Genetic Variations and Mutations PDF

19 GENETIC VARIATIONS AND MUTATIONS ILOs By the end of this lecture, students will be able to 1. Recognize the different types of mutation. 2. Predict the effect of types of mutation on amino acid sequence and protein structure. 3. Correlate the phenotypic outcome with type of...

19 GENETIC VARIATIONS AND MUTATIONS ILOs By the end of this lecture, students will be able to 1. Recognize the different types of mutation. 2. Predict the effect of types of mutation on amino acid sequence and protein structure. 3. Correlate the phenotypic outcome with type of mutation What is meant by mutations? Mutations are permanent changes in a DNA sequence. This altered DNA sequence can be reflected by changes in the base sequence of mRNA, and, sometimes, by changes in the amino acid sequence of a protein. Mutations can cause genetic diseases. Types of mutation I- Point mutation (single base substitution): (Figure 1) This entails the substitution of the original base in the gene by another. This can take either of two forms: 1- Transition: In which one purine is replaced by another purine or one pyrimidine is replaced by another pyrimidine. e.g. A >>>G or C>>>T 2- Transversion: In which a purine is replaced by a pyrimidine or a pyrimidine is replaced by a purine. e.g. T>>>> A, C >>>> A, T>>>>> G, C>>>> G Figure 1. point mutation Single-base substitutions may have no physiologic effect if they occur in a DNA region that is not part of the coding or regulatory regions of a gene. Mutations may alter regulatory sequences, eg, in promoter or enhancer regions, which can affect gene expression. Single-base changes that occur within a coding region of a gene may produce disease alleles Consequences of point mutation (Figure 2) 1- Silent mutation: The codon containing the changed base may code for the same amino acid. 1  For example, if the serine codon UCA is given a different third base (to become, say, UCU), it still codes for serine. This usually happens if the mutation happens in the 3 rd codon.(refer to wobble’s theory in translation lecture) Therefore, this is termed a “silent” mutation without any effect on protein structure. 2. Missense mutation: (Figure 2) The codon containing the changed base may code for a different amino acid. The substitution of an incorrect amino acid may result in variable effects on protein structure (e.g. hemoglobin β- chain). This type of mutation can result in one of the following: a- Acceptable missense mutation AAA>>>>>>>>> AAU (codons) Lysine>>>>>>>> Asparagine (amino acid) 61 This produces apparently normal functional hemoglobin. b- Partially acceptable missense mutation GAA>>>>>>>>>> GUA (codons) Figure 2. Consequences of point mutation Glutamic acid>>> Valine (amino acid) 6 This produces Hb S; it can bind and release O2 although abnormal, but doesn’t function in low O2 saturation. C- Unacceptable missense mutation: CAU>>>>>>>> UAU (codons) Histidine >>>>> Tyrosine (amino acid) 58 This produces Hb M; it cannot transport O2 and the only treatment is repeated blood transfusions. Clinical implications Hereditary hemochromatosis (HH) is one of the most common genetic diseases. It is associated with two well-known missense mutations in the HFE gene (Human homeostatic iron regulator protein). These mutations are used to screen ‘‘at-risk populations’’ for this disorder of iron metabolism, which results in liver damage (cirrhosis), diabetes, skin pigmentation, and heart failure. (refer to cardiovascular module) 2 3) Non-sense mutations The codon containing the changed base may become a termination codon. For example, if the Serine codon UCA is changed at the second base and becomes UAA, the new codon causes premature termination of translation at that point and the production of a shortened (truncated) protein II) Frame shift mutation: (Figure3) It results from deletion (removal) or insertion (addition) of one or more nucleotides in DNA that generates altered m RNAs with different effects on protein structure. The insertion or deletion results in shifting in the way the codons are read, the thing that produces totally different aminoacids. Figure 3. Frameshift mutations III) Trinucleotide repeat expansion: (Figure 4) Occasionally, a sequence of three bases that is repeated in tandem will become amplified in number so that too many copies of the triplet occur. If this happens within the coding region of a gene, the protein will contain many extra copies of one amino acid. For example, expansion of the CAG codon in exon 1 of the gene for Huntington protein leads to the insertion of many extra glutamine residues in the protein, causing the neurodegenerative disorder Huntington disease. The additional glutamines result in an abnormally long protein that is cleaved, producing toxic fragments that aggregate in neurons. 3  Also, Fragile X syndrome, the most common cause of mental disability in males results from a similar mechanism Figure 4.Trinucleotide repeat expansion IV). Splice site mutations: Mutations at splice sites can alter the way in which introns are removed from pre-mRNA molecules, producing abnormal proteins. Gene silencing can result from splicing alterations leading to lack of protein production. Polymorphisms A polymorphism is a change in genotype that can result in no change in phenotype or a change in phenotype that is harmless, causes increased susceptibility to a disease, or, rarely, causes the disease. It is traditionally defined as a sequence variation at a given locus (allele) in >1% of a population. Polymorphisms primarily occur in the 98% of the genome that does not encode proteins (that is, in introns and intergenic regions). Types (Figure 4) 1. Single-base changes: About 90% of human genome variation comes in the form of single nucleotide polymorphisms (SNPs, pronounced “snips”), that is, variations that involve just one base. 2. Tandem repeats: Polymorphisms in chromosomal DNA can also arise from the presence of a variable number of tandem repeats (VNTR). These are short sequences of DNA at scattered locations in the genome, repeated in tandem (one after another). The number of these repeat units varies from person to person but is unique for any given individual and, therefore, serves as a molecular “fingerprint.” Clinical implications  Paternity tests (to prove the parenthood of a father to a baby) rely on fingerprinting (VNTR)  Polymorphisms can increase the susceptibility to diseases such as cancer and cardiovascular diseases.  Polymorphisms can be used for screening people at high risk of certain diseases 4 Figure 4. Types of polymorphism 5