Download DNA MUTATIONS - American Medical Technologists

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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
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called polymorphisms
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
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stages
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)
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“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
Oriental rat flea
“Regurgitates”
+ 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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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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MUTATIONS
The Black Death, 1348 - DNA evidence
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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?
.
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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
Chromosome 3
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
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behavior
MUTATIONS
Mutations are caused by:
 Radiation:
Alpha particles, Beta particles, Gamma rays, Cosmic rays, and X-rays,
can wreak havoc on the molecules of your DNA
Cytosine and Thymine – are most vulnerable to radiation that can
change their properties
The 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
 Viruses
Viruses that use RNA as their genetic
material have rapid mutation rates
An advantage since these viruses will evolve constantly and rapidly,
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and thus evade the defensive responses of e.g. the human immune
system.
MUTATIONS
Mutations 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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MUTATIONS
Mutations 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
Mutations are caused:
 During DNA replication: (SNP/Point mutation)
 One can categorize point mutations as follows:
 Transitions: replacement of a purine base with another purine or
replacement of a pyrimidine with another pyrimidine
Purines are
Pyrimidines are
Adenine and Guanine
Cytosine , and Thymine
 Purines are the double ringed nitrogenous bases
 Pyrimidines are the single ringed nitrogenous bases
 Transversions: replacement of a purine with a pyrimidine or vice versa.
 Approximately two out of three single nucleotide polymorphisms
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(SNPs) are transitions.
MUTATIONS
Mutations 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
Lack the enzyme to break
down long chains of sugar
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MUTATIONS
Mutations 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
sickle-cell disease
Glutamine
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Aspartic acid
MUTATIONS
Mutations 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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MUTATIONS
Mutations 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”
Example
Original The fat cat ate the wee rat.
Deletion The fat ate the wee rat.
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Notice anything unusual?
Cri du chat syndrome / 5p- syndrome
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MUTATIONS
Mutations 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
Example
Original
The fat cat ate the wee rat.
Duplication The fat cat cat ate the wee rat.
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MUTATIONS
Mutations 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
•
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Original: The fat cat ate the wee rat.
Insertion: The fat tar eew eht eta tac.
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MUTATIONS
Mutations 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
MUTATIONS
Mutations 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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MUTATIONS
Mutations 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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MUTATIONS
Mutations 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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MUTATIONS
Mutations 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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MUTATIONS
Mutations 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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MUTATIONS
Mutations 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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MUTATIONS
Mutations 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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MUTATIONS
Myostatin- 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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MUTATIONS
Myostatin-related muscle hypertrophy
•
Who wants some “rump roast?”
“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
myostatin
modulator
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Shukran
Dziękuję
Merci
Toda raba
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