Transcript mutations

MUTATIONS
BEGINS
I’m here to talk to you about DNA errors and
the resultant mutations of the DNA
I’m sure you notice my three eye configuration. Yes
that’s right I am a mutant. Every cell in my body has the
mutation. I got this way from y mother’s egg that was
mutated and then was fertilized. That very first cell,
called a zygote matured into the fish you see today. The
mutation was caused by an error in meiosis. Thus that
DNA error now is embedded in the DNA of all my cells.
In addition, my offspring will now potentially either carry
my mutation or express it like I do.
Errors in the DNA used in meiosis = Mutation of entire organism
If you hear about birth defects due to mutations, they can be caused by a
number of things but all mutate the gametes (sex cells). If the mutation is
serious enough it may kill the embryo before it develops, leading to a
miscarriage or it may die before being delivered (stillbirth). Mutations are
certainly not the only reason for miscarriages or stillbirths, but they can
account for at least some of them.
Now the other situation that can arise is mutation of the somatic cells in your
body. When this happens, the DNA of individual cells in the body changes.
Often a mutation of the DNA will not result in any adverse effects (most of the
DNA actually is non-coding). Other times, the error in DNA will just result in
loss of function for the cell and the cell will die (not a big deal given thousands
of cells die naturally every day). There is the problem, however, that the
mutation will occur such that is affects a particular part of the genome
involved in cellular growth and control.......
Errors to the DNA of somatic cells can result in CANCER!!
When the cells escape the control of cell contact inhibition (cells stop
growing once they contact other cells) they expand into a tumor
mass. These cells are immortal, they continue to divide indefinitely.
Hey vampires
are immortal
Benign tumors – do not spread like cancer. Can be removed with
local surgery. Some may pose threats as they may put pressure on
organs (like the brain) and thus require prompt removal.
Malignant tumors- these are cancer and will spread. These cells are
abnormal in many ways and will grow into surrounding tissues. Cell
surfaces are altered and metabolic processes are deranged. Some
have unusual numbers of chromosomes. Most dangerous, though, is
their ability to break off from the mass and transfer to other parts of
the body. When the move beyond their original site it is METASTASIS!
I like these
malignant
cells. They
sound evil
like me.
DID YOU KNOW?
A tumor cell line has been reproducing in
culture since 1951. It is called HeLa after
Henrietta Lacks, the woman from whom the
tumor was removed.
The world’s largest tumour was a multicystic tumor mass
of the right ovary with a 1 meter diameter and weighing
137.6 kg (that’s 303 lbs!) The successful operation, took
over six hours, was performed at Stanford University
Medical Center, California, USA.
Cancer is so named because of its crab
like appearance(cancer astrological sign
of the crab). Cancer cells invade the
surrounding healthy cells in the area like
the legs and claws of a crab.
If a cancer metastasizes or is suspected of
metastasis, doctors will attempt to kill the cells by
utilizing radiation or chemotherapy.
RADIATION is used because it kills rapidly dividing cells by
destroying their DNA. This radiation, also will destroy normal
dividing cells and so there is a limit to the exposure the patient
can have to the radiation. If the tumour is fairly localized this
treatment is fairly effective.
Chemotherapy is preferred for most cancers because it
basically is a small amount of poison that is placed into the
blood stream and kills all dividing cells. Since it permeates a
person’s body, it will catch tumours which may be forming
anywhere in the body and kill them. The downside is that it
also will kill normal dividing cells in the body. This leads to
intense pain as new cells are not available to replace old ( ex
stomach lining cells normally are replaced every three days
– with chemotherapeutic agents the new cells are killed
leaving a raw layer of older cells)
A WARNING TO YOU – THE SUN’S RAYS CAN BE DANGEROUS AND CAUSE CANCER!
STAY AWAY AND PROTECT YOURSELF FROM SOURCES OF ULTRAVIOLET LIGHT
-- That means the Sun as well as Tanning salons
If you think you have a skin cancer growing on your body, it is important
that you recognize it and get it removed as soon as possible before it
metastasizes! Take a look at some samples shown below.
These are all examples of malignant melanomas. Identify them by:
A colour change to a mole
The edges of the mole are not defined
The mass is growing
The shape of the mole is irregular
If you ignore them,
they will metastasize
and KILL YOU!!!!
Watch out. A little sun is good for
your skin to make vitamin D . Too
much causes DNA damage and skin
cancer because of ultraviolet rays. UV
rays cause thymine dimers (DNA A-T
breaks apart and forms T-T bonds)
These are repaired , but sometimes
incorrectly, leading to serious
mutations, like cancer.
Mutagens and Carcinogens are very dangerous.
Stay away from them if possible. Wear protective
gear if you are anywhere near them!
Here are some of the most commonly discussed carcinogens
Radiation – X rays Gamma rays
UV light
This is the hazard
symbol for
carcinogenic chemicals
Inhaled asbestos and
tobacco smoke
Chemicals like dioxins, benzenes
formaldehyde, vinyl chloride of PVC
Some viruses are responsible
for certain forms of cancer
Break down of
pvc water
bottles in the
sun
contaminates
the water inside with vinyl
chloride!!
HPV shown here can
result in cervical cancer
after many years.
HPV= human papiloma virus contagious from person to person
AGENT ORANGE ISSUE
During the War in
Vietnam the US needed
to defoliate large areas of
the jungle to deprive the
enemy of cover.
Soldiers were persuaded
by their superiors as well
as Monsanto and Dow
that the defoliant used
called “Agent Orange”
was simply a plant
hormone and thus
harmless.
What they were not told
was that in the process of
making the artificial plant
hormone a by-product
of the most toxic dioxin,
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD),
was produced.
A UH-1D helicopter from the 336th Aviation Company sprays a
defoliation agent on a dense jungle area in the Mekong Delta.
07/26/1969/National Archives photograph.
As a result of this misinformation:
Agent orange was sprayed onto civilians and military
personnel walking on the ground beneath aircraft.
No safety gear was used in the handling of the chemical.
The chemical was applied to food crop areas and water
supplies without concern.
Vietnam veterans tell story after story of veterans who
suddenly age and prematurely die. First they suffer
from strange nerve disorders, irritableness, weight
loss, and palsies Then their hair turns white and falls
out in clumps. In every case these men were exposed
to Agent Orange.
Think that’s bad. Dioxin does not easily break down in
the environment. The Vietnamese people continue to
live with the contaminated water and soil even today.
Many Vietnamese suffered birth defects, were made
sick or died leaving families with no compensation .
Highly chlorinated
dioxins bioaccumulate
in fat cells Half life
up to 138 years
In 2004, a mystery chemical was thought to have been
responsible for the poisoning of President Viktor Yushchenko of
the Ukraine. This story read almost like a James Bond novel
where politics intrigue and treachery were involved.
Yushchenko‘s poison was identified as DIOXIN. How did it get into
his body – food-- drink -- a handshake – a kiss..... ?
Now it’s time to look at mutations and their effects on proteins.
There are basically two main types of mutations
1. Base-pair substitutions (conservative)mutations – changes the codon –three outcomes
are possible:
a)The substitution results in an incorrect amino acid that substitutes into the protein structure.
–missense mutation also called CONSERVATIVE if replaced amino acid is similar
b)The substitution results in an incorrect STOP signal that causes proteins to be only partially
copied – nonsense mutation
The substitution does not result in an amino acid change since the DNA code is redundant
(especially at the third nucleotide) – silent mutation
2. Base-pair insertion or deletion mutations
The deletion or insertion results in all codons being read incorrectly after the alternation. Once
this happens all the following amino acids are wrong –frameshift mutation
CAUTION – THE WORD POINT MUTATION means only one base pair changed – ALL ABOVE APPLY
There is another category of mutations, but they are
not point mutations. They involve large segments of
DNA that relocate on the genome.
Translocation of large genetic sequences can occur. Strips of code are cut
out of one area of DNA and insert into another. Term -TRANSPOSONS. If
this action disrupts the normal structure of genes, a mutation can result.
They can also copy themselves and then insert into another part of
the genome causing disruption and potential mutation.
Inversion - large genetic sequence has reversed its orientation in the
chromosome. Normal gene structure may be disrupted- a mutation.
Barbara
McClintock
discovered
these
“Jumping
Genes”
I must say that some of the transposon sequences bear a
remarkable resemblance to my virus group DNA. I see that some
even are capable of producing the enzyme reverse transcriptase.
Now forgive me, but there is just no way these cells developed it on
their own. It’s probably the remnants of a retrovirus that implanted
into these cells long ago –isn’t that called evolution all you smart
university bound students! (Retroviruses are RNA viruses like HIV)
Transposons with reverse transcriptase can copy themselves to RNA then to DNA and
insert in other parts of the gene. They are called RETROTRANSPOSONS
Okay you privileged landlubbers . Since you think you know your
stuff answer this question that all of us pirates always think about. If
a substitution of nucleotides occurs on the NON coding portion of
the DNA (its neither transcribed nor translated), is it a mutation?
THINK, THINK, THINK
How about this?
What if I change the
nucleotides that are
methylated?
Mutations must change the sequence of the DNA.
A mutation can happen anywhere
A mutation does not have to change the
protein coded to qualify
The answer is YES it is a mutation.
THINK, THINK, THINK
Mutations must change the sequence of the DNA.
Methylation does not change that sequence
The answer is NO it is not a mutation.
THINK, THINK, THINK
Lower molecular wt=shorter protein
NONsense mutation cuts translation short
It’ the nonsense
mutation!
I’m thinking
of a point
mutation
that results
in a
significant
lower
molecular
wt of the
protein .
People are always telling me to quit smoking because it causes cancer.
Yet, some people live long lives even though they expose themselves to
carcinogens every day. I know a guy, he’s 80 and he has been smoking
since he was 16.
Now compare that to this lady I know who eats healthy and takes care of
herself, yet get breast cancer at age 33. Explain that!
That is where genetics comes into play. There
appears to be a genetic predisposition for
some people to get certain types of cancer.
Breast cancer occurs in families. Genes, called
ONCOGENES seem to be connected to people
being more predisposed to developing cancer.
Activation of several oncogenes appears to be
necessary to develop cancer.
What now? I can’t even eat a
charcoal burger now? So big deal,
Don’t eat
burned meat. its a little burned. Do I have to stop
eating drinking and breathing to
The charred
avoid cancer. Why quit smoking
residue is a
everything causes cancer anyway.
carcinogen
You should remain vigilant in your efforts to avoid carcinogens. You
cannot change your genetics, but you can change your exposure!
It also should be mentioned
that cancer is a usually a slow
appearing disease. You can
see from the graph that the
smoking that was done many
years ago leads to the cancers
of today.
This applies to other cancers
so watch out!
Your sunburn of today could
become your malignant
melanoma when you have
your family.
I guess I should stop, but
how do I kick the
addiction?
That’s a whole other
lesson man.
So lets sum up alterations of Chromosome structure that
have harmful effects.
1. TRANSPOSONS – you can have genes that jump
around on chromosomes randomly changing their positions. They
can move from one nonhomologous chromosome to another.
They can switch with another chromosome region (reciprocal) or
just jump on to another chromosome (nonreciprocal)
I’m just a transposon, an everywhere I go People don’t like to see me
Git out of here afore you jump onto one of my exons (coding genes) and cause
me some serious mutation by frame-shifting the important DNA information
2.INVERSION –reverses a segment within the chromosome
3. Duplication- repeats a segment over and over
4. Deletion –removes a chromosome segment
Now let me tell you about aneuploidyabnormal chromosome number.
Nondisjunction –members of a pair of homologous chromosomes do
not move apart properly during meiosis.This means that the egg or
sperm get too many or not enough chromosomes.
Women over
the age of 30
have an
increased
risk of the
egg
containing
this extra
chromosome
Human egg with
extra chromosome
Fertilized
Egg
24Egg
chr
47 chr
This cell is TRISOMIC
for chromosome # 21
making it turn into a
Down’s syndrome child
Normal sperm
Trisomy 21 is
just one
example of
aneuploidy of
the
autosomsomal
chromosome
Sperm
23 chr
Karyotype of
Down’s
syndrome
Notice the 3
copies of
chromosome
#21
Here are some other examples of autosomal
chromosome aneuploidy.
Most embryos cannot survive with missing or extra
autosomal chromosomes. So most of these die as
spontaneous abortions -- a miscarriage.
Trisomy 21 Down’s syndrome Flat face, eyelid
epicanthic fold, oversize tongue, short stature
lowered IQ ....
Trisomy 18 is Edwards Syndrome low survival
heart-kidney- internal organ malformations Only 510% will survive their first year.
Trisomy 13 is Patau syndrome numerous
malformations low survival
Aneuploidy can also occur on the sex
chromosomes.
In normal humans if you get the sex chromosomes XX you are a girl
and if you get the XY combination, you are a boy. Aneuploidies here
involve non disjunction of the sex chromosomes.
People with
this disorder
appear male
but have
smaller
testes and
are sterile.
Breast and
female part
enlargement
Normal
intelligence
Human egg with
extra X chromosome
Fertilized
Egg
Egg
XX chr
XXY
chr
This cell is TRISOMIC
for Sex chromosome
making it turn into a
Klinefelter syndrome
child
Normal sperm
Klinefelter is
an example of
aneuploidy of
the sex
chromosomes
Sperm2
Y chr
Karyotype of
Klinefelter’s
syndrome
Notice the XXY
sex
chromosomes
Here are some other examples of sex
chromosome aneuploidy.
XXX is trisomy X and females are normal Normal
intelligence
XO is monosomy X called Turner’s syndrome.
These individuals appear female and have ovaries
but they are sterile as their sex organs do not
mature. Hormone therapy is necessary to make
secondary sex characteristics for them (breast
development) Normal intelligence
XYY normal male – a little taller than average.
Normal intelligence
MUTATIONS
ENDS