Mutations PDF - San Pedro College - MLS 420

MUTANT MUTATIONS Prelims: MLS 420  Overview on mutations Point mutations Learning Spontaneous vs Induced mutations Points Large-scale chromosomal changes Cancer: An Important Phenotypic Consequence Mutations ...

MUTANT MUTATIONS Prelims: MLS 420  Overview on mutations Point mutations Learning Spontaneous vs Induced mutations Points Large-scale chromosomal changes Cancer: An Important Phenotypic Consequence Mutations  Genetic variants Individuals showing phenotypic differences in one or more particular characters mutation recombination Change in the DNA sequence of a gene Grouping into new combinations  Change in the DNA sequence from the normal Can be small or in large-scale mutations May or may not produce detectable changes in the phenotype ranging from no change at all to lethal Point mutations  Base Base INDELS substitution (Insertions/Deletions)  Base substitution  #1 #2 The genetic Functional There exists code is stop codons consequences degenerate (Translation (Wobble hypothesis) termination)  Wobble hypothesis Francis Crick (1996) 1 Synonymous mutations Also called silent mutations Mutation changes one codon of an amino acid into another codon for the mRNA same amino acid Can result from base substitution 2 Missense mutations Also called nonsynonymous mutations The codon for one amino acid is changed into a codon for another AA mRNA conservative or nonconservative Can result from base substitution 3 Nonsense mutations The codon for one amino acid is changed into a translation-termination codon Results in premature chain mRNA termination Can result from base substitution 3 Nonsense mutations The closer this mutation is to the 3’ end of the open reading frame (ORF), mRNA the more likely it is that the resulting protein has biological activity 4 INDEL MUTATIONS There is an introduction or taking out of a new base in a sequence Affects all codons downstream of the mRNA mutation resulting in a frameshift Typically result in a complete loss of normal protein structure and function Strand slippage & Frameshifts  Take NOTE: Single base pair changes that INACTIVATE proteins are often due to splice site mutations 5 Noncoding region mutations Functional consequences in this region depend on whether it disrupts or creates a binding site mRNA Many elicit little to no phenotypic change  Spontaneous INDUCED Naturally occurring mutations Arise through the action of that arise in all cells mutagens that increase the rate of mutations Spontaneous mutations  Spontaneous: Illegitimate nucleotide pairs form in DNA synthesis (e.g. G-T instead of G-C) Errors in DNA May lead to transitions and transversions, or replication frameshifts  Spontaneous: Errors in DNA Tautomers replication  Depurination Spontaneous: Loss of a purine base Interruption of the N-glycosidic bond Spontaneous The resulting apurinic sites cannot specify a base complementary to the original purine lesions Depurination Spontaneous: Spontaneous lesions  Deamination Spontaneous: Spontaneous lesions Loss of an amino group (NH2) from cytosine  Oxidative damage Spontaneous: Reactive oxygen species are produced by normal aerobic metabolism Spontaneous Causes oxidative damage to DNA and its precursors (e.g. GTP) lesions Oxidative damage Spontaneous: Spontaneous lesions induced mutations  base replacement Mutagenesis base alteration base damage  induced: Some chemical compounds are sufficiently similar to the normal bases of DNA and are Base analog called base analogs Does not behave like normal bases incorporation Incorrect base pairing  induced: Base analog incorporation 2-aminopurine  Alteration of a base such that it will form a specific mispair Induced: Specific mispairing E.g. ethylmethanesulfonate and nitrosoguanidine  Induced: Specific mispairing  induced: Planar molecules that mimic base pairs Intercalating Can slip in between stacked nitrogen bases agents E.g. acridine orange (fluorescent stain)  induced: Intercalating agents  Damage to one or more bases Induced: No specific base pairing is possible, resulting in a replication block BASE E.g. UV light , ionizing radiation, aflatoxins DAMAGE  Induced: uv-light BASE DAMAGE  Induced: BASE DAMAGE  Induced: BASE DAMAGE Chromosomal changes  Allele – genetic variants controlling the same trait Let’s define Euploid – multiples of the basic chromosome set Aneuploid – one or more chromosomes missing or some terms! in surplus Polyploid – Extra set/s of chromosomes Change in chromosome number Aberrant Euploidy Changes in whole sets of chromosomes mRNA Having more or less than normal number of sets Monoploid and Polyploids  Femal e Male Human Karyotype Melitoma segmentaria karyotype Polyploids Change in chromosome number Aneuploidy Chromosome number differs from the wild type by a part of the chromosome set mRNA Can have a number greater or smaller than the wildtype  Nondisjunction Cause of most aneuploidy in the course of meiosis or mitosis  Monosomy (2n-1) Missing one copy of a chromosome Monosomic autosomes = die in utero e.g. Turner syndrome (XO)  Trisomy (2n+1) Has one extra copy of a chromosome Abnormality/death e.g. Klinefelter syndrome (XXY)  Trisomy (2n+1) Has one extra copy of a chromosome Abnormality/death e.g. Klinefelter syndrome (XXY)  Why are aneuploids so much more abnormal Gene than polyploids? balance Why are monosomics more severely affected than trisomics?  HOW IS THIS BALANCED? xy The X chromosome has house-keeping genes and it is kept similar in males and females by dosage compensation via X chromosome inactivation  Change in chromosome structure Unbalanced balanced rearrangements rearrangements Change the gene dosage of a Change in gene order only chromosome segment NA  Inversions On the same chromosome  reciprocal Translocation trading of acentric fragments of two nonhomologous chromosomes Clinical correlate: Cancer genetics  An important phenotypic consequence of mutations Aggregate of cells from a single clone Cancer Cancer-promoting mutations: ✔ Increase in proliferation ability ✔ Decrease susceptibility to apoptosis ✔ Increase general mutation rate of the cell ✔ Increased longevity  Cancer mutations Proto-oncogenes when they have a gain-of-function mutation, become oncogenes Tumor-suppressor genes become cancerous when they have loss-of-function mutations  p53 “Guardian of the Genome” Tumor-suppressor gene 50% of human tumors lack a functional p53 gene  Somatic translocation MUTATIONS