Genetics - Mutations Cancer Genetic Disease · Substitution Mutation An incorrect base is paired...
Transcript of Genetics - Mutations Cancer Genetic Disease · Substitution Mutation An incorrect base is paired...
Genetics
• We’ve Discussed:
� Types of genetic inheritance
� How to use a Punnett square to predict inheritance
� Sources of genetic diversity, including meiosis
� How to read a pedigree
• Now we will look at
� Mutations
� Cancer
� Genetic Diseases
• Changes to DNA (nucleotide sequence) or chromosomes
• Mutations are only harmful if they change:
� the amino acid sequence of a protein in a way that hinders or disables (“knocks out”) a protein, or
� the amount of the protein synthesized
– upregulates (makes too much of) a protein
– Downregulates (makes too little of) a protein
• Some mutations are beneficial – cause changes to proteins in a way that helps the organism survive or reproduce better
Mutations
Documentary on Mutations (49 minutes):
https://www.youtube.com/watch?v=qVmusHZtQms
Point Mutations Chromosomal Mutations
Mutations
Substitution
Substitution Mutation
An incorrect base is paired with the template strand
during DNA replication (does not follow A-T, G-C rule)
• The wrong base is connected during DNA replication
• Sometimes this results in the same amino acid
• A single change in one amino acid may change the conformation of a protein
� Usually bad
� Sometimes good
Chromosomal Mutations
Mutations
Point Mutations
SubstitutionFrame Shift
Insertion Deletion
An extra base is inserted during DNA replication, causing the entire reading frame
to shift to the right by one base, thus changing all of the subsequent codons
Chromosomal Mutations
Mutations
Point Mutations
SubstitutionFrame Shift
Insertion Deletion
A base is deleted during DNA replication, causing the entire reading frame to shift
to the left by one base, thus changing all of the subsequent codons
Chromosomal Mutations
Mutations
Point Mutations
NondisjunctionSubstitutionFrame Shift
Insertion Deletion
Aneuploidy
Chromosomal Mutations
Mutations
Point Mutations
NondisjunctionBreaks
Deletion Duplication Inversion Translocation
SubstitutionFrame Shift
Insertion Deletion
Deletion
Causes loss of genes
Honors
Chromosomal Mutations
Mutations
Point Mutations
NondisjunctionBreaks
Deletion Duplication Inversion Translocation
SubstitutionFrame Shift
Insertion Deletion
Duplication
Causes multiple copies of
genes per chromosome
(upregulation of proteins)
Honors
Chromosomal Mutations
Mutations
Point Mutations
NondisjunctionBreaks
Deletion Duplication Inversion Translocation
SubstitutionFrame Shift
Insertion Deletion
Inversion
Can cause upregulation or
downregulation of genes by
placing them next to new
promoter regions
Honors
Chromosomal Mutations
Mutations
Point Mutations
NondisjunctionBreaks
Deletion Duplication Inversion Translocation
SubstitutionFrame Shift
Insertion Deletion
Translocation (Transposons)
Can cause upregulation or
downregulation of genes by
placing them next to new
promoter regions
(similar to crossing over
but occurs between non-
homologous chromosomes)
Honors
Chromosomal Mutations
Mutations
Point Mutations
NondisjunctionBreaks
Deletion Duplication Inversion Translocation
SubstitutionFrame Shift
Insertion Deletion
Cancer
Mitosis
Mutation:
• Knocks out tumor suppressor gene, or
• Activates/upregulatesoncogene
activated
oncogenes
+inactivated
tumor suppressor
genes
Cell can reproduce in
defiance of normal
restraints on cell division
Cell can invade & colonize
territories normally reserved
for other cells
Mutations that Cause Cancer
activated
oncogenes
+inactivated
tumor suppressor
genes
Cell can reproduce in
defiance of normal
restraints on cell division
Cell can invade & colonize
territories normally reserved
for other cells
Mutations affecting• Cell cycle regulators
• Cell senescence
• Apoptosis
• Angiogenesis
Mutations Disrupt Chemical Pathways
activated
oncogenes
+inactivated
tumor suppressor
genes
Cell can reproduce in
defiance of normal
restraints on cell division
Cell can invade & colonize
territories normally reserved
for other cells
Mutations affecting• Cell cycle regulators
• Cell senescence
• Apoptosis
• Angiogenesis
Mutations Disrupt Chemical Pathways
activated
oncogenes
+inactivated
tumor suppressor
genes
Cell can reproduce in
defiance of normal
restraints on cell division
Cell can invade & colonize
territories normally reserved
for other cells
Mutations affecting• Cell cycle regulators
• Cell senescence
• Apoptosis
• Angiogenesis
Mutations Disrupt Chemical Pathways
activated
oncogenes
+inactivated
tumor suppressor
genes
Cell can reproduce in
defiance of normal
restraints on cell division
Cell can invade & colonize
territories normally reserved
for other cells
Mutations affecting• Cell cycle regulators
• Cell senescence
• Apoptosis
• Angiogenesis
Mutations Disrupt Chemical Pathways
Animation
Mutations affecting• Cell-cell communication
• Adhesion
• Apoptosis
Mutations Disrupt Chemical Pathways
activated
oncogenes
+inactivated
tumor suppressor
genes
Cell can reproduce in
defiance of normal
restraints on cell division
Cell can invade & colonize
territories normally reserved
for other cells
Mutations affecting
• Cell cycle regulators• Cell senescence• Apoptosis• Angiogenesis
Mutations affecting
• Cell cycle regulators• Cell senescence• Apoptosis• Angiogenesis
Mutations Disrupt Chemical Pathways
activated
oncogenes
+inactivated
tumor suppressor
genes
Cell can reproduce in
defiance of normal
restraints on cell division
Cell can invade & colonize
territories normally reserved
for other cells
Mutations affecting• Cell-cell communication
• Adhesion
• Apoptosis
Mutations affecting
• Cell cycle regulators• Cell senescence• Apoptosis• Angiogenesis
Mutations affecting• Cell-cell communication
• Adhesion
• Apoptosis
Mutations Disrupt Chemical Pathways
activated
oncogenes
+inactivated
tumor suppressor
genes
Cell can reproduce in
defiance of normal
restraints on cell division
Cell can invade & colonize
territories normally reserved
for other cells
Chromosomal Mutations
Mutations
Point Mutations
NondisjunctionBreaks
Deletion Duplication Inversion Translocation
SubstitutionFrame Shift
Insertion Deletion
Cancer
Mitosis
Mutation:
• Knocks out tumor suppressor gene, or
• Activates/upregulatesoncogene
It takes several mutations for a cell to progress to cancer (a mix of both deactivated tumor suppressor genes and activated oncogenes) resulting in:
• Loss of control over cell cycle (cell keeps dividing despite mutations or signals from other cells indicating crowding or tissue barriers)
• Cell gains ability to block apoptosis
• Cell gains ability to regenerate telomereshttp://www.learner.org/courses/biology/archive/animations/hires/a_cancer6_h.html
• Cell gains ability to stimulate angiogenesishttp://www.hhmi.org/biointeractive/media/vegf-lg.mov
• Cell loses necessity for adhesion and gains ability to travel through body and live in a foreign tissue environment
Honors
Chromosomal Mutations
Mutations
Point Mutations
NondisjunctionBreaks
Deletion Duplication Inversion Translocation
SubstitutionFrame Shift
Insertion Deletion
Cancer
Mitosis
Mutation:
• Knocks out tumor suppressor gene, or
• Activates/upregulatesoncogene
As a result, cancer cells gain the ability to:
• Reproduce in defiance of normal restraints on cell division
• Spread to other tissues
� Those adjacent to the tumor
� Tissues far from the tumor (metastasis)
http://www.hhmi.org/biointeractive/media/angiogenesis-lg.movhttp://www.pbs.org/wgbh/nova/cancer/program_t.html
http://www.learner.org/courses/biology/archive/animations/hires/a_cancer2_h.html
Honors
Chromosomal Mutations
Mutations
Point Mutations
NondisjunctionBreaks
Deletion Duplication Inversion Translocation
SubstitutionFrame Shift
Insertion Deletion
Cancer
Mitosis
Mutation:
• Knocks out tumor suppressor gene, or
• Activates/upregulatesoncogene
Cancer cells are unable to perform their normal function do to:
• rapid, uncontrolled cell growth and replication
• missing/damaged proteins due to accumulating mutations
Because cancer cells divide more rapidly than surrounding cells
and because they are able to invade and colonize foreign tissues:
• tumors grow to take over organs, crowding out normal cells
• patients die from organ failure
Honors
MutationActivate Oncogene
or
Inactivate Tumor
Suppressor Gene
increases rate
DNA repair mechanisms
Cell cycle regulators
Apoptosis / Senescence
The Self
Perpetuating
Cycle of
Progression
to Cancer
affects
MutationActivate Oncogene
or
Inactivate Tumor
Suppressor Gene
increases rate
DNA repair mechanisms
Cell cycle regulators
Apoptosis / Senescence
mutant cell (precancerous)
3 mutations (benign tumor)
2 mutations (precancerous)
malignant
tumor
(cancer) Invasive
Cancer Develops Over TimeNormal Benign Malignant
Case Study:One Possible Path to Colon Cancer
Normal
Epithelium Carcinoma
Accumulation of Mutations
Case Study:One Possible Path to Colon Cancer
Normal
Epithelium
Hyper-
proliferative
Epithelium
Accumulation of Mutations
APC
• represses stimulation of cell growth and proliferation
• promotes cell-cell adhesion
Case Study:One Possible Path to Colon Cancer
Normal
Epithelium
Hyper-
proliferative
Epithelium
Early
Adenoma
Accumulation of Mutations
APC Bcl-2
Blocks apoptosis
Case Study:One Possible Path to Colon Cancer
Normal
Epithelium
Hyper-
proliferative
Epithelium
Early
Adenoma
Intermediate
Adenoma
Accumulation of Mutations
APC P53Bcl-2
• drives mutant cells to apoptosis
• activates mechanisms that block cell division until DNA repaired
Case Study:One Possible Path to Colon Cancer
Normal
Epithelium
Hyper-
proliferative
Epithelium
Early
Adenoma
Intermediate
Adenoma
Late
Adenoma
Accumulation of Mutations
APC K-rasP53Bcl-2
Myctransmit cell growth and
proliferation signals
Case Study:One Possible Path to Colon Cancer
Normal
Epithelium
Hyper-
proliferative
Epithelium
Early
Adenoma
Intermediate
Adenoma
Late
Adenoma Carcinoma
Accumulation of Mutations
APC K-ras Smad4P53
Put brakes on
cell division
Bcl-2
Myc P16
Rb
Case Study:One Possible Path to Colon Cancer
Normal
Epithelium
Hyper-
proliferative
Epithelium
Early
Adenoma
Intermediate
Adenoma
Late
Adenoma Carcinoma Metastasis
Accumulation of Mutations
APC K-ras Smad4P53Additional
mutations that
enable cell to
survive in foreign
environment
Bcl-2
Myc P16
Rb
MetastasisMetastases lead to cancer deaths
1. Cancerous cells can:
• reproduce in defiance of normal restraints on cell division
• invade & colonize territories normally reserved for other cells
2. Cancer results from a collection of mutations:aberrant cells � benign tumor � malignant tumor
3. Metastasis requires an additional set of mutations
4. Mutations can be innate (naturally occurring during DNA
synthesis or mitosis) or induced (caused by the environment)
Cancer Overview
Chromosomal Mutations
Mutations
Point Mutations
NondisjunctionBreaks
Deletion Duplication Inversion Translocation
SubstitutionFrame Shift
Insertion Deletion
Cancer
Mitosis
Mutation:
• Knocks out tumor suppressor gene, or
• Activates/upregulatesoncogene
Genetic Variation
Meiosis
Mutation causes a change in the sequence of bases creating a new allele without affecting fetal viability
Chromosomal Mutations
Mutations
Point Mutations
NondisjunctionBreaks
Deletion Duplication Inversion Translocation
SubstitutionFrame Shift
Insertion Deletion
Cancer
Mitosis
Mutation:
• Knocks out tumor suppressor gene, or
• Activates/upregulatesoncogene
Genetic Variation
Meiosis
Mutation causes a change in the sequence of bases creating a new allele without affecting fetal viability
Genetic Disorders
Meiosis
Mutation causes a change in the sequence of bases that results in upregulation (too much) or downregulation (too little) of a protein that affects the person’s health in a detrimental way
http://www.pbs.org/wgbh/nova/genome/program.html
Genetic Disorders
• Mutation causes loss of or detrimental change to a protein
� Type 1 diabetes – loss of insulin protein
� Type 1 diabetes –defective insulin receptor protein
� Tay-Sachs disease – loss of hexosaminidase A protein caused by a genetic mutation on the HEXA gene on chromosome 15http://www.pbs.org/wgbh/nova/genome/program.html
• Nondisjunction causes missing or extra chromosome
� Trisomy 21 (Down Syndrome)
� Trisomy 18 (Edwards Syndrome)
� Trisomy 13 (Patau Syndrome)
� Monosomy X (Turner’s Syndrome)
� 47 XXY (Klinefelter’s Syndrome)
� Trisomy X (Triple X Syndrome)
What Causes Mutations?
Mutations can be spontaneous or induced
• Spontaneouspoint mutations or nondisjunction incurred during mitosis
• Inducedcaused by mutagens (e.g. chemicals, radiation)
What Causes Spontaneous Mutations?
Point mutations are incurred during DNA replication:
� Errors made every 1 in 100,000 nucleotides (pretty darn good!)
� When a nucleotide in the new strand of DNA is mismatched, enzymes will come remove that region of the DNA and then DNA polymerase and ligase will repair the “hole”
� After standard repairs, error rate drops to 1 in 10 billion (10-9) nucleotides in humans (Wow!)
DNA repair: http://www.hhmi.org/biointeractive/media/mismatch_repair-lg.mov
What Causes Spontaneous Mutations?
Aneuploidy
Nondisjunction can occur during mitosis or meiosis
What Causes Spontaneous Mutations?
Mutations can be spontaneous or induced
• Chemical Mutagens / Carcinogens
Aflatoxin Aflatoxin-2,3-Epoxide
Carcinogen bound to DNA
Aflatoxin M1 .Guanine
cytochrome
P450 oxidases
Aflatoxin B1
Examples:
• Aflatoxin
• chemicals in burnt food (like from BBQ)
• More than 100 chemicals in cigarette smoke
(many are also found in e-cigarette vapor)
What Causes Induced Mutations?
Smoking-induced lung cancer
What Causes Induced Mutations?
http://www.arpansa.gov.au/images/basics/emr.jpg
• ultraviolet
• x-rays
• gamma rays
Induced Mutations can be caused by:
• Chemical Mutagens / Carcinogens
• Radiation (breaks chromosome and/or forms dimers between bases)
What Causes Induced Mutations?
Induced Mutations can be caused by:
• Chemical Mutagens / Carcinogens
• Radiation (breaks chromosome and/or forms dimers between bases)
What Causes Induced Mutations?
integration of
viral DNA into
host genome
results in misregulation of
gene expression that can
interfere with the cell cycle
Induced Mutations can be caused by:
• Chemical Mutagens / Carcinogens
• Ionizing Radiation
• Viruses
What Causes Induced Mutations?
1. Why are insertion and deletion mutations usually more harmful than substitution mutations?
2. How does nondisjunction affect the genes present in an organism?Specifically, why does it cause deformities?
3. Compare and contrast oncogenes and tumor suppressor genes. What are they? How are they similar? How are they different?
4. Why is cancer primarily a disease of old age?
5. How do mutations cause genetic variation? Is this good or bad for the organism?
6. How do genetic diseases caused by point mutations differ from those caused by chromosomal mutations like nondisjunction?
7. What causes spontaneous mutations? What causes induced mutations?
8. How accurate is DNA replication? (That is, how often do point mutations occur?)
9. What type of mutation is shown here? AGTGCCGTCACTCACGGCCAGTG
Practice Questions