Preliminary syllabus
ANG 6469 (9599)/ ANT 4531 (9602) MOLECULAR GENETICS
OF DISEASE
Prof. Connie J. Mulligan
Class meets in 2336
Turlington
Class time: Monday
11:45-2:45, with a 15 min break
Contact information:
Prof. Mulligan
409 Genetics Institute
(352) 273-8092
mulligan@anthro.ufl.edu
Office hours: Monday,
9:30-11:30 in B119 Turlington, or by appointment in 409 Genetics Institute
Course
summary: This
course will examine the molecular genetics of disease in humans. The completion
of the human genome sequence and the availability of a public database of
genetic variants distributed throughout the human genome have greatly
accelerated the discovery of genes involved in disease, leading to breakthroughs
in diagnosis and treatment. We will discuss a range of genetic disorders from
single-gene recessive defects (e.g. myotonic
dystrophy and cystic fibrosis) to complex diseases (e.g. diabetes and
alcoholism). Methods to isolate genes involved in disease (e.g. whole genome
scans and linkage disequilibrium) and types of treatment (e.g. gene therapy)
will also be discussed.
Course design: This course is
intended for advanced undergraduate and graduate students who have an interest
in the molecular genetics of disease. Most human genetics courses spend only
1-2 weeks/semester discussing the genetics of disease, whereas this course
focuses on disease for the entire semester. We will discuss the basics of the
human genome and the basis of simple and complex diseases, including cause,
inheritance, diagnosis, and treatment. We will discuss a number of diseases in
detail, with the specifics determined by the state of research for a particular
disease, i.e. certain eye diseases are now being treated by gene therapy so we
will focus on gene therapies for that day, but will focus on the use of microarrays to diagnose different brain tumors on another
day. Throughout
the semester, guest lecturers (mainly from the medical school) will speak about
their research on the diseases that we discuss in detail in class.
The
course is intended for students from all
colleges and departments – in the past, I have had students from anthropology,
chemistry, English, molecular genetics and microbiology, pharmacology and
zoology to name a few. A diverse audience makes for a more interesting class
since everyone has different backgrounds, different perspectives and different
interests to contribute to class discussions. Active participation is one of
the strengths of the class in this regard. It also helps to have a class with
undergraduate and graduate students together. Contrary to what one might think,
the undergrads are typically as well prepared and as insightful as the graduate
students. I keep separate sets of grades for the undergraduate and graduate
classes so that each set of students is only compared to his/her cohort.
Course objectives and student goals: All students are expected to gain knowledge on the
molecular genetic basis of simple and complex diseases in general and the specific
genetic basis for a number of particular human diseases. The class is fairly
intense and demanding because knowledge across a broad range of fields is
fundamental to an exploration of the molecular genetics of human disease – in
fact, this course may be one of the most challenging courses you have taken
with respect to developing expertise and familiarity with a wide range of
materials, techniques, publications, etc. All students are expected to do all
of the required readings and to follow up with additional readings if you do
not understand something. Additional readings are listed in the textbook and
can be found in the references in the journal articles (a glossary of basic terms is
also provided in the textbook). Furthermore,
you should become familiar with searching PubMed for
supplementary, follow-up, or original readings. Finally, there are suggested
textbooks to provide additional and supplementary material. Although basic molecular
biological concepts will be reviewed, knowledge of DNA structure, Mendelian genetics, and molecular biology is expected (such
as Intro Bio, BCS 2011).
Course format: The course meets once a week
for three hours and the course format is lecture plus discussion with
substantial class participation. Evaluation of student performance is based on
class participation, oral and written assignments, and exams.
Grading: Final grades will be
determined by the following categories, each of which contributes 100 points to
the final grade (exams count for 100 pts each): participation (100 pts), 10
sets of summary/questions/comments (10pts each), 2-4 homework exercises (100
pts total), 1-2 exams (100 pts for each exam). Grades will be based on the
following point percentages: 90-100%=A, 87-89%=B+, 80-86%=B, 77-79%=C+,
70-76%=C, 67-69%=D+, 60-66%=D, < 59%=E.
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Participation is required of all students
and will be based on each student’s contribution of original comments,
questions, etc. to the class. Simply showing up for class does not constitute
participation. Remaining silent in class means that the highest grade a student
can receive is a B.
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At the beginning of each class, a 1-2 paragraph summary and 2-3 questions or comments for each
peer-reviewed journal article assigned for that day’s class will be turned in.
The summary/questions/comments are required only for the peer-reviewed journal
articles, not for the news-and-views type articles that are included in the
course pack to provide background or summary information. The
summary/questions/comments are intended to ensure that each student is prepared
to actively participate in class discussions.
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There will be approximately 2-4 homework exercises involving the analysis of hypothetical or real molecular
data. The exercises are intended to give students an opportunity to perform
analyses similar to those conducted in the discussion papers and will be graded
on effort and accuracy. Exercises must be turned in two weeks after they are
assigned. Students who miss a class in which an exercise is assigned are
expected to make up any missed material and to turn in exercises on time, i.e. two
weeks after the missed class.
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There will be one to two exams
that will consist of essay and short answer questions and exercises (similar to
the homework exercises). Questions must be answered during the exam period
without reference to books or notes of any kind. Calculators may be used, but
no personal communication devices will be allowed. Make-up exams will be
scheduled only in extenuating circumstances and will require a doctor’s note,
police report, or similar supporting documentation.
Useful websites:
Additional
information is provided by several websites:
http://www.clas.ufl.edu/users/mulligan/Webpage/MGD.2008/MGD.home.html
– website for class (lectures, problem sets, etc)
http://www.booksites.net/sudbery/molecular/ -
website companion to the textbook
http://www.uflib.ufl.edu/ej/ - UF
database of available electronic journals (may only be available from a campus
computer)
http://www.ncbi.nlm.nih.gov/sites/entrez
- National Library of Medicine database of over 11 million journal articles
dating back to the 1960s
http://www.genome.gov/glossary.cfm
– NIH-maintained glossary of genetic terms
http://medical.webends.com
- Online medical dictionary
http://www.genomesonline.org/
- status of genome sequencing projects
http://www.stanford.edu/group/morrinst/hgdp.html
– Human Genome Diversity Project (dated, good for
historical perspective)
http://geneticassociationdb.nih.gov
- NIH database of gene, variants, etc involved in diseases
www.hgmd.org
– Human Gene Mutation Database, database of genetic variants that cause
disease, maintained by
http://cgap.nci.nih.gov/Chromosomes/Mitelman
- Database of chromosome abberations in cancer
http://gmed.bu.edu – genetic associations in
Framingham Heart study
http://www.sciencemag.org/feature/plus/sfg/ -
breaking news in functional genomics
http://www.genome.gov/LegislativeDatabase
- Database of federal and state laws focused on genetic issues, such as genetic
testing and counseling, insurance and employee discrimination, etc.
Class attendance policy: Because the class meets
only one time per week and because the class format is mainly discussion, it is
very difficult to make up missed classes by borrowing notes, etc. Therefore,
students are strongly encouraged to attend all classes. Computers are allowed in class for taking
notes, but are not allowed during exams. Class discussions/lectures cannot be
recorded in any manner without special permission.
Copyright
information:
Lectures may not be tape-recorded without the prior express written permission
of Dr. Connie Mulligan. The contents of
the syllabus, lectures, lecture outlines, and handouts for this course are
copyrighted and intended for the private use of students registered in ANG
6461/ANT 4530. They therefore cannot
legally be reproduced, in part or in whole, by any commercial enterprise or for
any commercial purposes.
Accommodations for students
with disabilities: If you require accommodation due to a disability, please make an
appointment or visit during my office hours so that we may discuss your
needs. Students requesting classroom
accommodation must first register with the Dean of Students Office. The Dean of Students Office will provide
documentation to the student who must then provide this documentation to the
Instructor when requesting accommodation.
Academic honesty: As a result of completing
the registration form at the
Strategies for
success:
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It is important to complete all the readings on time and it is best to
read the readings throughout the week. In this way, you have time to think
about and process the information during the week and in between different
readings. Ideally, you would read some every night of the week. The amount of
reading material is very modest, particularly for an anthropology course. This
is because it is expected that you will re-read (gasp!) anything you do not
understand the first time. I often
re-read journal articles and find myself discovering things that I completely
missed on the first read. Or new items will come to light after having read a
different, but related article. This is the intent of the readings – that they
relate to each other and increase your knowledge and expertise in an
exponential way. During your reading, you should take copious notes and these
notes will form the basis of the summary + questions you must turn in for every
article.
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You have two weeks to work on the exercises. The intent is that you
will use the first week to start on the exercise and come to class the next
week (i.e. the week before the exercise is due) with any questions you have
about the exercise. Do not wait until the second week to start the exercise.
Also, I am always available by email to ask questions about the exercises.
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Finally, you should review material throughout the course rather than
trying to cram everything in the night before the exam. Ask for help in taking
notes, comprehending the material, or preparing any of the written or oral
assignments – I am available during office hours, you can schedule an
appointment outside of office hours, and I am always available by email.
UF Counseling Services: On-campus services are
available for students having personal problems or lacking clear career and
academic goals. They include:
Course
schedule:
January 7 – First day of classes!!!
Introduction
Video – Breaking the Code: Applying Genetic Techniques to Human Disease
January
14 – The structure of the human genome
-
Human Molecular Genetics (HMG), Chpt
2
-
Coursepack
§
“Dissecting Human Disease in the
Postgenomic Era”, Science, 2001
§
Challenges in human genetic diversity: Demographic history and
adaptation, Balaresque et al., Hum Mol Genet, 2007,
16:R134-R139
§
“In genetic control of disease, does ‘race matter?”, Nature Genetics,
2004
§
Paternal age at birth is an important determinant of offspring telomere
length, De Meyer et al., Hum Mol Genet, 2007, 16:3097-3102
§
Evolution and Genetic History, Genetics and the Search for Modern
Human Origins, Chpt 2
Lecture
-
Background material
-
How to read a scientific article
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PubMed search
January 21 - No classes – Martin
Luther King Jr. Day
January 28 – Mapping the human
genome /The sequence of the human genome
-
Human Molecular Genetics (HMG), Chpts
3, 4.1-4.8.4 (pp 52-116)
-
Coursepack
§
“The Human Genome”, Science, 2001
§
“Was the human genome project worth the effort?”, Science, 2005
§
“Venter’s genome sheds new light on human variation”, Science, Sept 7,
2007
§
“The race for the $1000 genome”, Science, 2006
§
Defining genes in the genomics era, Snyder and Gerstein, Science, 2003,
300:258-260
Guest lecturer – Joe Wilson, Dept of Anthropology –
fibroblast growth factor receptors and skeletal dysplasia
Exercise 1 assigned
February 4 - Analysis of the
human genome
-
Human Molecular Genetics (HMG), Chpt
4.8.5-4.10 (pp 116-139)
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Coursepack
§
Proteomic approaches in brain research and neuropharmacology,
Vercauteren et al., Eur J Pharmacol, 2004, 500:385-398
§
“Going from genome to pill”, Science, 2005
§
“Personal dose: In milestone, FDA pushes genetic tests tied to drug;
agency seeks to tame risks of blood thinner; some doctors protest”, The Wall
Street Journal, August, 2007
§
“Cancer sharpshooters rely on DNA tests for a better aim”, Science,
2004
§
A bill on genetic testing introduced into the US Senate in August, 2006
§
Pharmacogenomics: Challenges and opportunities, Roden
et al., Ann Int Med, 2006, 145:749-757
Guest speaker – Prof. Julie
Johnson, Professor, Dept of Pharmaceutical Sciences and Director, UF Center for
Pharmacogenomics – Pharmacogenomics - Confirmed
February 11 - Human genetic
disease
-
Human Molecular Genetics (HMG), Chpt
1
-
Coursepack
§
“The land between Mendelian and multifactorial inheritance, Burghes
et al., Science, 2001, 293:2213-2214
§
Do mitochondrial DNA mutations have a role in neurodegenerative
disease?, Krishnan et a., Biochem Soc Trans, 2007,
35:1232-1235
§
Alpha one antitrypsin deficiency: From gene
to treatment, Wood and Stockley, Respiration, 2007,
74:481-492
Guest
lecturer, 10:30-11:30 - Prof. Mark Brantly,
Professor, Dept of Medicine and Molecular Genetics and Microbiology – alpha
1-antitrypsin deficiency - Confirmed
Exercise 1
due
February 18 – Single gene disorders
-
Human Molecular Genetics (HMG), Chpt
5.1-5.6 (pp 140-164)
-
Coursepack
§
Cystic fibrosis gene variability in two southern Brazilian Amerindian
populations: Analysis of the delta-F508 mutation and the KM19 and XV2C
haplotypes, Raskin et al., Hum Biol,
2007, 79:79-91
§
A regulatory SNP causes a human genetic disease by creating a new
transcriptional promoter, De Gobbi et al. Science,
2006, 312:1215-1217
§
Myotonic dystrophy: Emerging mechanisms for DM1 and DM2, Cho
and Tapscott, Biochiim Biophys Acta, 2007, 1772:195-204
Guest speaker – Jason R O'Rourke ,
Dept of Molecular Genetics and Microbiology – myotonic
dystrophy -Confirmed
February 25 – Inherited
cancers
-
Human Molecular Genetics (HMG), Chpt
5.7-5.8 (pp 164-179)
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Coursepack
§
“Disease backs
cancer origin theory”, Science, 2004
§
The gene
topography of cancer,
§
Genetic variation
in the DNA repair genes is predictive of outcome in lung cancer, Matakidou et al., Hum Mol Genet, 2007, 16:2333-2340
§
Role of telomeres
and telomerase in genomic instability, senescence and cancer, Deng and Chang,
Lab Invest, 2007, 87:1071-1076
Guest
speaker in cancer ???
March 3 - The genetic
components of complex disease
-
Human Molecular Genetic (HMG), Chpt
6.1-6.4.4.3 (pp 180-210)
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Coursepack
§
The structure of common genetic variation in
§
The changing phenotype of the human species (affluent variety), Gale, Diabetologia, 2004, 47:1339-1342\
§
Allelic variation at alcohol metabolism genes (ADH1B, ADH1C, ALDH2) and
alcohol dependence in an American Indian population, Mulligan et al., Hum
Genet, 2003, 113:325-336
Guest speaker - Thomas Yang,
Professor, Dept of Biochemistry and Molecular Biology, Director, Center for
Mammalian Genetics – epigenetics????
March 10 - Spring break
March 17 - The genetic
components of complex disease/Alzheimer’s
-
Human Molecular Genetic (HMG), Chpt
6.4.4.4-6.5 (pp 210-224)
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Coursepack
§
A second generation human haplotype map of over 3.1 million SNPs,
International HapMap Consortium, Nature, 2007, 449:851-862
§
The double puzzle of diabetes, Diamond, Nature, 2003, 423:599-602
§
A review of current approaches to identifying human genes involved in
myopia, Tang et al., Clin Exp Optometry, 2008,
91:4-22
§
Towards compendia of negative genetic association studies: An example
for Alzheimer disease, Blomgvist et al., Hum Genet,
2006, 119:29-37
Guest speaker – Dr. Jeffrey Hughes, Dept of
Pharmaceutics – Alzheimer’s disease - Confirmed
March 24 - Human
population genetics
and evolution
-
Human Molecular Genetic (HMG), Chpt 9
-
Coursepack
§
Use of Y chromosome and mitochondrial DNA population structure in tracing human
migrations, Underhill and Kivisild, Annu Rev Genet,
2007, 41:539-564
§
Modern humans did not admix with Neanderthals during their range
expansion into
Exercise 2 assigned
March 31 - Genetic testing
-
Human Molecular Genetic (HMG), Chpt
8
-
Coursepack
§
“A risky business: Assessing breast cancer risk”, Science, 2003
§
“Genetic screen misses mutations in women at high risk of breast
cancer”, Science, 2006
§
“Genetic testing oversight”, Science 2006
§
“Fast technology drives new world of newborn screening”, Science
Magazine, 2001
§
“
§
“
§
Guest speaker
– Henry Baker, Professor, Dept of Molecular Genetics and Microbiology – Use of microarray data to diagnose brain tumors - Confirmed
April 7 - Gene therapy
-
Human Molecular Genetic (HMG), Chpt
7
-
Coursepack
§
“Gene therapy death prompts review of adenovirus vector”, Science, 1999
§
“Blood test flags agent in death of Penn subject”, Science, 2002
§
“A tragic setback”, Nature, 2002
§
“As Gelsinger case ends, gene therapy suffers
another blow”, Science, 2005
§
Efficient expression of CFTR function with adeno-associated
virus vectors that carry shortened CFTR genes, Zhang et al., Proc Natl Acad Sci,
1998, 95:10158-10163
§
AAV vectors for retinal gene therapy, Min et al. (Hauswirth’s
group), Parvoviruses (
Guest speaker
– Prof. William Hauswirth, Professor, Dept of
Ophthalmology and Molecular Genetics – Gene therapy and eye disease - Confirmed
Exercise 2
due
April 14 - Human genetics and society
-
Human Molecular Genetic (HMG), Chpt
11
-
Coursepack
§
“Taking the least of you”, The New York Times, April, 2006
§
Genome research and human subject privacy, Lin et al., Science, 2004,
305:183
§
“Long-awaited genetic nondiscrimination bill headed for easy passage”,
Science, 2007
§
“DNA gatherers hit snag: Tribes don’t trust them”, The New York Times,
December, 2006
§
Human genetic research: Emerging trends in ethics, Knoppers
and Chadwick, Nature Reviews Genetics, 2005, 6:75-79
§
Ethical, legal, and social issues in pharmacogenomics,
Allen, Pharmacogenomics: Applications to patient care, 2004, American
Guest speaker – Bill Allen, Director,
Program in Bioethics, Law and Medical Professionalism – Ethical, legal and
social issues
Review
for exam
April 21 DNA fingerprinting
-
Human Molecular Genetic (HMG), Chpt
10
-
Coursepack
§
“Gene hunt”, Science, 2006
§
Molecular evidence of HIV-1 transmission in a criminal case, Metzker et al., PNAS, 2002, 99:14292-14297
Gene Hunters
video
Exam
FINAL EXAM, Wednesday, April 30,
5:30-7:30