GENE MUTATION |GeneticsReporter: Jaycris C. Agnes1Introduction:Genetic CodeThe genetic code is the set of rules by which information encoded within genetic material(DNA or mRNA sequences) is translated into proteins (amino acid sequences) by living cells.Gene MutationA gene mutation is defined as an alteration in the sequence of nucleotides in DNA. This changecan affect a single nucleotide pair or larger gene segments of a chromosome. DNA consists ofa polymer of nucleotides joined together. During protein synthesis, DNA is transcribed into RNAand then translated to produce proteins. Altering nucleotide sequences most often results innonfunctioning proteins. Mutations cause changes in the genetic code that lead to geneticvariation and the potential to develop disease.Gene Mutation
GENE MUTATION |GeneticsReporter: Jaycris C. Agnes2Kinds of Gene Mutation1. Point MutationsPoint mutations are the most common type of gene mutation. Also called a base-pair substitution,this type of mutation changes a single nucleotide base pair. Point mutations can be categorizedinto three types:Silent Mutation: Although a change in the DNA sequence occurs, this type of mutation doesnot change the protein that is to be produced. This is because multiple genetic codons canencode for the same amino acid. Amino acids are coded for by three nucleotide sets calledcodons. For example, the amino acid arginine is coded for by several DNA codons includingCGT, CGC, CGA, and CGG (A = adenine, T = thymine, G = guanine and C = cytosine). If theDNA sequence CGC is changed to CGA, the amino acid arginine will still be produced.Missense Mutation: This type of mutation alters the nucleotide sequence so that a differentamino acid is produced. This change alters the resulting protein. The change may not havemuch effect on the protein, may be beneficial to protein function, or may be dangerous. Usingour previous example, if the codon for arginine CGC is changed to GGC, the amino acidglycine will be produced instead of arginine.Types of Missense Mutation:o Conservative mutations: Result in an amino acid change. However, theproperties of the amino acid remain the same (e.g., hydrophobic, hydrophilic, etc).At times, a change to one amino acid in the protein is not detrimental to theorganism as a whole. Most proteins can withstand one or two point mutationsbefore their functioning changes.o Non-conservative mutations: Result in an amino acid change that has differentproperties than the wild type. The protein may lose its function, which can resultin a disease in the organism. For example, sickle-cell disease is caused by a singlepoint mutation (a missense mutation) in the beta-hemoglobin gene that converts aGAG codon into GUG, which encodes the amino acid valine rather than glutamicacid. The protein may also exhibit a "gain of function" or become activated, suchis the case with the mutation changing a valine to glutamic acid in the braf gene;this leads to an activation of the RAF protein which causes unlimited proliferativesignalling in cancer cells. These are both examples of a non-conservative(missense) mutation.
GENE MUTATION |GeneticsReporter: Jaycris C. Agnes3Nonsense Mutation: This type of mutation alters the nucleotide sequence so that a stopcodon is coded for in place of an amino acid. A stop codon signals the end ofthe translationprocess and stops protein production. If this process is ended too soon, theamino acid sequence is cut short and the resulting protein is most always nonfunctional.In this example, the nucleotide cytosine is replaced by thymine in the DNA code, signaling the cell toshorten the protein.2. Frameshift MutationThis type of mutation occurs when the addition or loss of DNA bases changes a gene’sreading frame. A reading frame consists of groups of 3 bases that each code for oneamino acid. A frameshift mutation shifts the grouping of these bases and changes thecode for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions,and duplications can all be frameshift mutations.
GENE MUTATION |GeneticsReporter: Jaycris C. Agnes4A frameshift mutation changes the amino acid sequence from the site of the mutation.3. Repeat expansionNucleotide repeats are short DNA sequences that are repeated a number of times in arow. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and atetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is amutation that increases the number of times that the short DNA sequence is repeated.This type of mutation can cause the resulting protein to function improperly.In this example, a repeated trinucleotide sequence (CAG) adds a series of the amino acid glutamine to theresulting protein.
GENE MUTATION |GeneticsReporter: Jaycris C. Agnes5Specific diseases caused by gene mutationCystic fibrosisA defect in the cystic fibrosis transmembrane conductance regulator (CFTR) genecauses cystic fibrosis (CF). A protein made by this gene controls the movement of the water andsalt in and out of the bodys cells. Genes in people with CF incorrectly code proteins. This causesthick, sticky mucus and very salty sweat.CancerPoint mutations in multiple tumor suppressor proteins cause cancer. For instance, pointmutations in Adenomatous Polyposis Coli promote tumorigenesis.Sickle-cell anemiaSickle-cell anemia is caused by a point mutation in the β-globin chain of haemoglobin,causing the hydrophilic amino acid glutamic acid to be replaced with the hydrophobic aminoacid valine at the sixth position.The β-globin gene is found on the short arm of chromosome 11. The association of twowild-type α-globin subunits with two mutant β-globin subunits forms haemoglobin S (HbS).Under low-oxygen conditions (being at high altitude, for example), the absence of a polar aminoacid at position six of the β-globin chain promotes the non-covalent polymerisation (aggregation)of haemoglobin, which distorts red blood cells into a sickle shape and decreases their elasticity.Below is a chart depicting the first thirteen amino acids in the normal and abnormal sicklecell polypeptide chain.Sequence for Normal HemoglobinATG GTG CAC CTG ACT CCT GAG GAG AAG TCT GCC GTT ACTSTART Val His Leu Thr Pro Glu Glu Lys Ser Ala Val ThrSequence for Sickle Cell HemoglobinATG GTG CAC CTG ACT CCT GTG GAG AAG TCT GCC GTT ACTSTART Val His Leu Thr Pro Val Glu Lys Ser Ala Val Thr