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The Genetics of Health
EPI 6181
Beth Lowcock
22 November, 2004
Where We’re Going…
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A crash course in genetics
Simple genetic disorders
Environmental influences
Cancer
Genetics and behaviour
Some things to think about
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
PROTEIN
TYPES
Structural
Storage
Transport
Receptors
Contractile
Defensive
Hormonal
Enzymatic
Genes “act” via the proteins they code for
Factors Influencing Phenotype
• Dominance
• Polygenic Inheritance
– Multiple genes involved
• Environment
The observable
physical or
physiological
trait
Dominance
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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
“carrier” of
recessive trait
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 37x 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
TYPES
Structural
Storage
Transport
Hormonal
Receptor
Contractile
Defensive
Enzymatic
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
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)
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?
How do psychosocial
influences bring about
biological change?
The Systems
• Limbic
• Endocrine
• Immune
• 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
The Limbic System
• Evidence from
brain-damaged
animals and
people
• Loosely defined
• About the size of
a walnut (larger
in women than
men)
• 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
The Endocrine System
• Made up of all hormone-secreting
cells in the body
• Organs made up of hormonesecreting cells are endocrine
GLANDS
– Secrete directly into
bloodstream
(vs. exocrine glands)
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 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
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)
ANTIbody GENerating
• 2 types of specific immune responses
– Humoral response
– Cell-mediated response
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
The specific immune responses share
initial steps…
• Macrophages search for foreign materials
• Engulf and destroy them
• Fragments of antigen
displayed on
macrophage
membrane
• These macrophages
then activate
Helper T cells
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
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)