussion assistants: 4&7


Formal presenter: 2

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Autism resources to browse: NINDS Fact Sheet and Autism Speaks

Strachan and Read, Chapter 15 pages 477-494 (section on association studies).

Visscher et al., 2012. Five years of GWAS discovery. Amer. J. Hum Genet. 90: 7-24.

Veltman and Brunner, 2012. De novo mutations in human genetic disease. Nature Rev Genet 13: 565-575.

Main papers
Weiss et al., 2009. A genome-wide linkage and association scan reveals novel loci for autism. Nature 461: 802-808 plus supplementary methods within the PDF.

Sanders et al., 2012. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485: 237-241.

O'Roak et al., 2012. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338: 1619-1622.
[Also glance at the four papers in the "extra" folder to get a sense of the connections and the scope of progress in the past two years. No need to print or bring these to class.]

Supplementary paper
Chahrour et al., 2012. Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLOS Genetics 8: e1002635.

Chapters 4-6



study sheet


Topic proposals and annotated bibliographies are due by email Friday Feb 15th at 4PM.

Discussion assistants: 5&8

Formal presenter: 3

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Textbook reference material: Strachan and Read, chapter 21.

Background reading on the web:
Progeria Research Foundation (browse links in menus at the top).
Learning about Progeria

Worman et al. 2009. Laminopathies and the long strange trip from basic cell biology to therapy. J Clin Invest. 119: 1825-1836.

Main papers
Eriksson et al. 2003. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423: 293-8.

De Sandre-Giovannoli et al. 2003. Lamin A truncation in Hutchinson-Gilford progeria. Science 300: 2055. Also see 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 supplementary materials.

Supplementary paper
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.

[Glance at the following extra 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. Hum Mol Genet 20:436-444.]

Two final quick items for everyone
Recent news update on human clinical trials: Couzin-Frankel, 2012, Science 337: 1594-1595.

Scientific American article (skim it) on broader functional implications of lamins: Misteli, 2011, The Inner Life of the Genome.

Chapter 7-8


study sheet

Discussion assistants: 1&6

Formal presenter: 4


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Browse appropriate links to learn about the disorder at these sites:
National Parkinson Foundation
Parkinson's Disease Foundation
Michael J Fox Foundation for Parkinson's Research

Read about the company 23 and me and their Parkinson's disease research effort .

Van Laar and Berman, 2012. The interplay of neuronal mitochondrial dynamics and bioenergetics: Implications for Parkinson's disease. Neurobiol. Disease (epub ahead of print; no vol/page#'s designated yet).

Coune et al., 2012. Parkinson's disease: gene therapies. Cold Spring Harb Perspect Med 2: a009431 (15 pages).

Main paper
Ziviani et al., 2010. Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. PNAS 107: 5018-5023.
[Also read the abstracts and glance at the conclusions from six papers in the "extra" folder to get a broad view of the advancements (and competition!) from multiple labs in 2010.]

Supplementary paper
Sánchez-Danés et al., 2012. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Molec Med. 4: 380-395.

Chapter 9-10




study sheet


Discussion assistants: 2&7

Formal presenter: 5


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Lusis, 2000. Atherosclerosis. Nature 407: 233-241. Make an outline of the events underlying atherosclerosis, and bring your outline to class.

Skim these two papers to see how GWAS approaches have contributed to the field recently:
--Lusis and Pajukanta, 2008. A treasure trove for lipoprotein biology. Nature Genetics 40: 129-130. (Can obtain this online on a college computer through filling in the info here:
--Lusis, 2012. Genetics of atherosclerosis. Trends Genet. 28: 267-275.

Oram, 2002. Molecular basis of cholesterol homeostasis: lessons from Tangier disease and ABCA1. Trends Mol Med. 8: 168-73.

Pajukanta, 2004. Do DNA sequence variants in ABCA1 contribute to HDL cholesterol levels in the general population? J Clin Invest. 114: 1244-7.

Main paper
Joyce et al. 2002. The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. PNAS 99: 407-12.

Supplementary paper
Brunham et al. 2008. Tissue-specific roles of ABCA1 influence susceptibility to atherosclerosis. Arterioscler Thromb Vasc Biol 29: 548-554.

Chapters 11-12


Email me feedback on how the course is going so far.  


study sheet



Discussion assistants: 3&8


Formal presenter: 6


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Background on the web: Anatomy of the brain; Cross section of normal and Alzheimers brain; Diagram of amyloid plaques and neurofibrillary tangles (also browse other links here).

Bertram et al. 2010. The genetics of Alzheimer disease: back to the future. Neuron 68: 270-281.

Hardy and 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 papers
Jiang et al. 2008. ApoE promotes the proteolytic degradation of A-beta. Neuron 58: 681–693.

Beck et al., 2004. Somatic and germline mosaicism in sporadic early onset Alzheimer's disease. Hum. Molec. Gen. 13: 1219-1224. (Don't need to dissect every bit of this one--see study sheet for guidance on where to focus attention.)

Supplementary paper
Ferretti et al., 2012. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J. Neuroinflammation 9: 2 (16 pages).

Review whole book

STEM CELLS and REGENERATIVE MEDICINE with special guest Dr. Tony Atala from Wake Forest University, who is this year's Smith lecturer

study sheet


Discussion assistants: 1&4

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Textbook reference material: Strachan and Read, pp 114-119, 687-696

Info on Dr. Atala:
Slate article
TED talk
NPR story
His institute at Wake Forest

Hipp et al., 2010. Functional genomics: new insights into the 'function' of low level gene expression in stem cells. Current Genomics 11: 354-358.

Main papers
Tian et al., 2010. Differentiation of human bone marrow mesenchymal stem cells into bladder cells: potential for urological tissue engineering. Tissue Engineering: Part A 16: 1769-1779

Zhao et al., 2012. Safeguarding pluripotent stem cells for cell therapy with a non-viral, non-integrating episomal suicide construct. Biomaterials 33: 7261-7271.

Supplementary paper
Kobayashi et al., 2012. Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity. PLOS One 7:e52787 (13 pages).



study sheet



Formal presenter: 7

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Textbook reference material: Strachan and Read, Chapter 17, especially section 17.5.
help prepare for the Ellis paper, look up the following two phenomena and compare and contrast them.
Loss of heterozygosity by mitotic recombination
Sister chromatid exchange

Background reading on the web:
Bloom Syndrome from the Center for Jewish Genetic Diseases

Chu, W. and I. Hickson. 2009. RecQ helicases: multifunctional genome caretakers. Nature Rev Cancer 9 : 644-654. (Can obtain this online on a college computer through filling in the info here:

Main paper
Ellis, NA et al. 1995. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83: 655-666.

Supplementary paper
Luo, G. et al. 2000. Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nature Genetics 26: 424-429.
(Can obtain this online on a college computer through filling in the info here:

Extra paper only for the adventurous
Wu and Hickson. 2003. The Bloom’s syndrome helicase suppresses crossing over during
homologous recombination. Nature 426: 870-874.


For Easter: Peep research

Finish your mock grant proposals. They are due by email attachment on Monday April 8th at 4 PM. 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.)



study sheet


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Basics on sleep from NIH
Narcolepsy fact sheet from NIH
Center for Narcolepsy at Stanford (browse links)

Chabas et al., 2003. The genetics of narcolepsy. Annu Rev Genomics Hum Genet 4: 459-483.

Kornum et al., 2011. Narcolepsy with hypocretin/orexin deficiency, infections, and autoimmunity of the brain. Curr. Opin. Neuro. 21: 897-903.

Main papers
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.

Hallmayer et al. 2009. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nature Genetics 41: 708-712.

Supplementary paper
Hara et al. 2001. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30: 345-354.



study sheet


Discussion assistants: 2&5

Formal presenter: 8

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Textbook reference material: Strachan and Read, pp 294-306, also p. 472 Box 16.6

Background browsing:
Beckwith-Wiedemann Syndrome

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
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.

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. PNAS 102: 4085-4090.

Correspondence (2 pdfs) between the authors of the Sparago et al. and Prawitt et al. papers, from Nature Genetics 37: 785-787.

Supplementary paper
Beygo et al., 2013 (Epub ahead of print). The molecular function and clinical phenotype of partial deletions of the IGF2/H19 imprinting control region depends on the spatial arrangement of the remaining CTCF binding sites. Hum. Mol. Genet. (Vol and page numbers not yet determined).



study sheet

Peer reviews of grant proposals due as email attachments by Monday April 29th at 4PM. Also email your reviews to the original authors.

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Daxinger and Whitelaw, 2012. Understanding transgenerational epigenetic inheritance via the gametes in mammals.
Nature Reviews Genetics 13: 153-162.

Jirtle and Skinner, 2007. Environmental epigenomics and disease susceptibility. Nature Reviews Genetics 8: 253-262.

Main papers
Vassoler et al., 2013. Epigenetic inheritance of a cocaine-resistance phenotype. Nature Neuroscience 16: 42-49.

Manikkam et al., 2012. Dioxin (TCDD) induces epigenetic transgenerational inheritance of adult onset disease and sperm epimutations. PLOS One 7: e46249 (15 pages).

Supplementary paper
Wagner et al., 2008. RNA induction and inheritance of epigenetic cardiac hypertrophy in the mouse. Devel. Cell 14: 962-969.

Late breaking items! Just for browsing.
Fat Dads' Genetic Legagy
Soubry et al., 2013 (Paper on which the news item is based)




Topic(s) for today will be determined as things strike our interest during the semester.

Wrap up and course evaluations

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1:30-2:0-ish TOSLS test; if you have taken this in another class already, you can skip it and arrive at 2:00.

2:00-3:55 Color blindness
Neitz and Neitz, 2011. The genetics of normal and color vision. J. Vision Research 51: 633-651.
Sung and Chuang, 2010. The cell biology of vision. J. Cell Biology 190: 953-963 (read for the big picture only).
Main paper
Carvalho et al., 2011. Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy. Human Molecular Genetics 20: 3161-3175.

3:55-4:20 course evaluations

Picnic or food outing TBA.

5/9 to 5/13 Take home final exam .

This year's exam assignment is available!

It is due at 10 AM on Monday May 13th as an email attachment. Please include your last name at the beginning of the title of the file.

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Davidson Biology
Dr. Hales's home page

© Copyright 2013 Department of Biology, Davidson College, Davidson NC 28035
last modified May 21, 2013 by K. Hales