Beruflich Dokumente
Kultur Dokumente
Contents:
Introduction to mutation Types of Mutations Molecular mechanism Base Substitution mutations
Ex: Sickle Cell Anemia
Frameshift mutation
Ex: Huntingtons Disease - Insertion Cystic fibrosis Deletion
Induced mutations
Tautomers Base Analogs Alkylating agents Intercalating agents Deamination and free radicals
Summary
Introduction to mutation:
Sudden change in genetic material. Term Mutation introduced by Hugo de Vries in year 1900. Hermann Muller X rays mutation in Drosophila. Bruce Ames 1970s mutagenicity tests
Types of Mutation:
Spontaneous Mutations Induced Mutations
1. 2. 3. Radiations Temperature Chemicals
Molecular mechanism:
DNA at molecular level is made up of four molecules called nucleotides They are Purines : Adenine & Guanine Pyrimidines : Cytosine & Thymine Linked with sugar and phosphate group.
They exist in form of triplet code, to synthesize particular amino acids i.e, during protein synthesis, they are called CODONS
At molecular level mutation occurs by change in nucleotide sequence in the genetic material. Based on the molecular change there are: 1.Base substitution mutations
Transitions Transversions
1. 2. 3. 4. Neutral mutations Silent mutations Missense mutations Nonsense mutation
2.Frameshift Mutations
Addition mutations Deletion mutations
Based on the consequence of mutation, the substitution mutation may be grouped intoneutral, silent,missense andnonsensemutations.
Frameshift Mutations:
Reading frame is altered, either by insertion or deletion.
One or more nucleotides are inserted into a sequence. If the number of inserted bases is not a multiple of 3, it will causeframeshift, resulting in serious consequences. As shown in the following table, non-frameshift insertions may also cause diseases.
Huntingtons Disease:
Huntingtons is an inherited disease, characterized by the aggregates of the misfolded protein, huntingtin. Normal huntingtins function is not clearly known, but when patients have more than 36 repeats of the nucleotide sequence, CAG, they then acquire the mutant form of huntingtin. Although the huntingtin protein is found throughout the body, the neuronal degeneration is selective to the corpus striatum. This exploration into the unanswered mysteries of Huntingtons disease tries to find the answer as to why mutant huntingtin only kills striatal cells. In 2009, Srinivasa et al., discovered Rhes, a striatal specific protein, that they found played a significant role in the pathway of Huntingtons disease. Rhes proteins have a strong bond with mutant huntingtin, and in order for the aggregation of mutant huntingtin to take place, this bond must be intact. Srinivasa et al., also demonstrated that cell survival is completely dependent on the aggregation of mutant huntingtin. - EukaryonJournal, March 01, 2011.
Deletion Mutations
Involves elimination of one or more nucleotides from a DNA sequence. It may cause frameshift, producing a non-functional protein. Real examples of deletion mutations which cause diseases. (a)Deletion of"T" from the sequence "TTTTT" in theCFTRgene. (b)Deletion of"AT" from the sequence "ATAT" in theCFTRgene. (c)Deletion of"TTG" from the sequence "TTGTTG" in theFIXgene. (d)Deletion of"ATAG" from the sequence "ATAGATAG" in theAPCgene.
Cystic Fibrosis
Cystic Fibrosis Transmembrane conductance Regulator (CFTR gene). 1.Cytogenetic Location: 7q31.2 2.Molecular Location on chromosome 7: base pairs 117,120,016 to 117,308,718 Deletion in CFTR protein resulting abnormal channel breaks down shortly after it is made, so it never reaches the cell membrane to transport chloride ions. Lungs, pancreas, and other organs produce mucus that is abnormally thick and sticky. The abnormal mucus obstructs the airways and glands, leading to the characteristic signs and symptoms of cystic fibrosis.
Induced Mutation:
Chemical mutagens Radiations
Tautomerization:
Change in nitrogenous base, ie hydrogen from adjacent carbon atom shifts to keto group to make it an enol form.
Tautomeric shifts:
Base Analogs:
A molecule similar enough to a purine or pyrimidine base to substitute for the normal bases, resulting in abnormal base pairing, only during replication.
Alkylating agents:
These agents can mutate both replicating and nonreplicating DNA. Each of these classes of chemical mutagens has certain effects that then lead to transitions, transversions, or deletions. EX: EMS, MMS etc.
Intercalating agents:
Acridines (e.g., proflavin) are positively charged molecules. They may be inserted between two DNA strands, thereby altering DNA's structure and rigidity. As a result, DNA replication will not be faithful.
Summary:
Thesunwashotbuttheoldmandidnotgethishat. The sun was hot but the old man did not get his hat. Codon The sun was was but the old man did not get his hat Base Substituion T hes unw ash otb utt heo ldm and idn otg eth ish at. - Frameshift
Thank you.