1. 1 YORK UNIVERSITY Department of Biology Faculty of Science and Engineering Course outline Human Molecular Genetics (SC/BIOL 4285 3.0) W2015 Prerequisite: SC/BIOL 3130

2. 2 Instructor: Dr. Michael Scheid Rm. 236 Farqharson Building Website: scheid.blog.yorku.ca E-mail: mscheid@yorku.ca Office hours: Tuesday/Thursday 10:15-11:00 am

3. 3 STUDENT EVALUATION: There will be ONE Midterm exam, worth 30% of your grade: Midterm – February 13 You will submit a RESEARCH PAPER, worth 20% of your grade: Paper – due March 27 The FINAL EXAM will be worth 50% of your grade.

4. 4 Please note : There will be NO MAKE-UP of the midterm exams. For medical issues please have your physician fill out the Attending Physician Statement. This form is available from the Registrars website.

5. 5 Academic Integrity: Senate Policy on Academic Dishonesty Students are expected to be familiar with and follow York University’s Policies regarding academic integrity. Please consult the website below for more details: http://www.yorku.ca/academicintegrity/students.htm

6. 6 ACADEMIC MISCONDUCT WILL NOT BE TOLERATED. Cheating is the attempt to gain an improper advantage in an academic evaluation. Forms of cheating include: – Obtaining a copy of an examination before it is officially available or learning an examination question before it is officially available; – Copying another person’s answer to an examination question; – Consulting an unauthorized source during an examination; – Obtaining assistance by means of documentary, electronic or other aids which are not approved by the instructor; – Changing a score or a record of an examination result; – Submitting the work one has done for one class or project to a second class, or as a second project, without the prior informed consent of the relevant instructors; – Submitting work prepared in collaboration with another or other member(s) of a class, when collaborative work on a project has not been authorized by the instructor; – Submitting work prepared in whole or in part by another person and representing that work as one’s own; – Offering for sale essays or other assignments, in whole or in part, with the expectation that these works will be submitted by a student for appraisal; – Preparing work in whole or in part, with the expectation that this work will be submitted by a student for appraisal.

7. Overview of Gene Expression Mechanisms to control gene expression Spatial/temporal consideration

8. Overview of Gene Expression RNA Polymerase II –Transcription factors and cis-acting regulatory sequences

9. Overview of Gene Expression Ligand-inducible transcription factors –examples

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13. Overview of Gene Expression Epigenetic regulation

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18. Paula Quintero-Ronderos and GladisMontoya-Ortiz Autoimmune Diseases Volume 2012, Article ID 593720, 16 pages

19. DNA Methylation Host defense vs. Gene regulation Parent of origin: imprinting Biallelic vs monoallelic expression Inappropriate DNA methylation can cause problems eg. Cancer Beckwith-Wiedemann syndrome

20. DNA Methylation Determine the biological role of methylation Disrupt genes involved – DNMT (DNA methyltransferase)

21. Li E, et al. Cell, 1992, 69:915-26. “Homolgous knockout of DNA methyltransferase in mice leads to embryonic lethality.”

22. DNA Methylation Determine the biological role of methylation Disrupt genes involved – methyl-binding- domain proteins (eg MeCP2)

23. Tate, P., Skarnes, W. & Bird, A. Nature Genet. 12, 205-208 (1996). “The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse.”

24. Rett Syndrome Occurrence: 1 in 10,000 Neuron, November 2007, Pages 422-437

25. Rett Syndrome In humans, MeCP2 is mutated in 1 in 10,000 females Causes severe neurological disorders Rett Syndrome

27. 80% of females with Rett syndrome have mutations in MeCP2 Example of a strong single-gene disorder Result of inappropriate loss of gene silencing

33. Inappropriate Silencing of Genes Fragile-X Syndrome

34. LengthMethylationFemalesMales Stable6 to ~45UnmethylatedNot affected Gray zone~45 to ~55UnmethylatedNot affected Premutation~55 to ~200Unmethylated Usually not affected Full mutation>200 Completely methylated ~50% affected All affected

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38. Skewed X-Chromosome inactivation in a family with Fragile X

39. Southern Blot Analysis “A normal female will show an unmethylated 2.8-kb band and a 5.2-kb methylated band that correspond to the normal FMR1 gene present in the active and inactive X chromosome, respectively.” Blood sample Digest genomic DNA with EcoRI and EagI Electrophoresis and transfer to membrane Hybridize with FMR1 specific probe