Transcript unit 6 genetics 2010

Human Genetics
Concepts and Applications
Ninth Edition
RICKI LEWIS
18
Genetics
of Cancer
PowerPoint® Lecture Outlines
Prepared by Johnny El-Rady, University of South Florida
Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display
Foreign versus Self
• Immune system protects organisms from
foreign invaders
• Protection from harmful organisms
(pathogens) is based upon the ability to
identify foreign molecules as “nonself”
• Foreign may be bacteria, viruses, fungi,
tumor, or transplanted cells
• Molecules recognized by the immune
system are called antigens and are usually
protein fragments or carbohydrates
Foreign versus Self
Figure 17.1
Figure 1
Reading 17.1
Genetic Control of Immunity
• Genes affect immunity by conferring
susceptibility or resistance to infection
• A few types of single genes encode
antibodies and cytokines that directly
attack foreign antigens
• Genes also specify the cell surface
antigens that mark the body’s cells as
“self”
Genetic Control of Immunity
• Understanding how genes control
immunity makes it possible to enhance or
redirect the system’s ability to fight
disease
• Mutations can impair immunity causing:
•
- Immune deficiencies
•
- Autoimmune disorders
•
- Allergies
•
- Cancer
The Human Immune System
• A network of vessels called lymphatics and
bean-shaped structures called lymph nodes
• Lymph is the fluid filling the lymph ducts
•
- Carries macrophages and B- and Tlymphocytes
• Organs involved in production or
maturation of immune cells
•
- Spleen and Thymus
•
- Bone marrow
Figure 17.3
Immunity
• The immune response attacks pathogens,
cancer cells and transplanted cells with
two lines of defense
•
- Innate immunity is immediate and
generalized
•
- Adaptive immunity is specific and
slower
• These act after various physical barriers
block pathogens
Levels of
Protection
Figure 17.4
Figure 17.7
Physical Barriers
• The first line of defense
• Examples include:
•
- Unbroken skin
•
- Mucous membranes and secretions
•
- Waving cilia of the respiratory tract
•
- Flushing effect of tears, saliva,
urination, and diarrhea
• All of these are non-specific defenses
Innate Immune Response
• General defenses found in the body
• If pathogen breaches physical barriers
produces a rapid broad response
• Response time is in minutes
• A central part is inflammation
•
- A process that creates a hostile
environment for pathogens
•
- Sends in phagocytes that engulf
and destroy pathogens via
phagocytosis
Innate Immune Response
Figure 17.5
Innate Immune Response
• Collectins
• Cytokines
•
- Interferon = Anti-viral
•
- Interleukins = Fever-inducing
•
- Tumor necrosis factor a = Anticancer
• Cytokines also play a role in adaptive
immunity
Innate Immune Response
• Complement
•
- Plasma proteins that assist or
complement other defense responses
•
- Roles of complement proteins
include:
•
- Puncture bacterial cells
•
- Dismantle viruses
•
- Trigger histamine release to
dilate blood vessels
•
- Attract phagocytes
Adaptive Immunity
• Requires stimulation
• Response time is in days
• Has three basic characteristics:
•
- Diversity: many different pathogens recognized
•
- Specificity: distinguishes particular molecules
•
- Memory: responds faster with subsequent
exposure
•
- Primary immune response: reaction to
first
exposure
•
- Secondary immune response: reaction to
exposure using “memory” of first response
Table 17.4
Abnormal Immunity
Immune system malfunction may be
inherited or acquired
In addition, immunity may be too weak, too
strong, or misdirected
Abnormal immune responses may be
multifactorial or caused by a mutation in
a single gene
Inherited Immune Deficiencies
At least 20 types
Affect innate and adaptive immunity
Examples
- Chronic granulomatous disease:
Mutation of oxidase enzyme results in
neutrophils that cannot kill bacteria
- Severe combined immune deficiency
(SCID): Impacts both humoral and cellular
immunity due to lack of mature B cells
and/or T cells
Inherited Immune Deficiencies
David Vetter had an
autosomal recessive
form of SCID
- He was born
without a thymus
gland
- His T cells could
not mature and
activate B cells
Figure 17.11
Table 17.5
Human Immunodeficiency Virus (HIV)
An infectious virus enters the body with direct
contact of bodily fluids
Infects macrophages, and later, helper T cells
Virus replicates and bursts out of the helper T
cell, killing it
Loss of helper T-cells prevents B-cell
activation
Infections occur because the immune system
not functional
Replicates rapidly, mutates easily, and can
hide
Acquired Immune Deficiency
Syndrome (AIDS)
The disease resulting from HIV infection
The immune system impact of HIV infection has
progressed to impairment of immune function
Due to genetically diverse population of HIV in a
human host, treatment requires combination
of medication with different actions
Drugs block/inhibit different points of infection
- Entry of virus into T cells
- Replication of viral genetic material
- Processing of viral proteins
Autoimmunity
Immune system attacks the tissues of an
individual’s own body
Autoantibodies recognize “self” proteins
About 5% of the population has an
autoimmune disorder
The signs and symptoms reflect the cell
types under attack
Allergy
Immune response to a non-threatening
foreign substance called an allergen
Size of allergens may determine type of
allergic response
- Larger (e.g., grass pollen) produces hay fever
- Smaller (e.g., cat dander, dust mites) trigger
asthma
Asthma is a chronic disease
- Contraction of the airways, inflammation
and mucus production block air flow
Allergic Response
Severe allergic reaction throughout the body
is called anaphylatic shock
Vaccination
A vaccine uses antigens from a pathogen to
invoke immunity before an individual has
been exposed to the pathogen
Antigens are chosen to be harmless alone
Ability to respond rapidly to subsequent
exposure prevents infection to a degree
that would cause disease
Vaccine technology dates back to 11th
century China
Edward Jenner used cowpox as a vaccine
for smallpox
Vaccination
Smallpox has not
naturally infected a
human since 1977
- So vaccination are
now unnecessary
Figure 17.15
Uses of Monoclonal Antibodies
• Basic research and disease diagnosis
• Home pregnancy test strips
– - Contain anti-hCG monoclonal antibody
– - If hCG is present in the urine it binds
and changes the color of the test strip
• Herceptin
– - A monoclonal antibody-based drug
– - Blocks receptors on breast cancer
cells
– - Prevents reception of cell-division
Transplantation
Organs are moved from one individual to
another
Hearts, kidneys, livers, lungs, corneas,
pancreases, skin, and bone marrow are
routinely transplanted
- Sometimes, several organs at a time
Today, thousands of transplants are
performed annually and recipients gain
years of life
Successful transplants lie in genetics
Transplantation
Types of transplantation are defined by the
relationship between the donor and
recipient:
- Autograft:
- Isograft:
- Allograft:
- Xenograft:
from one person to self
from identical twin
members of same species
from another species
Transplantation
Figure 17.21
Figure 17.17
Graft Rejection
• The immune system reacts to grafted
tissue recognized as foreign by trying to
destroy it
• Hyperacute rejection reaction
•
- A severe form of graft reaction in which
the blood supply to the graft tissue is cut off
• Graft versus host disease
•
- Occurs in bone marrow transplants
•
- Immune cells of the grafted bone
marrow recognize host body as foreign and
Genomic View of Immunity
• Sequencing genomes of pathogens
•
- Can help us understand how they infect,
and aid in development of treatments
• Crowd diseases
•
- Spread rapidly through unexposed
populations
•
- Examples: smallpox, measles, pertussis,
typhus, influenza, and SARS
• Bioweapons
•
- Bacteria and viruses have been used
throughout history as weapons
•
- In their natural state or genetically-
Introduction
• Cancer has been part of human existence
for eons
• By 300 B.C., Hippocrates coined the term
“cancer” to describe the crablike shape of
a tumor invading normal tissue
• Cancer has or will affect one in three of
us
• Diagnosis and treatment are becoming
increasingly individualized
Introduction
• Cancer is genetic, but is not usually
inherited
• Carcinogens are substances that cause
cancer
•
- Most are mutagens (damage DNA)
• Cancer is a group of diseases caused by
loss of cell cycle control
•
- If a cell escapes normal control over its
division rate, it forms a growth called a
tumor
Figure 18.1
Introduction
• A tumor is benign if it does not spread or
“invade” surrounding tissue
• A tumor is cancerous or malignant if it
infiltrates nearby tissues
• Metastasis
•
- The tumor spreads to other parts of
the body via the blood or lymph vessels
Cancer-Causing Genes
• Oncogenes
•
- More than 100
•
- Cause cancer if inappropriately
activated
• Tumor suppressor genes
•
- More than 30
•
- Deletion or inactivation causes cancer
•
- Cell cycle control/checkpoints
• In addition, changes in gene expression
accompany cancer
Cell Cycle Control
• Timing, rate, and number of cell divisions
depend on:
•
- Protein growth factors
•
- Signaling molecules from outside the
cell
•
- Transcription factors within
• Checkpoints control the cell cycle
•
- Ensure that mitotic events occur in the
correct sequence
Cell Cycle Control
Figure 18.2
Loss of Cell Cycle Control
• Many types of cancer result from faulty
check points
• Cancer sends a cell down a pathway of
unrestricted cell division
• Cancer cells either lose specializations
or never specialize
Figure 18.3
Telomeres and Telomerase
• Loss of control of telomere length may
also contribute to cancer
• Telomerase is the enzyme (complex of
RNA and protein) that adds telomere
sequences to the ends of chromosomes
• Normal, specialized cells have
telomerase turned off, limits cell division
• Cancer cells have to express
telomerase to be able to divide
indefinitely
Inherited vs. Sporadic Cancer
• Somatic mutations
•
- Occur sporadically in nonsex cells
•
- Result from a single dominant mutation or
two recessive mutations in the same gene
•
- Cancer susceptibility not passed on to
offspring
• Germline mutations
•
- Cancer susceptibility passed on to offspring
•
- Usually requires second somatic mutation
•
- Rarer but strike earlier than sporadic
Inherited vs. Sporadic Cancer
Figure 18.4
Origin of Cancer
• Cancer begins at the genetic and cellular
levels
• If not halted, cancer spreads through
tissues to take over organs and organ
systems
• The origin and spread of cancer are
summarized next
Figure 18.5
Origins of Cancer Cells
• Cancer can begin at the cellular level in at
least four ways:
•
- Activation of stem cells that produce
cancer cells
•
- Dedifferentiation
•
- Increase in proportion of a tissue that
consists of stem cells or progenitor cells
•
- Faulty tissue repair
Figure 18.8
Uncontrolled Tissue Repair
May Cause Cancer
Figure 18.11
Oncogenes
• Proto-oncogenes are normal versions of
genes that promote cell division
• Expression at the wrong time or in the
wrong cell type leads to cell division and
cancer
• Proto-oncogenes are called oncogenes in
their mutated form
• One copy of an oncogenic mutation is
sufficient to promote cell division
Oncogenes:
Overexpression of a Normal Function
• Viruses integrated next to a protooncogene can cause transcription when the
virus is transcribed
• Moving a proto-oncogene next to a highly
transcribed gene can lead to
overexpression of the proto-oncogene
• Example: Burkitt lymphoma
•
- A translocation places a protooncogene next to an antibody gene
Oncogenes:
Overexpression of a Normal Function
Chromosome 8
Figure 18.12
Chromosome
14
Breast Cancer
• Two main forms
•
- Familial form: A germline mutation is
inherited and then a somatic mutation
occurs in a breast cell
•
- Sporadic form: Two somatic
mutations affect the same cell
• Mutations in many genes can cause
cancer
BRCA
• The two major breast-cancer
susceptibility genes are BRCA1 and
BRCA2
•
- Encode proteins that join two others
to form a complex that allows repair of
double-stranded DNA breaks
• Mutations in these genes have different
incidences in different populations
• Inheriting BRCA mutations increases the
risk of other types of cancer
Other Genes
• Genes whose protein products affect
those of BRCA1, BRCA2, and p53 can
cause breast cancer
• Example: The ATM gene product adds a
phosphate to the CHEK2 gene product,
which then adds a phosphate to the
BRCA1 protein
•
- Mutations in ATM and CHEK2 can
cause breast cancer
Familial Adenomatous Polyposis
(FAP)
•
•
•
•
•
•
•
•
•
5% of colon cancer cases are inherited
1 in 5000 in U.S. has FAP
Causes multiple polyps at an early age
Several mutations contribute
- APC genes mutate
- Activation of oncogenes (E.g. K-Ras)
- Mutations in TGF, p53, and other genes
- PRL-3 triggers metastasis
- Caretaker genes cause genomic instability
Familial Adenomatous Polyposis
(FAP)
Figure 18.14
The Cancer Genome
• Several large-scale projects are analyzing
genomes of cancer cells
•
- These allow construction of
descriptive “atlases” containing different
types of information
• Many mutations accompany cancer, but
they interact in only a few pathways
•
- Once a pathway is implicated,
scientists can look for or develop drugs to
target it
Environmental Causes of
Cancer
Environmental factors contribute to cancer
by mutating or altering the expression of
genes that control the cell cycle,
apoptosis, and DNA repair
Inheriting a susceptibility gene places a
person farther along the road to cancer
- However, cancer can happen in somatic
cells in anyone
Environmental Causes of
Cancer
Individuals can lower the chance of
developing cancer by:
- Avoiding high-risk environmental factors,
such as smoking and excess sun
exposure
- Taking “chemopreventative” nutrients
such as folic acid and vitamin D
Cruciferous
Vegetables
Can Lower
Cancer Risk
Figure 18.15
Methods to Study CancerEnvironment Links
Population Study: Compares incidence of a type
of cancer among different groups of people
Case Control: Identify differences between
patients with a type of cancer and healthy
individuals matched for multiple characteristics
Prospective Studies: Two or more groups of
individuals follow a specific regimen ( e.g., diet
or activity plan) and are checked regularly for
cancer
Cancer Diagnosis and Treatment
• Most often, discovery of cancer follows a
screening test
• Oldest treatment is surgery, which removes
the tumor
• Radiation and chemotherapy nonselectively destroy rapidly dividing cells
• Other drugs help patients tolerate the side
effects
Cancer Diagnosis and Treatment
• New types of cancer drugs:
•
- Stimulate cells to regain specialized
characteristics
•
- Inhibit telomerase
•
- Induce apoptosis
•
- Inhibit angiogenesis
• Genomics information is increasingly
used
•
- Enables physicians to better match
Genes and Behavior
• Behavior is a complex continuum of
emotions, moods, intelligence, and
personality
• Behavior occurs in response to
environmental factors, but how we respond
has genetic underpinnings
• Behavioral genetics considers nervous
system function and variation
•
- Including mood and mind
The Human Brain
• The human brain weighs about 3 pounds
•
- Consists of 100 billion neurons and at
least a trillion other supportive and
nurturing cells called neuroglia
• Neurons communicate across synapses
using neurotransmitters
• Genes control the production and
distribution of these chemical signals
Neurotransmission
Figure 8.1
Behavioral Genetics
• Uses empirical risk, twin studies, and
adoption studies
• Association studies with SNPs and
analysis of specific mutations that are
present in individuals with the behavior
• Genetic studies of behavioral disorders
are challenging traditional psychiatric
classification
•
- These disorders may lie on a
continuum with many genes having input
Eating Disorders
• In the US, 5-10 million people have eating
disorders
•
- About 10% are male
• Twin studies reveal a heritability ranging
from 0.5-0.8
• Genes whose products control appetite or
regulate certain neurotransmitters may
predispose to eating disorders
Eating Disorders
• Anorexia nervosa – Psychological
perception of obesity and intentional
starvation
• Bulimia – Psychological perception of
obesity and intentional vomiting
• Muscle dysmorphia – Psychological
perception of being too small
Sleep
• Without sleep animals die
• The function remains unclear
• Twin studies indicate 4 of the 5 stages of
sleep have a hereditary component
•
- The fifth stage, REM sleep, is
associated with dreaming and so reflects
input of experience more than genes
Narcolepsy with Cataplexy
• Daytime sleepiness with tendency to
rapidly fall asleep (narcolepsy) and
periods of muscle weakness (cataplexy)
The genetic basis
was first identified
in dogs, then
humans
Figure 8.3
Familial Advanced Sleep
Phase Syndrome
• A disorder characterized by a very
unusual sleep-wake cycle
•
• Affected members of a large family
enabled researchers to identify the first
“clock” gene in humans
•
- The period gene enables a person to
respond to day and night environmental
cues
Familial Advanced Sleep
Phase Syndrome
A pedigree of the autosomal dominant form of the
disease
Figure 8.4
Figure 8.4
Intelligence
• A complex and variable trait subject to
multiple genes, environmental influences,
and intense subjectivity
• Refers to the ability to reason, learn,
remember, synthesize, deduce, and create
• The IQ (intelligence quotient) test was first
developed in France in 1904
•
- To predict academic success of
developmentally disabled children
The IQ Test
• Was later modified at Stanford University
to assess white, middle-class Americans
• IQ is normally distributed around a mean of
100
•
▪ Below 50 = Severe mental retardation
•
▪ 50-70 = Mild mental retardation
•
▪ 85-115 = Average intelligence
•
▪ Above 115 = Above average
intelligence
• IQ has been a fairly accurate predictor of
success in school and work
Figure 8.5
• IQ tests verbal fluency, mathematical reasoning,
memory, and spatial visualization ability
• The “g” value measures a general intelligence
factor that represents the inherited portion of IQ
• The environment has less of an influence on IQ
as a person ages
Drug Addiction
• Compulsively seeking and taking a drug
despite knowing its adverse effects
•
• Characteristics:
•
- Tolerance = The need to take more of
a drug to achieve the same effect
•
- Dependence = The onset of
withdrawal symptoms with cessation of
drug
Drug Addiction
• Heritability is 0.4-0.6
•
- Twin and adoption studies support
role of genes in drug addiction
• Drug addiction produces long-lasting
changes in the brain
• Brain changes that contribute to addiction
are in the limbic system
The Events of Addiction
Figure 8.6
Drugs of Abuse
• Abused drugs are often derived from plants
•
- Cocaine, opium, and
tetrahydrocannabinol (THC), the main
ingredient in marijuana
•
- These chemicals bind receptors in
human neurons
• Endorphins and enkephalins are the human
equivalents of opiates
•
- Are pain relievers
Mood Disorders
• Mood disorders represent the extremes of
normal behavior
• The two most prevalent are:
•
- Major depressive disorder = Marked
by unexplained lethargy, sadness, and
chronic depression
•
- Bipolar affective disorder = Marked
by depression interspersed with mania
Major Depressive Disorder
• Affects 6% of the US population
• A likely cause is a deficiency of the
neurotransmitter serotonin, which affects
mood, emotion, appetite, and sleep
• Many antidepressant drugs are selective
serotonin reuptake inhibitors (SSRIs)
Major Depressive Disorder
Figure 8.7
Bipolar Disorder
• Also called manic-depression
• Affects 1% of the population
• Associated with several chromosome
sites
• Its genetic roots are difficult to isolate
Schizophrenia
• Loss of ability to organize thoughts and
perceptions – withdrawal from reality
• Worldwide – 1% affected
• Typically early adult onset
• Progression
•
- Difficulty paying attention, memory
and learning difficulties, psychosis
(delusions and hallucinations)
Schizophrenia
• Disjointed drawings by schizophrenic
patients display the characteristic
fragmentation of the mind
Figure 8.8
Schizophrenia
• A heritability of 0.8 and empiric risk values
indicate a strong genetic component for
schizophrenia
Schizophrenia
• Dozens of genes may interact with
environmental influences to cause this
disease
• One powerful candidate is infection during
pregnancy
•
- Prenatal exposure to the influenza or
herpes viruses
Autism
• Autism is a spectrum of disorders
•
- Characterized by loss of language,
communication, and social skills, beginning
in early childhood
•
- Seizures and mental retardation may
occur
• Autism affects 3-6 children out of every
1,000
•
- It strikes four times as many boys as
Autism
• More than 30 genes so far have been
associated with autism
• Two genes in particular may finally
explain how autism develops
•
- They encode the cell adhesion
proteins neurexins and neuroligins
•
- These proteins strengthen synaptic
connections in neurons associated with
learning and memory
Understanding Autism
Autism may arise from failure of synapses to form
that enable a child to integrate experiences
Figure 8.9