1. EPI 6181 Beth Lowcock 22 November, 2004 The Genetics of Health

2. A crash course in genetics Simple genetic disorders Environmental influences Cancer Genetics and behaviour Some things to think about Where We’re Going…

3. Chromosomes Humans have 23 pairs –22 pairs of autosomes –1 pair of sex chromosomes Only gametes have one set of chromosomes Condensed strands of DNA located within the nucleus of every cell

4. DNA Double strand of nucleotides (A, T, C, G) form double helix Regions of DNA that code for proteins are called “genes” Proteins are polypeptides of amino acids

5. From DNA to Protein 3 DNA nucleotides 1 Codon 1 Amino Acid Mutation??

6. Proteins More than 50% of dry weight in most cells Drive and regulate all bodily processes Genes “act” via the proteins they code for Structural Storage Transport Receptors Contractile Defensive Hormonal Enzymatic PROTEIN TYPES

7. Factors Influencing Phenotype Dominance Polygenic Inheritance –Multiple genes involved Environment The observable physical or physiological trait

8. Dominance 2 copies of each gene Allele – a particular form of a gene Homozygous – 2 copies of same allele Heterozygous – 2 different alleles Dominant vs. Recessive “carrier” of recessive trait AA Aa aa

9. Recessive Genetic Disorders Thousands of diseases or disorders are inherited as simple recessive traits (aa genotype) Disorder occurs if recessive allele codes for an ineffective protein, or no protein at all Cystic Fibrosis –4% of Caucasians are carriers of gene –defective gene for chloride ion transport protein Tay Sach’s disease –Defective enzyme doesn’t break down lipids in brain

10. Dominant Genetic Disorders AA and Aa genotypes Lethal dominant genes are rare – why? –People can’t “carry” the gene Huntington’s Disease X-linked Genetic Disorders Expressed mainly in males Haemophilia

11. Polygenic Inheritance Most traits don’t result from expression of only one gene – so for most traits we don’t see discrete variation –Many traits vary along a continuum –Normal distribution Certain diseases may result from mutations of one or more genes involved in polygenic inheritance –A number of mutated genes linked to diabetes mellitus, asthma, heart disease, etc. Complex, and gene interaction not well understood

12. Environment Environment influences gene action in many ways –Proteins must use elements from the environment to build structures –Influences gene regulation (temperature, light, nutrients, toxins, stress, etc) –Demonstrated in genetically identical plants, twin studies

13. Nature Vs Nurture Debate over relative contributions of genes and environment Biological determinism wrong Genes provide a range of phenotypic possibilities – Norm of Reaction May be narrow (eye colour, CF) or broad (height, heart disease)

14. Cancer A genetic disease of somatic cells (non sex cells) “The class of disease characterized by rapid and uncontrolled proliferation of cells within a tissue” Normal growth and maintenance requires cell division – involves DNA replication Mutations may occur in genes that regulate this process Spontaneous mutation, or environmental influence –Chemical carcinogens, UV light, Viruses Cancer is genetic, but is it inherited?

15. The “Breast Cancer Genes” Genes identified –BRCA1 – normal gene functions as a transcriptional regulator and growth inhibitory protein –BRCA2 – also a tumor suppressor gene, exact function not well known Mutation of these genes associated with 3- 7x increased lifetime risk of breast cancer

16. 5-10% of breast cancer is “hereditary” –You inherit genes that predispose you to cancer, not cancer itself Just because you have the mutation doesn’t mean you’ll get cancer Just because you don’t have the mutation doesn’t mean won’t get cancer Some people are genetically PREDISPOSED to cancer

17. Genetics and Behaviour Evidence that genes do influence behaviour –“Innate” behaviours we observe in many different species –Changes to biological structures, such as brain areas, may lead to change in behaviour –Behaviours of closely related species, e.g. humans and chimpanzees

18. How Genes May Influence Behaviour Behaviours are highly complex traits, and likely involve many genes Remember – Genes code for proteins TYPES Structural Storage Transport Hormonal Receptor Contractile Defensive Enzymatic

19. Example: Tobacco Use Nicotine binds to nicotinic-acetylcholine receptors in the brain, which in turn modulate release of dopamine The gene CHRNA4 codes for one subunit of the nicotine receptor –There are several different forms of this gene Feng et al 2004 found a form of the gene to be protective against nicotine addiction Genetics may influence susceptibility to nicotine-addiction

20. Genes Proteins Many factors influence phenotype –Dominance –Number of genes involved –ENVIRONMENT There are many “simple” genetic disorders Genes may PREDISPOSE people to certain health outcomes (e.g., cancer) or health related behaviours (e.g., smoking) Summary

21. Some Things to Think About… Genetics and SES health gradient –Is there a relationship? –Genetic quality –Evolution – survival of the fittest? Implications for society –Is there such thing as free will? –Gene therapy –Designer babies Are genes the problem?

22. The Systems Limbic Endocrine Immune How do psychosocial influences bring about biological change?

23. In order for the body to react to a psychosocial influence, we must first perceive the influence and develop an emotional response to it Much of our discussion has centered around the emotional aspects of health –Mental stress –Social support – love or isolation –Emotions generated from health behaviours, such as relaxation from smoking, runner’s high –SES – worry, shame, helplessness

24. Evidence from brain-damaged animals and people Loosely defined About the size of a walnut (larger in women than men) The Limbic System

26. Amygdala –Receives sensory information from other regions –Organization of emotional information –Role in memory (damage results in amnesia for non-procedural memories) –Connected to olfactory bulb – memory and scent –Stimulation causes aggression, damage leads to passivity and lack of reaction to fearful stimuli

28. Hippocampus –Involved in converting short-term memory (things in your mind) into long-term memory –Damage prevents formation of new memories

30. Thalamus –A relay station –Links “thinking brain” with sensory and emotional areas –Damage results in emotional apathy

32. Hypothalamus –Important in homeostatic regulation (the body’s thermostat) –Regulates drives (hunger, thirst, sex), autonomic nervous system (stress response), aggressive behaviour –Linked to pituitary gland (and thereby the endocrine system)

33. Together, these structures: Set the emotional tone –Activity Negative tone –Inactivity Positive tone –Depression/mania, PMS Regulate motivation and drive Store emotional components of memory –Emotional memories help set emotional tone (cf. life events) Facilitate bonding –Damage prevents animals from bonding with young

34. Limbic system connected to the frontal lobe (the “thinking brain”) –Frontal lobotomy to treat emotional disorders Also connected to endocrine system –Hypothalamus connected to pituitary (“master gland”) Limbic system links “thinking brain” and endocrine system

35. Made up of all hormone-secreting cells in the body Organs made up of hormone- secreting cells are endocrine GLANDS –Secrete directly into bloodstream (vs. exocrine glands) The Endocrine System

36. Function of Endocrine System Internal communication (complementary to nervous system) Maintains homeostasis and long-term control –Regulates slower processes than nervous system (e.g., growth, stress response) Hormones are the messengers for this communication

37. Hormones Def – “a substance produced by one tissue and transported to another tissue where it induces a specific physiological response” More than 50 known human hormones Grouped into 3 classes: –Peptides –Amines –Steroids

38. Peptide Hormones Most hormones are peptide hormones Peptides are short chains of amino acids Amine Hormones Derivatives of the amino acid tyrosine

39. Steroid Hormones Lipids derived from cholesterol Include the sex hormones secreted by the gonads

40. Hormone Action Hormones trigger actions in specific TARGET CELLS Target cells have receptor molecules that hormones bind to –Lock and key analogy

41. Hormone Action Binding changes the shape of the receptor, eliciting a chemical/physiological response Receptors are proteins (form = function) Action of steroid hormones occurs inside the cell, while peptide and amine hormones bind with receptors on the cellular membrane

42. Action of Steroid Hormones Steroids can enter cell since they are lipids and can cross the cellular membrane

43. Action of Non-Steroid Hormones Peptides and amines cannot cross the cell membrane Bind to receptor on membrane, which causes chemical signal (second messenger) inside the target cell

47. Homeostasis and Regulation Negative feedback regulates secretion of almost every hormone

48. The Endocrine System: Allows for communication between the brain and other parts of the body Allows for homeostasis and regulation of bodily processes

49. The cells and tissues which enable us to mount a response to invading microorganisms, parasites and other foreign substances General immunity – 1 st line of defense Specific immunity – 2 nd line of defense The Immune System

50. General Immunity Physical barriers –Skin and mucous membranes Inflammatory response –Damaged cells release histamine resulting in increased blood flow and temperature Complement System –Proteins that cause pores in microorganism to open so that fluids and salts enter, causing cell to burst Phagocytosis –Neutrophils are a type of white blood cell

51. Phagocytosis by a Neutrophil

52. Specific Immunity Specific responses generated by specific invaders Involves production of ANTIBODIES to specific ANTIGENS (a foreign molecule) 2 types of specific immune responses –Humoral response –Cell-mediated response ANTIbody GENerating

53. The Humoral Response Antibody-mediated immunity Defend against invading bacteria and viruses in body fluids The Cell-mediated Response Active against bacteria and viruses within cells, cancerous cells, fungi, protozoa and parasitic worms

54. Macrophages search for foreign materials Engulf and destroy them Fragments of antigen displayed on macrophage membrane These macrophages then activate Helper T cells The specific immune responses share initial steps…

55. Humoral Response Helper T cell activate B cells B cells have 2 functions 1. Produce and secrete antibody molecules 2. Serve as “memory” cells Antibodies bind to antigen, flagging it for destruction by phagocytes and complement

56. Cell-Mediated Response Helper T cells active Killer T cells Killer T cells recognize antigen on surface of infected cells A protein called PERFORIN is released and forms holes in infected cell’s membrane, causing cells to burst –Infecting organism then subject to circulating antibodies

57. Secondary Immunity Resistance to certain disease after having had them once Memory cells produced during first exposure to antigen Second exposure to an antigen results in larger, faster response Vaccination –Stimulates production of antibodies and memory cells without causing disease (killed pathogen)