1. Genes Epigenetics Nutrition Injury-toxicity Infection Immune dysfunction Neoplasia What can make you ill ? Scurvy Hemophilia Prostate cancer Crohn’s disease Fracture Tuberculosis Angelman Syndrome

2. However, most diseases are multifactorial Tuberculosis Infectious agent Quality of immune response Genetic susceptibility Nutritional condition Lung cancer Neoplasia Toxicity Genetic susceptibility Quality of immune response

3. Genes

5. Why do some tissues express certain proteins and not others?

6. Gene expression is regulated especially at the level of transcription

7. Some useful terms: Genome: Gene: Alelle: Haplotype: All genetic information of an organism (stored as DNA) DNA segment that goes from the transcription start site to the transcription end site “Version” or variant of a gene. Frequently refers to variants involving a single nucleotide Version of a gene comprising several point differences.

8. Promoter: Replication: Transcription: Translation: Epigenetics: DNA region close (usually upstream) of a gene, that regulates its expression Synthesis of an identical copy of a DNA molecule Synthesis of an RNA molecule using a DNA molecule as template. Synthesis of a protein following the code given by a RNA molecule. The study of changes in DNA that do not change the nucleotide sequence, but alter function and are heritable.

9. Gene Function Protein RNA Structure Folding Regulation By John Quackenbush

10. Two randomly selected persons differ on average in 0.09% of their nucleotides. By John Quackenbush

11. … CACGGTACCATCACACATCGACGCGGCGATGCTACGATCGCACAGCAGCGATCAGCG AGCACGAGCATCTATTACTATCGGCAGCATCGTACTACGATCTACACTCGCGCACAGC CTCGTACGATCGTAGCATCGATGCTAGCATGCTAGCTAGCTGCTGCTGACTGCTGCTA GCTAGCTAGCTAGCTAGCTAGCTGCGATGCATCATCGATCTAGCTATCGATCGGGATC GATGCACGATGCTAGCACGATCAATTACGATCGATGCGGCTATATAGCATGCATTATC TTCCGGCGATATGCGCGCATGCTAGCGCATGCTAGCATCGAGCTAGCATCGAGCGCGC ATATCGACGGAGAGCGGCAGAGCGGAGAGCTCTCTATATTCTATACTCCTCTATTATT ATATATCCTCGGGCGGCGCTCCTTCTTCAATCGAGGCGCTACTTCTGCCGGATTCGAT TATATAATACCGGAGAGAGCTCTATACGAGCGGCCGATACGAGCAGCGAGCGAGGCGG CAGCGAGCGTATACTATTATAGCGCGATATCGAGCGAGCGACGAGCGAGCAGCGGAGC GTATTCTAGCGACGGAGCGACGAGCAGCGAGCGACGCCGAGCTATTTATCGGCGAATT CGAGCGCCGCGTATAGCTAGCGCGCGCGTCTCTAGAGCTATTCTTATCGGCGCGAGAG GCGCGAGGCGAGGGAGAGACTATACATGCGGATTACTATTCTATCGAGCGCAGCAGCG TATTACTAGCAGCGAGCACTAGCGGCAGCTAGCATGCAGCGCGATCTACTTACGAGGC GGACGGACGGACGGGCGATATATCGAGCGGAGCTACGATGCTCGTAGCTGGTACGAGC TAGCTAGCTAGCGGCGCATATATTACGCGCGGCGGCATATGCTAGACTGACTAGCTAG CGCGATCGACTAGCGACGCGGATCGAGCGCGGACGAGCGGCGAGCGGACGGGAGGATT CATAGGGATCACGATCTTGGAGCATTATATGCGAGCGAGCGATCGCGCTACGGAGTCG AGCGACGATCGATCGAGCAGCGAGCGTTCTCTAGCGGAGCGGGAG …

12. … CACGGTACCATCACACATCGACGCGGCGATGCTACGATCGCACAGCAGCGATCAGCG AGCACGAGCATCTATTACTATCGGCAGCATCGTACTACGATCTACACTCGCGCACAGC CTCGTACGATCGTAGCATCGATGCTAGCATGCTAGCTAGCTGCTGCTGACTGCTGCTA GCTAGCTAGCTAGCTAGCTAGCTGCGATGCATCATCGATCTAGCTATCGATCGGGATC GATGCACGATGCTAGCACGATCAATTACGATCGATGCGGCTATATAGCATGCATTATC TTCCGGCGATATGCGCGCATGCTAGCGCATGCTAGCATCGAGCTAGCATCGAGCGCGC ATATCGACGGAGAGCGGCAGAGCGGAGAGCTCTCTATATTCTATACTCCTCTATTATT ATATATCCTCGGGCGGCGCTCCTTCTTCAATCGAGGCGCTACTTCTGCCGGATTCGAT TATATAATACCGGAGAGAGCTCTATACGAGCGGCCGATACGAGCAGCGAGCGAGGCGG CAGCGAGCGTATACTATTATAGCGCGATATCGAGCGAGCGACGAGCGAGCAGCGGAGC GTATTCTAGCGACGGAGCGACGAGCAGCGAGCGACGCCGAGCTATTTATCGGCGAATT CGAGCGCCGCGTATAGCTAGCGCGCGCGTCTCTAGAGCTATTCTTATCGGCGCGAGAG GCGCGAGGCGAGGGAGAGACTATACATGCGGATTACTATTCTATCGAGCGCAGCAGCG TATTACTAGCAGCGAGCACTAGCGGCAGCTAGCATGCAGCGCGATCTACTTACGAGGC GGACGGACGGACGGGCGACATATCGAGCGGAGCTACGATGCTCGTAGCTGGTACGAGC TAGCTAGCTAGCGGCGCATATATTACGCGCGGCGGCATATGCTAGACTGACTAGCTAG CGCGATCGACTAGCGACGCGGATCGAGCGCGGACGAGCGGCGAGCGGACGGGAGGATT CATAGGGATCACGATCTTGGAGCATTATATGCGAGCGAGCGATCGCGCTACGGAGTCG AGCGACGATCGATCGAGCAGCGAGCGTTCTCTAGCGGAGCGGGAG …

13. Difference of only one nucleotide in the DNA sequence…TAGC……TGGC… Example: Some people have in a given site an A, while others have a G. Each option is called an allele. By John Quackenbush

14. - The set of alleles beared by an organism is called his genotype. -For this SNP, there are three possible genotypes: AA, AG, or GG.…TAGC……TGGC… There are about 11 million SNPs in human populations By John Quackenbush

15. Regulation of gene expression

16. All somatic cells have the same 46 chromosomes

17. Why do some tissues produce some proteins while some others do not ?

18. The central dogma, again

19. Chromatin

20. The structure of chromatin

21. The acetylation of histones LOOSENS chromatin STIMULATES gene expression

22. DNA methylation Happens at some “C” sites.

23. Methylation of DNA: TIGHTENS chromatin INHIBITS gene expression

24. Thrifty genotype: Genetic variation + selection Good energy storers survive …even though they change looks Their genes are still the same And now they get A LOT of energy Food is scarce and sporadic

25. Thrifty genotype: Epigenetic imprinting in utero Poor nutrition during fetal life Body systems get tweaked (by epigenetic mechanisms) to make the most of little energy Adult organism good at saving and storing energy And now gets A LOT of energy

26. Inflammation

27. Inflammation as a clinical phenomenon 1 st century AD: Cornelius Celsus (“De Medicina”) “ Rubor et Tumor cum Calore et Dolore “ Traditionally associated with wounds and infection A strong inflammatory response to environmental challenges provided an evolutionary advantage Redness and swelling with heat and pain

28. Inflammation at the cellular level

29. Inflammation gone awry causes/aggravates disease Atherosclerosis Obesity Inflammatory bowel disease Blunt head trauma Inflammation in the wall of arteries causes heart attacks/strokes Inflammatory mediators from adipose tissue cause insulin resistance/diabetes Targeting of normal intestinal cells by the immune system leads to diarrhea/malnutrition Inflammation of the brain parenchyma may cause brainstem herniation and death

30. Sequence of events during synaptic transmission

32. The neurotransmitter : 1. Is released in the synaptic cleft. 2. Binds to its receptor 3. Is degraded enzymatically

33. An actual synapse “d” = dendrite “R” = axon Which one is the postsynaptic neuron here? faculty.washington.edu/chudler/java/em.html

34. Many neurological diseases are associated with excess/deficit of a given neurotransmitter at some synapses Parkinson’s disease Alzheimer’s disease Major depression Deficit of dopamine at basal ganglia Deficit of acetylcholine at cerebral cortex Deficit of serotonin and norepinephrin at several key locations (ie. limbic system) Schizophrenia Excess dopamine at sensory cortex

35. Ischemic stroke Vs Hemorragic stroke Atherosclerosis in arteries that feed the cerebral circulation In situ formation of a blood clot on Top of the atherosclerotic plaque Cerebral artery Direct obstruction Carotid artery Embolization to the brain Lack of oxygen in an area of the brain Neuronal death Neurological deficit Rupture of a blood vessel within the CNS: Aneurism in a cerebral artery Arterial-venous malformation Bleeding from the meninges Sub-arachnoideal hemorrage Epidural hematoma Subdural hematoma/ Intraparenchymal hemorrage Inflammatory reaction to the presence of blood Mechanical pressure from blood in closed space