MUTATIONS

REYMEL B. MAGORA, RMT

Mutation
permanent change in the DNA sequence
result in a change to either a DNA base pair or a chromosome
responsible for the huge diversity of genes found among organisms because mutations
are the ultimate source of new genes
Mutations of one or a few nucleotides can affect protein structure and
function
Point Mutations
changes in a single nucleotide pair of a gene
When it occurs in a gamete or in a cell that gives rise to gametes, it may be
transmitted to offspring and to future generations
If the mutation has an adverse effect on the phenotype of a person, mutant
condition = genetic disorder or hereditary disease
Point mutation- a change in a single DNA base
Transition- a purine replaces a purine (A to G or G to A)
or a pyrimidine replaces a pyrimidine (C to T or T to C)
Transversion- a purine replaces a pyrimidine or
vice versa (A or G to T or C)

Types of Small-Scale Mutations

Point mutations within a gene:
(1) Single nucleotide-pair substitutions
(2) Nucleotide-pair insertions or deletions
Insertions and deletions can involve one or more nucleotide pairs
Substitutions
Nucleotide-pair substitution
replacement of one nucleotide and its partner with another pair of nucleotides
Some substitutions have no effect on the encoded protein, owing to the
redundancy of the genetic code
Example: if 3’-CCG-5’ on the template strand mutated to 3’-CCA-5’, the
mRNA codon that used to be GGC would become GGU, but a glycine would
still be inserted at the proper location in the protein
A change in a nucleotide pair may transform one codon into another that is
translated into the same amino acid = silent mutation
Silent mutation- has no observable effect on the phenotype (can occur
outside genes as well)
Missense mutations
substitutions that change one amino acid to another one
Such a mutation may have little effect on the protein
Alteration of a single amino acid in a crucial area of a can significantly alter
protein activity
Substitution mutations are usually missense mutations: altered codon still
codes for an amino acid and thus makes sense, although not necessarily the
right sense.
Point mutation can also change a codon for an amino acid into a stop codon:
nonsense mutation-; the resulting polypeptide will be shorter it causes
translation to be terminated prematurely than the polypeptide encoded by
the normal gene
Nearly all nonsense mutations lead to nonfunctional proteins
HEMOGLOBINOPATHIES
Abnormal Hemoglbins
Hemoglobin S
-AA substitution in the beta chains- substitution of valine for
glutamic acid in the 6th position in the normal beta chain
-causes sickling of RBC underconditions of reduced oxygen
concentration
Hemoglobin C
-substitution of lysine for glutamic acid on the 6th position of beta
chain
-RBC appear as target cells, or, less often, precipitated Hb C
crystal may be demonstrated
NOTE!!!
VALINE replaces GLUTAMIC ACID at 6th position=
Hb S (insoluble)

LYSINE replaces GLUTAMIC ACID at 6th position=

Hb C (insoluble)

LYSINE replaces GLUTAMIC ACID at 26th position= Hb E

Insertions and Deletions
Additions or losses of nucleotide pairs in a gene
Insertion or deletion of nucleotides may alter the reading frame of the
genetic message, the triplet grouping of nucleotides on the mRNA that is
read during translation = Frameshift Mutation
Frameshift Mutation- occurs whenever the number of nucleotides inserted
or deleted is not a multiple of three
All nucleotides downstream of the deletion or insertion will be improperly
grouped into codons
The result will be extensive missense, usually ending sooner or later in
nonsense and premature termination
Unless the frameshift is very near the end of the gene, the protein is almost
certain to be nonfunctional
CHROMOSOME MUTATIONS
Chromosomal Mutations or Chromosomal Aberrations
variations from the normal condition in chromosome structure or chromosome number
Alterations of chromosome number or structure
Phenotype of an organism can be affected by small-scale changes involving
individual genes
Large-scale chromosomal changes can also affect an organism’s phenotype
Physical and chemical disturbances, as well as errors during meiosis, can damage
chromosomes in major ways or alter their number in a cell
Large-scale chromosomal alterations in humans and other mammals often lead to
spontaneous abortion (miscarriage) of a fetus, and individuals born with these types
of genetic defects commonly exhibit various developmental disorders
Abnormal Chromosome Number
Nondisjunction
members of a pair of homologous chromosomes do not move apart properly during
meiosis I or sister chromatids fail to separate during meiosis II
One gamete receives two of the same type of chromosome and another
gamete receives no copy
If either of the aberrant gametes unites with a normal one at fertilization, the
zygote will also have an abnormal number of a particular chromosome =
Aneuploidy
Types of Aneuploidy
Nullisomy- loss of both members of a homologous pair of chromosomes. It is
represented as 2n – 2, where n refers to the haploid number of chromosomes.
Thus, among humans, who normally possess 2n = 46 chromosomes, a nullisomic
zygote has 44 chromosomes.
Monosomy- loss of a single chromosome, represented as 2n –1.
A human monosomic zygote has 45 chromosomes.
Trisomy- gain of a single chromosome, represented as 2n + 1. A human trisomic
zygote has 47 chromosomes.
The gain of a chromosome means that there are three homologous copies of one
chromosome
Tetrasomy- gain of two homologous chromosomes, represented as 2n + 2.
A human tetrasomic zygote has 48 chromosomes. Tetrasomy is not the gain of any
two extra chromosomes, but rather the gain of two homologous chromosomes; so
there will be four homologous copies of a particular chromosome.
Fertilization involving a gamete that has
no copy of a particular chromosome will
lead to a missing chromosome in the
zygote (the cell has 2n – 1 chromosomes);
the aneuploid zygote is said to be
monosomic for that chromosome
If a chromosome is present in triplicate
in the zygote (the cell has 2n + 1
chromosomes), the aneuploid cell is
trisomic for that chromosome
Nondisjunction can also occur during mitosis.
If such an error takes place early in embryonic development, then the
aneuploid condition is passed along by mitosis to a large number of cells and
is likely to have a substantial effect on the organism.
Some organisms have more than two complete chromosome sets in all
somatic cells
The general term for this chromosomal alteration is polyploidy; the specific
terms triploidy (3n) and tetraploidy (4n) indicate three or four chromosomal
sets, respectively.
Alterations of Chromosome Structure
Errors in meiosis or damaging agents such as radiation can cause breakage of
a chromosome, which can lead to four types of changes in chromosome
structure.
Deletion occurs when a chromosomal fragment is lost
The affected chromosome is then missing certain genes.
“Deleted” fragment may become attached as an extra segment to a sister
chromatid, producing a Duplication
Alternatively, a detached fragment could attach to a nonsister chromatid of
a homologous chromosome
In that case, though, the “duplicated” segments might not be identical
because the homologs could carry different alleles of certain genes.
Tandem duplication - mutation generates
duplicated segments that are adjacent to
each other with the order of the genes in both
segments the same as the order of the original
Reverse tandem duplication - order of genes
in the duplicated segment is the opposite of
the order of the original
Terminal tandem duplication - duplicated
segments are arranged in tandem at the end of
a chromosome
A chromosomal fragment may also
reattach to the original chromosome but in
the reverse orientation, producing an
Inversion.
An inversion is a chromosomal mutation
that results when a segment of a
chromosome is excised and then
reintegrated at an orientation 180 degrees
from the original orientation.
Paracentric inversion- does not include the
centromere
Pericentric inversion- includes the
centromere
A fourth possible result of chromosomal breakage is for the fragment to join
a nonhomologous chromosome = Translocation
 Deletions and duplications are especially likely to occur during meiosis
In crossing over, nonsister chromatids sometimes exchange unequal-sized
segments of DNA, so that one partner gives up more genes than it receives.
The products of such an unequal crossover are one chromosome with a
deletion and one chromosome with a duplication
A diploid embryo that is homozygous for a large deletion (or has a single X
chromosome with a large deletion, in a male) is usually missing a number of
essential genes, a condition typically lethal
If a chromosome segment changes position within the same chromosome =
Nonreciprocal intrachromosomal (within a chromosome) translocation
If a chromosome segment is transferred from one chromosome to another =
nonreciprocal interchromosomal (between chromosomes) translocation if a
one-way transfer is involved
Reciprocal interchromosomal translocation if an exchange of segments
between the two chromosomes is involved
Translocations and inversions can alter phenotype because a gene’s
expression can be influenced by its location among neighboring genes, which
can have devastating effects
Human Disorders Due to Chromosomal Alterations
Down Syndrome (Trisomy 21)
 Named after John Langdon Down
The result of an extra chromosome 21, so that each body cell has a total of 47
chromosomes
Because the cells are trisomic for chromosome 21, Down syndrome is often called
trisomy 21.
Characteristic facial features, short stature, correctable heart defects, and
developmental delays; increased chance of developing leukemia and Alzheimer’s
disease but have a lower rate of high blood pressure, atherosclerosis (hardening of
the arteries), stroke, and many types of solid tumors.
Almost all males and about half of females with Down syndrome are sexually
underdeveloped and sterile.
Trisomy 18 (Edward Syndrome)
Children who have trisomy 18 have great physical and mental disabilities, with
developmental skills usually stalled at the 6-month level.
Major abnormalities: heart defects, a displaced liver, growth retardation, and
oddly clenched fists.
Milder signs: overlapping placement of fingers, a narrow and flat skull,
abnormally shaped and low-set ears, a small mouth and face, unusual or absent
fingerprints, short, large toes with fused second and third toes, and “rocker-
bottom” feet.
Most cases of trisomy 18 are traced to nondisjunction in meiosis II of the oocyte.
Trisomy-13 (Patau Syndrome)
Most striking is a fusion of the developing eyes, so that a fetus has one large
eyelike structure in the center of the face. More common is a small or absent
eye.
Major abnormalities affect the heart, kidneys, brain, face, and limbs.
Characteristics: cleft lip and palate, small eyes, polydactyly (extra fingers
and toes), mental and developmental retardation, and cardiac anomalies
Most infants die before the age of 3 months.
Sex Chromosome Aneuploids: Female
XO Syndrome (Turner syndrome)
Persons who have Turner syndrome are female and often have underdeveloped
secondary sex characteristics.
Affected women are frequently short and have a low hairline, a relatively broad
chest, and folds of skin on the neck.
Most women who have Turner syndrome are sterile; have weblike necks, poorly
developed breasts, and immature internal sexual organs.
Triplo-X
About 1 in every 1,000 females has an extra X chromosome in each of her cells, a
condition called triplo-X.
The only symptoms are tall stature and menstrual irregularities. Although triplo-X
females are rarely mentally retarded.
The lack of symptoms reflects the protective effect of X inactivation—all but one
of the X chromosomes is inactivated.
Sex Chromosome Aneuploids: Male
XXY Syndrome (Klinefelter syndrome)
Severely affected men are underdeveloped sexually, with rudimentary testes and prostate
glands and sparse pubic and facial hair.
They have very long arms and legs, large hands and feet, and may develop breast tissue.
XXY syndrome is the most common genetic or chromosomal cause of male infertility.
XXYY Syndrome
A male with an extra X chromosome and an extra Y chromosome was until recently classified
as having Klinefelter syndrome.
Childhood and adolescence often include attention deficit disorder, obsessive compulsive
disorder, and learning disabilities.
In the teen years, testosterone level is low, development of secondary sexual characteristics is
delayed, and the testes are undescended.
A man with XXYY syndrome is infertile.
XYY Syndrome
The only symptoms attributable to the extra chromosome may be great height, acne, and
perhaps speech and reading problems.
Disorders Caused by Structurally Altered Chromosomes
Cri du chat (“cry of the cat”)
Results from a specific deletion in chromosome 5
A child born with this deletion is severely intellectually disabled, has a small head
with unusual facial features, and has a cry that sounds like the mewing of a
distressed cat.
Such individuals usually die in infancy or early childhood.
Chronic myelogenous leukemia (CML)
This disease occurs when a reciprocal translocation happens during mitosis of cells
that will become white blood cells.
The exchange of a large portion of chromosome 22 with a small fragment from a
tip of chromosome 9 produces a much shortened, easily recognized chromosome22,
called the Philadelphia chromosome).
Such an exchange causes cancer by activating a gene that leads to uncontrolled
cell cycle progression.
GENETIC TESTING
Fetal Testing
a. Amniocentesis
A syringe needle is inserted carefully through the mother’s uterine wall and
into the amniotic sac, and a sample of amniotic fluid is taken.
The fluid contains cells that the fetus’s skin has sloughed off; these cells can
be cultured in the laboratory and then examined for protein or enzyme
alterations or deficiencies, DNA changes, and chromosomal abnormalities.
b. Chorionic villus sampling
Physician inserts a narrow tube through the cervix into the uterus and
suctions out a tiny sample of tissue from the placenta, the organ that transmits
nutrients and fetal wastes between the fetus and the mother.
The cells of the chorionic villi of the placenta, the portion sampled, are
derived from the fetus and have the same genotype and DNA sequence as
the new individual.
These cells are proliferating rapidly enough to allow karyotyping to be
carried out immediately.
This rapid analysis represents an advantage over amniocentesis, in which the
cells must be cultured for several weeks before karyotyping.
Another advantage of CVS is that it can be performed as early as the 8th–
10th week of pregnancy.
c. Ultrasound technique
reflected sound waves are used to produce an image of the fetus by a simple noninvasive
procedure
d. Fetoscopy
needle-thin tube containing a viewing scope and fiber optics (to transmit light) is inserted
into the uterus
Newborn Screening
Testing for genetic disorders in newborn infants
Populationwide testing for several treatable inborn errors of metabolism.
Most newborn testing is done by collecting a drop of an infant’s blood on a card
soon after birth.
The card is then shipped to a laboratory for genetic analysis.
In the Philippines: RA 9288- Newborn Screening Act of 2000
Congenital hypothyroidism, Congenital adrenal hyperplasia, Galactosemia,
Phenylketonuria, G6PD deficiency: DOH memorandum No. 2012-0154 (May 15,
2012)-inclusion of Maple Syrup Urine Disease