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Overview of mutation

Overview of mutation



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    Mutation Mutation Presentation Transcript

    • MUTATION Mutation: An Overview Salwa Hassan Teama
    • Mutation  A mutation is a change in genetic material.  A mutation is a change in the DNA sequence or chromosomal mutation.  Most mutation are the result of error during DNA replication process/ error during DNA repair. Some types of mutations are known to be caused by certain chemicals and ionizing radiation, UV.
    • Mutation A mutation that arises naturally and not as a result of exposure to mutagens. Induced mutations caused by mutagens; Radiation, Chemicals, or Viruses,…
    • Spontaneous Mutations Spontaneous mutations on the molecular level can be caused by : Tautomerism: A base is changed by the repositioning of a hydrogen atom, altering the hydrogen bonding pattern of that base, resulting in incorrect base pairing during replication. Depurination: Loss of a purine base (A or G) to form an apurinic site (AP site). Deamination: Hydrolysis changes a normal base to an atypical base containing a keto group in place of the original amine group. Examples include C → U and A → HX (hypoxanthine), which can be corrected by DNA repair mechanisms; and 5MeC (5-methylcytosine) → T, which is less likely to be detected as a mutation because thymine is a normal DNA base. Slipped strand mispairing: renaturation in a different spot ("slipping") after denaturation of the new strand from the template during replication. This can lead to insertions or deletions. www.wikipedia
    • Mutagen A Mutagen is an agent of substance that can bring about a permanent alteration to the physical composition of a DNA gene
    • Mutation Small scale mutation  Point mutation  Insertion/Deletion Large scale mutation  Amplifications  Deletions of large chromosomal regions, leading to loss of the genes within those regions.  Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct fusion genes (e.g., bcr- abl). These include:  Chromosomal translocations  Interstitial deletions  Chromosomal inversions: reversing the orientation of a chromosomal segment.  Loss of heterozygosity: loss of one allele, either by a deletion or a recombination event, in an organism that previously had two different alleles.
    • Mutation Germline mutation  A heritable change in the DNA.  Occurred in a germ cell and incorporated in every cell of the body.  Can be transmitted to the next generation.  Germline mutations play a key role in inherited genetic diseases. Somatic mutation  Alterations in DNA that occur after conception.  Occur in any of the cells of the body except germ cell.  Can not transmitted to the next generation.  These alterations can (but do not always) cause cancer or other diseases.
    • Mutation Gain-of-function mutations  Change the gene product such that it gains a new and abnormal function.  These mutations usually have dominant phenotypes.  Often called a neomorphic mutation. Loss-of-function mutations  The gene product having less or no function.  These mutations usually have recessive phenotypes. Exceptions are when the organism is haploid, or when the reduced dosage of a normal gene product is not enough for a normal phenotype (haploinsufficiency).  When the allele has a complete loss of function (null allele) it is often called an amorphic mutation. Lethal mutations are mutations that lead to the death of the organisms that carry the mutations. A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype
    • Point Mutation
    • Point Mutation Base substitutions are those mutations in which one base pair is replaced by another. Transition: The replacement of a base by the other base of the same chemical category (purine/ purine; pyrimidine/ pyrimidine). Transversion: The replacement of a base of one chemical category by a base of the other (pyrimidine/ purine; purine/ pyrimidine).
    • Effect of Point Mutation Silent mutation: Single substitution mutation when the change in the DNA base sequence results in a new codon still coding for the same amino acid. Missense mutation: One triplet codon altered, results in one wrong codon and one wrong amino acid.  Acceptable missense: This occur when single base change results in replacement of one A.A by another with rather same function.  Non acceptable missense: This occur when single base change result in the replacement of one amino acid with another with completely different function. Nonsense mutation: Change a codon that specifies an amino acid into a termination codon lead to shortened protein because translation of the mRNA terminate prematurely.
    • Introduction to Genetic analysis, Ninth edition, W.H. Freeman and Company
    • Sickle Cell Disease It results from a single base change in the gene for B-globin. The altered base cause insertion of the wrong amino acid into one position of B globin protein. These altered protein results in distortion of red blood cells under low oxygen conditions
    • Insertion/Deletion Source:
    • Insertion/Deletion Insertion/deletion can disrupt the grouping of the codons, resulting in a completely different translation. Deletions: Remove information from the gene. A deletion could be as small as a single base or as large as the gene itself. Insertions: Occur when extra DNA is added into an existing gene. Multiple of 3 (codon) / Not multiple of 3 Multiple of 3 (codon) causes loss or gain of codons and subsequently amino acids in translated product. Not multiple of 3 Altered reading frame or fram-shift, altered amino acid sequence, often premature termination of protein through generation of termination codon with loss of function/activity.
    • RNA Processing Mutation RNA processing mutation destroy consensus splice sites, cap sites, polyadenylation sites, ..Abnormal splicing often leads to frameshift mutations and premature stop codon.
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    • Chromosomal Mutation Source: Wikipedia
    • Structural Abnormalities Result from: Misrepair of chromosome breaks or Malfunction of the recombination system. Balanced: no net gain or loss of chromosomal material, Example: Translocation, inversion, ring chromosome. UnBalanced: net gain or loss of chromosomal material Example: Loss or duplication of whole chromosome arms.
    • Variation in Chromosome Number Variations in the chromosome number (heteroploidy) can be mainly of two types:  Euploidy  Aneuploidy Euploidy: Change in whole chromosome sets.  Monoploidy  Diploidy  Polyploidy Aneuploidy: Changes in part of chromosome sets. An additional or missing chromosome.  Hypoploidy: Monosomy, nullisomy  Hyperploidy: Trisomy, Tetrasomy
    • Effect of Mutation No effect (silent mutation) Beneficial Harmful effect that leads to outright disease or death. Mutation that occur in utero are incompatible with life. Enencephaly
    • On rare occasions, A mutation result in a new characteristic which can help the organism survive in unfavorable environmental condition. The new characteristic will be passed to its offspring who can survive and others may die.
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    • Human chromosomes segmented by rates of four types of mutations; human DNA is compared with DNA from other primates (e.g., orangutans – in background) and then processed using a statistical segmentation technique. Credit: K. Makova and F. Chiaromonte Source:
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    • DNA Damage and Mutation
    • DNA Damage The various forms of spontaneous and induced DNA damage give rise to a different types of molecular mutation:  Nucleotide mismatch  Large deletion  Addition  Translocation  …
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    • The quality of existing in several different forms. POLYMORPHISM Polymorphism
    •  SNP represents a variation of one base in the DNA.  The most common type of genetic variation.  Each individual has many single nucleotide polymorphisms that together create a unique DNA arrangement for that individual. Single Nucleotide Polymorphism
    • SNP is a source variance in a genome. SNPs are the most simple form and most common source of genetic polymorphism in human genome. SNPs begin their existence as point mutations (nonsense mutation). Two types of nucleotide base substitutions resulting in SNPs: Transition: Substitution occurs between purines or pyrimidines. Account 2/3 of all SNPs. Transversion: Substitution occurs between purines and a pyrimidines. Single Nucleotide Polymorphism
    • Distribution of SNPs
    • Coding region SNPs The substitution causes no amino acid change to the protein it produces (silent mutation). The substitution results in an alteration of the encoded amino acid. A non sense mutation results in a misplaced termination codon. Synonymous Non Synonymous
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    • Mutation Polymorphism Change in DNA sequence within cell. Some mutation cause disease, others cause genetic variation Change in DNA sequence lead to genetic variation within individuals, groups or population. No single allele is regarded as the standard sequence. Instead there are two or more equally acceptable alternatives. Less common differences occurring in less than 1% of the population. Occurring in at least 1% of the population, Mostly have been associated with disease (or risk of disease) and May resulted from damage by external agents (such as viruses or radiation). Polymorphic DNA sequences can be used as markers for determining allelic inheritance of disease causing genes and for identity testing Common mutation can be classified as polymorphism. However, many mutation are not polymorphic, they represented a rare genetic event. A rare disease allele in one population can become a polymorphism in another if it confers an advantage and increases in frequency.
    • References and Online Further Reading  Ali Khalifa. Applied molecular biology; eds: ( Fathi Tash and Sanna Eissa). 109 pages. Egypt. University Book Center. 2002.  Daniel H. Farkas. DNA Simplified: The Hitchhiker's Guide to DNA. 110 pages. Washington, DC: AACC Press, 1996, ISBN 0- 915274-84-1. Available in paper copy from the publisher  Daniel P. Stites, Abba T. Terr. Basic Human Immunology: 336 Pages. Appleton & Lange (November 1990). ISBN. 0838505430.  Innis, David H. Gelfand, John J. Sninsky. PCR Applications: Protocols for Functional Genomics: 566 pages. Academic Press; 1 edition (May 17, 1999). ISBN:0123721865.  Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter. Molecular Biology of the cell. 1392 pages. Garland Science; 5 edition (November 16, 2007).ISBN. 9780815341055.  Robert F. Mueller, Ian D. Young. Emery's Elements of Medical Genetics: Publisher: Churchill Livingstone. 1995 ISBN. 044307125X.  Robert F. Weaver. Molecular Biology. 600 Pages. Fourth Edition. McGraw-Hill International Edition. ISBN 978-0- 07-110216-2.  William B. Coleman, Gregory J. Tsongalis . Molecular Diagnostics. For the Clinical Laboratorian: 592 pages. Humana Press; 4th Printing. edition (August 15, 2005). ISBN 1588293564  Eukaryotic promoter . Internet. Available from: Transcription factor. Available from. Fred Hutchinson Cancer Research Center  Transcription factor . Internet. Table. Available from;
    • All images belong to their respective authors Thank You Salwa Hassan Teama 2014