After
stating that single genetic mutations, such as Huntington’s
disease, account for 5 percent of the total disease burden in
developed countries, Shenk stresses how it is important not to let those
diseases give the wrong impression of how healthy genes work (Pg 25).
Yet some types of genetic mutations, like substitution, cause no
frameshift and can possibly have no effect on the primary structure
of the protein the mutated gene codes for. This instance can create
variation for evolution by creating a source for new genes. The
phenotype of an organism can be affected by small-scale changes
involving individual genes. In what ways can this type of mutation
effect or benefit humans in the dynamic development and GxE ideas
that The Genius in All of Us describes? How does this relate
to the core biology theme of evolution (themes of continuity and change and
the relationship between structure and function can also be mentioned)? Information
concerning point mutations can be found in chapter 17 of Campbell.
Neil Edat (neil.edat@gmail.com)
This comment has been removed by the author.
ReplyDeleteSubstitution is the ‘replacement of one nucleotide and its partner with another pair of nucleotides...a change in a base pair may transform one codon into another that is translated into the same amino acid’ (Campbell, 344). In other words, substitution does affect a gene, but it may not affect the expression due to the redundancy of the genetic code. These are known as silent mutations. Silent mutations may be beneficial to humans in many ways as they may be a pathway towards improved genes. In 2006, a study was conducted to better understand silent mutations. The gene called multidrug resistance 1 (MDR-1) was found to often contain the silent mutation called C3435T in cancer cells, a peculiar outcome since the mutation seemed to do nothing. The gene produces P-gp, a protein that pumps chemotherapy drugs out of cancer cells. The study compared cells with the normal MDR-1 gene, a version with the C3435T mutation, versions with either of two other mutations known to occur sometimes along with C3435T, and versions with various combinations of two or three of the mutations. The results showed that the point mutations on their own did nothing, but that ‘cells with the MDR-1 gene containing the C3435T mutation plus one or two of the other two mutations did a much better job of ridding cancer cells of the drugs, allowing the cells to live another day.’ (http://news.sciencemag.org/sciencenow/2006/12/22-02.html) This astounding discovery shows that these mutations, although silent, can build up to benefit the cells in which they affect. The researchers suggested this could be because the mutant P-gp has a slightly different three-dimensional shape, which could slow down the cell’s protein-making machinery. Amino acid chains folding into a protein structure is speed-dependent, and so the slower productions could cause the final form of the protein to be altered. ‘The cell might be able to compensate for one silent mutation but not for multiple rarely used triplets.’ This study implies that silent mutations can in fact have long term affects as they build up. These changes show not only the effects of evolution, but of the relationship between structure and function. The study shows that the structure of a protein can in fact be affected by multiple silent mutations, which in turn can directly affect their function.
ReplyDeleteHow does this relate to the GxE model by Shenk? Mutations are the ultimate source of new genes and genetic expression. If a mutation has an adverse affect on the phenotype of an organism, the altered gene will not be favored by natural selection and so the genes will not have any evolutionary changes in the long run to recreate the expression (Campbell, 344). Similarly, if a beneficial gene is expressed from environmental stimuli or from a person working hard to alter their gene expression, the beneficial mutation will prevail and accumulate to result in an entirely changed gene. An example of this can be seen in history. Lactase tolerance is an evolutionary adaptation for humans. The ability to digest lactose, a sugar found in milk, usually disappears before adulthood in mammals, and the same is true in most human populations. However, for some people, largely individuals of European descent, the ability to break down lactose persists because of a mutation in the lactase gene. This suggests that the allele became common in Europe because of increased nutrition from cow's milk, which became available after the domestication of cattle. (http://www.nature.com/scitable/topicpage/evolutionary-adaptation-in-the-human-lineage-12397). This shows that a beneficial mutation can prevail for positive natural selection through environmental stimuli. This is a perfect example to show that structure can in fact change to improve function.
Michaela Margolis (mmargolis989@gmail.com)
Shenk brings up how single genetic mutations work as evidence that genes are never single-handedly responsible for a certain characteristic. Certain single genetic mutations, such as a frame shift, can throw off the entire process of translation and transcription because, if not inserted in groups of three, “all the nucleotides that are downstream of the insertion or deletion will be improperly grouped into codons, and the result will be extensive missense, usually ending sooner or later in nonsense and premature termination…the protein is almost certain to be nonfunctional” (Campbell 346). An example of a disease that results from a frame shift is Tay-Sachs disease, which is caused by various frame shift mutations on chromosome 15, and results in a lack of the protein hexosaminidase A, rendering the body unable to break down buildup in nerve cells (http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002390/). However, while acknowledging the potential influence of single genetic mutations, Shenk asserts that the breakdown of that single section of coding cannot mean that that section of coding keeps the body running correctly: “a genetic defect causing a series of problems does not mean that the healthy version of that gene is single-handedly responsible for normal function” (Shenk 25), and makes the analogy that while a breakdown of a wire could render the car useless, it doesn’t mean that the wire itself is responsible for making the car run; similarly, while the gene is the cause of the disease, the gene alone is not responsible for normal body function and staying healthy; that is the product of many gene interactions, as well as gene interaction with the environment.
ReplyDeleteSometimes, single genetic mutations such as substitutions have no visible effect on gene expression; many nucleotide sequences/codons code for the same proteins, and due to this “redundancy of the genetic code, they have no effect on the encoded protein”, and are called silent mutations (Campbell 344). However, it is important to recognize how so-called “silent” mutations can actually build up to have a tangible effect. “A single mutation can have a large effect, but in many cases, evolutionary change is based on the accumulation of many mutations with small effects.” (http://www.nature.com/scitable/topicpage/genetic-mutation-1127). Michaela mentioned how silent mutations can benefit a cell to make it more resistant to anti-cancer drugs; this is obviously not a selective advantage because it makes it harder for the body to combat cancer and thus the patient cannot survive and reproduce. The interactions of several mutations made what a single silent mutation would not have changed, into something highly dangerous. In addition, other than causing harm by interacting with other supposedly silent mutations, silent mutations can actually also affect the process of transcription directly, causing a change on their own. “Silent point mutations can change how the cell recognizes exons and introns. Exons are the useful, coding parts of a gene, while introns are non-coding "garbage" DNA found among the exons. Before a protein can be synthesized, the cell machinery must find and remove the introns from the mRNA. Researchers have found that silent mutations can cause errors in the intron-seeking process, causing the protein to be translated incorrectly.”
(http://www.brighthub.com/science/genetics/articles/39340.aspx) Introns are normally cut out by a spliceosome, leaving the coding exons to be translated once they are exported out to the cytoplasm and to the ribosomes. “Splice site recognition” is a big part of this process, ensuring that the correct parts are cut out (Campbell 335). However, silent mutations could throw off splice site recognition, thus affecting the protein synthesis although on paper the letter sequence should code for the same amino acid. In addition, the spliceosome itself is affected by the environment. “We have further found that the spliceosome is in a highly dynamic state during catalytic steps. The spliceosome can catalyze versatile reactions when fully assembled. In response to the change of the environment, the spliceosome can catalyze forward or reverse splicing”( http://www.imb.sinica.edu.tw/~mbscc/). This means that the environment can dictate whether or not a silent mutation stays truly silent or takes an effect. This can have positive or negative effects on evolution; since mutations occur randomly and without consideration to whether or not their consequences would benefit the organism, the likelihood that a detrimental mutation will occur is just as high as the likelihood of a helpful mutation that will lead to increased fitness and be passed down according to Darwinian evolution (http://www.nature.com/scitable/topicpage/genetic-mutation-1127). If a mutation in a certain environment in an organism enhances their potential to survive and reproduce, they will be more likely to do so than organisms with “normal” gene expression, and that mutation can be passed down in the gene pool to benefit future generations. However, as Michaela mentioned, people’s efforts themselves can also alter gene expression, so it is important to recognize GxE’s role in mutations. “Mutations can be acquired. This happens when environmental agents damage DNA, or when mistakes occur when a cell copies its DNA prior to cell division” (http://learn.genetics.utah.edu/archive/sloozeworm/index.html). In addition, once a person’s genetic code has acquired a mutation, environmental factors determine how much of an impact this mutation will have. “Genes are several steps removed from the process of trait formation” (Shenk 26), and environmental interactions and epigenetics can all play a role in the final way that trait turns out. Overall, single genetic mutations can have very drastic results as the result of a frame shift, or initially invisible results if they are silent, but environmental factors can change this as well. Environmental factors interact to determine the strength of this mutation, and the helpfulness of a mutation in terms of natural selection is random.
ReplyDeleteVivian Wang (vivian.wang9895@gmail.com)