CHAPTER 16: From Genes to ProteinsSECTION 1: Early History of Molecular GeneticsA) Garrod, Sumner, and Alkaptonuria

1) The idea that proteins control most of what goes on inside of a cell is not a new one. Even in the early 20th century, lots of people thought this.

2) The notion that some sort of proteins control the metabolism of a cell is also not new.3) Back then, no one knew what DNA was, and they only had a foggy notion about the

biochemistry of proteins, other than that they were important biologically.4) In 1908, the disorder Alkaptonuria was described by Dr. Archibald Garrod. He described

patients that had massive levels of homogentisic acid in their urine.5) When this compound is in the urine, it reacts with air and turns their urine a black color.6) He noticed that alkaptonuria was only common in certain areas among people who were the

offspring of first cousin marriages.7) He hypothesized that the problem was a metabolic problem that was genetic in nature.8) In 1926, he was proven to be correct, when James Sumner purified the urease enzyme and

showed that it was a protein.9) Though this was a different enzyme, working on a different pathway, the cause of alkaptonuria

was then deduced to also be a missing enzyme.10) It turns out that individuals with alkaptonuria are missing an enzyme for the digestion of the

amino acids phenylalanine and tyrosine.11) This enzyme is SUPPOSED to break down the intermediate homogentisic acid into carbon

dioxide and water, but it is defective. Instead, the intact acid molecule exits the urine.12) So in summary, the notion that enzymes are proteins that control biochemical pathways, and

that the proteins are INHERITED was proven by a bunch of people peeing into cups.13) By the way, if you’re going to pick a genetic disorder to have, you could do worse than this one.14) Yes your pee turns black, and I mean black like used motor oil black….but, hey, if you know that

you’re not dying, then so what? Makes you unique.15) Another potentially annoying drawback, is that the acid can cause dark ‘stains’ under the skin

and make it look like a ballpoint pen exploded in your face. But again, so what?16) About the only really horrible side effect is occasional arthritis….but you could get that anyway.

B) Beadle and Tatum and the One Gene: One Enzyme Idea1) Beadle and Tatum came along in 1940. At the time no one knew for sure whether DNA or

protein controlled the genetic code. Most though protein did.2) Recall that these guys would have been contemporaries with Hershey and Chase, who were just

then testing out the idea that DNA was the molecule in control.3) However, in theory, it didn’t really matter. The idea was now out and accepted, that a gene was

some sort of molecular code in control of traits. This is what they tested.4) Beadle and Tatum believed that each enzyme in an organism had its own specific gene.

5) Overall, they believed that every step of metabolism was controlled by a specific gene, because each enzyme had to be coded for by a specific gene.

6) Beadle and Tatum tested this idea by introducing mutations to Neurospora fungi by X-raying them. At the time, they did not know that they were causing DNA mutations. They just knew that X-rays CAUSED some sort of mutations and genetic changes.

7) They figured it was easier to induce mutations than to try to find an organism with one.8) The Neurospora fungus is a common bread mold. It was ideal for the experiment because it is

easy to grow and has a fast life cycle.9) More importantly, fungi are haploid, meaning that any gene that gets mutated is GOING to

cause an effect, because there’s no 2nd dominant gene there to bail the useless one out.10) So Beadle and Tatum set about X-raying a bunch of fungi. 11) No word on whether their wives/fathers/mothers etc. gave them the repeated lecture about

“throwing their lives away cooking fungus all day for a living….I mean who DOES that?”12) A diagram of their experiment is shown below, and explained in detail afterward.

13) After X-raying all the samples, they grew them all up on complete media, which contained all the amino acids and nutrients the fungi would need to avoid starving.

14) This media even contained non-essential amino acids. Non-essential amino acids are ones that are capable of being made by the cell, while essential amino acids must be gotten in the diet.

15) The reason they included all of them, is that they reasoned that mutated Neurospora cells might have lost the gene(s) that gave them the ability to make certain amino acids.

16) After growing up a healthy population of the fungus, they made transfers to 3 sets of cultures.17) The first culture contained minimal media. This was a control. NO fungus was capable of

growing on this, since it contained no vitamins or essential amino acids.18) The second culture contained minimal media supplemented with vitamins, which contained

only the bare minimum nutrients to keep a normal fungus alive.19) None of the mutated fungi were able to grow on minimal media. This proved that they HAD

lost the ability to make SOME amino acid. Now Beadle and Tatum had to figure out which one.20) The third set of cultures was a panel of 20 tubes of minimal media. EACH tube was

supplemented with ONE amino acid.21) The only tube where the fungi grew was in the arginine supplement.22) Therefore, Beadle and Tatum concluded that the X-rays had induced a mutation to the gene for

arginine synthesis. The DNA mutation had destroyed the function of a key enzyme.23) The fact that mutated fungi DID grow on arginine showed that the mutation was specific.24) From the experiment, Beadle and Tatum proposed the one gene: one enzyme hypothesis, which

states the one gene controls the production of one enzyme.

C) Linus Pauling Edits the Hypothesis to One Gene: One Polypeptide1) The name Linus Pauling should ring a bell by now. He’s the one that nearly discovered the

structure of DNA. Now on what he DID win a Nobel Prize for.2) Pauling was working with hemoglobin, the protein that carries oxygen in the blood.3) He hypothesized that something was wrong with the protein in sickle cell anemia patients.4) He managed to show that one specific component of the four polypeptide chains that make up

hemoglobin was consistently messed up in sickle cell patients.5) The globin portion, not the heme portion, was always different in sickle cell patients.6) They figured this out by running some of the first electrophoresis experiments, and showing

that normal hemoglobin and sickle cell hemoglobin run through gels at different rates.7) Though they did not know the sequence of the protein at the time, they still knew that the

proteins were clearly different in structure by a few positive charges.8) It turns out that normal hemoglobin is more negatively charged (and migrates more quickly

through a gel), since it contains the polar glutamic acid in the correct position, rather than the valine (non-polar) found in sickle cell mutants.

9) From this experiment, Pauling proposed a change in the one gene: one enzyme hypothesis to the edited one gene: one polypeptide hypothesis.

10) This is because hemoglobin is NOT an enzyme.11) The hypothesis was also not one gene: one protein, because proteins can be made of many

polypeptides coded by different genes and be assembled into the final quaternary structure.

12) In this case, the heme and globin portions of the 4 unit hemoglobin clearly had to be controlled at different gene loci, since only one component showed errors.

13) Later in 1971, when hemoglobin was sequenced by Imamura, this proved Pauling correct.14) The picture below shows the mutation that causes sickle cell anemia.

15) Changing just one DNA base can change the amino acid in the sequence.16) In turn, remember that different amino acid R groups interact differently in the tertiary

structure. The wrong amino acid will cause the wrong folding and the wrong 3-D shape.17) In the case of hemoglobin, the glutamic acid that is supposed to be there has negative charges

that interact with positive charges elsewhere in the protein to fold the shape.18) Since valine is non-polar, not only can it not do this, it is actually repelled by charge.

D) The Central Dogma of Molecular Genetics1) As time went on, the notion of DNA controlling the genetic code was settled. 2) We will discuss one of the major experiments where this was shown later in the chapter.3) The importance of RNA began to be understood as the go between from DNA to proteins.4) The central dogma of molecular genetics states that DNA code is transcribed to a temporary

RNA code, which the ribosome interprets to build proteins, which make up most of the structures of living cells.

5) The condensed dogma: DNA RNA Protein.6) With that point emphasized, we will now discuss the role that RNA plays in a cell.

SECTION 2: Transcription from DNA into RNA.A) RNA Molecules vs. DNA Molecules

1) Ribonucleic acid (RNA) serves different purposes in a cell than DNA, though they are similar in molecular structure. Like DNA, it has purines and pyrimidines and a sugar-phosphate backbone.

2) As you know by now, DNA in eukaryotic cells is packaged into chromosomes.3) As you also know, there are thousands of genes in these chromosomes interspersed with introns

that don’t code for anything.

4) On top of this, chromosomes are piled up on one another like spaghetti.5) At any one time, a cell only needs access to a few of these genes. Leaving all genes ‘on’ all the

time would be incredibly wasteful and useless. Why make proteins you don’t even need?6) Remember also, that there are hundreds of thousands of ribosomes in a cell, all making protein.7) When a cell needs to make a protein, it wants to do make many copies of it, as quickly as

possible. Thousands of ribosomes can do the job quickly, like thousands of factory workers.8) However, if factory workers all had to share ONE blueprint, work would nearly come to a halt.9) Likewise, if the cell wants to work quickly, it must make COPIES of the gene and distribute them.10) This is exactly what happens. When cells need to make proteins, thousands of copies of

messenger RNA, which are copies of the gene in RNA form, are distributed.11) In addition to the practical problems associated with one copy, there are other problems with

using DNA directly. 12) First of all, the DNA would either have to leave the nucleus (risking damage) or every ribosome

would have to jam inside the nucleus and wait their turn.13) Second, 99.99% of the DNA code is NOT NEEDED at any one point in time. For instance, the

gene to grow an ear is totally irrelevant to making insulin after you eat a candy bar.14) All that matters is making enough insulin protein to store sugars at that moment.15) This is coded for by just one gene, not the other hundred thousand.16) If you want to learn about penguins, you go to the library and find a book about penguins. You

don’t get a dump truck and check out every dang book in the building.17) So it is with genes. Only the gene needed at the moment is transcribed from DNA to RNA.18) The molecular structure of RNA differs from DNA in several areas.19) First, the name ribonucleic acid comes from the ribose sugar in its backbone, rather than

deoxyribose, which has one less oxygen atom.20) Second, the nitrogen base Uracil replaces the pyrimidine Thymine in RNA.21) Finally, the molecular shape of RNA is not a double helix. The shape varies by the type of RNA.22) Messenger RNA, as previously discussed, is just a single strand.23) Transfer RNA, used to deliver amino acids to the ribosome during protein production, is roughly

shaped like a cloverleaf with a stem.24) Ribosomal RNA, which is found as part of ribosomes (and made by the nucleolus) is a huge

convoluted structure that bends back on itself many times. 25) The first picture below shows messenger RNA being built from DNA, the second its structure.

Messenger RNA is a single-stranded molecule made from the sense side of DNA.

Messenger RNA: Note the sugars are Ribose and the base Uracil replaces Thymine.

B) Transcription from DNA to Messenger RNA1) As previously discussed, the DNA code cannot and should not be used as the main template for

ribosomes to make proteins from. 2) It would be like letting every law student use the original constitution, rather than

reproductions, for studying law. Too valuable and highly impractical.3) The DNA code is copied when protein synthesis is needed.4) Transcription is the first step of protein synthesis. At the ribosome, translation follows.5) The lefthand diagram below shows a schematic of the whole process.

6) When transcription starts, the needed gene is unzipped by DNA helicase, DNA topoisomerase, and DNA gyrase, just like it is when DNA is replicated.

7) A bubble forms in the double helix, where the gene is located.8) The diagram (above right) shows a simplified version of what happens in transcription.9) Only ONE side of the DNA, the sense strand (coding side) is transcribed into mRNA. The non-

sense strand is ignored. Enzymes tell the difference between genes and non-genes by differences in the DNA sequences leading up to genes.

10) From there, the enzyme RNA polymerase, recognizes the single stranded open DNA.11) To distinguish sense from nonsense strands, there is a region before genes known as a

promoter, which is often a long stretch of A’s and T’s called the TATA box in eukaryotes.12) The RNA polymerase binds at the promoter and begins to copy the sense strand at the

initiation codon, which is always AUG in mRNA or TAC in the original DNA code.13) RNA polymerase adds complementary bases to the open sense strand.14) Another set of proteins known as transcription factors push or pull on the RNA polymerase

enzyme to control the rate of transcription.15) Remember that it pairs adenine with uracil, since this base replaces thymine in RNA.

16) For instance, a stretch of DNA that was GAT CAT would be complement with CUA GUA.17) Every 3 letters in the genetic code is known as a codon. Each codon is the code for one amino

acid in the protein. The growing messenger RNA’s codons are complementary to the ones in the DNA. Kind of like a negative to a photograph.

18) When the RNA polymerase nears the end of the gene, it knows because of the presence of termination codons. These codons DO NOT stand for any corresponding amino acid.

19) In mRNA , the termination codons are UGA, UAA, and UAG. Therefore, in the original DNA code, they are ACT, ATT, and ATC.

20) After capping the messenger RNA with a long stretch of adenines to form a poly-A tail, the RNA polymerase lets go and the mRNA leaves the nucleus through a nuclear pore.

21) Meanwhile, once all of the enzymes and helix destabilizing proteins leave, the DNA double helix reforms and twists closed again. Kind of like shutting a book after running a photocopy.

22) The significance of the poly-A tail is that it protects the RNA from degradation by recycling enzymes in the cytoplasm. More later on this.

23) Once out of the nucleus, the mRNA finds its way to a ribosome. The ribosome then reads the mRNA code and begins assembling the coded protein.

24) Translation of the mRNA into protein is the next step of protein synthesis.25) mRNA is a short-lived molecule. Enzymes called RNAses begin to degrade RNA in the cytoplasm

and recycle the nucleotides for new RNA molecules. This prevents too much wasteful protein production. mRNAs have the poly-A tail to slow this down.

SECTION 3: Translation from RNA to proteins

A) The Genetic Code1. Remember that in the old days, people thought that proteins carried the genetic message.2. There was good reason for this, even after they discovered the four major DNA bases. 3. It is much easier to write a code in an alphabet with 20 letters (there are 20 amino acids) than it

is to write a code in an alphabet of just 4 letters (there are only 4 DNA bases).4. At the time, people assumed that one code letter stood for one amino acid in a protein. 5. They failed to recognize that DNA code is written in triplets, where every THREE LETTERS codes

for one amino acid in a protein.6. When understood this way, there are 64 possible codons of 3 letters (4 x 4 x 4), such as AAU,

AAC, AAG, AAA, etc. There are only 20 amino acids, so this is more than enough codes.7. In most amino acids, there are multiple codes for the same amino acids. More often than not,

only the first two letters matter. For instance, GUA, GUU, GUC, and GUG are ALL codes for the amino acid valine.

8. Why would this be so? It provides a measure of protection against mutations. If the DNA code is accidentally changed at the 3rd position, it will still not affect which amino acid is coded.

9. In the early 1960’s, Nirenberg and Matthei decoded the entire genetic code. 10. It took them nearly 10 years, many pots of coffee, and a lot of bacterial petri dishes. In the end,

they got a Nobel prize out of the deal, which they pawned to buy a sweet Les Paul.11. Nirenberg and Matthei used E. Coli bacteria cultures as test subjects.

12. They synthesized artifical mRNA molecules with repeating motifs by the bucketload. For instance, they made molecules of GGG GGG GGG and ACA CAC ACA…..etc.

13. They then extracted ribosomes from the bacteria and gave them the artificial mRNAs and a stash of amino acids. They watched and waited to see what protein the ribosomes made.

14. For instance, the bacterial ribosomes given repeating GGG codons made proteins containing a long chain of ONLY glycine. Give them CCC and the chain contained ONLY proline.

15. Eventually, they figured out the codons that worked for all 20 amino acids and published a chart. The codon chart is written as an mRNA translation, since mRNA was the original material used to figure out the amino acid code.

16. Later, the genetic code was shown to be universal. It doesn’t matter if you’re talking about a bacteria, a platypus, or a palm tree. GGG codes for glycine in ANY living cell.

17. Warning: If you want to know the amino acids coded for by DNA codons, you must first CONVERT BACK TO DNA FROM RNA or you’ll interpret it wrong.

18. The codon chart is shown below, along with the Nirenberg and Matthei experiment.

B)Translation from mRNA to Proteins1) When they aren’t making proteins, ribosomes are actually floating around in the cytoplasm in

TWO pieces. These are the small subunit and the large subunit.2) When the messenger RNA arrives at the small subunit of the ribosome, it starts the process of

translation. This triggers the large subunit to join it.3) The mRNA then threads through the gap between them, like tape going through a cash register.4) Though it is something an oversimplification, ribosomal RNA molecules and proteins in the

small subunit bind the mRNA and interpret the code. rRNA and proteins in the large subunit interact with transfer RNA, which delivers amino acids for producing the protein.

5) This is shown in the diagram below:

6) From there, translation works something like an assembly line.7) Each mRNA codon threads its way into the gap between the subunits. At any one time, three

codons can fit inside the ribosome on a little ‘platform’8) The first codon occupies the P site as it enters, while the second occupies the A site. 9) When the first codon enters the P site, the ribosome then waits for the first transfer RNA to

arrive. Transfer RNA delivers amino acids to the ribosome, used to make the protein.10) The transfer RNA that arrives is SPECIFIC to THAT codon. For instance, there is a different type

of tRNA for the CCC codon, than for the GAA codon, or for the UCC codon.11) Kind of like a truck full of French fries is going to pull into McDonald’s not Home Depot. The

tRNA delivers its cargo to the SPECIFIC place that it is needed.12) In all, there are 61 types of tRNA. The reason for this, is there are 64 possible codons (4 x 4 x 4)

minus 3 stop codons, for which there are no specific tRNAs.13) The correct tRNA has an anticodon that is complementary to the mRNA codon. The tRNA

binds to the mRNA at this point.14) On the other end of the tRNA, the amino acid SPECIFIC to that codon, is carried.15) Look at the first diagram below. It shows the first tRNA landing at the P site.16) The mRNA codon AUG matches the tRNA anticodon UAC. This particular codon is for the amino

acid methionine. This tRNA is SPECIFIC to this codon & ONLY carries methionine.17) The second picture shows the second codon on the A site. GAA is the mRNA code. The tRNA

anticodon for this is CUU. This particular tRNA will always carry glutamic acid.

18) Once TWO amino acids are sitting side by side in the ribosome (like the right hand picture above), that’s when it acts. This stage is known as elongation.

19) The tRNA on the P site releases its amino acid, and the ribosome sticks it to the amino acid on the A site. The amino acid is taken off by an enzyme called a ribozyme, which is unique, in that it is one of the few enzymes known that are NOT proteins. Ribozyme is made of RNA.

20) From there, a second enzyme called peptidyl transferase forms a peptide bond between amino acids, and starts the protein chain.

21) After this occurs, the empty tRNA goes to the E site (exit site) and leaves the ribosome. 22) The empty tRNA is analogous to a transfer truck that has visited a warehouse and has been

unloaded of all its goods. Obviously, the truck leaves to go pick up another load then.23) tRNA molecules have loop shaped regions above their anticodon known as an amino-acyl

synthetase recognition site. These RNA cloverleaves are recognized by a enzymes.24) These aforementioned enzymes, called amino-acyl synthetases, are constantly floating around

in the cytoplasm, looking to load up tRNA molecules with more amino acids.25) Amino-acyl synthetases are analogous to dock workers loading ships or warehouse workers

loading up 18 wheelers with supplies. Likewise, they load the right cargo on the right truck.26) The enzyme bonds the appropriate amino acid to the attachment site, on the end opposite the

anticodon. A picture of these sites on a tRNA molecule.

27) From there, the amino acid sitting on the A-site shifts to the P-site and the whole process continues like an assembly line. A new tRNA matching the next codon arrives at the A site.

28) The whole process repeats like an assembly line for the length of the protein.29) This is pictured above on the right.30) Eventually, the ribosome comes to a STOP codon (UGA, UAA, or UAG).31) There are no tRNAs for these 3 codons. When the ribosome tries to grab the next non-existant

amino acid, it drops the chain and the protein is finished.32) Translation occurs at about 20 amino acids per second per ribosome in prokaryotes, and about 6

amino acids per ribosome per second in eukaryotes.

C) Post-Translational Modifications1) When mRNA is made, this is merely a ‘rough draft’ stage of protein production.2) This differs between prokaryotes and eukaryotes.3) In prokaryotes, translation may begin before transcription has even finished, since there is no

nuclear membrane blocking the ribosomes from getting access to the mRNA.4) The average mRNA only lasts 2 minutes in a prokaryote, before enzymes degrade and recycle it,

to prevent waste excess protein from being made.5) These enzymes are known as RNAses and are constantly floating around the cytoplasm.6) However, the presence of a nuclear membrane slows this process down considerably in

eukaryotes. Eukaryote mRNAs hang around for around 10 hours, before being recycled.7) RNAses also operate in eukaryotes.8) To slow down the degradation process even more (and give the mRNA a chance to get to the

ribosome and be translated), eukaryotes have several protections.9) Eukaryote DNA has a 5’ cap sequence of useless junk that is not part of the protein. 10) The amino acids that make it onto the protein that are part of the 5’ cap sequence must be

clipped off in the Golgi apparatus before the protein can be activated.11) The 3’ end is capped with a 3’ poly-A tail. This long string of adenines occur AFTER the stop

codon, so they don’t get translated. 12) However, they slow down RNAses by giving them something to chew on that doesn’t matter.13) Remember that eukaryotes also have introns and exons. Introns are junk DNA that don’t do

anything. They are 90% or more of eukaryotic DNA as a mutation safeguard.14) Exons are the coding regions that contain genes.15) Depending on the gene, sometimes introns are transcribed along with the exons, because it’s

easier that way. Then, enzymes called sRNPs (small ribonucleoprotein enzymes) clip the intron sequences out, before the RNA goes to the ribosomes.

16) This is especially common in modular proteins, where the finished product is actually more than one protein joined together (which came from more than one exon).

17) The picture below shows how introns are processed out

18) We will go over post-transcriptional and translational processing in more detail in the chapter on gene control. Go there now for more details.

D) Point Mutations and Changes in the Genetic Code1) As we have mentioned, the genetic code is pretty specific. 2) While some amino acids have multiple codons, some do not.3) In some cases, wobble at the 3rd position in a codon will forgive a mistake. For instance, GGU,

GGC, GGA, and GGG will all result in the ribosome putting a ‘glycine’ into the protein chain.4) However, many changes to codons will cause change in the meaning of the code.5) For instance, let’s suppose DNA polymerase makes a mistake during replication and

inadvertently changes CCG to GCG.6) This, in turn, will change the mRNA code from GGC to CGC.7) As a consequence of this change, the amino acid arginine will be substituted for glycine in the

protein. This could potentially be a problem.8) Arginine and glycine have dramatically different properties. In turn, this will cause the R-groups

of nearby amino acids to act much differently, and to fold the protein in a different way.9) If the re-folding happens at a critical location on the protein, it may ruin its intended function.10) Sometimes a mutation is a silent mutation, where the protein is affected in a non-critical way.11) Other times, the mutation may be noticeable, but not harmful, as in the case of brown eye color

genes mutating to produce blue eyes.12) Sometimes, mutations can even be helpful mutations, such as the mutated knockout gene for

fur pigmentation that makes polar bears white instead of brown (and hence camouflaged).13) However, sometimes the mutation can be a harmful or lethal mutation.14) Just such an example of this is seen in the point mutation that causes sickle cell anemia.15) Point mutations are changes in the DNA code at specific DNA bases. They differ from the large

scale chromosomal mutations that affect entire genes and segments of chromosomes.16) Point mutations can arise spontaneously in anyone in any cell.17) The cause of a point mutation is an incorrect placement of a DNA base during DNA replication or

repair by DNA polymerase enzyme. As previously mentioned, polymerase is a sloppy enzyme.18) In the case of sickle cell, the codon GAG is changed to GTG in the DNA.19) In turn, this results in a change in the mRNA code from CUC to CAC.20) As a result, hemoglobin is made with a valine in the position that glutamic acid should occupy.21) Valine is highly non-polar, while glutamic acid is very polar. The effect is predictable. The

hemoglobin protein folds into an incorrect conformation and the protein is wrong.22) The mutation is shown below in the picture.

A mutation that gives an actualSurvival ADVANTAGE in Arctic

23) The hemoglobin of sickle cell patients, as a result, does a very poor job of carrying oxygen.24) Consequently, sickle cell results in constant fatigue, misshapen blood cells that get stuck in

blood vessels, and a host of heart, kidney, and metabolic problems.25) This is all because of a change of ONE DNA base.26) There are 3 basic ways that point mutations can occur.27) A missense mutation occurs when the DNA polymerase accidentally puts the wrong DNA base

in place and creates a code for the wrong amino acid.28) Missense mutations are the ‘safest’, as they are sometimes silent, harmless, or helpful, but

many of them are also harmful or lethal.29) For instance, the change from GAG to GTG in sickle cell results in valine instead of glycine in the

protein. It is a missense mutation.30) A nonsense mutation occurs when the DNA polymerase accidentally inserts a letter that either

removes or adds a STOP codon to the DNA code.31) The resulting protein will either be way too short or way too long. Nonsense mutations

ALWAYS cause some sort of problem that usually leaves the protein functionless.32) Examples of missense and nonsense mutations are shown below.

33) The ‘worst’ case of a point mutation is a frameshift mutation.34) In frameshift mutations, a DNA polymerase enzyme either completely leaves out a DNA base or

inserts an extra base into the DNA. 35) This causes the entire reading frame of the DNA to shift by one letter over. From the location of

that mutation, the rest of the protein is trash. Everything past that point is wrong.36) Consider the sentence: The dog bit the boy. Now add a random ‘j’ some place.37) Thj edo gbi tth ebo y is the resulting sentence. It means absolutely nothing.38) The picture below shows how frameshift mutations screw up the whole DNA code afterward.

Mutated Pandas

39) Point mutations cause A LOT of problems noted in medicine.40) The MAJORITY of genetic disorders are NOT caused by chromosomal mutations. Most of them

are caused by point mutations to exactly the wrong gene at exactly the wrong spot.41) They result in defective recessive genes many times, which can be passed on reproductively.42) Point mutations to cell cycle genes (tumor suppressor and protooncogenes) lead to cancer.43) The table below lists a few common problems related to point mutations. The diagram below

that shows a codon chart with specific problems identified.

Genetic Disorder Cause Symptoms and ProblemsSickle Cell Anemia Mutated hemoglobin gene Misshapen blood cells that carry oxygen poorly. Blood cells get stuck in vessels.

Heart problems, kidney problems, easy bruising, fatigue.Cystic Fibrosis Mutated gene for ion channel

proteins in lungs. Lungs fail to keep proper osmotic balance and get flooded with fluid. Patients almost always die of pneumonia or choke to death on their own mucous before they reach 30 years of age.

Huntington’s Disease

Mutated gene for brain peptides. Oddly, its dominant.

Brain, like Alzheimer’s, gets cluttered with ‘junk proteins’ which eventually accumulate to levels that kill cells. Leads to degenerative nerve and brain disorder similar to Alzheimer’s.

Phenylketonuria Mutated gene for enzyme for amino acid metabolism

Toxic by-products accumulate, due to enzyme’s inability to break them down. If enough accumulates, does permanent brain damage or can kill patient. Patient must eat low amino acid diet for life (i.e. vegan).

Breast Cancer Mututation, usually to identified BRCA genes.

Breast cancer. Cells in breast begin to ignore inhibitors to cell division and divide rapidly to form masses, which can metastasize & be deadly.

D) Mutagenic Factors1) We have established that the cause of mutations is DNA polymerase screwing up and putting

the wrong letter in the DNA.2) However, this is about like saying that the cause of death is dying.3) There are REASONS that mutations occur beyond this.4) Obviously, just like in a typing class, the MORE you type, the HIGHER the chances you will make

a mistake and have to go get the white out.5) The same is true of DNA being copied. Give a DNA polymerase enzyme enough chances, and it

will eventually be bound to make a mistake.6) Usually, the proofreading DNA polymerases will STILL catch the mistake.7) However, every few hundred millionth time or so, something will slip and a mutation pops up.8) Think about textbooks. It isn’t common to find a textbook with a typo, but it does happen (and

the kids that find them are usually really proud of themselves and call the publishers idiots).9) Like we said…the more chances to make a mistake…the more likely it happens.10) Certain chemical agents called mutagens are known to react with DNA and change or damage

their chemical structure. Some react directly with the DNA, while others just interfere.11) Examples of chemicals that react with DNA include nitrites in smoked sausages, a slew of toxic

chemicals found in cigarettes, and a number of natural poisons made by molds, etc.12) Nutrasweet is also extremely deadly….if you eat 5 pounds of it every day and stand under a

powerline talking on your cell phone and forget to wear your healing magnetic bracelet.13) Intercalating agents insert themselves directly in between the bases and block access to the

DNA by enzymes, resulting in the DNA polymerase having to ‘guess’ what to put there. 14) Benzene is the greatest cleaning solvent ever discovered. It’s also banned for casual use,

because it is also a wonderful intercalating agent.15) In addition to these agents, high energy radiation like UV, X-rays, or gamma rays will cause

spontaneous chemical reactions in DNA bases that change their structures or destroy them.16) Either way, DNA polymerases have to clean up the mess, and eventually, they’ll make a mistake.17) Anything that causes continuous tissue damage also increases the likelihood of mutations, since

the cells continually have to copy their DNA as they divide to replace dead cells.18) This is why dipping leads to oral cancer like clockwork. In addition to the nicotine (which is a

mutagen itself), the glass shards in the dip continually introduce cuts which have to be healed.19) This is also why skin cancer and colon cancer are more common than others. There is

continuous replacement of tissue in those places. 20) Transposable elements are another source of mutation that most people have never heard of,

even though they have them in their own chromosomes.21) Transposable elements or transposons are also called jumping genes. They are genes in your

DNA capable of copying themselves multiple times, excising themselves with a special enzyme called transposase, and re-inserting themselves at other random places in the DNA.

22) Transposons were discovered in Indian corn in the 1950s by Barbara McClintock. She found that there was no possible genetic explanation for the color patterns she was getting.

23) The ears of corn had white stripes on top of a red background on a single kernel. She finally figured out that a transposon was knocking out the pigment gene in certain cells.

24) This is actually common in plants. Most variegated plants (white stripes) are caused by this.25) The picture below shows the type of Indian corn she worked with. The stripes come from

transposon knocking out pigment genes.

26) MOST transposons behave themselves and help create more genetic diversity. However, some of them can randomly insert themselves into cell cycle genes and cause big problems.

27) The effect of a transposon insertion into a gene, is that it usually knocks it out, because it causes a frameshift mutation from the point forward that it inserted itself.

28) As scary as that sounds, we all have transposons.29) The number of copies of a transposon on chromosome 16 of humans, has been used to trace

the human haplotype and genetic lineage of races (by the number of copies people have).30) The other interesting theory about transposons is that viruses are transposons gone bad.31) For instance, some viruses can induce cancer by turning protooncogenes into oncogenes by

inserting themselves at exactly the WRONG point in the victim’s DNA. 32) Human papilloma virus (warts) is now known to greatly increase a woman’s risk for ovarian

cancer later. 33) The collective effect of all the mutations and damage accumulated over a lifetime is also why

old people get cancer at rates dozens of times higher than younger people.34) All mutagens are not always strong carcinogens (cancer-causing agents), but all carcinogens are

ALWAYS some type of mutagen.35) Remember from the chapter on mitosis, that tumor suppressor genes SLOW DOWN the rate of

cell division, while protooncogenes SPEED UP the rate of cell division.36) The protein products of EACH of these types of genes must be BALANCED to keep cyclins

running the cell cycle at the correct rate.37) Damage to EITHER type of gene can cause problems. Damage to BOTH virtually guarantees

cancer, unless the immune system finds and kills those cells.38) Live long enough…and the chances of this not happening are eventually ‘slim’ and ‘none’.39) Fortunately, there is hope for us all. Scientologists like Tom Cruise have discovered that

wearing a magnetic bracelet and eating mass quantities of gingko biloba will protect you until the mother ship arrives to take humans away from this dying corrupt stinking oppressive planet.

40) Both are available from QVC at 3:00 AM between re-runs of ‘Gilligan’s Island’ and ‘The Magic Donkey’. If you act now, they’ll double your order absolutely for free.

41) Beware of Sham-Wow imitators.