EPI 6181Beth Lowcock

22 November, 2004

The Genetics of Health

• A crash course in genetics

• Simple genetic disorders

• Environmental influences

• Cancer

• Genetics and behaviour

• Some things to think about

Where We’re Going…

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

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

From DNA to Protein

3 DNA nucleotides

1 Codon

1 Amino Acid

Mutation??

Proteins

• More than 50% of dry weight in most cells

• Drive and regulate all bodily processes

Genes “act” via the proteins they code for

StructuralStorageTransport

ReceptorsContractileDefensive

HormonalEnzymatic

PROTEINTYPES

Factors Influencing Phenotype

• Dominance

• Polygenic Inheritance

– Multiple genes involved

• Environment

The observable physical or

physiological trait

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

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

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

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

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

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)

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?

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

• 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

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

How Genes May Influence Behaviour

• Behaviours are highly complex traits, and likely involve many genes

• Remember – Genes code for proteins

TYPESStructuralStorageTransport

HormonalReceptorContractile

DefensiveEnzymatic

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

• 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

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?

The Systems• Limbic• Endocrine• Immune

How do psychosocial influences bring about

biological change?

• 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

• Evidence from brain-damaged animals and people

• Loosely defined• About the size of

a walnut (larger in women than men)

The Limbic System

• 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

• Hippocampus– Involved in converting short-term memory

(things in your mind) into long-term memory– Damage prevents formation of new memories

• Thalamus– A relay station– Links “thinking brain” with sensory and

emotional areas– Damage results in emotional apathy

• 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)

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

• 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

• 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

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

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

Peptide Hormones

• Most hormones are peptide hormones

• Peptides are short chains of amino acids

Amine Hormones

• Derivatives of the amino acid tyrosine

Steroid Hormones

• Lipids derived from cholesterol

• Include the sex hormones secreted by the gonads

Hormone Action

• Hormones trigger actions in specific TARGET CELLS

• Target cells have receptor molecules that hormones bind to– Lock and key

analogy

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

Action of Steroid Hormones

• Steroids can enter cell since they are lipids and can cross the cellular membrane

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

Homeostasis and Regulation

• Negative feedback regulates secretion of almost every hormone

The Endocrine System:

• Allows for communication between the brain and other parts of the body

• Allows for homeostasis and regulation of bodily processes

• 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

The Immune System

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

Phagocytosis by a Neutrophil

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

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

• 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…

Humoral Response• Helper T cell activate B cells• B cells have 2 functions

1. Produce and secrete antibody molecules2. Serve as “memory” cells

• Antibodies bind to antigen, flagging it for destruction by phagocytes and complement

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

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)