Gene and Chromosomal Mutations PDF

CENTRAL PHILIPPINE UNIVERSITY COLLEGE OF MEDICAL LABORATORY SCIENCE GENE AND CHROMOSOMAL MUTATIONS MUTATION Any heritable alteration in a gene or chromosome Permanent alteration of the nucleotide sequence of the genome of an organism , virus, or other genetic elements Could b...

CENTRAL PHILIPPINE UNIVERSITY COLLEGE OF MEDICAL LABORATORY SCIENCE GENE AND CHROMOSOMAL MUTATIONS MUTATION Any heritable alteration in a gene or chromosome Permanent alteration of the nucleotide sequence of the genome of an organism , virus, or other genetic elements Could be beneficial, neutral, or detrimental to the organism GENE MUTATIONS GENE MUTATIONS Major Types of Gene Mutations Classified According To: 1. Origin A. Loss-of- 5. Molecular mous A. Spontan function Change B. Missens eous B. Hypomo 5. Base e B. Induced rphic substitu C. Nonsen C. Hyperm tion se 2. Cell Type orphic 6. Transitio D. Frames A. Somatic D. Gain-of- n hift B. Germ- function 7. Transver line sion 3. Expression 8. Insertio A. Conditio n nal 9. Deletion B. Uncondi tional 6. Effect on translation 4. Effect on A. Synony function 1. ORIGIN A. Spontaneous Mutation – Occurs in the absence of known mutagen B. Induced Mutation – Occurs in the presence of a known mutagen  Mutagen – An agent that is capable of increasing the rate of Potassium bromate, a common baking mutation ingredient can cause oxidative damage to – Ex. Bromine, Benzene, X- the DNA rays, UV radiation, etc. 2. CELL TYPE A. Somatic Mutation – Occurs in non- reproductive cells – Most common cancers result from somatic-cell mutations – Not passed along to the next generation by sexual means B. Germ-line Mutation The Royal Disease. The X-linked – Occurs in reproductive cells blood disorder hemophilia in European royal families is thought – Mutation can be passed to have arisen in the germ cell line on to the next generation of Queen Victoria or one of her parents. 3. EXPRESSION A. Conditional Mutation – Expressed only under restrictive conditions (e.g. high temperatures) – Ex. temperature-sensitive mutations B. Unconditional Mutation – Expressed under permissive as well as restrictive conditions  Permissive condition An enzyme involved in the deposition of  Condition in which the melanin in Siamese Cats is blocked at phenotype of a conditional normal body temperature but expressed mutation is not expressed at colder temperatures. The extremities of  Restrictive condition the cat (tips of the legs, ears, snout, and  Condition in which a phenotype tail) have a characteristic pigmentation of a conditional mutation is because these areas are cooler than the expressed rest of the body 4. EFFECT ON FUNCTION A. Loss-of-function Mutation – AKA Knockout or Null Mutation – Mutation that results in complete gene inactivation or in a completely non-functional gene product – Ex. Deletion of all parts of a gene, amino acid replacement that inactivates CHON B. Hypomorphic Mutation – AKA Leaky Mutation – Mutation that reduces, but does not completely eliminate gene expression or the activity of the gene product – Ex. Nucleotide substitution that reduces level of transcription, amino acid replacement that impairs protein function 4. EFFECT ON FUNCTION C. Hypermorphic Mutation – Produces a greater than normal level of gene expression – Typically affects gene regulation D. Gain-of-function Mutation – Qualitatively alters the gene action – May cause a gene to become active in type of cell or tissue in which the gene is not normally active – May result in the expression of a gene at a time in which the gene is not normally expressed 5. MOLECULAR CHANGE A. Base Substitution – One base pair in the DNA is replaced with a different base pair – Ex. A is replaced by G resulting to a temporarily mismatched G-T base pair 5’-ATCCGGAA-3’ 5’-ATCCGGGA-3’ 3’-TAGGCCTT-5’ 3’-TAGGCCTT-5’ – But at the very next replication the mismatch is resolved as a proper G-C base pair in one daughter strand and A-T base pair in other daughter strand 5’-ATCCGGGA-3’ 5’-ATCCGGGA-3’ MUTANT 3’-TAGGCCCT-5’ 3’-TAGGCCTT-5’ 3’-TAGGCCTT-5’ NON-MUTANT 5’-ATCCGGAA-3’ 5. MOLECULAR CHANGE B. Transition Mutation – One pyrimidine base is replaced with the other pyrimidine base or one purine base with the other purine base – The four possible transitions are: PyrimidinePyrimidine TC or CT PurinePurine AG or GA 5. MOLECULAR CHANGE C. Transversion Mutation – A pyrimidine base is replaced with a purine base or the other way around – The eight possible transversions are: PyrimidinePurine TA TG CA CG PurinePyrimidine AT AC GT GC 5. MOLECULAR CHANGE D. Insertion – One or more nucleotides are added 5’-ATCCGGAA-3’ 5’-ATCCGGACA-3’ C E. Deletion – One or more nucleotides are missing 5’-ATCCGGAA-3’ 5’-ATCCGG_A-3’ A 6. EFFECT ON TRANSLATION A. Synonymous Substitution – AKA Silent substitution – Mutations in the nucleotide sequence do not change the amino acid sequence – Particularly in mutations that occur in the third codon position B. Missense Mutation – AKA Nonsynonymous mutation – Mutations in the nucleotide sequence alter the amino acid sequence – Ex. Replacement in the AA sequence of phenylalanine hydroxylase resulting to phenylketunuria C-G base pair is replaced by T-A at codon 408 of the gene The resulting mRNA is UGG (Tryptophan) instead of CGG (Arginine) 6. EFFECT ON TRANSLATION C. Nonsense Mutation – A base substitution creates a new STOP codon (UAA, UAG, or UGA) – Almost always result in loss of gene function – Ex. UGG (Try)  UGA (Stop) D. Frameshift Mutation – Mutation that shifts the reading frame of the codons in the mRNA – Deletions or Insertions in the mRNA sequence shifts the phase in which the ribosome reads the triplets – Ex. Addition of an Adenine CUGCUGCUGCUG CUGACUGCUGCUG │CUG │ CUG │ CUG │ CUG │ │CUG │ ACU │ GCU │GCU │ Leu Leu Leu Leu Leu His Ala Ala Synonymous Mutation Nonsense Mutation  Frameshift Mutation A CUG CUG CUG CUG Leu Leu Leu Leu  Frameshift Mutation CUG ACU GCU GCU Leu His Ala Ala A sentence comprised of three-letter words provides analogies to the effects of mutations on a gene’s DNA sequence: Normal THE ONE BIG FLY HAD ONE RED EYE Missense THQ ONE BIG FLY HAD ONE RED EYE Nonsense THE ONE BIG ---------------------------------- Frameshift THE ONE QBI GFL YHA DON ERE DEY Deletion THE ONE BIG HAD ONE RED EYE Insertion THE ONE BIG FLY WET HAD ONE RED EYE Duplication THE ONE BIG FLY FLY HAD ONE RED EYE CHROMOSOMAL MUTATIONS CHROMOSOMAL MUTATIONS OUTLINE OF TOPICS A. Chromosomes C. Summary of Aberrations I. Structure D. Advantages and II. Parts Disadvantages of III. Types Mutations IV. Groups V. Bands VI. Banding Nomenclature B. Chromosomal Mutations I. Structural Chromosomal Mutations II. Chromosomal Number Mutations III. Other Chromosomal Structural Abnormalities B. CHROMOSOMAL MUTATIONS I. Structural Chromosomal Mutations II. Chromosomal Number Mutations III. Other Chromosomal Structural Abnormalities B. CHROMOSOMAL MUTATIONS Any change or error that occurs within the chromosome Affects the entirety of the chromosome Types: I. Mutations on the structure of chromosomes II. Mutations on chromosome number I. STRUCTURAL CHROMOSOMAL MUTATIONS Usually occurs during any errors in cell division Classification: 1. Deletion 2. Duplication 3. Inversion 4. Translocation 1. DELETION A part of DNA is not duplicated or lost during DNA replication The deleted region could range from a mere nucleotide or can be as large as an entire chromosome Ex. Cri Du Chat, Duchenne muscular dystrophy, Di George’s syndrome, etc. 2. DUPLICATION An extra copy of a region or regions in the DNA is produced The extra copy can be located in its normal location, other parts of the chromosome, or even in another chromosome Ex. Charcot-Marie-Tooth disease type I 3. INVERSION A portion in the chromosome is reversed and gets inserted back into the chromosome Individual is often normal unless inversion breakpoint is in the middle of a gene or affects the centromere Types: – Pericentric: encompasses the centromere of the chromosome – Paracentric: involves either the short or long arm of the chromosome and does not include the centromere 4. TRANSLOCATION A fragmented chromosome tends to join with a non-homologous chromosome The newly-formed segment then detaches from the chromosome and moves to a new position on another chromosome Types: – Reciprocal Translocation – Robertsonian Translocation 4A. RECIPROCAL TRANSLOCATION – Two different chromosomes exchange parts – Individual is usually normal unless the translocation break point is in the middle of a gene 4B. ROBERTSONIAN TRANSLOCATION – Two q arms of two different chromosomes come together but the two p arms lost entirely – This results to an overall chromosome number of 45 instead of 46 – Commonly occurs between chromosome 13/14 and 14/21 – Ex. Translocation Down Syndrome, Trisomy 13 B. CHROMOSOMAL NUMBER MUTATIONS “Ploidy” refers to the number of sets of chromosomes in a cell Terms: 1. Euploidy 2. Aneuploidy 3. Polyploidy 1. EUPLOIDY Cells contain correct and complete set of chromosomes Examples include but are not limited to: – Monoploidy (x) One copy of each homolog – Diploidy (2x) Two copies of each homolog Humans are diploid organisms (one set of chromosomes from each parents) 2. ANEUPLOIDY The chromosome number of the new individual is different from its wild type – Wild type: most common genotype or phenotype in a given population Typically a result of non-disjunction of chromosomes during mitosis – Non-disjunction: Unequal division of chromosomes during meiosis – One gamete has two copies of the same chromosome whereas the other gamete contains zero copy of that chromosome NON-DISJUNCTION 2. ANEUPLOIDY As a result, offsprings have either extra or lost chromosomes (in humans having 47 or 45 chromosomes instead of 46) The naming of aneuploid conditions is based on the chromosome number added or deleted A. Monosomy (2n-1) B. Trisomy (2n+1) C. Tetrasomy (2n+2) D. Nullisomy (2n-2) 2A. MONOSOMY 2n-1 Refers to lack of one chromosome of the normal complement Ex. Turner Syndrome (45,X or 45,X0) – Female is partly or completely missing an X chromosome – Affected individuals have short stature, low hairline, abnormal bone development and eye features, webbed necked, and a “cave-in” appearance to the chest 2B. TRISOMY 2n+1 Refers to presence of three copies, instead of the normal two, of a particular chromosome Only Trisomy 13 (Patau syndrome), 18 (Edwards syndrome) and 21 ( Down syndrome) are viable Trisomy of sex chromosomes is also possible (47, XXX), (47, XXY) (47, XYY) 2C. TETRASOMY/ PENTASOMY 2n+2/2n+3 Presence of four or five copies of chromosome, respectively Rarely seen in autosomes Tetrasomy/pentasomy of sex chromosomes have been reported 2D. NULLISOMY 2n-2 Lack of both the normal chromosomal pairs Humans with this condition will not survive 3. POLYPLOIDY Refers to numerical change in a whole set of chromosomes An individual bears more than one set of chromosomes Common phenomenon among plants as well as certain groups of fish, salamander, frogs, and leeches 3. POLYPLOIDY Rarely occurs in humans (although it occurs in highly-differentiated tissues such as liver parenchyma and heart muscle) Occurs as (Humans): A. Triploidy B. Tetraploidy 3A. TRIPLOIDY 3x or 3 sets of chromosomes  3 x 23 = 69 chromosomes Majority of triploid conceptions end as a miscarriage Those that do survive to term typically die shortly after birth May be a result of either: – Digyny: extra haploid set is from the mother – Diandry: extra haploid set is from the father 3B. TETRAPLOIDY 4x or 4 sets of chromosomes  4 x 23 = 92 chromosomes More rarely diagnosed than triploidy Also end up to miscarriage III.OTHER ABNORMAL CHROMOSOMAL STRUCTURES Isochromosomes – Two identical chromosome arms – Two p’s or two q’s Ring chromosomes – One end of chromosome attaches to one end forming a ring due to lost or non-functional telomeres – Cannot undergo mitosis successfully SUMMARY OF ABBERATIONS ADVANTAGES OF MUTATIONS 1. Survival – Help some individuals of the population to adapt to their environment – Important force in evolution because they balance out frequency of allelles present in a population – Examples: Malaria resistance, lactose intolerance 2. Diversity – Without genetic diversity, some of the fundamental mechanisms of evolutionary change cannot and continue to operate DISADVANTAGES OF MUTATIONS 1. Genetic Disorders – Mutations can cause a wide variety of genetic disorders which can be highly devastating 2. Other diseases – Aside from inheritable disorders, certain mutations can also bring about the onset of other diseases (e.g. Lung, breast, and bladder cancer)