Biology 363: Human Genetics

Fall 2017, Davidson College

Tuesdays 1:40-4:20 PM in Wall 307
Dr. Karen Hales, Wall 321

Weekly schedule
Jump to assignments for
Aug 22, 29, Sep 5, 12, 19, 26,
Oct 3, 17, 24, 31, Nov 7, 14, 28, Dec 5

Learning outcomes
This seminar will focus on specific human genetic conditions, using a case-study format with primary research papers as our main resource. By the end of the course, students will be able to dissect and critique research papers from the literature with sophistication and to explain with fluency the experimental techniques and genetic principles underlying the biological basis and treatment approaches for many genetic disorders. Students will be able to devise, propose, and describe genetic experiments to address unanswered questions in the format of an NIH grant proposal, and students will be able to write peer reviews highlighting key strengths and weaknesses of a classmate's proposal. Students will be able to explain aspects of the sociology, politics, and serendipity of science.

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.

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 writing resource: A Short Guide to Writing about Biology by J. Pechenik (Addison-Wesley; any recent edition will do).

Office hours
Any mutually agreeable time by appointment. There will be quick signups at the Slotted web site for Wednesdays 10:30-11:45 AM and other rotating times such as Common Hours when I don't have other meetings. You'll get a personalized link for signups. If those times don't fit your schedule, email me for other appointments--list three possible dates/times in your email and I'll get back to you. Or, stop by any time my door is open.

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, the extent to which you prepare for class and take initiative to figure out the harder concepts, and your willingness to explain things and go out on a limb even if you aren't completely sure.

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 Class preparation, participation, initiative, engagement
24% (12% each)
(5% for topic proposal/bibliography,
20% for finished product)
16% (8% each) 20%

Reading assignments
We meet only once a week, so pace yourself and spread your reading across many days. Papers are available from links below or through another means announced in class. You must have papers in front of you during class either as printed copies or on a laptop/tablet.
Some papers have color figures in which the color is essential to the meaning.
Important notes:
--As you read, take notes and annotate the figures so that you can quickly recall the meaning during class. 
Be prepared to explain anything covered in the reading.
--I will provide study questions below.
--If you don't understand something, be proactive and seek information to figure it out.

Weekly class routine
We will typically break class time into three portions each week with short breaks in between.
1. Discuss background information. Start discussing research paper(s).
2. Dissect research papers, often in smaller groups . Discussion assistants then lead class as we explore the student-led paper.
3. Student presentation. (Student can alternatively choose to present at the beginning of class).

Discussion leaders
Twice during the semester, you and a partner will be designated as discussion leaders. Your jobs are to read the student-led paper especially carefully, send study questions to the group by noon Monday (day before class), and then lead the class interactively and authoritatively through the most important data figure(s) to elucidate the main point(s). Do NOT try to cover the entire article--part of the challenge is determining which are the key elements that deserve the most focus.

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 presentation during the semester on a genetic disorder of your choice that we do not otherwise cover. No two students can choose the same topic. Background information should occupy half of your presentation and analysis of a research paper the other half. I must approve your research paper  and you must have it in hand seven days before your presentation. Don't try to explain the entire research paper--instead, pick the most crucial two or three figures and explain those in detail. Prepare an outline, along with any important images, to distribute to the class by email beforehand. Take advantage of the Speaking Center, a resource to help you develop an effective public speaking style. Grading rubric: background depth, 25 points; background clarity, 25 points; explanation of research paper, 50 points; fielding questions from audience, 20 points; outline distributed beforehand, 10 points; effectiveness of powerpoint content and formatting, 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. Read original research papers on a human genetic disorder that we don't cover in class (usually the same one you present on) and then propose the next research questions to address, explaining the experiments you would perform to answer those questions. 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 examine sample grant proposals. Within the samples, focus in on the sections relevant to you--Specific Aims, Background and Significance, and Research Plan (skim past budgets, biographical sketches, etc). The mock grant proposal should be >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 (50 pts or 5% of grade) is due in September--see schedule below. You must put significant effort into acquiring and reading references before writing the topic proposal. It should be at least 300 words, including background on the disease (10 pts), a few sentences on recent research (15 pts), and a few sentences on your proposed goals/experiments (15 pts). Proper in-text citations and a list of references at the end are worth 10 pts. You must use Zotero or other automated citation manager, with an author-date citation format such as the one described here: Davidson Department of Biology statement on plagiarism. The title of the file you send must begin with your last name.
--Remind me and I will send you a sample grant proposal from a previous year, once I know your selected topics.
--The actual mock grant proposal is due in November--see schedule. 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. Evaluate the clarity and completeness of the background/significance section, and assess the plausibility, logic, and value of the proposed experiments. You should read sources on the topics at hand to enable you to make informed assessments. 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

Discussion leaders &
Student presenter
(will be finalized 1st week of class)


Decoding Darkness reading
T 8/22

Intro to class

Presentation scheduling, how to find papers in the literature, accessing articles.

Brief review of essential concepts in genetics.

Main topic:
(First human genetic disorder characterized)

study sheet

Class roster for presentation scheduling:
1. Christine
2. Anna
3. Claude
4. Natalie
5. Vickie

At Sickle Cell Disease; follow the first eight links under "Overview." It's an old web site but still information-rich.

Ingram, 2004. Sickle-cell anemia hemoglobin: the molecular biology of the first "molecular disease"--the crucial importance of serendipity. Genetics 167: 1-7.

Hoban et al., 2016. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood 127: 839-848.

Research paper
Ye et al., 2016. Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia. PNAS 113: 10661-10665.

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.

T 8/29

(Traditional linkage analysis via lod scores)

study sheet

Marfan and Related Disorders (follow the five red button links)

Marfan Syndrome: a Silent Killer from Sports Illustrated, 1986, and Through her Death... from Houston Chronicle, 2014.

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

Recombination Mapping book excerpt

Research papers
Kainulainen et al., 1990. Location on chromosome 15 of the gene defect causing Marfan syndrome. New Engl. J. of Med. 323:935-939 (find the "download PDF" link).

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.

Park et al. 2017. Recapitulating and correcting Marfan Syndrome in a cellular model. Int J Biol Sci 13: 588-603.

T 9/5

(Genomic methods for dissecting chromosomal disorders)

study sheet

Review information from your genetics class on 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.
*Read only through the top of the 5th page; then move on to the next review paper for a more up-to-date view.

Antonarakis, 2017. Down Syndrome and the complexity of genome dosage imbalance. Nat Rev Genet 18: 147-163.

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

Hibaoui et al., 2014. Modeling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21. EMBO Molecular Medicine 6: 259-277. 

Chapters 1-2
T 9/12

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

study sheet

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.

Browse Autism Spectrum Disorder Fact Sheet

Video: Decoding the Autism Puzzle (watch from the beginning to 26:30 and then 30:30-46:50, skipping the Q&A) 

Chahrour et al., 2016. Current perspectives in autism spectrum disorder: from genes to therapy.

Research papers
Yu et al., 2013. Using whole-exome sequencing to identify inherited causes of autism. Neuron 77: 259-273.

D'Gama et al., 2015. Targeted DNA sequencing from autism spectrum disorder brains implicates multiple genetic mechanisms. Neuron 88: 910-917.

Chapters 3-4

T 9/19


study sheet

Discussion leaders:
2 and 4

Progeria Research Foundation (browse links within the "About Progeria" menu 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.

Research 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.

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.

Chapter 5-6
T 9/26


study sheet

Topic proposals/ bibliographies are due by email Friday Sep 29th at 4PM.

Discussion leaders:
3 and 5

Formal presenter: 1


Browse appropriate links (mostly in the "understanding Parkinsons" menu) to learn about the disorder at this site: Michael J Fox Foundation for Parkinson's Research.

Browse info about the 23&Me Parkinson's disease research effort.

Mouton-Liger et al., 2017. PINK1/Parkin-dependent mitochondrial surveillance: from pleiotropy to Parkinson’s Disease. Frontiers in Molecular Neuroscience 10:120.

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

Research papers
Ziviani et al., 2010. Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. PNAS 107: 5018-5023.

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 7-8


T 10/3


study sheet


 Formal presenter: 2

Zimmer, 2013. The girl who turned to bone. The Atlantic, June 2013.

Kaplan et al., 2012. Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis. Disease Models and Mechanisms 5: 756-762.

Sanchez-Duffhues et al., 2016. Towards a cure for Fibrodysplasia ossificans progressiva. Annals of Translational Medicine 4(Suppl1): S28.

Research papers
Hatsell et al., 2015. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Science Translational Medicine 7: 303ra137.

LaBonty et al., 2017. A zebrafish model of human fibrodysplasia ossificans progressiva. Zebrafish 14: 293-204.

Chapters 9-10

T 10/10


Email me feedback on how the course is going so far.  
T 10/17


study sheet


Discussion leaders:
1 and 5


Formal presenter: 3


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

Skim/glance through these two papers to see how GWAS approaches have contributed to the field:
--Lusis and Pajukanta, 2008. A treasure trove for lipoprotein biology. Nature Genetics 40: 129-130.
--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.

Research papers
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.

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

Chapters 11-12
T 10/24


study sheet

This week you must come meet with me individually about your progress on your mock grant proposal.

Discussion leaders:
1 and 2

Formal presenter: 4

Background infographics: Anatomy of the brain;
Progression of Alzheimers; Cross section of normal and Alzheimers brain; Diagram of amyloid plaques and neurofibrillary tangles

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 old but has useful figures.

Naj et al., 2017. Genomic variants, genes, and pathways of Alzheimer's disease: an overview. Am J Med Genet Part B 174B:5–26.

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

Hudry et al., 2013. Gene transfer of human ApoE isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Science Translational Medicine 5: 212ra161.

Commentary on future treatments
McDade and Bateman, 2017. Stop Alzheimers before it starts. Nature 547: 153-155.
Review whole book
T 10/31


study sheet


 Discussion leaders:
3 and 4

Formal presenter: 5

To prepare for understanding how the gene was identified, look up the following two phenomena and compare and contrast them.
Loss of heterozygosity by mitotic recombination
Sister chromatid exchange

Cunniff et al., 2017. Bloom's syndrome: clinical spectrum, molecular pathogenesis, and cancer predisposition.

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

Luo, G. et al. 2000. Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nature Genetics 26: 424-429.

Extra paper for the adventurous (at least give it a shot to figure out their ingenious setup)
Wu and Hickson. 2003. The Bloom's syndrome helicase suppresses crossing over during
homologous recombination. Nature 426: 870-874.

T 11/7


study sheet


Brain basics: understanding 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.

Research 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.

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

T 11/14



study sheet

We will make choices of topics for 11/28 and 12/5.


Beckwith-Wiedemann Syndrome

Caring for children with 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.

Research 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.

Hur et al., 2016. Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver–Russell syndrome phenotypes. PNAS 113: 10938-10943.

T 11/21 NO CLASS

Finish your mock grant proposals. They are due by email attachment on Monday November 20th at noon. 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.)

T 11/28

We'll pick a disorder/condition not covered this semester to explore briefly.


Fragile X Syndrome short overview

Davis and Broadie, 2017. Multifarious functions of the Fragile X mental retardation protein. Trends in Genetics 33: 703-714.

Korb et al., 2017. Excess translation of epigenetic regulators contributes to Fragile X syndrome and is alleviated by Brd4 inhibition. Cell 170: 1209-1223.



T 12/5

FOLLOW UP DAY We'll pick a disorder covered earlier this semester on which to pursue the most late-breaking findings. 

Wrap up discussion of peer review process

Course evaluations

FOP follow up: Hino et al., 2017. Activin-A enhances mTOR signaling to promote aberrant
chondrogenesis in fibrodysplasia ossificans progressiva. J. Clin. Invest. 127: 3339-3352.

Peer reviews of grant proposals due as email attachments by Wednesday December 6th at 4PM. Also email your reviews to the original authors.

12/8 to 12/14 Optional extra credit  take home final assignment, worth up to 50 points (5% of total grade)

Optional final assignment for extra credit: devise a new case study module for this class. Write a paragraph justifying your choice of disorder(s) and how that focus would add novel elements beyond what the current modules cover. List (with links) appropriate background sources and research articles. This list must be a suitable length for one week's worth of homework. For each article, write a couple of sentences to explain why you chose it.

Due at noon on Thurs Dec 14 as an email attachment. Please include your last name at the beginning of the title of the file.

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Copyright 2017 Department of Biology, Davidson College, Davidson NC 28035
last modified August 2017 by K. Hales