ozzie skinner mt(amt), clt, maom james a. haley va hospital molecular diagnostics 03/23/2013
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DNA Mutations. p. OZZIE SKINNER MT(AMT), CLT, MAOM JAMES A. HALEY VA HOSPITAL MOLECULAR DIAGNOSTICS 03/23/2013. Pocket Hercules. MUTATIONS What and how do mutations occur?. A mutation is a permanent change in the DNA sequence of a gene - PowerPoint PPT PresentationTRANSCRIPT
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OZZIE SKINNER MT(AMT), CLT, MAOM
JAMES A. HALEY VA HOSPITAL
MOLECULAR DIAGNOSTICS
03/23/2013
MUTATIONS What and how do mutations occur?
A mutation is a permanent change in the DNA sequence of a gene Can cause problems with growth, development, and function of the body’s systems
Mutations in a gene's DNA sequence can alter the amino acid sequence of the protein encoded by the gene
These changes can affect many genes along the chromosome and disrupt the proteins made from those genes
The effects of structural changes depend on their size and location, and whether any genetic material is gained or lost
Can affect the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus
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MUTATIONS What and how do mutations occur?
Mutations range in size from a single DNA building block
(DNA base) to a large segment of a chromosome
Gene mutations occur in two ways: they can be inherited
from a parent or acquired during a person’s lifetime Hereditary (or germline) mutations: are passed from parent to child
Acquired (or somatic) mutations: occur in the DNA of individual cells at some time during a person’s life
These changes can be caused by environmental factors or if a mistake is made as DNA copies itself during cell division
Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation
Some genetic changes are very rare; others are common in the population
Genetic changes that occur in more than 1 percent of the population are called polymorphisms 3
MUTATIONS Affects on health and development
A gene is a recipe for making a protein
Each cell depends on thousands of proteins to do their jobs in the right places at the right times
By changing a gene’s instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely
When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition
A condition caused by mutations in one or more genes is called a genetic disorder
Incompatible with life: changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stages
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MUTATIONS Affects on health and development
Only a small percentage of mutations cause genetic disorders
Some mutations alter a gene’s DNA base sequence but do not change the function of the protein made by the gene
Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed (makes a protein)
Although most mutations that change protein sequences are harmful or neutral, some mutations have a positive effect on an organism (e.g. 32 base pair deletion in human CCR5/Delta 32 mutation/HIV resistance)
5“Mutations are often Bad, but,……………………..…..………… some can be Good”
MUTATIONS
First, Smallpox, then The Black Death of 1348 Came out of the East, and reached the shores of Italy in
the spring of 1348. Unleashed a rampage of death across Europe. Within three years, anywhere between 25% and 50% of
Europe's population had fallen victim to the pestilence.
The plague presented itself in three interrelated forms: The bubonic variant (the most common)
+ swellings or buboes that appeared on a victim's neck, armpits or groin.
+ Victims had a life expectancy of up to a week
+ Infected fleas that attached themselves to rats and then to humans spread this bubonic type of the plague.
Pneumonic plague
+ attacked the respiratory system and was spread by merely breathing the exhaled air of a victim.
+ life expectancy was measured in one or two days.
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Oriental rat flea“Regurgitates”
MUTATIONS The Black Death, 1348 Septicemic version of the disease attacked the blood system
Having no defense and no understanding of the cause of the pestilence, the men, women and children caught in its onslaught were bewildered, panicked, and finally devastated
The plague disease, generally thought to be caused by Yersinia pestis. (Gram negative, bipolar staining coccobacilli)
The "black death" again devastated Europe during the 14th century over a 5 year period causing 25 million deaths
Who was to blame?
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MUTATIONSThe Black Death, 1348 - DNA evidence
Survivors However, some were able to survive the devastating Black Plague,
such as the residents of Eyam, England The village had quarantined itself in order to stop the plague from
spreading beyond the village
Investigation In October 2010 a multinational medical group investigated the role
of Yersinia pestis in the Black Death They tested DNA and protein signatures specific for Y. pestis in
human skeletons from widely distributed mass graves all over Europe that were associated archaeologically with the Black Death.
The new research ends the debate about the etiology of the Black Death, and decidedly demonstrates that Y. pestis was the causative agent of the epidemic plague that devastated Europe during the Middle Ages
The obvious question,
How did the residents of Eyam survive?. 8
MUTATIONS They developed the Delta 32, CCR5 Mutation in the gene for the human chemokine receptor 5 (
CCR5)
How HIV Enters the White Cells – The Mechanism
Some rare strains of HIV infect via the CXCR4 receptor so by no means does a positive result for CCR5 delta 32 allow someone to engage in risky behavior
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Chromosome 3
MUTATIONSMutations are caused by:
Radiation: Alpha particles, Beta particles, Gamma rays, Cosmic rays, and X-rays,
can wreak havoc on the molecules of your DNACytosine and Thymine – are most vulnerable to radiation that can
change their propertiesThe effect of the radiation may not be to kill the cell, but to alter its
DNA code in a way that leaves the cell alive but with an error in the DNA blueprint
VirusesViruses that use RNA as their genetic
material have rapid mutation rates
An advantage since these viruses will evolve constantly and rapidly, and thus evade the defensive responses of e.g. the human immune system.
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MUTATIONSMutations are caused by: Transposons: (jumping genes)
Sequences of DNA that can move or transpose themselves to new positions within the genome of a single cell
The mechanism of transposition can be either "copy and paste" or "cut and paste“
Oncogenes (genes that cause tumors) may be activated by the random reshuffling of transposons to a position adjacent to the oncogene
Barbara McClintock found that they were responsible for a variety of types of gene mutations: insertions, deletions and translocations
In developing somatic tissues like corn kernels, a mutation that alters color will be passed on to all the descendant cells
This produces the variegated pattern
which is so prized in Indian corn
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MUTATIONSMutations are caused by:During DNA replication: (SNP/Point mutation)
The replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA
Single-nucleotide polymorphisms may fall within coding sequences of genes, non-coding regions of genes, or in the intergenic regions (regions between genes)
Often the term point mutation also includes insertions or deletions of a single base pair
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MUTATIONS
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MUTATIONSMutations are caused: During DNA replication: (SNP/Point mutation)
Point mutations can also be categorized functionally: Nonsense mutations: Premature stop codon in a DNA sequence
or in the transcribed mRNA Nonsense mutations are known to cause Cystic fibrosis, Beta
thalassaemia , and Hurler syndrome Start codon (ATG) Methionine DNA stop codons are TAG, TAA, and TGA RNA stop codons are UAG, UAA, and UGA
14Lack the enzyme to break down long chains of sugar molecules
MUTATIONSMutations are caused by: During DNA replication: (SNP/Point mutation)
Point mutations can also be categorized functionally: Missense mutations: point mutation in which a single nucleotide
is changed, resulting in a codon that codes for a different amino acid
Missense mutations are known to cause sickle-cell disease
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sickle-cell disease
Aspartic acid
Glutamine
MUTATIONSMutations are caused by: During DNA replication: (SNP/Point mutation)
Point mutations can also be categorized functionally: Silent mutations: DNA mutations that do not result in a change to the
amino acid sequence of a protein A point mutation that changes a codon to a synonym (one that codes for
the same amino acid) is also known as a synonymous mutation About 50 genetic diseases have been linked to synonymous mutations This includes silent mutations in CFTR, the gene that is linked with
Cystic fibrosis.
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MUTATIONSMutations are caused by: Deletions:
A mutation in which a part of a chromosome or a sequence of DNA is missing
Deletion is the loss of genetic material Deletions can be caused by errors in chromosomal crossover during
meiosis (process of cell division in sexually reproducing organisms)
Small deletions are less likely to be fatal; large deletions are usually fatal
Deletions genetic disorders can range from:
Male infertility to Duchenne muscular dystrophy to “Cri du chat”
ExampleOriginal The fat cat ate the wee rat.
Deletion The fat ate the wee rat.17
MUTATIONSMutations are caused by: Duplications
Duplications occur when part of a chromosome is copied (duplicated) too many times
This type of chromosomal change results in extra copies of genetic material from the duplicated segment
Duplications arise from an event termed unequal crossing-over that occurs during meiosis between misaligned homologous chromosomes (corresponding chromosomes from each parent)
Duplications of oncogenes are a common cause of many types of cancer
ExampleOriginal The fat cat ate the wee rat.
Duplication The fat cat cat ate the wee rat.
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MUTATIONSMutations are caused by: Inversions
An inversion involves the breakage of a chromosome in two places; the resulting piece of DNA is reversed and re-inserted into the chromosome
Genetic material may or may not be lost as a result of the chromosome breaks
An inversion that involves the chromosome’s constriction point (centromere) is called a pericentric inversion
An inversion that occurs in the long (q) arm or short (p) arm and does not involve the centromere is called a paracentric inversion
Example
• Original: The fat cat ate the wee rat.
• Insertion: The fat tar eew eht eta tac.20
MUTATIONSMutations are caused by: Inversions
On the left of the diagram is human chromosome
number 5 (of 23)
On the right of the diagram is the matching
chromosome from a chimpanzee
The region from p14.I to q14.I, the order has been
flipped
Evolutionist calls this a inversion mutation between
Man and Chimp
Overall, there are nine inversion mutations between
man and chimpanzee
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Chromosome 5
MUTATIONSMutations are caused by: Isochromosomes
An isochromosome is a chromosome with two identical arms
Instead of one long (q) arm and one short (p) arm, an isochromosome has two long arms or two short arms
As a result, these abnormal chromosomes have an extra copy of some genes and are missing copies of other genes
Associated diseases Girls with Turner syndrome Pallister-Killian syndrome Some tumors
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MUTATIONSMutations are caused by: Dicentric chromosomes: human chromosome 2
Unlike normal chromosomes, which have a single constriction point (centromere), a dicentric chromosome contains two centromeres
Dicentric chromosomes result from the abnormal fusion of two chromosome pieces, each of which includes a centromere. These structures are unstable and often involve a loss of some genetic material
Associated diseases Myelodysplasia (MDS):
A collection of conditions that result when
bone marrow cells produce damaged
cells that don't mature properly
Acute Myeloid Leukemia (AML)
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MUTATIONSMutations are caused by: Ring chromosomes Ring chromosomes usually occur when a chromosome breaks in two places and
the ends of the chromosome arms fuse together to form a circular structure
The ring may or may not include the chromosome’s constriction point
In many cases, genetic material near the ends of the chromosome is lost
Ring chromosomes may form in cells following genetic damage by mutagens like radiation, they may also arise spontaneously during development
Associated diseases Ring chromosome 20 syndrome - epilepsy Ring chromosome 14/13-mental retardation Ring chromosome 15 - dwarfism
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MUTATIONSMutations are caused by: Translocation: juxtapositioning
When chromosomes break and the fragments rejoin to other chromosomes
A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer
It is detected on cytogenetics or a karyotype of affected cells
Translocations can be balanced or unbalanced
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MUTATIONSMutations are caused by: Translocation: balanced translocation
In a balanced translocation, pieces of chromosomes are rearranged but no genetic material is gained or lost in the cell
When a person's cells divide to create egg or sperm cells for reproduction, the egg or sperm cells can end up with extra genetic material or missing genetic material
This could lead to miscarriage depending on which chromosome and genes are affected
In about 4.5% of all couples with recurrent miscarriages, one or both parents has a balanced translocation
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MUTATIONSMutations are caused by: Translocation: unbalanced translocation
An unbalanced translocation occurs when a child inherits a chromosome with extra or missing genetic material from a parent with a balanced translocation
This is usually in the form of a loss of genetic material, called Monosomy and a gain to genetic material, which is Trisomy
Monosomy/ Trisomy Both types of are “aneuploidy” :
(having an abnormal number of
chromosomes)
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MUTATIONSMutations are caused by: Trisomy 21/Downs S.
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MUTATIONS
Mutations are caused by: Monosomy X - genotype 45, X,
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MUTATIONS
Different Types of Mutations
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MUTATIONSMyostatin- is a gene that limits muscle growth The protein is a member of a superfamily of molecules called transforming
growth factors beta (TGF-b) or growth differentiation factor 8 Discovered that a mutation in the myostatin gene is responsible for increased
muscle mass, also known as 'double muscling‘ Scientists hope that myostatin inhibitors may be able to treat diseases such as
muscular dystrophy There is some concern about the possibility of abuse of myostatin inhibitors
by athletes In humans, myostatin is encoded by the
MSTN gene Animals lacking myostatin, have significantly
larger muscles
Transgenic Rainbow Trout
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MUTATIONSMyostatin-related muscle hypertrophy
•
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Who wants some “rump roast?”
myostatin modulator
“It taste God awful;You said it tasted like chicken”. You lied mama, you lied.
If you see me coming at you, don’t run. My muscles are so tight, I couldn’t catch a cold.
Siblings
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