The Genetics of Health

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

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

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 Structural Storage Transport Receptors Contractile Defensive Hormonal Enzymatic PROTEIN TYPES Genes “act” via the proteins they code for

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 AA Aa aa “carrier” of recessive trait

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 influencebehaviour • “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 Hormonal Receptor Contractile Structural Storage Transport Defensive Enzymatic TYPES

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. Summary • 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)

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

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

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. The Endocrine System • 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)

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

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