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Misformed amino acid as source of genetic mutation

  1. Dec 12, 2011 #1
    When I first encountered the term genetic mutation, I envisioned a gene that had somehow spoiled – like an orange with mole on it.

    A little research indicated that a gene is a linear string of amino acids that codes for a protein. The term mutant gene was being used to indicate a gene in which there had been an alteration in the amino acids sequence that was coding for a protein.

    I have not been able to find anything on when it is not an insertion or a deletion within a sequence but the amino acid itself is misformed. Surely this happens. Is this just considered a deletion?

    Any information on the above would be appreciated.
  2. jcsd
  3. Dec 12, 2011 #2


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    Conjecturing from first principles, I'd think it wouldn't be able to participate in the process of transcription if it was malformed; at least, not in a way that would be propagated in offspring.
  4. Dec 12, 2011 #3
    I actually learned about this in my High School Biology and AP Biology classes. I hope this helps:

    Last edited: Dec 12, 2011
  5. Dec 12, 2011 #4
    It makes sense that a mutated gene would not be propagated in offspring, but some genetic diseases such as sickle-cell anemia are caused by a single point mutation.

  6. Dec 12, 2011 #5


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    huh, I think something just clicked...

    Wow, my PI would be disappointed; we are studying the huntingtin gene.
  7. Dec 12, 2011 #6
    What do you mean by PI?
  8. Dec 13, 2011 #7


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    principle investigator (head of lab).

    I'm still not sure, though. I see now the article only explicitly said sickle cell anemia is a single point mutation. Huntingtin mutation results in glutamine chains that are too long; not sure what the source of the mutation is though. Possibly just insertion and not point-mutation at all, but I think I need a genetics class to really understand my conceptual block.
  9. Dec 13, 2011 #8


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    Here's a general overview of how genetic information works. First, a few basics:

    Genes are segments of DNA that determine the traits of an organism. Many genes encode for proteins, and these proteins are the molecule in the cell that perform the work that give an organism its properties.

    DNA is a molecule that encodes information. It consists of a string of nucleotides. There are four different nucleotides that make up DNA, and they differ in the type of base they contain. These four different bases are adenine (A), thymine (T), cytosine (C), and guanine (G).

    Proteins are a class of molecules that carry out important jobs in the cell. Proteins are composed of a chain of amino acids. There are twenty different amino acids that can be found in human proteins.

    Therefore, the information you found is incorrect. A gene is not a linear string of amino acids. Because genes are DNA, they are linear strings of nucleotides. The information in the DNA, however, does encode a linear string of amino acids. Below is a bit more information on how the information from DNA gets translated into the language of proteins and how mutations affect the process.

    Here is what a segment of a gene might look like:


    This segment of DNA encodes for a protein. Now, you may see a problem here; somehow, a language consisting of only 4 characters (the four types of nucleotides in DNA) needs to be translated into a language consisting of 20 characters (the twenty protein amino acids). Obviously, one DNA base cannot code for one protein amino acid, and two DNA bases do not give enough combinations to cover the 20 protein amino acids. Therefore, nature has evolved a code (the genetic code) by which three DNA bases code for one protein amino acid. Of course, since there are 64 possible three base combinations (codons), the genetic code is degenerate; each amino acids can be specified for by multiple codons. The correspondence between codons and amino acids can be found here (http://tigger.uic.edu/classes/phys/p...odon_table.jpg note: for our purposes U and T are the same).

    Using the genetic code table, we can now translate the above DNA sequence to a protein sequence:

    Leu Thr Pro Glu Glu Lys Ser

    The sequence of amino acids in a protein gives it certain chemical and physical properties.

    Mutation (changing one DNA base to another DNA base) can often cause changes in the amino acid sequences of proteins. However, this is not always the case. First, the cell has ways of fixing DNA damage, so not all DNA damage causes permanent changes to the DNA. Second, even if the mutation evades the DNA repair machinery, not all of the DNA in a cell codes for protein. Changes in non-protein coding sequences can have huge effects on the cell, but we still do not know what the vast majority of the DNA in cells does and putting changes in some of those regions doesn't seem to have any noticeable effect. Third, even if the mutation hits a protein-coding sequence, a change to the DNA bases might not cause a change in protein seqeunce because the genetic code is degenerate. As an example, consider the mutation to our original sequence:


    Here the change is from GAG to GAA both of which code for the amino acid glutamine. Because this mutation does not change the amino acid sequence of the protein, it will not have an affect on the function of the protein. Mutations such as these are known as silent mutations.

    Some single base pair substitutions, however, can cause huge changes in the function of a protein. For example, consider the mutation:


    This mutation changes GAG, which codes for glycine, to GTG, which codes for valine. Thus, this mutation causes a change in the protein that is produced. This mutation that I've shown you is the mutation in the gene for hemoglobin (the protein that makes our blood red) that causes sickle-cell anemia (http://en.wikipedia.org/wiki/Sickle-cell_disease note: the sequence is only a small portion of the hemoglobin gene). This is an example of a single base pair change that leads to the change in the shape of an entire cell!

    As it turns out, the mutation can have positive effects too. While having two copies of the sickle-cell gene turns out to be very bad, having one copy is thought to make one more resistant to malaria.

    Now, lets consider the effect of a deletion on our sequence:


    The sixth base has been deleted. Now, if you try to translate the sequence, you notice something. The deletion not only affects the codon containing the mutation, but everything after the deletion as well! The mutation causes a frameshift. The sequence would now be translated to the following protein sequence:


    Leu Thr Leu Arg Arg Ser

    The protein sequence is now completely different than the original protein sequence (Leu Thr Pro Glu Glu Lys Ser), and the resulting mutant protein will have completely different properties (most likely it won't be functional).

    Hopefully, this information helps to clarify your question.
  10. Dec 13, 2011 #9


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    Here's some information on the source of the trinucleotide repeat expansions that result in Huntington's disease: https://en.wikipedia.org/wiki/Trinucleotide_repeat_disorder

    The trinucleotide repeats that lead to the long glutamine chains in the huntingin protein are thought to arise from slippage of the DNA replication machinery. In regions with highly repeated sequences, DNA polymerase can more easily lose its place and accidentally insert extra copies of the repeated sequence. So yes, Huntington's disease is due to insertion mutations.
  11. Dec 13, 2011 #10


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    Hrm, I see...

    but what would be the genetic source of the disease then? A mutation in the coding for the DNA polymerase?
  12. Dec 13, 2011 #11


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    Most cases of Huntington's disease are inherited, meaning that a person who has a defective huntingtin gene inherited that gene from a parent (this is as opposed to genetic diseases that arise spontaneously, where neither of the individual's parents had the defective gene, so the defective gene came about due to some mutation that arose in the mother's egg/father's sperm). Although normal DNA synthesis can sometimes cause a normal huntingtin gene to become a defective huntingtin gene (through the trinucleotide repeat expansion mechanism I discussed above), this occurs rarely so there are not many cases of Huntington's disease that arise spontaneously.

    So if you inherit a copy of the huntingtin gene with a large number of CAG repeats, you will have the disease. If both copies of the huntingtin gene you inherit do not have a large number of repeats you will not have the disease.
  13. Dec 13, 2011 #12


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    ah ok, so the highly repeated sequence, CAG, is the mutation?

    I know the chains can be particular lengths like 19, 88, 181 long. Does this correspond to how over-represented the CAG sequence is in the gene?
  14. Dec 13, 2011 #13
    I want to thank Davrinkin for his link to mutations with illustrations. Ygggdrasil (are the g's a transcription error) gets an above and beyond. If there was a Physics Forum when I was in school I would probably have a Nobel Prize by now. Let's get carried away - maybe I would have two/to/too.

    I apologize for my misformed statements. I have some acquaintance with The Central Dogma – DNA – RNA – protein.

    I have a vague understand of sources of mutation – DNA (mitosis, meiosis) – RNA (transcription error) – protein (transcription error).

    The direction I was heading in was the chemical endurance of the nucleotides/bases themselves. They seem to be very resilient. Must be the beauty of chemistry. What little reading I have done on this implies that if via radiation or chemical, that the bonds between the nucleotides/bases would break before the actual structures would be jeopardized.

    Reflection has yielded greater clarity on the whole process of mutation and I do want to thank everyone for that.

    I do have an additional question. Who coined the term “mutation” for what we are talking about? Also, from the way everyone is using the term, “mutation” seems to represent a transmittable change?
  15. Dec 13, 2011 #14


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    Interesting question, I'm not sure when the first use of the term would have been but I guess in the "DNA era" of genetics. Regarding transmittable change I take it you mean inheritable? If so this is not the case. Mutations can occur in any nucleated cell; if they occur in somatic (body) cells then they are not inherited, if they occur in germline (give rise to sperm and egg) cells then they are inherited.
  16. Dec 13, 2011 #15


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    I believe the guys who coined the term "mutation" as pertaining to biology were the re-discoverers of Mendel's work; Hugo de Vries and Carl Correns around the turn of the 19th century (late 1800's early 1900's).

    Though "mutation" is really a vague general term in biology. As others have expounded, there are many, many types of mutations--So the term "mutation" isn't all that descriptive in and of itself.

    A mutation (general) doesn't necessarily have to be heritable. Mutations that arise in cells of the soma, or body, aren't heritable. While those that arise in the sex cells, which go on to form new organisms, are.
  17. Dec 13, 2011 #16


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    This is not true. In the case of DNA, there are many ways in which nucleotides become chemically damaged in the cell. UV radiation can cause adjacent bases to become chemically crosslinked (https://en.wikipedia.org/wiki/Pyrimidine_dimers). Oxidizing agents and free radicals also chemically modify DNA. One common modification is the oxidation of guanine bases to 8-oxoguanine (https://en.wikipedia.org/wiki/8-Oxoguanine). This type of DNA damage can be problematic because 8-oxoG tends to mispair with adenine and can therefore cause G->T mutations. Another common type of DNA damage is the deamination of cytosine into uracil (https://en.wikipedia.org/wiki/Deamination#Cytosine). Because uracil pairs with A instead of T, this type of damage can induce C->T mutations.

    While these types of DNA damage occur frequently, they very infrequently lead to permanent changes to the DNA of an organism because the cell maintains a large complement of DNA repair proteins that have the ability to recognize these types of DNA damage, tell the cell to stop replicating until the damage is fixed, recruit the proper machinery to remove the damaged base, and replace it with a new base.

    Similar types of chemical damage can occur to RNA and proteins, but these types of damage are not as consequential to the cell because these classes of biomolecules turnover quite rapidly in the cell. Damaged molecules can simply be degraded and replaced by newly synthesized copies.

    Yes, the number of CAG repeats in the huntingtin gene should correspond to the length of the polyglutamine chain in the protein.
  18. Dec 13, 2011 #17


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    Yes and no. Like Yggg pointed out in most cases of Huntington's the expansion is inherited as is. However the sequence can expand during production of gametes, in a somewhat analogous way to "stuttering" that is done in viral replication. So while the offspring will inherit the mutation (its inherited in an autosomal dominant fashion), this further expansion can lead to a faster onset and more severe symptoms we call genetic anticipation.

    How long the expansion is will correlate to the age of onset and rapidity of the disease process. The more CAGs you have the faster you loose neurons in places like the caudate nucleus, etc. The more number of CAGs you have the more soluble the Huntingtin protein is and the more inclusion bodies and clumps of protein you get in affected neurons.
  19. Dec 13, 2011 #18

    “have the ability to recognize these types of DNA damage, tell the cell to stop replicating until the damage is fixed, recruit the proper machinery to remove the damage”

    Is it this or is it that the chemistry just doesn't work. I am not that good to know about bondings and angles and all that stuff, but it was easier for me to understand that a mistake was made and then when it was time to add the next piece it just didn't fit - production process stops - can't go forward.

    Probably got it wrong again.
  20. Dec 13, 2011 #19


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    Different repair machinery works in different ways. Eukaryotic repair machinery can "read as it goes", so if it accidentally uses a chain-terminator without an available 3'-OH the inability of the DNA polymerase to continue can cause it to remove back a couple of nucleotides then continue on again.

    Nucleotide excision repair enzymes, the kind which fix UV damage, are "scanning" the geometry of the helix. UV damage causes "knots" or irregularities in the DNA helix through formation of things like pyrimidine dimers. When the enzymes recognize this they knick the phosphodiester backbone and excise the bases around it. They can recruit DNA polymerases to fill in the excised bases with the correct ones. The cell can keep track of parent strands via methylation.

    Other types of repair, like Base excision repair, recognize non-helix distorting damage. For example with Yggg's 8-oxoguanine--Human 8-oxoguanine-DNA glycosylase the "recognition" occurs because of correct conformational binding--Which ultimately alters the enzymes shape and initiates excision and repair.

    All these ways of recognition are going to be accomplished by correct/incorrect binding which alters the enzymes conformation to initiate repair steps.
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