Bio 5285: Fundamentals of Mammalian Genetics.

Course organizers: M. Lovett (Lovett@genetics.wustl.edu) and A.M. Bowcock (Bowcock@genetics.wustl.edu). Teaching Assistant Jevon Plunkett (jevon.plunkett@gmail.com)

This course aims to provide both biologists and those with mathematical backgrounds with a basis in mammalian genetics. This is a required first year course for the Human and Statistical Genetics (HSG) Ph.D. program. The assigned textbook for this course is Human Molecular Genetics Third Edition by T. Strachan and A.P. Read. Garland Science 2004. It should be noted that not all of the course material is covered by this textbook. Lecture Notes (restricted, password required)

The final grade assessment on this course is based upon the following breakdown:

Lecture 1 Introduction Bowcock September 6th: DNA structure, polarity, DNA replication, transcription, translation, histone organization, mitosis, meiosis.

Lectures 2 and 3 Gene and chromosome organization Lovett September 11th and 13th: Euchromatin, heterochromatin, centromeres, telomeres, artificial chromosomes, gene distribution, mRNA structure and processing, pseudogenes, synteny, noncoding RNAs, rRNA, repetitive elements, large scale genomic polymorphisms. Gene regulation, splicing, RNA editing, Pol I, II and III transcripts, cis-acting control elements, transcription factors.

Lecture 4 Mutations and DNA repair Bowcock September 18th: Numerical chromosome abnormalities, aneuploidy, translocations, smaller changes, sister chromatid exchange, pathogenic mutations, fragile sites, L1 insertions, DNA repair.

Lecture 5 Introduction to modern human genetics Bowcock September 20th: Patterns of inheritance, oligogenic and polygenic traits, susceptibility genes, quantitative traits, penetrance, expressivity, anticipation, examples of types of mutations and specific human diseases.

Lectures 6 The mitochondrial genome and mitochondrial diseases Bowcock September 25th: Structure of the mitochondria and its genome, homoplasmy and heteroplasmy, genetic bottlenecks, reactive oxygen species, organ systems and characteristics of mitochondrial disease, mitochondrial migrations.

Lectures 7 and 8 Genomics and genome methodologies Lovett September 27th and October 2nd: Nucleic acid hybridization and reassociation kinetics, advanced molecular cloning systems. Comparative genomics, physical maps, molecular cytogenetics, methods for expression profiling, genotyping, copy number detection and resequencing. Comparative genomic hybridization, genomic representations, genomic tools for exploring epigenetic modifications.

Lecture 9 Pharmacogenetics TBA October 4th: Pharmacokinetics, pharmacodynamics, interindividual variability in the response to drugs, polymorphisms in drug metabolism, deposition or targets, examples of each type for known drugs and known pathways.

Clinical Rotation Reimschisel October 9th: A review of interesting cases in the pediatric genetics clinic.

Lectures 10 Epigenetics 1 Lovett October 11th: Genome wide epigenetic alterations, DNA methylation and its regulation, histone modifications, RNAi, polycomb and trithorax proteins, imprinting, X-chromosome inactivation.

Lecture 11 Human biochemical genetics/metabolic genetics Reimschisel October 16th: Clinical presentation, molecular mechanisms, diagnostic strategies, treatment options for the major classes of inborn errors of metabolism.

Lectures 12 Epigenetics 2 Lovett October 18th: More on epigenetics.

Lecture 13 Introduction to Human Population Genetics Fay October 23rd : Phenotypic variation in natural populations, Hardy Weinberg, mutation, genetic drift, recombination, selection, population structure, molecular evolution.

Lecture 14 Cancer genetics Watson October 25th: Evolution of cancer, characteristics and examples of mutated oncogenes, tumor suppressors and DNA repair genes in cancers, mutation/rearrangement detection systems, loss of heterozygosity, epigenetic silencing, translocations, genomic instability and cancer.

Lectures 15, 16 and 17 Applications of modern human genetics: Introduction to complex disease Bowcock October 30th, November 1st and November 6th: Genetic mapping, marker informativity, recombinants, LOD scores, parametric vs nonparametric analyses, genetic heterogeneity, genome wide scans, haplotypes, homozygosity mapping. Strategies for positional cloning complex disease loci, common disease: common variant hyphothesis, lambda S, linkage disequilibrium, case control and family-based association mapping.

November 8th Midterm Exam

Lectures 18 and 19 Neurodegenerative disorders Goate November 13th and November 15th: Diseases of unstable repeat expansion, inheritance patterns and characteristics, age of onset and numbers of repeats, anticipation, genetic modifiers, animal models, genetic testing, therapeutic development. Alzheimer's disease, animal models, the amyloid hypothesis, frontotemporal dementias, prion diseases, rare dementias.

Lecture 20 Psychiatric/behavioral genetics Saccone November 20th: Heritability and characteristics of major psychiatric diseases, diagnostic criteria, endophenotypes, the impact of diagnostic error, animal models of behavioral/psychiatric disease.

Lectures 21, 22, 23 and 24 Murine genetics and mice as models of human genetic disease Cheverud and Lovett November 27th, November 29th December 4th and December 6th: Transgenics, knockouts, conditionals, ENU and insertional mutagenesis screens, identifying modifier genes, haplotype-based genetic analysis, mouse strains, congenics, recombinant inbreds, advanced intercrosses, quantitative trait loci mapping.

Take Home Exam handed out on December 11th

Final Exam December 18th

Take Home Exam is due by December 21st.