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MUTATION

Mutation classification and types.

Genetic mutation:

1. Base substitution
2. Base insertion
3. Base deletion
4. Base inversion

Chromosomal mutation

• Structural change/Chromosomal aberration
• Alterations of chromosome number
• Aneuploidy
• Euploidy/Polyploidy

INTRODUCTION

The genetic message can be altered in two broad ways:

• Mutation and recombination.
• Mutation:
  1. A change in the content of the genetic message the base sequence of one or more genes alter the identity of the particular nucleotides or remove or add nucleotides to the gene.

• It can be passed to the next generation.
• Recombination: a change in the position of a portion of the genetic message move a gene to a different chromosome or alter the location of only part of the gene.
• Mutant: A mutated gene,alternatively,an organism carrying a gene that has undergone a mutation.
• Mutagen: An agent that induces changes in DNA includes physical agents that DNA/chemical that alters DNA bases or by radiation.
• Example:

Normal fruit flies have one pair of wings extending from the thorax. This fly is a mutant because changes in bithorax,a gene regulating a critical stage of development; it possesses two thoracic segments and thus two sets of wings.

• Type of mutation

·  Spontaneous mutation

Mistakes happen spontaneously during DNA replication

·  Induced mutation

Organism exposed to mutagen.

• Mutation agents

·  Physical agent:

·  Ultraviolet ray

·  Ionizing radiation(X-ray, gamma ray, alpha particles,neutron,and electron)

·  Chemical agent:

·  Mustard gas, nitrous acid, base analogous etc.

GENE MUTATION/POINT MUTATION

·        Caused by rearrangement of base pairs in the in one segment of DNA molecules.

·        As a result=>change the amino acid sequence and thus, change the protein.

·        Different protein produced as the effect of mutation may not function as normal.

·        Eg: sickle cell anemia

POINT MUTATION

• Base substitution-one or a few base pairs in the nucleotides sequences in genes substitute.
• Base insertion-addition of one or a few base pairs in the nucleotides sequences in genes.
• Base deletions-loss of one or a few base pairs in nucleotides sequences

• Base inversion-2 base pairs or more inverted in nucleotides sequence.

• Change in base sequence-result in changes of codon(UAU/UGU)
• 3 base/nucleic acid=one codon(coding for one amino acid)
• Changes in codon:-

v     Amino acid changes(missense mutation)

v     Changes a codon to stop codon.(nonsense mutation)

SICKLE CELL ANEMIA

• Missense mutation.
• Defective red blood cell
• Abnormal HB-Sickle shape
• Hb-4 poly peptide chain(2 ALPHA & 2 BETA)
• Encode by different gene.
• Happens because substitution mutation
• Amino acid valine replaces glutamic acid at a single position in the protein(BETA STRAND)
• Patient suffer fro anemia~Hb-S stiff & tend to accumulate in small capillary.
• Hb is not efficient of transporting oxygen.
• One case of codominan

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 acid.
• Different polypeptide is produced. 
• Usually harm human.
• Example: Major thalesmia(mutant homozygote alleles.

BASE INVERSION

• 2 base pairs or more in nucleotide sequence are inverted.
• Change the codons=>changes in amino acid.
• Usually the effect is minor phenotype abnormality.

CHROMOSOME MUTATION

• Definition: Abnormalities in chromosomal structure(chromosome aberration) & changes in chromosome number (aneuploidy/euploidy)
• Types of chromosome mutation

Ø      Chromosome aberration

Ø      Alterations in chromosome number

v     Aneuploidy

v     Euploidy(polyploidy)

CHROMOSOME ABERRATION

• Rearrangement a certain segment @ parts of chromosome.
• 4 types:

ü      Deletion

ü      Inversion

ü      Translocation

ü      Duplication

• Deletion: the lost of one segment containing one or more genes.
• One syndrome is cri du chat  (cry of the cat)
• A child born with this specific deletion in chromosome 5 is mentally retarded, 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.
• Inversion: a region of a chromosome breaks off and rotates through 180 before rejoining the chromosome.
• Inversion usually do not alter gene expression.
• Recombination within region that is inverted on one homologue but not the other leads to serious problems : none of the gametes that contain chromatids produced following such a crossover event will have a complete set of genes.
• Inverted segment:

1. When a segment of a chromosome is inverted
2. It can pair in meiosis only by forming an internal loop.
3. Any crossing over that occurs within the inverted segment during meiosis will result in non-viable gametes: some genes are lost from each chromosome, while others are duplicated(4 & 5).

The pairing that occurs between inverted segments is sometimes visible under the microscope as a characteristic loop.

• Translocation : involves a region of a chromosome breaking off and rejoining  either the other end of the same chromosome or another non-homologous chromosome.
• Chromosomal translocations have been implicated in certain cancers.
• Examples: Chronic myelogenous leukemia (CML)
• In CML a portion of chromosomes 22 has switched places with a small fragment from a tip of chromosomes 9.
• Duplication : a region of a chromosome becomes duplicated; an additional set of genes exists.
• Chromosomal mutation

      Alterations of Chromosomal Structures

v     Deletion

v     Duplication

v     Inversion

v     Translocation

      Alterations of Chromosomal Number

v     Aneuploidy

v     Polyploidy

ALTERATIONS OF CHROMOSOME NUMBER OF STRUCTURE CAUSE SOME GENETIC DISORDERS

• Ideally, the meiotic spindle distribute chromosomes to daughter cells without error.
• Nondisjunction occurs when problems with the meiotic spindle cause errors in daughter cells.
  • This may occur if tetrad chromosomes do not separate properly during meiosis 1.
  • Alternatively, sister chromatids may fail to separate during meiosis 2.

• As a consequence of nondisjunction, some gamete receives no copy.
• Offspring results from fertilization of a normal gamete with one after nondisjunction will have an abnormal chromosome number or aneuploidy.

Ø      Trisomic cells have tree copies of a particular chromosome type and have (2n+1) total chromosomes.

Ø      Monosomic cells have only one copy of a particular chromosome type and have (2n-1)

• If the organism survives, aneuploidy typically leads to a distinct phenotype.
• Aneuploidy can also occur during failures of the mitotic spindle
• If aneuploidy happens early in development, this condition will be passed along by mitosis to a large number of cells.
• This is likely to have a substantial effect on the organism
• Several serious human disorders are due to alterations of chromosome number and structure.
• Although the frequency of aneuploid zygotes may be quite high in humans, most of these alterations are so disastrous that the embryos are spontaneously aborted long before birth.
  • These developmental problems results from an imbalance among gene products.

• Certain aneuploid conditions upset the balance less, leading to survival to birth and beyond.
  • These individuals have a set of symptoms –a syndrome- characteristic of the type of aneuploidy.

ANEUPLOIDY

• Condition where the diploid cell (2n) gain @ loss one @ more chromosomes,.
• Disjunction: homologous chromosomes separated to the opposite poles during meiosis
• Nondisjunction : both sets of chromosomes pass to the same pole of the cell.
• 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): Trysomy;e.g Down’s syndrome
• Fusion gametes between chromosome (n-1) and normal gamete (n), produced embryo with chromosome (2n-1): Monosomy; e.g. Turner Syndrome.

ANEUPLOIDY

• Abnormalities in the sex chromosome number

      Non-disjunction during spermatogenesis

      Non-disjunction during oogenesis

• Abnormalities in the autosome number.

NON DISJUNCTION DURING SPERMATOGENESIS

v     If non disjunction during meiosis 1&2

      Sperm will have the abnormal sex chromosome:XX,XY @ YY.

v     Abnormal sperm x ovum (X)

      Klinefelter syndrome (XXY)

      Super male syndrome (XYY)

      3X female (metafemale,XXX)

NON DISJUNCTION DURING OOGENESIS

ü      If non disjunction happened

      Some ovum might not carry any chromosome X & some others might carry 2 chromosome X.

ü      Abnormal ovum (o) x sperm

      Turner syndrome (X0)

      Y0 : dead

ü      Abnormal  ovum (XX) x sperm

      Klinefelter syndrome (XXY)

      3X female

TRISOMY(XXX)

• A female with one functional X chromosome and two Barr bodies (1:2000 live births)
• Barr body: deeply staining structure, seen in the interphase nucleus of a cell of an individual with more than  one X chromosome, that is a condensed and inactivated X.Only one X remains active in each cell after early embryogenesis.
• She is sterile but usually normal in other respect.

KLINEFELTER SYNDROME(XXY)

• Occurs once in every 500 live births.
• These individuals have male sex organ, but are sterile.
• They may be feminine characteristics, but their intelligence is normal.
• In some cases, diminished mental capacity.

JACOB’S SYNDROME(XYY)

• The Y chromosome can also fail to separate in meiosis, leading the formation of YY gametes.
• When these gamete combine with X gamete, the XYY zygotes develop into fertile males of normal appearance (1:1000)
• XYY is approximately 20 times higher among males in penal and mental institution.

OY

·        If an O gamete fuses with a Y gamete , the resulting OY zygote is nonviable and fails to develop further because humans cannot survive when they lack the genes on the X chromosome.

MONOSOMY X (TURNER SYNDROME,XO)

·        Occurs in every 5000 births.

·        The XO zygote develops into short sterile female of short stature, with a webbed neck and immature sex organs that do not undergo changes during puberty.

·        The mental abilities are in the low-range.

NONDISJUNCTION INVOLVING AUTOSOME

 

INTRODUCTION

• Each human somatic cell normally has 46 chromosomes, which in meiosis has 23 pairs.
• Of the 23 pairs, 22 are perfectly matched in both males and females and are called autosomes.
• Human who have lost even one copy of autosome (monosomic) do not survive development.
• In all but a few cases, human who has gained an extra autosome (trisomic) also do not survive.
• However, five of the smallest autosome-those numbered 13,15,18,21, and 22- can be present in human as three copies and still allow the individual to survive for a time.
• The presence of an extra chromosome 13,15 or 18 causes severe developmental defects and infants with such genetic makeup die within a few months.
• In contrast, individuals who have an extra copy of chromosome 21 or 22, usually survive to adulthood.
• In such individuals, the maturation of the skeletal muscle is delayed, so they generally are short and have poor muscle tone.
• Their mental development is also affected, and children with trisomy 22 are always mentally retarded.

PHYSICAL CHARACTERISTICS

v     A flat facial profile

v     Upslanting eyes

v     Unusual eyelid (known as epicanthic folds)

v     A flat nasal bridge

v     A prominent tongue

v     Small ears

DOWN SYNDROME (TRISOMY 21)

• First describe in 1866 by J.Langdon Down.
• About 1:750 children exhibits Down Syndrome.
• In human, the defect is associated with chromosome 21.
• In 97% of the human cases examined, all of chromosome 21 is present in three copies.
• In the other 3% a small portion of chromosome 21 containing the critical segment has been added to another chromosomes by a process called translocation, it exists along with a the normal copies of chromosome 21.
• This condition is known as translocation Down Syndrome.

HOW DOES DOWN SYNDROME ARISES.

• Most cases of Down Syndrome result from nondisjunction during gamete production in one parent.
• Primary nondisjunction are far more common in woman than in men because all of the eggs a women will ever produce have developed to the point of prophase in meiosis 1 by the time she has born.
• The frequency of Down  Syndrome correlates with the age of the mother
  • This may be linked to some age-dependent abnormality in the spindle checkpoint during meiosis1, leading to nondisjunction.

POLYPLODY

• Organisms with more than two complete sets of chromosomes, has undergone polyploidy.
• This may occur when a normal gamete fertilizes another gamete in which there has been nondisjunction of  all its chromosomes.

Ø      The resulting zygote would be triploid(3n)

• Alternatively, if a 2n zygote failed to divide after replicating its chromosome, a tetraploid(4n) embryo would result from subsequent successful cycles of mitosis.
• Organism with multiples of the haploid number of chromosome (3n,4n,5n,…………..)

• Polyploidy is relatively common among plants and much less common among animals.

      The spontaneous origin of polyploidy individuals plays on important role in evolution of plants.

      Both fishes and amphibians have polyploidy species.

      Recently, researchers in Chile have identified a new rodent species which may be the product of poly ploid

• Polyploids are more nearly normal in phenotype than aneuploids.
• One extra or missing chromosome apparently upsets the genetic balance during development more than does an entire extra set of chromosomes.

POLYPLOIDY

• AUTOPOLYPLOIDY

v     Increase in number of chromosomes within the same species.

v     The chromosomes set are homologous with the parent cell

• ALLOPOLYPLOIDY

v     Chromosome number in a sterile hybrid becomes doubled and produces fertile hybrids.

v     F1 hybrids produced from different species

• An individual can have more that two sets of chromosomes from a single species if a failure in meiosis results in a tetraploid (4n) individual.
• This autoploid mutant can reproduce with itself (cell pollination) or with other tetraploid.
• It can mate with diploids from the original population, because of abnormal meiosis by the triploid hybrids.
• In the early 1900’s botanist Hugo de Vries produced a new primrose species, the tetraploid  Oenotheria gigas, from the diploid Oenotheria lamarckiana.
  • This plant could not interbreed with the diploid species.
• Another mechanism of producing polyploid individuals occurs when individuals are produced by the mating of two different species, an alloplyploid

v     While the hybrids are usually sterile, they may be quite vigorous and propagate asexually

v     A various mechanisms can transform a sterile hybrid into a fertile polyploid

v     These polyploid hybrids are fertile with each other but cannot interbreed with either parent species.

• One mechanism for allopolyploid speciation in plants involves several cross-pollination events between two species of their offspring and perhaps a failure of meiotic disjunction to a viable fertile hybrid whose chromosome number is the sum of the chromosomes in the two parent species.
• A hybrid between two species is normally sterile because its chromosomes are not homologous and cannot pair during meiosis. However, the hybrids may be able to reproduce asexually.

EVOLUTIONARY HISTORY OF WHEAT

·          Domestic wheat arose in southern Asia in the hilly country of what is now called Iraq.

·          In this region, there is a rich assembly of grasses of the genus Triticum

·          Domestic wheat (Triticum aestivum) is a polyploid species that arose through two allopolyploid events.

1.      Two different diploid species symbolized here as AA and BB, hybridized to form an AB polyploid;the species were so different that A and B chromosomes could not pair in meiosis, so the AB diploid are sterile. However in some plants, the chromosome number spontaneously doubled due to failure of chromosomes to separate in meiosis, producing a fertile tetraploid species AABB. This wheat is used in the production of pasta.

2.      IN a similar fashion, the tetraploid species AABB hybridized with another diploid species CC to produce, after another doubling even, the hexaploid, T.aestivum,AABBCC.

=>this bread wheat is commonly used throughout the world.

THE ROLE OF POLYPLOIDY IN SPECIES FORMATION

·        Among plants, fertile individuals often arise from sterile ones through polyploidy, which double the chromosome number of the original sterile hybrid individual.