Study abnormalities and mutations

1. Chromosomal Abnormalities

2. Chromosome
• A threadlike structure of nucleic acids and protein found in the
nucleus of most living cells.
• They carry genetic information in the form of genes.

3. ​KARYOTYPE
• A karyotype is an individual’s complete set of chromosomes.
• The term also refers to a laboratory-produced image of a person’s
chromosomes isolated from an individual cell and arranged in
numerical order.
• A karyotype may be used to look for abnormalities in chromosome
number or structure.

4. • For a century, scientists studied chromosomes by looking at them
under a microscope.
• In order for chromosomes to be seen this way, they need to be
stained.
• Once stained, the chromosomes look like strings with light and dark
"bands," and their picture could be taken.

6. • To help identify chromosomes, the pairs have been numbered from 1 to 22,
with the 23rd pair labeled "X" and "Y."
• In the past decade, newer techniques have been developed that allow
scientists and doctors to screen for chromosomal abnormalities without
using a microscope.
• These newer methods compare the patient's DNA to a normal DNA sample.
• The comparison can be used to find chromosomal abnormalities where the
two samples differ.
• One such method is called non-invasive prenatal testing.
- This is a test to screen a pregnancy to determine whether a baby has an
increased chance of having specific chromosome disorders.
- The test examines the baby's DNA in the mother's blood.

7. Chromosome Abnormalities
• There are many types of chromosome abnormalities. However, they
can be organized into two basic groups:
1. Numerical abnormalities.
2. Structural abnormalities.

8. Numerical Abnormalities
• When an individual is missing one of the chromosomes from a pair,
the condition is called monosomy.
• When an individual has more than two chromosomes instead of a
pair, the condition is called trisomy.

9. Chromosomal Disorders
• Down syndrome (Trisomy 21).
• FragileX syndrome.
• Klinefelter syndrome.
• Triple-X syndrome.
• Turner syndrome.
• Trisomy 18.
• Trisomy 13.

10. Down Syndrome
• A mental disability.
• Learning difficulties.
• A characteristic facial appearance and poor muscle tone
(hypotonia).
• An individual with Down syndrome has three copies of
chromosome 21 rather than two.
• For that reason, the condition is also known as Trisomy 21.

11. Symptoms of Down Syndrome

12. Turner Syndrome
• An example of monosomy, in which an individual lacks a
chromosome, is Turner syndrome.
• In Turner syndrome, a female is born with only one sex chromosome,
an X.
• It leads to infertility.

13. Edward Syndrome
• Trisomy 18, also called Edward’s syndrome.
• It is a chromosomal condition associated with abnormalities in many
parts of the body.
• Individuals with trisomy 18 often have slow growth before birth and a low
birth weight.
• Sadly, most babies with Edwards' syndrome will die before or shortly
after being born.
• A small number (about 13 in 100) babies born alive with Edwards'
syndrome will live past their 1st birthday.

15. Structural Abnormalities
• A chromosome's structure can be altered in several ways.
oDeletions: A portion of the chromosome is missing or deleted.
oDuplications: A portion of the chromosome is duplicated, resulting in extra
genetic material.
oInversions: A portion of the chromosome has broken off, turned upside down,
and reattached. As a result, the genetic material is inverted.
oRings: A portion of a chromosome has broken off and formed a circle or ring.
This can happen with or without loss of genetic material.

16. oTranslocations: A portion of one chromosome is transferred to another
chromosome.
- There are two main types of translocation. In a reciprocal translocation,
segments from two different chromosomes have been exchanged.
- In a Robertsonian translocation, an entire chromosome has attached to
another at the centromere.

18. • Most chromosome abnormalities occur as an accident in the egg or
sperm.
• In these cases, the abnormality is present in every cell of the body.
• Some abnormalities, however, happen after conception; then some
cells have the abnormality and some do not.
• Chromosome abnormalities can be inherited from a parent (such as a
translocation) or be "de novo" (new to the individual).
• This is why, when a child is found to have an abnormality,
chromosome studies are often performed on the parents.

19. How do chromosome abnormalities happen?
• Chromosome abnormalities usually occur when there is an error in cell division.
• There are two kinds of cell division, mitosis and meiosis.
• Mitosis results in two cells that are duplicates of the original cell.
• One cell with 46 chromosomes divides and becomes two cells with 46
chromosomes each.
• This kind of cell division occurs throughout the body, except in the reproductive
organs.
• This is the way most of the cells that make up our body are made and replaced.
• Meiosis results in cells with half the number of chromosomes, 23, instead of the
normal 46.
• This is the type of cell division that occurs in the reproductive organs, resulting in
the eggs and sperm.

20. Factors leading to Abnormalities
1. Maternal Age:
• Women are born with all the eggs they will ever have.
• Some researchers believe that errors can crop up in the eggs' genetic
material as they age.
• Older women are at higher risk of giving birth to babies with chromosome
abnormalities than younger women.
2. Environment:
• Although there is no conclusive evidence that specific environmental
factors cause chromosome abnormalities, it is still possible that the
environment may play a role in the occurrence of genetic errors.
• Family History.

21. Abnormal Cell Proliferation

22. • Abnormal regulation of the cell cycle can lead to the over
proliferation of cells and an accumulation of abnormal cell numbers.
• Cancer cells arise from one cell that becomes damaged, and when
divided, the damage is passed on to the daughter cell and again to
the granddaughter cells and so on.
• Such uncontrolled, abnormal growth of cells is a defining
characteristic of cancer.

23. • The total number of cells composing the human body is determined not
only by the rate of proliferation of cells but also by the rate of cell loss.
• Excess cells and those that are aged or have sustained damage that impairs
normal functioning are eliminated to prevent accumulation of abnormal
numbers of cells.
• The mechanism for regulating the removal of excess and impaired cells is
known as apoptosis.
• Also referred to as cell suicide or programmed cell death, apoptosis is an
orderly process during which internal cellular structures are progressively
dismantled, the impaired cell shrinks and finally is rapidly destroyed by
immune cells.

24. Mutation at Cell Cycle Checkpoints
• When cell cycle control checkpoints fail, the following may occur:
- Mutation results in the production of an abnormal protein or enzyme.
- Mutation occurs near or around the proto-oncogene turning on cell
division when not required.
- Mutation occurs near or around tumour suppressor gene (e.g. the
p53 gene that normally inhibits the growth of tumours) resulting in
inability to stop uncontrolled cell division.

26. Mutations

27. What is mutation?
• A mutation is a change in the DNA sequence of an organism.
• Mutations can result from errors in DNA replication during cell division, exposure
to mutagens or a viral infection.
• Germline mutations occur in eggs and sperm and can be passed on to offspring.
• Somatic mutations occur in body cells and are not passed on.
• A mutation is a permanent change in the nucleotide sequence of DNA.
• Damaged DNA can be mutated either by substitution, deletion or insertion of
base pairs.
• Mutations, for the most part, are harmless except when they lead to cell death or
tumour formation.
• Because of the lethal potential of DNA mutations cells have evolved mechanisms
for repairing damaged DNA.

28. Types of Mutations
• There are three types of DNA Mutations:
1. Base substitutions.
2. Deletions.
3. Insertions.

29. 1. Base Substitutions
• Single base substitutions are called point mutations.
• Point mutations are the most common type of mutations and there
are two types:
1. Transition: This occurs when a purine is substituted with another
purine or when a pyrimidine is substituted with another pyrimidine.
2. Transversion: When a purine is substituted for a pyrimidine or a
pyrimidine replaces a purine.

31. Point Mutations
• Point mutations that occur in DNA sequences that encodes for
proteins are either:
1. Silent.
2. Missense.
3. Nonsense.

32. • Silent: If a base substitution occurs in the third position of the codon there is
a good chance that a synonymous codon will be generated. Thus the amino
acid sequence encoded by the gene is not changed and the mutation is said to
be silent.
• Missense: When base substitution results in the generation of a codon that
specifies a different amino acid and hence leads to a different polypeptide
sequence. Depending on the type of amino acid substitution the missense
mutation is either conservative or nonconservative. For example if the
structure and properties of the substituted amino acid are very similar to the
original amino acid the mutation is said to be conservative and will most likely
have little effect on the resultant proteins structure / function. If the
substitution leads to an amino acid with very different structure and
properties the mutation is nonconservative and will probably be bad for the
resultant proteins structure / function.
• Nonsense: When a base substitution results in a stop codon ultimately
truncating translation and most likely leading to a non-functional protein.

34. 2. Deletions
• A deletion results when one or more base pairs are lost from the
DNA.
• If one or two bases are deleted the translational frame is altered
resulting in non-functional product.
• A deletion of three or more bases leave the reading frame intact.
• A deletion of one or more codons results in a protein missing one or
more amino acids.

35. 3. Insertions
• The insertion of additional base pairs may lead to frameshifts
depending on whether or not multiples of three base pairs are
inserted.
• Combinations of insertions and deletions leading to a variety of
outcomes are also possible.

37. Causes of Mutations
• Errors in DNA Replication
On very, very rare occasions DNA polymerase will incorporate a noncomplementary base into the
daughter strand. During the next round of replication the miss-incorporated base would lead to a
mutation. This, however, is very rare as the exonuclease functions as a proofreading mechanism
recognizing mismatched base pairs and excising them.
• Errors in DNA Recombination
DNA often rearranges itself by a process called recombination which proceeds via a variety of
mechanisms. Occasionally DNA is lost during replication leading to a mutation.
• Chemical Damage to DNA
Many chemical mutagens, some exogenous, some man-made, some environmental, are capable of
damaging DNA. Many chemotherapeutic drugs and intercalating agent drugs function by damaging
DNA.
• Radiation
Gamma rays, X-rays, even UV light can interact with compounds in the cell generating free radicals
which cause chemical damage to DNA.

38. DNA Repair
1. Mismatch Repair
• Sometimes DNA polymerase incorporates an incorrect nucleotide during strand
synthesis and the 3' to 5' editing system, exonuclease, fails to correct it.
• These mismatches as well as single base insertions and deletions are repaired by
the mismatch repair mechanism.
• Mismatch repair relies on a secondary signal within the DNA to distinguish between
the parental strand and daughter strand, which contains the replication error.
• Human cells posses a mismatch repair system similar to that of E. coli.
• Methylation of the sequence GATC occurs on both strands sometime after DNA
replication.
• Because DNA replication is semi-conservative, the new daughter strand remains
unmethylated for a very short period of time following replication.
• This difference allows the mismatch repair system to determine which strand
contains the error.
• A protein, MutS recognizes and binds the mismatched base pair.

39. • Another protein, MutL then binds to MutS and the partially
methylated GATC sequence is recognized and bound by the
endonuclease, MutH.
• The MutL/MutS complex then links with MutH which cuts the
unmethylated DNA strand at the GATC site.
• A DNA Helicase, MutU unwinds the DNA strand in the direction of the
mismatch and an exonuclease degrades the strand.
• DNA polymerase then fills in the gap and ligase seals the nick.
• Defects in the mismatch repair genes found in humans appear to be
associated with the development of cancer.

40. 2. Nucleotide Excision Repair (NER)`
• Nucleotide excision repair is another pathway used to remove and
replace damaged bases.
• Nucleotide excision repair is also used to fix some types of damage
caused by UV radiation.
• UV radiation can make cytosine and thymine bases react with
neighbouring bases that are also Cs or Ts, forming bonds that distort
the double helix and cause errors in DNA replication.
• The most common type of linkage, a thymine dimer, consists of two
thymine bases that react with each other and become chemically
linked.

42. 3. Direct Repair of Damaged DNA
• Sometimes damage to a base can be directly repaired by specialized
enzymes without having to excise the nucleotide. Example: DNA-
alkyltransferases.
4. Recombination Repair
• This mechanism enables a cell to replicate past the damage and fix it
later.

43. Regulation of Damage Control
• DNA repair is regulated in mammalian cells by a sensing mechanism
that detects DNA damage and activates a protein called p53.
• p53 is a transcriptional regulatory factor that controls the expression
of some gene products that affect cell cycling, DNA replication and
DNA repair.
• Loss of p53 function can be harmful, about 50% of all human cancers
have a mutated p53 gene.