Mutation
The Objective : To give information about : 1- What mutation means and how mutation occurs and how it cause genetic disease . 2- Types of mutation based on location . 3- Types of mutation based on molecular change . 4- Types of genetic diseases or disorders caused by mutation such as : * Single gene change such as sickle cell anemia, and inherited metabolic disorder such as alkaptonuria . * Chromosomal variation in structures and numbers that lead to many syndromes such as down syndrome . * Somatic mutation or cancer . 5- The difference between cancer and other genetic diseases .Mutation :
A change in the DNA at a particular Locus in an organism . The Term is used Loosely to include Point Mutations involving single gene change , as well as chromosomal change .Mutation Based on Location of Mutation :
1- Germ line mutations : are mutations occurring in gametes . 2- Somatic mutations : are mutations occurring in any cell in the body except germ cells . 3- Autosomal mutations : are mutations within genes located on autosomes (chromosomes 1- 22 ) . 4- X- Linked mutations : are mutations within genes located on the X- chromosome .Mutation Based on Type of Molecular change :
Point Mutation : Involve the Addition or Deletion or Inversion or Substitution of a few bases with in genes . ( Figure 1 ) . Mutation at DNA Level : A- Transition : Purine replaced by different Purine , or Pyrimidine replaced by different Pyrimidine : AT GC , GC AT. B- Transversion : Purine replaced by Pyrimidine , or Pyrimidine replaced by a Purine : AT CG , GC CG .
Mutation at protein Level :
A-Silent Mutation : Triplet Codes for same amino acid : GCA GCC both code for alanine (amino acid). (Figure 2). B- Neutral Mutation : Triplet codes for different but functionally equivalent amino acid :AAA AGA changing basic Lysine to basic Arginine ( at many positions , will not alter Protein Function ) . C- Missense Mutation : a mutation that changes a codon specifying an amino acid to a codon specifying a different and non functional amino acid . D- Nonsense Mutation : a mutation that changes a codon specifying an amino acid to atermination codon . CAA UAA changing from a codon for Glycine to a termination codon .Frame Shift Mutation :
Any Addition or Deletion of base pairs that is not a multiple of 3 result in a frame shift in DNA segments that code for Proteins . (Figure 2 ) . Molecular Bases of Mutation : gene Mutation can arise Spontaneously or they can be Induced. Spontaneous Mutations : arise from a variety of sources including: 1-Errors in DNA replication . 2-Spontaneous Lesions . 3-Transposible genetic elements . Induced Mutations : are produced when an organism is exposed to Mutagenic agent or Mutagen ( Radiation , Chemical agent ). Such Mutations typically occur at much Higher Frequencies than Spontaneous Mutations do . Example for gene mutation Sickle cell anemia in humans .Sickle cell Anemia ( SCA )
SCA: is a group of inherited blood disorder characterized by chronic anemia, painful events, and various complications due to associated tissue and organ damage . SCA: Is caused by a change in the chemical composition of the Hemoglobin a protein found in the Red blood cells that helps carry oxygen throughout the body . Normal hemoglobin is rounded or ball shaped folded molecule composed of 4 polypeptide chains two α-chains and two β-chains each of which is associated with a heme group . Each polypeptide chain is encoded by a spesific gene . Each β-chain is 146 amino acid long . (Figure3).The mutational origin of Sickle Cell Hemoglobin ( Hemoglobin S ) :
SCA : is produced when Missense mutation occurs , when a single DNA base change ( Adenine replaces Thymine ) at the sixth position of β- globin gene which located on chromosome 11 .Leads to single amino acid change ( Valine replaces Glutamic acid ) at the sixth position of β- globin polypeptide chain . ( Hemoglobin S )Glutamic acid a negatively charged amino acid that is normally the sixth amino acid in the β- globin polypeptide chain .Valine no charged amino acid . Valine at this position changes the surfaces of hemoglobin molecules and they aggregate into long, curved rods . The RBCs elongate and form sickle shaped cells . These sickle shaped cells clog small blood vessels and cut of oxygen transport to various tissues .The sickling of RBCs , has many effects on the phenotype of sickle cell patient, such as: 1- Breakdown of red blood cells leads to anemia and impaired mental function . ( figure ) 2- Clumping of cells and clogging of small blood vessels lead to heart failure, brain damage and damage to other organs and cause paralysis, kidney failure and rheumatism , pneumonia and other infections . 3- Accumulation of sickled cells in spleen leads to spleen damage .
Inheritance of Sickle cell anemia :
SCA follow a pattern of Autosomal Recessive Inheritance : The inheritance pattern of two autosomal alleles causing a phenotype, which can affect males and females and can skip generation through carriers . When both parents are carriers of sickle cell trait, there is a 25 % chance in each pregnancy for the baby to inherit two sickle cell gene and have sickle cell anemia, correspondingly there is a 50% chance the baby will have sickle cell trait ( carriers ) and a 25% chance that the baby will have the usual type of hemoglobin . ( figure ) .Inheritance of Sickle cell anemia
Inheritance of Sickle cell anemiaInheritance of Sickle cell anemia
Inheritance of Sickle cell anemiaChromosomal Variations :
There are 2 types of Chomosomal Variations : 1-Variations in Chromosome Structure : A- Deficiencies : Part of chromosomes Lost or Deleted . B- Duplications : Part of chromosomes Added or Duplicated . C- Inversions : Sections of chromosomes detached and reunited in reverse order . ( Figure 1 ) . D-Translocations : Parts of chromosomes detached and joined to non Homologous Chromosomes .1-Variations in Chromosome Structure
- Deficiency (deletion) - Duplication - Inversion - Translocation * Simple * ReciprocalVariation in chromosome structure :
Example of Variation in chromosome structure :
Cri du chat syndrome : The syndrome associated with a deletion of part of short arm of chromosome 5 . The syndrome includes microcephaly and cat like cry .( figure ) .2-Variations in Chromosome Number :
Variation in chromosome number results from nondisjunction during meiosis . Nondisjunction : a chromosome pair fails to separate at anaphase of either the first or second meitotic division . Meiotic nondisjunction : Can occur during meiosis I , all resulting gametes are aberrant (aneuploid ) . ( figure ) Can occur during meiosis II , half of resulting gametes are aberrant-Meiotic nondisjunction *Can occur during meiosis I All resulting gametes are aberrant (aneuploid) *Can occur during meiosis II Half of the resulting gametes are aberrant (aneuploid)
2-Variation in chromosome number : Variation in chromosome number results from nondisjunction during meiosis .
A- Euploid :Asomatic cell with the normal number of chromosomes for the species B- Aneuploid :Individuals are formed that have More or Less than the normal number of any one chromosome . ( 2n + 1) called Trisomy, ( 2n + 2 ) called Tetrasomy, ( 2n–1 ) called Monosomy, ( 2n –2 ) called Nullisomy.These Aneuploid usually come about by Non Disjunction .C- Polyploid :The condition of the cell or organism with More than two complet sets of chromosomes . (3n)Triploid, (4n) Tetraploid, and so on .
Examples of Autosomal Aneuploids :
1- Down Syndrome : Achild with Down Syndrome has 47 chromosomes instead of 46 chromosomes because Trisomy for chromosome 21 ( three copies of chromosome 21 ) all other chromosomes are Disomy (usual pair). (Figure 9).Patient with Down Syndrome : were short in stature ( about 4 feet Tall ) and had An Epicanthalfold ( thus the earlier name Mongolism ) . Broad short Skulls , Large Tongue , Stubby hands , Low in Mentality .2- Patau Syndrome : ( Trisomy – 13 ) ( figure )3- Edwards Syndrome : ( Trisomy – 18 ) ( figure )Examples of Autosomal Aneuploids :
2- Patau Syndrome : ( Trisomy – 13 )Examples of Autosomal Aneuploids :
3- Edwards Syndrome : ( Trisomy – 18 )Examples of Sex chromosome Aneuploids :
1- Turner Syndrome : abnormal Female with 45 chromosomes , the sex chromosome is X chromosome only . ( Figure 8 and 10 ).Examples of Sex chromosome Aneuploids : 2- Klinefelter Syndrome :
Abnormal male with 47 chromosome, the sex chromosomes are XXY . Male who are sterile and in the some cases have enlargement of the breast . ( Figure 8 and 11 )
Examples of Sex chromosome Aneuploids : 3-Triple X Syndrome :
Female with 47 chromosomes, the sex chromosomes are : XXX . The Female with usually normal genitalia and limited fertility . Slight mental retardation . ( figure ) .Genetic Control of Metabolism :
Metabolism occurs by sequences of chemical reactions , each step of which is catalyzed by a specific enzyme . each enzyme is , in turn , specified by one or more genes . The genetic control of metabolic pathway may thus be diagrammed as in ( Figure 12 ) :When Mutations occur in genes, leads to the enzyme is not produced or canot function . Genetic disorders that result from loss of enzyme activity resulting from mutation in genes encoding these enzymes are called Inherited Metabolic Disorders. Example of Inherited Metabolic Disorders The metabolism of Phenylalanine and Tyrosine in Humans . ( Figure 13 ) .
Phenylalanine
PhenylketonuriaPhenylalanine hydroxylase
Tyrosine
Albinism(Tyrosinase –negative type) Tyrosinase
3,4Dihyroxy phenylalanine
-hydroxyphenylpyruric acid Melanin
(Dark pigment in skin and hair)
-hydroxyphenylpyruric Acid oxidase Tyrosinemia
2,5 Dihydroxyphenyl pururic acid (homogentisic acid)
Homogentisic acid oxidase
Alkatonuria
Acetoacetic acid + Fumaric acid
Co2 + H2O
Phenylpyruric acid
Albinism(Tyrosinase –positive type) (Toxic to Central Nervous System)
Tyrosine Tyrosinosis Transaminase
Inherited human disorders with defects in phenylalanine – tyrosine metabolism
1- Phenylketonuria: (PKU) :
The Failure of Brain to develop in infancy . PKU results from arecessive Mutation that causes aloss of Phenylalanine Hydroxylase activity which converts Phenylalanine to Tyrosine , the first step in the catabolism of Phenylalanine . As Protein is consumed Phenylalanine accumulates in the blood of individuals with PKU , some times up to 100 times the normal Level . as a result , metabolic derivatives of Phenylalanine , such as Phenylpyruvic acid , are formed . some of the derivatives are toxic to the Central Nervous System and produce irreversible Brain damage . If PKU is diagnosed in newborns, however, subsequent mental retardation can be avoided by placing the child on a carefully controlled diet .2-Alkaptonuria :
Is caused by a recessive Mutation that results in the Loss of activity of the Enzyme Homogentisic acid Oxidase . In the presence of this enzyme ( in normal people ) Homogentisic acid is normally oxidized and eventually converted to carbon dioxide and water . ( Figure 13 ) . In the absence of this enzyme Homogentisic Acid accumulates and is excreted in the Urine and turns urine black when exposed to air . Alkaptonuria with many symptoms illustrated in ( figure ) .Alkaptonuria
3- Albinism :Is another Recessive condition caused by adefect in Phenylalanine- Tyrosine Metabolism . In certain types of Albinism , the enzyme Tyrosinase is inactive or Lacking , resulting in ablock in the Pathway of conversion of Tyrosine to the Dark – colored Pigment Melanine .
4- Tyrosinosis : Result from the lack of the Tyrosine Transaminase . Individuals with tyrosinosis show pronounced increases in tyrosine levels in their blood and urine and have various congenital abnormalities . 5- Tyrosinemia : Result from the lack of the enzyme p- Hydroxyphenulpyruvic acid oxidase . Individuals with Tyrosinemia have elevated levels of both Tyrosine and p- Hudroxyphenylpyruvic acid in their blood and urine . Most newborns with Tyrosinemia die with in six months after birth because of liver failure .