Test 5 Review

Chapter 22 & 23 Which of the Following is NOT true about the genetic circuits referred to as feed-forward loops? Coherent feed-forward looped are persistence detectors that only responf to long –lived or persistent signals. Feed-forward loops are oscillating gene circuits Incoherent feed-forward loops are pulse generators that cause gene expression to switch ON and then OFF A combination of coherent and incoherent feed-forward loops can be used in a complex gene regulatory pathway Evolution has favored two different feed-forward motifs. In the first motif, called a coherent feed-forward loop, two transcriptional activators each directly stimulate transcription of a third "target" gene. Because one of the activators is also responsible for directly stimulating the production of the second activator protein, a strong sustained signal is output. Thus, this type of genetic circuit cannot be confused with an oscillatory circuit. In the second motif, which is called an incoherent feed-forward loop, the three genes involved code for one activator protein, a repressor protein, and a target protein. The activator directly stimulates the target and the repressor genes, which results in switching the target gene ON. However, after a short time, enough repressor is made to turn the target OFF. Thus, an incoherent feed-forward loop is termed a pulse generator. An oscillatory regulatory circuit differs from an incoherent feed-forward loop by showing true oscillatory behavior as a result of two genes being produced out of phase with each other—as one product starts to accumulate the other product starts to fall, and so on. Define autoregulation What is the biological significance of negative autoregulation, and why has it been repeatedly selected in evolution? Autoregulation is the regulation process by which regulatory genes control their own transcription as well as other target genes, usually by a feedback mechanism. Autoregulation can be either negative or positive. If a regulatory gene is negatively controlled by its gene product (for example, an excess gene product inhibits its own expression), it is described as negative autoregulation. Conversely, positive autoregulation occurs when the gene product activates, or positively regulates, its own expression. Negative autoregulation is a homeostasis mechanism by which the level of the regulatory protein is maintained at a constant level. It is efficient, fast, and conserves resources and minimizes wasteful production. Using a repressor protein as an example, transcription of the repressor gene will go up if the level of the repressor falls below a threshold for repression. The resulting increase in transcription will raise the cellular concentration of repressor and restore repression. However, if transcription overshoots and the level of repressor becomes too high, negative autoregulation will "switch off" transcription while the level of the repressor will fall during cell growth and division or by proteolytic degradation. Without negative autoregulation, the use of a very strong promoter will ensure rapid production but eventually result in overproduction and waste. A comparative weaker promoter, on the other hand, will eventually achieve a proper level of repressor but take a long time to do so. Both mathematical modeling and experiments have shown that negative autoregulation allows a more rapid response time for the same level of protein accumulation than simple regulation. Thus, negative autoregulation appears to have the best of both worlds. An appropriate amount of repressor is produced without additional expenditure of energy if excessive repressor was produced. The efficiency of regulating energy expenditures by the cell confers a selective advantage to the organism and maintained in the population. Define the “steady state” condition of a gene product The time required to each steady state after a gene is switched on in the case of the positive autoregulation is longer than the case of negative autoregulation or no feedback. Why? Is there any benefits for such regulation that requires a longer response time? A gene product, such as a protein, is in a steady state condition when the rate of its synthesis is equal to the rate of its loss through degradation or dilution during cell growth/division. Thus, an equilibrium is reached between protein synthesis and degradation/loss, and there is negligible variation in the level of the protein in a steady state. A gene with positive autoregulation requires a longer time to reach steady state because the rate of its product production, which is initially very slow but increases over time, depends on the accumulation of the product that serves as an activator for its own synthesis (figure below, curve C). By comparison, a gene with negative autoregulation (figure below, curve A) will have fast response time and reach steady state sooner for reasons as shown in Answer 2b. Lastly, the time for a gene with a simple switch to reach steady state is in between those with positive or negative autoregulation (Figure below, curve B) since it is not subjected to product feedback activation or inhibition. Positive autoregulation can be useful in biological processes that take time and unfold slowly, such as development, which can benefit from the slow accumulation of proteins involved in cell signaling and morphogenesis. In addition, positive autoregulation is also the basis in regulation of gene expression that utilizes a bistable switch, for example, when the gene(s) is switched ON, it remains locked ON for relatively long periods of time even when the concentration of the activator has dropped beneath the threshold to switch on the gene. Models The choice of which system depends on the question E. Coli Phage (lambda, T) Saccharomyces cerevisiae (yeast) Caenorhabditis elegans Drosophila melanogaster Mus musculus (Rattus) Danio rerio Zebra fish Arabidopsis thaliana maize Medicago truncatula rice Clamydemonas Fundamental problems are best solved in the most accessible system in which the problem can be addressed Critical mass of investigators Must have molecular genetics ability to make genetic crosses Ability to mutate genes Short generation time/easy to raise Ability to introduce genes Large number of progeny Cancer Genetics Tumor suppressor genes usually cause cancer when they pick up dominant mutations True False Cell cycle regulation is conserved from yeast to humans True False All of the following are involved in programmed cell death except activation of executioner caspases shrinking of the cell attack of macrophages bursting of the cell Different Cancers, Same mutations The team then asked which of these 479 genetic events occurred in each cancer sample, paving the way for new categories of cancer based on the particular constellations of aberrations they possessed. Interestingly, the team found that cancers with abundant single gene mutations tended not to have many copy-number alterations and vice versa. “What both groups come to in conclusion is that we have a spectrum of tumors that are driven by copy number abnormalities . . . and then another set of tumors that are driven primarily by a series of mutational events,” said Gordon Mills, chair of systems biology at the University of Texas MD Anderson Cancer Center, who was not involved in the work. “The two papers provide . . . a very cogent argument that these are two of the major driving events,” he said. Beyond learning more about the mechanisms behind the disease’s origins, said Sander, such pan-cancer studies “might lead to a new kind of clinical trial.” Sander described such studies as basket or matrix trials, in which patients with different tumor types—for example, breast, ovarian, or colorectal—but similar constellations of genetic alterations, would be treated with the same drug or drugs. Of course, Mills stressed, tissue type is still important. It’s possible that the same mutation in differentcancer types could indicate different responses to drugs. Sept 2014 Types of cancer mutations Copy number abnormalities Chromatin remodeling genes CpG methylation pattern changes Replication, repair genes Growth stimulating, grow suppressing genes Cell proliferation Cell migration Cell cycle Cracking Your Code SCENARIO 1-Should you test your embryos for gene mutations or other abnormalities before having a baby? You and your husband are about to start a family. Your husband has a genetic mutation that greatly increases his chances, sometime in his life, of getting a rare form of colon cancer, a type that killed his mother and an uncle. Preimplantation genetic diagnosis, or PGD, makes it possible to test your embryos for the mutation and transfer only those that do not have it into your uterus to continue development. PGD involves removing one of eight cells in an embryo that, if deemed healthy, is transferred back into you for development—minus that one cell. However, even if you don't do PGD and your baby were to inherit the mutation, there is no certainty that he or she would later get the disease. PGD can help parents avoid passing on mutations Some who know they have a mutation that increases their chances of contracting a deadly disease want to make sure that their unborn children do not inherit it: "I couldn't imagine them [later] telling me my daughter has cancer, when I could have stopped it [when she was at the embryo stage]." —Chad Kingsbury, who has a genetic mutation that makes him susceptible to an inherited form of colon cancer, and decided, with his wife Colby, to do PGD; as a result, their daughter Chloe does not have the misspelled gene. To some, PGD smacks of eugenics To some people, even if they have a dreaded mutation, PGD seems like a kind of eugenics—the now-repudiated policy of past governments, in the U.S. and elsewhere, to prevent certain people from reproducing because they were considered genetically inferior: "It's like children are admitted to a family only if they pass the test. It's like, 'If you have a gene, we don't want you; if you have the potential to develop cancer, you can't be in our family.'” Some use PGD to create "savior siblings" Some couples have begun turning to PGD to help them have a baby that could provide a cell transplant to treat a desperately ill older sister or brother: "You could say it was an added perk to have Adam be the right bone marrow type, which would not hurt him in the least and would save Molly's life. We didn't have to think twice about it." —Lisa Nash, who used PGD with her husband to find an embryo that would not have the deadly blood disease Fanconi anemia that her six-year-old daughter Molly has, and would also be a tissue match for Molly. The chosen embryo became her son Adam, whose umbilical-cord blood cells were used to successfully treat Molly. PGD's success rate is not perfect Some worry about PGD's failure rate, which is up to 5 percent: "You feel so guilty because you're trying to help one daughter and you end up hurting two other children. Now we understand that it's not an exact science and there's room for error." —Doreen Flynn, 29, who did PGD with her husband to find embryos free of Fanconi anemia, which their young daughter has. Two selected embryos became two more daughters, who, despite PGD, were born with the disease. SCENARIO 2 Should you ask your doctor for a genetic test, or order a direct-to-consumer test, that can offer some idea of your risk for contracting Alzheimer's later in life? Several members of your family have developed Alzheimer's disease late in life. You're thinking about getting tested for the genetic factors that scientists have identified as raising a person's chances of developing the disease later in life. There is currently no cure or treatment for Alzheimer's, nor is there convincing evidence that medication or diet will delay or prevent its onset in a susceptible individual. Some wonder why learn their risk if no treatment or cure Because there is little you can do if you have, say, one or two copies of the e4 allele and thus an increased risk of Alzheimer's, some people feel why get tested for such mutations? "[M]y father was diagnosed with Alzheimer's. …[T]he reason I didn't pursue genetic testing for Alzheimer's was because if I had it identified, there really isn't any cure for it. At this stage in my life, I didn't want to know that at some point I was going to encounter it. There really isn't any treatment. … So, why make your life more depressing?" —Anonymous Some want a chance to prepare Others believe knowing about an increased risk would at least give them and their loved ones a better opportunity to ready themselves for it should it occur: "I talked with my doctor about getting a genetic test, and he wasn't keen on it. His comment was, 'Well, what would you do?' And I said, 'Plan.' … It would prompt me to make plans to do a lot of things through my sixties and seventies if I am in good health." —Anonymous you could contribute to research Some people feel that if they were found to have a higher risk for Alzheimer's that they would help with studies into the disease: "I think I would become more active in Alzheimer's research. …[I]f… I knew I was more likely to get it, I would go ahead and do that [to help in] detecting it early and finding better ways to measure what is happening." —Anonymous subject with Alzheimer's among immediate family members some would rather leave everything to fate Others would prefer not to test and let fate take its course: "My uncle died of Alzheimer's, and I think he was like eighty-something, and my mother who is eighty-five has it… So, I am looking at the fact if it does hit me I am looking at being about the age of my mother. I leave my life up to God. And He has His plans for me, and if I get struck down with the disease so be it. I will just have to do the best I can with it and my husband will do the best he can with it too." —Anonymous Some fear genetic discrimination Some decide not to get tested for fear that health insurers or employers could discriminate against them if they learned that those individuals had a higher risk for Alzheimer's*: "I talked to my internist about it, and at the time he was telling me that there was testing that could be done but it's one of those things that is two-sided because one thing, you could find out nothing definite—that you were predisposed I guess for getting Alzheimer's—and the other thing is it would be like a preexisting condition for insurance purposes. I guess I just decided not to go any further with it." —Anonymous Note: The 2008 Genetic Information Nondiscrimination Act, or GINA, protects individuals against discrimination in health coverage and employment on the basis of genetic information, but it does not extend to life, disability, or long-term care insurance. SCENARIO 3: You have a family risk of breast cancer. Should you ask your doctor about getting your genes tested for mutations that increase your risk? You are a 25-year-old unmarried woman. Someday you plan to have children. You're worried because you have a family history of cancer: Your mother and aunt died of breast cancer, and one of your grandmothers of ovarian cancer. You've learned that women with a mutation in the BRCA1 gene have a 60 to 80 percent greater chance than the average woman of getting breast cancer, and a 40 percent increased risk of developing ovarian cancer. Your doctor has advised you to get specialized genetic testing to see if you have such a BRCA1 mutation—or one or more less common genetic glitches that also increase your likelihood of getting breast or ovarian cancer. If you have a mutation, you can do something about it Women who learn that they have a BRCA or other mutation that increases their risk of developing breast or ovarian cancer have a range of care options, from getting earlier mammograms or other screening, to undergoing risk-reduction surgery (removal of healthy breasts and/or ovaries before any cancer has developed). In order to consider such preventative measures in time, it is wise to be tested, if possible, before about age 35: "[W]hen I tested positive, [I said] Okay God, now what do I do next? … I struggled with it. It was a very difficult few weeks. … I got there, but it was a difficult realization to come to, really emotional and really hard. … I decided actually to do everything. I came to the conclusion first on the breast thing, and continued my research and decided the ovaries had to go too. … Looking back, I have no regrets." —Anonymous Many fear getting bad news Getting tested can be scary, especially if you have a family history of breast or ovarian cancer: "I do remember the day that I went to find out the results. Panic. Terror. I mean, what was I going to find out? Talking about, you know, the blood surging through your temples. I mean I just remember sheer terror." —Lori Siegel, sister of Melanie, who died of ovarian cancer, and of Lissa, who has a BRCA mutation and has had breast cancer Some want to alert their close relatives of risk Some women who have had breast cancer want to know if they have a predisposing BRCA1 or other breast-cancer-related variation so they can inform their children or other close family members of potential risks and thereby encourage them to get early screening and take other steps to prevent the disease: "[A]s soon as I felt the lump, I kicked myself and asked myself why didn't I get tested three years ago when I had the [single] mastectomy? This time, I was tested immediately because I have two daughters and [now] three granddaughters. Now it had urgency because I needed to know if I carried the mutation for more daughters and granddaughters to know. That was absolutely imperative." —Anonymous Family may not agree on testing Even your closest kin may not agree with you about testing, and after getting results you have to be prepared for how best to inform your relatives—or not: "I was arguing with my husband. He didn't want me to have testing, saying I was 'playing God.' While we were arguing, my twelve-year-old daughter overheard and we had to explain it to her. She faltered. She was frightened, and even had to come home from school one day." —Anonymous Parents can experience guilt It is common for parents to feel guilty for having passed on a mutation to their children: "He was really sad. … It wasn't his own mortality, it wasn't the fact that he could be at risk, but he was undone at the thought that he has passed this on to his daughters." —Anonymous, about her father who has a BRCA1 mutation For some, timing can be an issue For some people, the timing may simply not be right for getting tested, with all its attendant emotional baggage: "After my mother's surgery, the doctor came out and explained to us that she had ovarian cancer and then he looked straight at me and said, 'I would highly recommend genetic testing for you at this point.' … I have not been tested yet, and it's been one of those things hanging over my head for the last two years. My children are young and they need me. I help my husband run his business. … There is only so much I can afford to have hanging at once. My life is not in the place where I could take that on." —Anonymous SCENARIO 4 Should you get a direct-to-consumer genetic test to help better take control of your health? You feel fine, and you don't have a strong family history of any single disease, but you're curious about what your genes can tell you. You may want to know, for example, what your lifetime risk might be for developing certain common diseases or for passing defective genes onto your children—or perhaps more mundane things such as whether you have a gene that makes you sneeze in the sun. Instead of consulting with your doctor or a genetic counselor, you want to try testing on your own with a direct-to-consumer (DTC) genetic test from one of the companies now offering them. You realize that DTC genetic testing is still in its early days, and such tests only look for the most common genetic markers—bits of DNA that vary from person to person and have been associated with an increased risk of a particular disease. If you have a strong family history of breast cancer or other serious disease, you would want to order a more comprehensive screening through your doctor, not rely on a far more limited DTC test. You also understand that DTC tests are all about probabilities, not guarantees, and that even if you have a mutation linked to heightened chances of getting a disease, you may never get the disease. Knowledge can be power Some prefer to know what their risk factors are, so they can better prepare for what might be coming later in life: "I'm glad I took the tests. I went on a trip into my past, present, and future. It's an experience that gave me a new perspective on life. …[M]aybe it will help me someday, when I'm trying to piece together my medical mysteries." —Boonsri Dickinson, a reporter for Discover Magazine, who underwent DTC testing through three different companies Knowledge can also be a burden For others, the emotional strain that would come with potentially learning that one had a genetic mutation or other variation that increases risk of disease would not be worth it: "You know, I almost feel better not having genetic testing than knowing, oh my oh my, I have these mutations on these genes. … So are you going to sit there waiting for a time bomb to go off? When is it going to happen? Is it going to happen? No, I am not going to live that way." —Anonymous Many are concerned about privacy Companies offering DTC tests typically promise confidentiality, an issue of great importance to many clients, some of whom do not want even their doctors to know their results: "Finally we found a lab that … allows the patient to do the entire thing—confirm or rule out hemochromatosis [a build-up of iron in the tissues that can result in heart failure, diabetes, and other serious conditions]—and basically diagnose yourself. … So, a person can order the testing themselves, get the results themselves. No one else gets the results or sees them." —Anonymous Expert guidance is valuable Many people feel it's important to have personal contact with a genetic counselor: "The Internet is wonderful, and it can also be dangerous. Sometimes too much information, when you are not able to handle it, can scare you to death. I think you need to sit down and talk with a human being who has training in the whole genetics picture." —Anonymous DTC genetic tests differ—and so can their findings A few years ago, Francis Collins, the geneticist who headed the Human Genome Project, asked three different DTC gene-testing companies to examine his genome for mutations. (He used an assumed name to preclude any preferential treatment.) The three tests differed in cost and in the range of genetic variants tested for. While the three companies agreed on most results, each came back with a different assessment of Collins's risk for developing prostate cancer: One said lower-than-average, another said slightly elevated, and the third said 40 percent higher than the average male. "There's a really important lesson here—the field is moving so quickly that any genetic risk predictions based on today's understanding will need to be revised in the context of new discoveries tomorrow. That applies not just to prostate cancer but to all of the rest of my risk predictions—what is possible now is only a blurry picture of reality." —Francis Collins Epigenetics Which of the following is not regulated through epigenetic mechanisms? Transposon silencing Imprinting Flowering time Circadian rhythms Embryonic development Worker bee behavior Euchromatin is silenced by condensing the histones through modifications of individual histones True False note-this depends on how you think of the answer-modification of histones can bring in silencing machinery, but other things can as well. Some aspects of the epigenome, such as transposon silencing are “reset” in each generation True False Which of the following influences can NOT make epigenetic changes that affect your gene expression? Stress Diet Exercise your parent’s exposure to events & chemicals Your children’s exposure to events & chemicals Early Life Stress affects the ability of subsequent generations to cope True False but in a positive way. The offspring of the mice that were stressed (maternal deprivation) inherited better problem solving Harmful changes to the epigenome can be corrected through Diet Drugs Sequencing A&B B&C Environment x Genome Although biologists have generally considered Lamarck’s ideas to contain as much truth as Kipling’s fables, the burgeoning field of epigenetics has made some of us reconsider our ridicule. While no biologist believes that organisms can willfully change their physiology in response to their environment and pass those changes on to their offspring, some evidence suggests that the environment can make lasting changes to the genome via epigenetic mechanisms—changes that may be passed on to future generations. Ethics Blood Spots Are Epigenetic Time Capsules Researchers show that blood spotted onto Guthrie cards, usually at birth, can be a high quality source of methylated DNA for long-term epigenetic studies.