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Genetic Mutations (Review) Recall: The Central Dogma Normal gene DNA (antisense strand) mRNA Polypeptide GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Glu-Cys-Gly Amino acids The antisense strand is the DNA strand which acts as the template for mRNA transcription What Causes Mutations? • There are two ways in which DNA can become mutated: – Mutations can be inherited • Parent to child (germline mutation) – Mutations can be acquired • Environmental damage • Mistakes when DNA is copied (somatic mutation) Significance of Mutations • Most are neutral • Eye color • Birth marks • Some are harmful • Sickle Cell Anemia • Down Syndrome • Some are beneficial • Sickle Cell Anemia to Malaria • Immunity to HIV • Point Mutations – change in one nucleotide – Substitution • THE FAT CAT ATE THE RAT • THE FAT HAT ATE THE RAT – Insertion (Frameshift) • THE FAT CAT ATE THE RAT • THE FAT CAT HATE THE RAT – Deletion (Frameshift) • THE FAT CAT ATE THE RAT • THE FAT CAT AT THE RAT __________________________________________________ Substitution Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Glu-Cys-Gly Amino acids Substitution mutation GGTCACCTCACGCCA ↓ CCAGUGGAGUGCGGU ↓ Pro-Arg-Glu-Cys-Gly Substitutions will only affect a single codon Their effects may not be serious unless they affect an amino acid that is essential for the structure and function of the finished protein molecule (e.g. sickle cell anaemia) Nonsense Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Glu-Cys-Gly Amino acids Substitution mutation GGTCTCCTCACTCCA ↓ CCAGAAGAGUGAGGU ↓ Pro-Glu-Glu-STOP _________________________________________________ No change Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Glu-Cys-Gly Amino acids Substitution mutation GGTCTTCTCACGCCA ↓ CCAGAAGAGUGCGGU ↓ Pro-Glu-Glu-Cys-Gly The genetic code is degenerate (What does this mean?) Degenerate = ________________________________ Changes in the third base of a codon often have no effect. • Frameshift Mutations – shifts the reading frame of the genetic message so that the protein may not be able to perform its function. – Insertion • THE FAT CAT ATE THE RAT • THE FAT HCA TAT ETH ERA T H – Deletion • THE FAT CAT ATE THE RAT • TEF ATC ATA TET GER AT H Inversion Inversion mutations, also, only affect a small part of the gene Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons ↓ Pro-Glu-Glu-Cys-Gly Amino acids Inversion mutation GGTCCTCTCACGCCA ↓ CCAGGAGAGUGCGGU ↓ Pro-Gly-Glu-Cys-Gly What happens to “bad” mutations overtime? Why can’t we get rid of “bad” mutations? What happens to “good” mutations? Mutation Example 1: Sickle Cell Anemia Sickle cell anemia Image Credit: http://explore.ecb.org/ Blood smear (normal) Image Credit: http://lifesci.rutgers.edu/~babiarz/ Mutations of haemoglobin • Haemoglobin is a tetramer = 2 and 2 -chains • The genes for these polypeptides are found on different chromosomes • The -chain gene is found on chromosome 11 • The -chain gene is found on chromosome 16 • Several inherited diseases occur on the -chain, which contains 146 amino acids. Mutation S (sickle cell anaemia) Codon Change to DNA sense strand 6 GAG to GTG Change in Amino Acid Glu to Val Why does sickle cell anemia persist in the population? • The malarial parasites grow poorly in red blood cells from either homozygous sickle-cell patients or healthy heterozygous carriers • Malaria is rarely found among carriers of this mutation • Malaria has served to maintain the otherwise deleterious sickle-cell mutation at high frequency in regions of Africa Mutation Example 2: Cancer Genes • Cancer genes are causally implicated in oncogenesis • Mutations in cancer genes can occur somatically or can be inherited • Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children Tumour suppressor gene These genes normally function to PREVENT cell growth/division TS ____________________ ____________________ ____________________ ____________________ ____________________ Oncogene Genes which normally function to PROMOTE cell growth/division in a controlled manner Ras _________________ _________________ _________________ _________________ A nutritional example: the lactase gene Many adult humans cannot metabolize lactose (milk sugar). A single nucleotide polymorphism (SNP), i.e., a one base-pair difference in DNA sequence, correlates with activation of the lactase promoter and with lactose tolerance/intolerance. agataatgtagTccctggcctca agataatgtagCccctggcctca ability to activate Oct-1 binding phenotype ++ ++ tolerant + + intolerant Olds, L. C. and E. Sibley (2003). Hum. Mol. Genet. 12(18): 2333-2340. Now on to… Gene Regulation! KEY CONCEPT Gene expression is carefully regulated in both prokaryotic and eukaryotic cells. Control of Gene Expression • Prokaryotic organisms regulate gene expression ____________________________ • Eukaryotic cells regulate gene expression _____________________________________ _ Control of Gene Expression • Controlling gene expression is often accomplished by controlling transcription initiation • Regulatory proteins bind to DNA to either block or stimulate transcription, depending on how they interact with RNA polymerase Prokaryotic Regulation • Prokaryotic cells often respond to their environment by changes in gene expression • Genes involved in the same metabolic pathway are organized in _____________ • Some operons are _____________ when the metabolic pathway is needed • Some operons are _____________ when the metabolic pathway is no longer needed Prokaryotic cells turn genes on and off by controlling transcription • A promoter is a DNA segment that allows a gene to be transcribed • An operator is a part of DNA that turns a gene “on” or ”off” • An operon includes a promoter, an operator, and one or more structural genes that code for all the proteins needed to do a job Prokaryotic Regulation • Control of transcription initiation can be: – ________________________– increases transcription when ________________ bind DNA – ________________________– reduces transcription when ______________ bind to DNA regulatory regions called ______________ lac Operon – Operons are most common in prokaryotes – The lac operon was one of the first examples of gene regulation to be discovered – The lac operon has three genes that code for enzymes that break down lactose lac Operon • The lac operon contains genes for the use of lactose as an energy source. • Regulatory regions of the operon include the CAP binding site, promoter, and the operator. • The coding region contains genes for 3 enzymes lac Operon • The lac operon is negatively regulated by a repressor protein: – lac repressor binds to the operator to block transcription – in the presence of lactose, _________________________________________ – repressor can no longer bind to operator – transcription proceeds lac Operon • In the presence of both glucose and lactose, bacterial cells prefer to use glucose • Glucose prevents use of the lac operon – binding of CAP – cAMP complex to the CAP binding site is required for use of the lac operon – high glucose levels cause low cAMP levels – high glucose low cAMP lac operon _______ lac Operon • The lac operon acts like a switch – ___________________________________________ – ___________________________________________ trp Operon • The trp operon encodes genes for the biosynthesis of tryptophan • The operon is not expressed when the cell contains sufficient amounts of tryptophan • The operon is expressed when levels of tryptophan are low trp Operon • The trp operon is negatively regulated by the ______________________________ – trp repressor binds to the operator to block transcription – binding of repressor to the operator requires a ________________________ which is tryptophan – low levels of tryptophan prevent the repressor from binding to the operator Eukaryotic Regulation • Controlling the expression of eukaryotic genes requires ____________________________ – general transcription factors are required for transcription initiation • required for proper binding of RNA polymerase to the DNA – specific transcription factors increase transcription in certain cells or in response to signals Gene expression must be regulated in several different dimensions— In time: 10 wks 6 mos 14 wks 1 day 12 mos 18 mos At different stages of the life cycle, different genes need to be on and off. © M. Halfon, 2007 Eukaryotic Transcription • General transcription factors bind to the promoter region of the gene • RNA polymerase II then binds to the promoter to begin transcription at the start site • Enhancers are DNA sequences to which specific transcription factors (activators) bind to increase the rate of transcription • Transcription is controlled by regulatory DNA sequences and protein transcription factors – Most eukaryotes have a TATA box promoter – Enhancers and silencers speed up or slow down the rate of transcription – Each gene has a unique combination of regulatory sequences Eukaryotic Chromosome Structure • Methylation (the addition of –CH3) of DNA or histone proteins • Clusters of methylated cytosine nucleotides bind to a protein that prevents activators from binding to DNA • Methylated histone proteins are associated with inactive regions of chromatin Protein Degradation • Proteins are produced and degraded continually in the cell • Proteins to be degraded are tagged with ubiquitin • Degradation of proteins marked with ubiquitin occurs at the proteasome