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

Mutations

Point Mutations

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

Mutations

Point Mutations

NondisjunctionSubstitutionFrame Shift

Insertion Deletion

Aneuploidy

Mutations

Point Mutations

NondisjunctionBreaks

Deletion Duplication Inversion Translocation

Insertion Deletion

Deletion

Causes loss of genes

Honors

Mutations

Point Mutations

Insertion Deletion

Duplication

Causes multiple copies of

genes per chromosome

(upregulation of proteins)

Honors

Mutations

Point Mutations

Insertion Deletion

Inversion

Can cause upregulation or

downregulation of genes by

placing them next to new

promoter regions

Honors

Mutations

Point Mutations

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

Mutations

Point Mutations

Insertion Deletion

Cancer

Mitosis

Mutation:

• Knocks out tumor suppressor gene, or

• Activates/upregulatesoncogene

activated

oncogenes

+inactivated

tumor suppressor

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

defiance of normal

for other cells

Mutations affecting• Cell cycle regulators

• Cell senescence

• Apoptosis

• Angiogenesis

Mutations Disrupt Chemical Pathways

activated

oncogenes

+inactivated

tumor suppressor

defiance of normal

for other cells

• Cell senescence

• Apoptosis

• Angiogenesis

activated

oncogenes

+inactivated

tumor suppressor

defiance of normal

for other cells

• Cell senescence

• Apoptosis

• Angiogenesis

activated

oncogenes

+inactivated

tumor suppressor

defiance of normal

for other cells

• Cell senescence

• Apoptosis

• Angiogenesis

Animation

Mutations affecting• Cell-cell communication

• Adhesion

• Apoptosis

activated

oncogenes

+inactivated

tumor suppressor

defiance of normal

for other cells

Mutations affecting

• Cell cycle regulators• Cell senescence• Apoptosis• Angiogenesis

Mutations affecting

activated

oncogenes

+inactivated

tumor suppressor

defiance of normal

for other cells

• Adhesion

• Apoptosis

Mutations affecting

• Adhesion

• Apoptosis

activated

oncogenes

+inactivated

tumor suppressor

defiance of normal

for other cells

Mutations

Point Mutations

Insertion Deletion

Cancer

Mitosis

Mutation:

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

Mutations

Point Mutations

Insertion Deletion

Cancer

Mitosis

Mutation:

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

Mutations

Point Mutations

Insertion Deletion

Cancer

Mitosis

Mutation:

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

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

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

(cancer) Invasive

Cancer Develops Over TimeNormal Benign Malignant

Case Study:One Possible Path to Colon Cancer

Normal

Epithelium Carcinoma

Accumulation of Mutations

Normal

Epithelium

Hyper-

proliferative

Epithelium

• represses stimulation of cell growth and proliferation

• promotes cell-cell adhesion

Normal

Epithelium

Hyper-

proliferative

Epithelium

Adenoma

APC Bcl-2

Blocks apoptosis

Normal

Epithelium

Hyper-

proliferative

Epithelium

Adenoma

Intermediate

Adenoma

APC P53Bcl-2

• drives mutant cells to apoptosis

• activates mechanisms that block cell division until DNA repaired

Normal

Epithelium

Hyper-

proliferative

Epithelium

Adenoma

Intermediate

Adenoma

APC K-rasP53Bcl-2

Myctransmit cell growth and

proliferation signals

Normal

Epithelium

Hyper-

proliferative

Epithelium

Adenoma

Intermediate

Adenoma

Adenoma Carcinoma

APC K-ras Smad4P53

Put brakes on

cell division

Myc P16

Normal

Epithelium

Hyper-

proliferative

Epithelium

Adenoma

Intermediate

Adenoma

Adenoma Carcinoma Metastasis

APC K-ras Smad4P53Additional

mutations that

enable cell to

survive in foreign

environment

Myc P16

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

Mutations

Point Mutations

Insertion Deletion

Cancer

Mitosis

Mutation:

Genetic Variation

Meiosis

Mutation causes a change in the sequence of bases creating a new allele without affecting fetal viability

Mutations

Point Mutations

Insertion Deletion

Cancer

Mitosis

Mutation:

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

Aneuploidy

Nondisjunction can occur during mitosis or meiosis

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

http://www.arpansa.gov.au/images/basics/emr.jpg

• ultraviolet

• x-rays

• gamma rays

Induced Mutations can be caused by:

• Radiation (breaks chromosome and/or forms dimers between bases)

integration of

viral DNA into

host genome

results in misregulation of

gene expression that can

interfere with the cell cycle

• Ionizing Radiation

• Viruses

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

Genetics - Mutations Cancer Genetic Disease · Substitution Mutation An incorrect base is paired...

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