Mutation PDF

MUTATION Prof.Dr.Selma Yılmazer  Mutation Mutation is a change in the DNA sequence that can lead to production of defective protein or Loss of the encoded protein Mutation may cause disease or different phenotypes to occur  The effected organism is called Mutant They are i...

MUTATION Prof.Dr.Selma Yılmazer  Mutation Mutation is a change in the DNA sequence that can lead to production of defective protein or Loss of the encoded protein Mutation may cause disease or different phenotypes to occur  The effected organism is called Mutant They are identified by differences in their appearence, physiology or behavior properties compared with normal (wild-type=nonmutant) organism  DNA damage, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day. Occurs due to the environmental factors and Normal metabolic processes inside the cell,  Most changes in DNA are temporary because they are immediately corrected by a set of processes called DNA repair For DNA repairment there are several DNA repair enzymes  DNA repair a set of processes by which a cell identifies and corrects DNA damage A failure to repair DNA produces a mutation. In human genome 130 genes participate in DNA repair.(i.e DNA glycosylases, uracil glycosylase- photolyase )  Mutations can occur 1-Spontaneously (endogeneous mutations) or can be 2-Induced (environmental factors)  Spontaneous mutations They arise at low frequency As a result of chemical instability of purine and pyrimidine bases and (results from attack by reactive oxygen species ) errors during DNA replication (incorporation of incorrect bases during replication ) Most of these changes are quickly repaired. mutation is a failure of DNA repair.  2-Induced Mutations Caused by certain environmental factors , such as Physical mutagens (i.e U.V. Light,) and Chemical mutagens (Chemical carcinogenes) aflotoxin B1) They induce point mutations, whereas ionizing radiation gives rise to large chromosomal abnormalities. 2-Induced mutations caused by environmental factors such as ▪ Ultraviolet radiation from the sun ▪ ionizing radiation including x-rays ▪ thermal disruption Hydrolysis ▪ Toxins (aflotoxin) ▪ Cancer chemotherapy and radiotherapy ▪ Viruses  Types of Mutations 1.Gene Mutations 1. Single-base substitutions Missense mutations Nonsense mutations Silent mutations Splice-site mutations 2. Large Scale Changes (Chromosome structure and number changes) Nucleotide Insertions and Deletions Duplications Translocations  1-Single-base substitutions (point mutations) A single base becomes replaced by another. Single base substitutions are also called point mutations Transition. If one purine [A or G] or pyrimidine [C or T] is replaced by the other,The substitution is called a transition Transversion.If a purine is replaced by a pyrimidine or vice-versa, the substitution is called a transversion  Single-base substitutions Based on the effects of mutation, the substitution mutation may be grouped into three types 1-silent, 2-missense and 3-nonsense mutations  1- Silent mutations Most amino acids are encoded by several different codons. For example, if the third base in the TCT codon for serine is changed to any one of the other three bases, serine will still be encoded. TCT- TCA- SERINE TCC- TCG  1- Silent mutations Such mutations are called silent because they cause no change in their product and cannot be detected without sequencing the gene (or its mRNA). Purine Pyrimidine Transition Transversion  2-Missense mutations New nucleotide changes the codon so as to produce an altered amino acid in the protein product, (change in protein structure) May cause disease example: sickle-cell disease Sickle-cell disease Caused by mutation at the 17th nucleotide of the beta hemoglobin gene The replacement of A by T changes the codon GAG (for glutamic acid) to GTG ( encodes valine). Thus the 6th amino acid in the protein chain becomes valine instead of glutamic acid.  Thus the 6th amino acid in the beta hemoglobine chain becomes valine instead of glutamic acid.  3-Nonsense mutations The new nucleotide changes a codon that encodes one of the STOP codons (TAA, TAG, or TGA). Therefore, translation of the mRNA of this mutant gene will stop prematurely , and are produced the truncated defective proteins (Nonfunctional (mutant protein) Cystic fibrosis; these mutations occurs in a huge gene that encodes a transport protein (of 1480 amino acids) responsible for transporting chloride ions out of cells. Defects in the protein cause the various symptoms of the disease. In a patient with cystic fibrosis at nucleotide 1609 a glutamine codon (CAG) converted to a STOP codon (TAG)  Cystic fibrosis As a result of the substitution of a T for a C The protein produced by this patient had only the first 493 amino acids of the normal chain of 1480 and could not function. Absence of functional protein  - Splice-site mutations During pre-mRNA processing to form a mature mRNA, the removal of intron sequences, must be done with great precision. There are specific nucleotide signals at the splice sites the enzymes cut the introns at this signals If a mutation alters one of the splice site signals then the intron is not removed and remains as part of the final mRNA molecule. The translation of this mRNA produces an altered protein product.  Large Scale Changes Insertions and Deletions Extra base pairs may be added (insertions) or removed (deletions) from the DNA of a gene. The number of base pairs can range from one to thousands. Insertions and deletions involving one or two base pairs (or multiples ) can have devastating results to the gene because translation of the gene is "frameshifted".  This figure shows how by shifting the reading frame one nucleotide to the right, the same sequence of nucleotides encodes a different sequence of amino acids.  Deletion The deletion mutation involves elimination of one or more nucleotides from a DNA sequence. It may cause frameshift, producing a non-functional protein.  Deletion The deletion mutation involves elimination of one or more nucleotides from a DNA sequence. It may cause frameshift, producing a non-functional protein. (a) Deletion of "T" from the sequence "TTTTT" in the CFTR gene. (b) Deletion of "AT" from the sequence "ATAT" in the CFTR gene. (c) Deletion of "TTG" from the sequence "TTGTTG" in the FIX gene. (d) Deletion of "ATAG" from the sequence "ATAGATAG" in the APC gene.  Insertions and deletions of three nucleotides or multiples of three may be less serious because they preserve the reading frame However, a number of inherited human disorders are caused by the insertion of many copies of the same triplet of nucleotides. The Fragile -X Syndrome are examples of such trinucleotide repeat diseases.  Fragile- X Syndrome A locus on the human X chromosome contains triplet CGG repeats (CGGCGGCGGCGG, etc.). The number of CGGs may be as few as 5 or as many as 50 without causing a harmful phenotype Number of these repeats can increase from one generation to the next (to as many as 4000 repeats This causes a constriction in the X chromosome, which makes it quite fragile.  Males who inherit such a chromosome (only from their mothers,) show a number of harmful phenotypic effects including mental retardation. Females who inherit a fragile X (also from their mothers); only mildly affected (males with the syndrome seldom become fathers)  Translocations Translocations are the transfer of a piece of one chromosome to a nonhomologous chromosome. Translocations can alter the phenotype in several ways: the break may occur within a gene destroying its function the breakpoint may occur within a gene creating a hybrid gene.  Example;The Philadelphia chromosome found in chronic myelogenous leukemia (CML) is the result of a translocation which produces a hybrid gene (bcr-abl).  Somatic -Germline Mutations The significance of mutations is influenced by the distinction between germline and soma. Mutations that occur in a somatic cell ( in the bone marrow or liver etc) , may * damage the cell * make the cell cancerous * kill the cell somatic mutation disappears when the cell in which it occurred, or its owner, dies. germline mutations, will be found in every cell produced from the zygote every cells will contain the mutation.