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Definitions Drugs- a chemical substance used in the treatment, cure, prevention, or diagnosis of disease. Genome- a full set of chromosomes. Gene- the basic physical unit of heredity. Nucleotides- subunits of nucleic acid formed from a simple sugar, a phosphate group, and a nitrogenous base. Mutation- permanent change in a cell’s DNA DNA- the material that transfers genetic characteristics in all life forms, constructed of two nucleotide strands coiled around each other in a double helix with the sidepieces composed of alternating phosphate and deoxyribose units and the rungs composed of the purine and pyrimidine bases adenine, guanine, cytosine, and thymine. mRNA- RNA, synthesized from a DNA template during transcription, that mediates the transfer of genetic information from the cell nucleus to ribosomes in the cytoplasm. Transcription- the transfer of genetic information from DNA to mRNA. Splicing- to join segments of DNA or RNA together. Introns- a noncoding segment in a length of DNA that interrupts a gene-coding sequence or nontranslated sequence. Exons- any part of an interrupted gene that is represented in the RNA product and is translated into protein. Translation- The process by which mRNA, tRNA, and ribosomes effect the production of a protein molecule from amino acids, the specificity of synthesis being controlled by the base sequences of the mRNA. Amino Acids- (building blocks of protein) carbon compound joined by peptide bonds. Codon- a three-base code in DNA or RNA. Non-coding DNA- components of an organism's DNA that do not encode protein sequences. SNP- (single nucleotide polymorphism) genetic variation in a DNA sequence that occurs when a single nucleotide in a genome is changed. Alleles- alternative form that a single gene may have for a particular trait. Hydrophilic- Attracted to water Hydrophobic- Water-repellant, fearing water. Signaling pathways- a group of molecules in a cell that work together to control one or more cell functions. Ex: Cell division or cell death. Genetic linkage- Genetic linkage is the tendency of genes that are located next to each other on a chromosome to be inherited together during meiosis. Pharmacogenomics- the study of human genetic variability in relation to drug action. Questions How does a gene become a protein? A: A gene becomes a protein through the processes of transcription and translation. In a given gene, what kind of DNA mutation would not change the protein that is made? A: In a given gene, a point mutation would not change the protein that is made. Why is non-coding DNA important? A: Non-coding DNA is important because it is a large percentage of an eukaryotic organism’s total genome size. Many types have biological functions such as the transcriptional and translational regulation of protein-coding sequences. What makes some amino acids hydrophobic and others hydrophilic? A: Some amino acids are hydrophilic because they interact with water by forming hydrogen bonds. Others are hydrophobic because they are nonpolar and they do not dissolve in water. Why is it important for pharmaceutical companies to test new drugs on a large number of people? A: It is important because those companies need to make sure that the drugs react the same to everyone. Also so that the drugs aren’t defective. Procedure Determining How Genetics Change Drug Responses 2. a) What does the entry on celecoxib tell you about its medical use? What kind of patientswould use celecoxib? How does the drug function, in general? The entry told me about how it is used medically to treat osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps. Celecoxib is used in patients with familial adenomatous polyposis. It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site. Both COX-1 & COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. b) i: The generic and trade (brand) names of the drug. Generic names: Celocoxib and Celecoxib Brand names: Celebra, Celebrex, and Onsenal. ii. What kind of chemical the drug is, and what other drugs it is related to. You may want to draw its chemical structure Celecoxib is a selective cyclooxygenase. Celecoxib is related to the following drugs: acenocourmarol, anisindione, dicumarol, fluconazole, warfarin, rifampin, and lithium. iii. What medical condition the drug is used to treat. Celecoxib is used to treat rheumatoid arthritis, osteoarthritis, and familial adenomatous polyposis (FAP). iv. The drug's general effect on the body. Symptoms of overdose include breathing difficulties, coma, drowsiness, gastrointestinal bleeding, high blood pressure, kidney failure, nausea, sluggishness, stomach pain, and vomiting. 4) a. Since celecoxib metabolism is predominantly mediated via CYP2C9, polymorphisms in CYP2C9 are likely to have a direct impact on celecoxib pharmacokinetics and variability in drug responses. CYP2C9 is an allele carrier. b. They are all allele carriers and they interact with the same drug. c. e. 5. (d) i.. How does the protein this gene encodes for interact with the drug in the pathway? Individuals who are poor metabolizers of CYP2C9 substrates (eg. CYP2C9*3 allele carriers) have increased exposure to celecoxib when compared to those with normal CYP2C9 activity. Drugs that inhibit CYP2C9 should therefore be used with caution in patients taking celecoxib. ii. How do you think the change in the allele affects how the body responds to the drug? After oral insertion, celecoxib is rapidly absorbed and achieves peak serum concentration in about 3 hours. It is extensively metabolized in the liver with very little drug (< 3%) being eliminated unchanged. It probably takes a while for the body to get used to the drug because so much is coming in in such a small amount of time. Identifying the Mutations 1. Protein that Generic Name of the Drug has Variable Response to the Drug Celecoxib CYP2C9 How this rsID of Exon,in Codon Codon Amino Protein an tron, or Sequence Sequence Acid Interacts with identified other? Change Change Sequence the Drug allele (DNA) (mRNA) Change It largely rs1057 ATT→ AUU→ I[Ile]→ goes from a catalyzes the 910 CTT CUU L[Leu] nonpolar Exon drug. Effect amino acid to another nonpolar amino acid iv. If the normal amino acid is different from the one made by the allele change, what DNA mutations would not have caused a change in the amino acid that is made? The amino acid stays the same as before. v. If the amino acid that is made by the mutant allele did not change, what DNA mutations would have caused a change? Substitution because if the DNA sequence changed a single nucleotide to another letter, it would code for different protein, messing up the entire sequence. How Amino Acid Changes Matter 3) a. How do you think these differences affect how the protein as a whole functions? I think that if the mutant amino acid has a different polarity the protein may not react to the genes the same way or even at all, and the drug will have a big difference in the pathways. b. What kind of amino acid mutations would be less likely to change the protein's normal function? Substitution, if you take out a nucleotide and replace it with another, it could still code for the same amino acid as the regular sequence. Some sequences of nucleotides have the same amino acid. 4) a. If the function of this protein changes, how do you think this affects how the drug functions in the pathway? The drug may not react the same way, have a different affect, or it may not have any effect on the consumer at all. b. Is your hypothesis similar to what is known about how this allele mutation changes a patient's response to the drug? Yes. The Importance of Non-Coding DNA Some mutations may be involved in how DNA is turned into mRNA. There are two main ways to know if your allele fits this category. The first is if your allele contains a mutation in an intron or another DNA area that is not an exon; "non-coding DNA". The second is if your allele contains a mutation in an exon that does not change what amino acid is normally made. In both cases of "non-coding DNA," the mutation may be in the middle of instructions for how the gene should be properly turned into mRNA, such as how the pre-mRNA should be cut apart and reassembled into mRNA. Additionally, DNA that is inside of one gene may actually be important for how a nearby gene is processed.