MUTATION

MUTATION

(4 hour) 

Objective. At the end of this topic, students should be able to:

• Explain mutation
• Classify mutation
• state types of mutation
• define mutagen
• state types of mutagen
• explain gene/point mutation
• classify gene mutation
• describe base substitution as point mutation eng. Sickle cell anemia
• explain frameshift mutation
• describe base insertion as a frameshift mutation
• describe base deletion as a frameshif mutation
• explain chromosomal mutation
• classify chromosomal mutation
• explain chromosomal aberration (structural changes)
• state and describe type of chromosomal aberration
• explain alteration of chromosome number
• state the types of the alteration
• explain aneuploidy
• describe the cause and the affect aneuploidy
• explain autosomal abnormalities and their effects
• explain sex chromosomal abnormalities
• explain euploidy
• explain polyploidy

What is mutation?

• A mutation is a change in the amount, arrangement or structure of the DNA of an organism.
• Mutations produce sudden and distinct differences between individuals cause alternation of chromosome.
• Alteration of chromosome number or structure cause some genetic disorders such as Sickle Cell Anemia and Down Syndrome
• Mutation can occurring in gamete cells or somatic cells.

1. gamete cells 
   are inherited, It passed to subsequent generations as part of the hereditary endowment of the games derived from that cell.
2. somatic cells
   can only be inherited by daughter cells produced by mitosis.

• A mutant is an individual or new genetic character arising or resulting from an instance of mutation the blue lobster is an example of a mutant.

• Type of mutation
  i) spontaneous mutation
  - Mistakes happen spontaneously during DNA replication, repair and recombination
  
  - eg. nondisjunction
  ii) induced mutation
  - Organism exposed to mutagen

What is mutagen ?

• a mutagen (Latin, literally origin of change) is a physical or chemical agent that changes the genetic material
• Operate either by causing changes in the DNA of the genes or by causing chromosome damage
• type of mutagen
  i) Physical agent
      Ultraviolet ray
      Ionizing radiation (X-ray, gamma ray, alpha particles, neutron and electron)
  ii) Chemical agent
      eg. Colchicine (usually to treat rheumatic complaints, especially gout)
      Ethidium bromide (is an intercalating agent commonly used as a fluorescent tag in laboratories for   techniques such as agarose gel electrophoresis)

CLASSIFICATION OF MUTATION:

• Classify of mutation
  i) gene / point mutation
  ii) chromosomal mutation

GENE MUTATION (POINT MUTATION)

• Producing alterations in the sequence of DNA nucleotide.
• involve only one or a few base pair in the coding sequence.
• Arise due to spontaneous pairing errors that occur during DNA replication,
• Arise due to mutagens like radiation or chemicals cause damage to the DNA.
• As a result :
  - Change the amino acid sequence and thus, changes the protein
  - Different protein produced as the effect of mutation may not function as normal
• Classify gene mutation
  i) Base substitution
  ii) Base insertion
  iii) Base deletion
  iv) Base inversion
• mutation of base deletion and insertion make cause frame shift mutation
• Alteration of gene mutation cause some genetic disorders such as Sickle Cell Anemia

Classification of Gene mutation:

Base substitution :

• One or a few base pairs in the nucleotide sequences in genes is substitute
• Changes in base sequence – results in changes of codon (UAU/UGU)
• 3 base/ nucleic acid = 1 codon (coding for 1 amino acid)
• Changes in codon:-

a) amino acid changes (missense mutation)

b) changes a codon to stop codon (nonsense mutation)

• Missense mutations are those that still code for an amino acid but change the indicated amino acid eg. Sickle Cell Anemia.
• Nonsense mutations change an amino acid codon into a stop codon, nearly always leading to a nonfunctional protein.
  
  Sickle cell Anemia
• mutant Hb^s cause defective red blood cell. The cells are shaped like a crescent or sickle
• occurs more commonly in people regions where malaria is or was common. there is a survival value in carrying only a single sickle-cell gene Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria plasmodium is halted by the sickling of the cells which it infests.
• sickle shape body produces abnormally shaped red blood cells.
• Hb^s stiff & tend to accumulate in small capillary, Hb is not efficient of transporting oxygen

• polypeptide chain encode by different gen, cause differ one base only

Normal Mutant

DNA chain C T T C A T

transcript

mRNA G A A G U A

translation

code of amino acid glutamic valine

type of protein HB normal HB S

• A change in a single nucleotide from T to A in the DNA template leads to an abnormal protein.
• Amino acid valine replaces glutamic acid at a single position in the protein

Base insertions

• Addition of 1 or a few base pairs in the nucleotide sequences in genes
• mutation of base insertion make cause frame shift mutation

Normal Mutant

DNA chain AGA GTC TTC AGA GGT CTT

transcript

mRNA UCU CAG AAG UCU CCA GAA

translation

code of amino acid Ser Gln Lys Ser Pro Glu

frame-shift happen

Base deletions

• Loss of 1 or a few base pairs in the nucleotide sequences in genes
• mutation of base deletion make cause frame shift mutation

Normal Mutant

DNA chain AGA GTC TTC AGA GCT TCG

transcript

mRNA UCU CAG AAG UCU CGA AGC

translation

code of amino acid Ser Gln Lys Ser Arg Ser

frame-shift happen

Base inversion

• 2 base pairs or more are inverted in nucleotide sequence

Normal Mutant

DNA chain AGA GTC TTC AGA TGC TTC

transcript

mRNA UCU CAG AAG UCU ACG AAG

translation

code of amino acid Ser Gln Lys Ser Thr Lys

Frame-shift Mutations

• Involve insertion/deletion of a base pair or more into the nucleotides sequence of DNA
• Many of these deletions/insertion start in the middle of a codon
• Shifting the reading frame by one or two bases
• Frame shift mutations cause the gene to be read in the wrong three base groups (codon)
• From the mutation point,
• It abrupt the coding sequence of amino acid.
• Changes in codons results in changes in amino acids
• Different polypeptide is produced
• Effect ~ usually harmful to human
• e.g. Major Thalasemia (mutant homozygote alleles)

CHROMOSOMAL MUTATION

• Definition: Abnormalities ~ in chromosomal structure (chromosome aberration) & changes in chromosome number (aneuploidy / euploidy)
• Chromosomal mutations take place when the number of chromosomes changes or when structural changes occur in the chromosomes
• Classification chromosomal mutation

i) Chromosomal aberration (structural of chromosomal change)ii) Chromosomal number alteration
- Aneuploidy
- Euploidy (polyploidy)

Chromosomes aberration

• Changes in the chromosomes structure, are most frequently formed during mitosis or meiosis
• Rearrangement a certain segment @ parts of chromosome

• 4 types of chromosomal aberration
  i) Translocation
  ii) Deletion (segmental deletion)
  iii) Inversion
  iv) Duplication

Translocation

Translocation : involves a region of a chromosome breaking off and rejoining either the other end of the same chromosome or another non-homologous chromosome

• e.g. Robertsonian translocation
• Robertsonian translocation involves breaks at the extremes ends of the short arms of two nonhomologous chromosomes (13, 14, 15, 21 and 22)
• Named after the American insect geneticist W.B.Robertson
• Also called whole-arm translocation or centric-fusion translocation

Deletion

Deletion : the lost of 1 segment containing 1 or more genes

• When the chromosome breaks at two places and lead to the loss of the middle segment
• The segment lost may contain one or more genes
• The remaining end of chromosome will join again and become shorten
• Genetic disease: Cri du chat syndrome (usually mentally retarded and cries like a cat mewing)
• Loss of a small part of the short arm of chromosome 5
• Cri du chat is a rare syndrome (1 in 50,000 live births) caused by a deletion on the short arm of chromosome 5.
• The name of this syndrome is French for "cry of the cat," referring to the distinctive cry of children with this disorder.
• The cry is caused by abnormal larynx development, which becomes normal within a few weeks of birth.
• Infants with cri du chat have low birth weight and may have respiratory problems.
• Some people with this disorder have a shortened lifespan, but most have a normal life expectancy.
• Where does the abnormal chromosome 5 come from? In 80 percent of the cases, the chromosome carrying the deletion comes from the father's sperm.

Inversion

Inversion : a region of a chromosome breaks off and rotates through 180° before rejoining the chromosome

Duplication

Duplication : a region of a chromosome becomes duplicated; an additional set of genes exists

• When a single locus or a large piece of a chromosome is present more than once in the genome

Alteration of chromosomes number

• Type of the alteration of chromosomal number
  i. aneuploidy
  ii. euploidy / polyploidy
• Human somatic cells containing a number of chromosomes which is not a multiple of 23 are called aneuploids

Aneuploidy

• Aneuploidy is a condition in which the number of chromosomes is abnormal due to extra or missing chromosomes, in other words, it is a chromosomal state where the number of chromosomes is not a multiple of the haploid set.
• Normal diploid species have 2n chromosomes, where n is the number in the haploid set.
• Aneuploid individuals would have 2n-1 chromosomes (monosomy), 2n+1 chromosomes (trisomy), or some other such arrangement.
• A change in the number of chromosomes can lead to a chromosomal disorder. Aneuploidy is common in cancerous cells.
• Aneuploidy occurs during cell division when the chromosomes do not separate properly between the two cells

Type of aneuploidy	Genome situation
Monosomy	2n - 1
Trisomy	2n + 1
Tetrasomy	2n + 2

Disjunction: chromosomes separated to the opposite poles during meiosis

Non disjunction : failure of pair of chromosome to separate and to move to the opposite poles

both sets of chromosomes pass to the same pole of the cell

Cause of aneuploidy


Nondisjunction in meiosis I & II


Nondisjunction in meiosis

• Half the daughter cells produced have an extra chromosomes (n+1) whilst the other half have a chromosome missing (n-1)
• Fusion gametes between chromosome (n+1) and normal gamete (n), produced embryo with chromosome (2n+1) : Trisomy; eg. Down’s syndrome
• Fusion gametes between chromosome (n-1) and normal gamete (n), produced embryo with chromosome (2n-1) : Monosomy; eg. Turner Syndrome

Autosomal abnormalities


Monosomy 21
Trisomy 21 (down syndrome)

Monosomy

• Monosomy is the presence of only one chromosome from a pair in a cell's nucleus.
• Monosomy in human very rare, the majority embryos don't be survive, For live infant reported in human, the only of monosomy 12

Monosomy 21

• The syndrome is generally lethal and only several cases of living newborn infants have been reported, most of whom die between 3 weeks and 20 months of life but some survive into childhood.
• Symptoms:

- Short distance between eyes

- Large ears

- Contracted muscle

- Large nose with a broad base

- cleft lip and/or palate

- Short neck

- Short thorax

- Small hands and feet, overlapping and/or flexed fingers and toes,

- hyperactive reflexes (nervous system)

Trisomy

• Trisomy is a presence genetic abnormality in which there are three copies, instead of the normal two, chromosomes of a particular numbered type in an organism
• A trisomy is a type of aneuploidy (an abnormal number of chromosomes)
• Human trisomy can occur with any chromosome. Most trisomies, like most other abnormalities in chromosome number, result in distinctive and serious birth defects. Most trisomies result in spontaneous abortion; the most common types that survive to birth in humans are:
  - Trisomy 21 (Down syndrome)
  - Trisomy 18 (Edwards syndrome)
  - Trisomy 13 (Patau syndrome)
  - Trisomy 9
  - Trisomy 8 (Warkany syndrome 2)
  - Trisomy 16 is the most common trisomy in humans, occurring in more than 1% of pregnancies. This condition, however, usually results in spontaneous miscarriage in the first trimester

A trisomy is the
Thus the presence of an extra chromosome 21 is called trisomy 21


Symptoms Down syndrome / trisomy 21

• Short stature. A child often grows slowly and, as an adult, is shorter than average.
• Weak muscles (hypotonia) throughout the body. A child may seem to have less strength than other children of the same age.
• A short, wide neck with excess fat and skin. Usually, this trait is less obvious as the child gets older.
• Short, stocky arms and legs. Some children also have a wide space between the big toe and second toe.

re does the extra chromosome come from?

• In 90% of Trisomy 21 cases, the additional chromosome comes from the mother's egg.
• This karyotype is an example of Down Syndrome (trisomy 21), the most common numerical abnormality found in newborns. It is characterized by an extra chromosome 21 and the karyotype is written as: 47,XY,+21. The key to the karyotype description is as follows:
• 47: the total number of chromosomes (46 is normal).
• XY: the sex chromosomes (male).
• +21: designates the extra chromosome as a 21.

Sex chromosomal abnormalities

• Aneuploidy, abnormalities in the sex chromosome number

• Non disjunction during spermatogenesis dan oogenesis
• e.g. Klinefelter syndrome (47,XXY) and Turner syndrome (45,XO)

Non disjunction during spermatogenesis

• If non disjunction during meiosis I & II
• sperm will have the abnormal sex chromosome : XY, XX @ YY
• Abnormal sperm x ovum (X)
• Klinefelter syndrome (XXY)
• Super male syndrome (XYY)
• 3X female (metafemale, XXX)

Non disjunction during Oogenesis

•    non disjunction happened
• Some ovum might not carry any chromosome X & some others might carry 2 chromosome X
• Abnormal ovum (O) x sperm
• Turner syndrome (XO)
• YO : dead
• Abnormal ovum (XX) x sperm
• Klinefelter syndrome (XXY)
• 3X female

Klinefelter syndrome (47,XXY)

• Klinefelter's Syndrome is a genetic disorder that happens in 1 in every 500 to 1000 male births.
• Instead of the normal XY chromosomes, these individuals have and extra X chromosome making them XXY.
• Males with Klinefelter's syndrome have two X chromosomes (47-XXY), The X-chromosomes carry genes in terms of development of testicles, sex hormone production and physical sex development in general as well as to a certain extent also height growth.

• It is named after Dr. Harry Klinefelter, a medical researcher at Massachusetts General Hospital, Boston, Massachusetts, who first described this condition in 1942.
• Symptoms

• delayed speech
• sensory integration difficulties, including sensitivity to noise
• hypotonia or low muscle tone
• auditory processing problems
• language-based learning disabilities, including reading difficulties
• anxiety
• depression
• gynecomastia or swelling of breast tissue during puberty
• Feminised male (soft voice
• Sterile male (small testis), failed to produce sperm
• long hand and leg

Turner syndrome (45,XO)

• Turner syndrome results from a chromosomal abnormality in which a female infant is born with only one X chromosome (instead of the usual two) or is missing part of one X chromosome.
• Symptoms

• short stature
• "webbing" of the skin of the neck (extra folds of skin extending from the tops of the shoulders to the sides of the neck)
• a low hairline at the back of the head
• low-set ears
• abnormal eye features, including drooping of the eyelids
• abnormal bone development, especially the bones of the hands and elbows
• a lack of breast development at the expected age (usually by age 13)
• an absence of menstruation (amenorrhea)
• a larger than usual number of moles on the skin

Abnormal Phenotype


Klinefelter Syndrome (XXY) : 2n+1 (Trisomy)

• Sterile male (small testis), failed to produce sperm
• Feminised male (soft voice) & big breast, long hand and leg
• Non disjunction during oogenesis

Turner Syndrome (XO) : 2n-1 (Monosomy)

• Sterile female (failed to ovulate)
• Small breast & undeveloped ovary
• dwarf, deaf, abnormal heart & low IQ

Aupiody / Polyploidy

• cell of organism that has an exact multiple of the haploid number (n) of chromosomes in a nucleus.
• Gametes fusion will produce cell which have more than 2 set of chromosome, for example: diploid (2n), triploid (3n), and tetraploid (4n) nuclei or cell are euploid

• Occurred when a set of chromosome did not separate during gametogenesis
• Common in plants than in animals, cause gamete not occur in animal, while in plant can produce vegetative propagate.
• Triploid (3n) occurs when
  i) a gamete (2n) occur non disjunction fused with a normal gamete (n)
  
  Gamete A x AA (non disjunction gamete)

individual of triploid AAA

ii) chromosomes disable to segregate during meiosis to produce diploid gamete iii) gamete from tetraploid organism (4n) fused with diploid organism gamete (2n).
• e.g. plant triploid is a banana, lemon, rose, watermelon (seedless) and crysanthemum

• Tetraploid plants can be produced by :

1) Somatic duplication of chromosome number

• duplication of chromosome at callus (tip)

origin plant : AA (2n)

(Duplicate)

tetraploid plant AAAA (4n)

2) Fusion of two diploid gametes

P : AA (2n) AA (2n)

G : AA AA

FI: AAAA

• 2 types of polyploidy
  - Autopolyploidy
  - Allopolyploidy

Autopolyploidy :

• Is an individual that has more than two chromosome sets, all derived from a single species
• The chromosomes set are homologous with the parent cell
• Importance in economic value which autopolyploid plants produce flowers and fruits bigger than normal diploid plants
• Involve parent cell from one species mean homologous chromosome

P : AA (2n) AA (2n)

G : AA x AA

FI: AAAA

Allopolyploidy

• A polyploid resulting from 2 different species (hybridization) interbreeding and combining their chromosomes
• The chromosome sets are different to parental cell mean non homologous chromosome sets involve
• F1 hybrids produced from different species are usually sterile (haploid set of chromosome from one species cannot pair during meiosis with the haploid set from the other species)
• Chromosome number in a sterile hybrid becomes doubled and produces fertile hybrids (synapsis and segregation can occur and viable gametes can be produced)
• Importance in producing new species
• e.g. plant (wheat)

Triticum diccoccum (2n = 4x = 28) x Aegilops squarrosa (2n = 2x = 14)

Tetraploid plant

Triticum vulgare (2n = 6x = 42)

Hexaploid plant

P : AA BB

Gamete A x B

Hybrid ( sterile ) AB

duplication

AABB

Gamete, 2n = 2x ( fertile ) AB

Retold by:

Amran Md Said,

Kolej Matrikulasi Pahang.

The end.

Analogy of frame-shift mutation

one sentences

CAN YOU BUY CAT FOR HER SON

after insertion only one alphabet , A at CAT in the sentence,

CAN YOU BUY ACA TFO RHE RSO N

we can't read that sentence

after delete only one word, C at CAT in the sentence

CAN YOU BUY ATF ORH ERS ON

we can't read that sentence

*peringatan analogi ini untuk kefahaman sahaja ianya tidak boleh digunakan dalam peperiksaan