This case tells the story of Elise, a college freshman whose identical twin sister has recently been diagnosed with schizophrenia. Elise is concerned about her own risk for developing this disease.(link)
Part 1 – Beginning
- What exactly are twins, and how do they arise?
In terms of living species, twins are organisms that are typically born at the same time. There are two types of twins, identical, and fraternal. Dizygotic or fraternal twins derive from two separate ova fertilized at the same time (Medical Dictionary, 2014). Identical twins occur when an egg is fertilized by a single sperm cell; later on, it divides, thus making the twins identical. Monozygotic or identical twins develop from single ova that will divide after fertilization. (Medical Dictionary, 2014).
- Are identical twins completely identical? Why or why not?
The leading factor that causes twins to not be completely identical relates to epigenetics. Epigenetics has the ability to turn genes on and off (Roddie, 2016). Epigenetics differ in twins according to external factors such as chronic stress and chemical toxins. This may cause the body to produce its own peculiar epigenetic functions such as deciding which cells are brain cells or skin cells. Even though the underlying DNA will remain the same, the phenotypes of the twins will most definitely be altered if introduced to relatively diverse life experiences.
Identical twins are not completely identical. Since identical twins harbor the same DNA, it could become mutated. This will cause a difference between the twins. For example, a twin may have thicker eyebrows than another twin due to a genetic mutation. Many differences between twins have largely been attributed to environmental influences (Scientific American, 2008). For example, a twin that is exposed to indoor air pollution may incur asthma attacks. The differences in nurturing can make a difference in a mental, physical, and emotional sense. The mutation is rare when it comes to making twins less identical.
- What can studying twins tell us about the genetic influence on a particular trait?
Studying twins informs us heavily, regarding the genetic influence for particular traits. Identical twins are important because it allows us to identify any changes between the two and, we are able to rule out that it is a genetic change. This allows researchers to identify the outside influences that affect the epigenome. Lifestyle and environmental factors (smoking, diet and infectious disease) can expose a person to pressures that prompt chemical responses. These responses, in turn, often lead to changes in the epigenome, some of which can be damaging. (National Genome Institute, 2016). In conclusion, this states that outside sources may affect the genome, and twins allow us to determine these factors. For example, if a twin lives in an area that has a relatively dangerous pollution index (Index 7 or higher) It will make that twin prone to disease, aside from the other twin that was exposed to a safe air quality index.
Part 2 – The Diagnosis
- What causes genetic variation? For example, what causes some people to have curly hair and others do not? What causes some people to have a genetic disease such as cystic fibrosis and others do not?
Genetic Variations: This can be caused by organisms mating randomly; this introduces new alleles to the environment. Moreover, the recombination for homologous pairs (chromosomes) causes a variation of genotypes within the same organism; this is why siblings may possess different physical traits. Random fertilization describes the concept that the probability of any set of genes has an equal likelihood of combining to form an offspring. For example, a human egg does not differ in the chance of being fertilized by a sperm that retains the widow’s peak trait or the straight hairline trait. Next, even though it is not common in humans, mutations occur randomly in the human body and can alter genotypes.
Genetic Variation causes humans to have curly hair. Random mating can be a large factor in causing curly hair since humans with straight hair and curly hair could be constantly mating, if a human with a recessive allele for curly hair mates another human with a recessive allele for curly hair, they have the capacity to produce curly haired offspring.
Offspring may also have curly hair due to genetic mutation; however, this is a rare occurrence and will most likely not happen.
Cystic Fibrosis is a trait that is inherited. The reason cystic fibrosis occurs in various people because inheriting this disease is dependent on the traits of your parents, and grandparents, etc. Cystic fibrosis is a gene that is inherited on chromosome 7. Genetic variation may cause certain family pedigrees to retain this trait, thus causing cystic fibrosis to occur in others depending on family pedigrees.
(E.M. Collings, 2010) This figure demonstrates how two recessive alleles can result in an offspring that will inherit the prominent genotype.
(Google images, 2006)
Straight hair (Dominant) vs. Widow’s peak (Recessive)
- What does it mean when a trait or a disease “runs in families”?
This means that there are many humans within the family pedigree that harbor the trait or disease. They can either have this disease as a dominant allele, you can physically notice it, or as a recessive trait, you cannot physically notice it. These diseases are sources of genetic variation that has occurred previously in the family’s lifetime. Moreover, this genotype is able to be inherited by various family members, meaning they are more likely to inherit the disease.
- What could be some possible genetic and non-genetic causes of Shannon’s schizophrenia?
Schizophrenia is known as a disease that runs in the family. Regarding genetic factors and identical twins, A person that genetically inherited schizophrenia means that their identical twin has an approximately 50% chance of getting schizophrenia. People with schizophrenia tend to have higher rates of rare genetic mutations (Web Medicine, 2015). Many scientists also believe that schizophrenia is not caused by one gene, but many genes increase the risk of causing schizophrenia. Another theory is that: schizophrenia may result in part when a certain gene that is key to making important brain chemicals malfunctions (Wed Medicine, 2015).
Schizophrenia can develop from non-genetic causes. Many environmental factors may be involved, such as exposure to viruses or malnutrition before birth, problems during birth, heavy adolescent marijuana use (Web Medicine, 2015). This lets people know that even though schizophrenia is genetic, it is still a preventable illness.
Part 3 – Just How “Identical” Are We?
- Briefly describes what you know about the structure of DNA and how DNA is packaged in a cell.
DNA stands for Deoxyribonucleic acid. Virtually every cell within the human body consists of DNA. Most DNA is located within the nucleus. The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T) (National Institute of Health, 2016). The human body consists of approximately 3 billion bases. Even though every human, aside from identical twins, share approximately 99% of their DNA. The orders of the sequence of nitrogenous bases are fairly important in the function of DNA; similar to the way in which letters of the alphabet appear in a certain order to form words and sentences (National Institute of Health, 2016). Each DNA base is attached to phosphate and a sugar molecule to create a double helix. DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone.
DNA while being combined with proteins is organized into a dense structure called chromatin; this will condense more into a chromosome during the division of cells.
The DNA molecule consists of nucleotide monomers for DNA and RNA. Nucleotides consist of a phosphate group, a nitrogenous base, and a five-carbon sugar.
In terms of packaging, DNA undergoes a certain method to become packaged into a cell nucleus. Firstly, DNA is attached to proteins named histones; histones contain amino acids. These acids are able to create ionic bonds, (metal, to non-metal) to the phosphate group of the DNA helix structure. When DNA forms chromosomes it is coiled tightly, which helps fit smoothly into the cell nucleus.
DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone.
(Us National Library of Medicine, 2012)
(Us National Library of Medicine, 2012)
This is an example of a DNA molecule that is uncoiled. The deoxyribose attaches to another molecule by connecting is 5′ carbon to another 3’carbon.
- At the molecular level, speculate on some ways that the environment might have an influence on DNA and its packaging.
DNA is unique in the sense it can be altered by external sources. University of Leicester researchers writing in the journal Chemical Research in Toxicology say they have found “convincing evidence” that cannabis smoke damages DNA (Leicester University, 2009). The evidence from Leicester suggests that cannabis can inhibit the DNA’s ability to complete transcription. DNA transcription is a process that involves transcribing genetic information from DNA to RNA. This ensures that the information contained within the DNA does not become tainted (Biology Research, 2014). Due to the cannabis inhibiting transcription, it alters the DNA; this is how twins begin to differ as they age due to lifestyle changes. Inhibiting transcription can prevent the expression of certain genes.
Next, during mitosis chromosomes are constantly stretched apart and moved around, this puts the DNA structure in danger of being damaged. This is the reason why the DNA structure needs to be tightly coiled around the histone in order to prevent this from happening.
Physiological stress encourages methylation which in turn causes the DNA to become loosely coiled (loose packaging); this increases the chances of the DNA being damaged during mitosis.
Part 4 – What really is “Epigenetics”?
- Examine the data shown in Figures 2 and 3. Carefully compare the DNA methylation profiles from the 3-year old twins versus the 50-year-old twins and summarize your observations. Which set of twins (3-year-old or 50-year-old)has the most similar DNA methylation profiles? Provide a brief explanation of your observations.
Observations: The gel structures appear to be in differing locations for the 50-year-old twins but the three-year-old twins have DNA in the same position,
The reason the structure of the 3-year-old twins more similar is that they were exposed to a more similar environment than the 50-year-old twins. Various environmental factors result in a variety of genes. Since environmental factors have an effect on the epigenome, the longer a person exposed to various environmental factors, the larger the impact on the epigenome. Since the three-year-olds had less time to become exposed to relatively diverse genetic factors there would be less potential for the demethylation samples as you can see in figure 3 they are more similar. This is in comparison to the 50-year-old twins that had a total of 47 extra years to have their methylation profiles become more altered.
The most likely reason may be that one of the twins genotype was methylated while the other was not, this could be due to embryonic development, carcinogens, or chromosome stability. Methylation results in a lower reelin count, thus preventing neurological pathways. (Roddie, 2016)
2.) What types of environmental factors can influence DNA methylation?
Influences that can influence that influence DNA methylation:
- Poor Dieting
- Recreational drugs and tobacco
- Pharmaceutical drugs.
- Psychological Activity: Anxiety, Stress
- Air Pollution
- Explain how they cause DNA methylation
Poor Dieting: The food we eat has an impact on the structure of our DNA. The nutrients extracted from food are molded into molecules the body uses, methyl groups; nutrients such as Folic acid, B vitamins, and SAM-e. This would mean that if your diet did not consist of these nutrients it would poorly influence your epigenome; it wouldn’t be able to properly use the methyl groups to turn genes on and off. This would have a stronger influence in altering the genome in the earlier stages.
(Utah Education, 2016)
Air Pollution: Air pollution introduces carcinogens to the human body. This causes the cell to evade programmed cell death. This causes the defective cell to constantly reproduce, thus influencing DNA methylation by inhibiting the epigenome from using DNA methylation to halt the development of DNA.
3.) Aside from DNA methylation, what other types of epigenetic modifications can occur within the genome to influence gene expression?
All chromosomes have a single DNA wrapped around the histone protein cores (Kyrk, 2014). If there is a modification of the Histone, the DNA would be altered; thus causing the genome to become expressed differently. If the histone is modified then this will alter the genes the epigenome turns on and off because it may be coiled differently.
Acetylation is used to modify the histone, Acetylation modifies the histone by dictating how the histone reacts with protein structures. This will regulate the structure of the chromatin. When the structure of the chromatin tampers with the genome expression will result in a change.
4.) Do you think Elise needs to be worried about her own mental health? Why or why not? If you were a health-care professional, what would you advise Elise to do?
Elise does not need to worry about her mental health. According to the brochures in the case study: Environmental factors influence genotype (Hickerson, 2011) the information given in the case study shows that Elise’s DNA is not considered like her sister. The chances of Elise getting schizophrenia is fairly slim due to the fact that their siblings are exposed to considerably different environments. Elise’s DNA did not methylate when she was younger, this means she shouldn’t worry because methylation encourages schizophrenia (Roddie, 2016). What she should be worried about are her future children, which are at risk of getting schizophrenia. The sole cause of schizophrenia is unknown. Since her identical twin has schizophrenia, there is a 48% chance that Elise will get schizophrenia.
Secondly, if I was a healthcare professional I would advise Elise to collaborate with her sister’s doctors to make sure she is not exposing herself to the same environments that Shannon is exposed to. I would also recommend therapy to help her de-stress in her situation because stress can result in an increased chance of schizophrenia. I would tell Elise that the chance of her getting schizophrenia is really low because this would de-stress her as well. I would also give her gel electrophoresis, to examine her DNA fragments to see if her progress is straying away from her sister. I would also make sure that she consults with an expert in genetics to evaluate the chances of her future children getting schizophrenia; this will allow her to decide if she wants children. If Elise’s kid is born she has approximately a 3% chance of developing schizophrenia.
Part 5 – What Does The Research Say?
- What is the role of reelin in the brain? According to Figure 5, how does the expression of reelin in the prefrontal cortex of schizophrenic patients differ from reelin expression in non-psychotic subjects?
Reelin is a glycoprotein that activates the pathways for brain signaling (Scientific American). Reelin is responsible for the development of the brain and the neurological functions of the brain. In figure 5 of the case study, patients that were diagnosed with schizophrenia had a lower reelin content. This means that non-psychotic subjects have a higher reelin content, which makes sense because it is responsible for brain development. In the first two layers, non-psychotic patients have a double positive reelin count then the psychotic patients. Reelin prevents the DNA from becoming methylated. In layers 5-6, the reelin levels are practically even.
- Study the promoter methylation data shown in Figure 6. How does the overall level of methylation of the reelin promoter in schizophrenic brains compare to the methylation of the reelin promoter in non-psychotic control brains? What would be the most probable effect of this methylation pattern on the expression of reelin in patients with schizophrenia?
The methylation of the reelin promoter in the schizophrenic patients is higher in comparison to the non-psychotic patient’s control brains. After the start site of the RNA, the reelin count decreases in schizophrenic patients. Moreover, this leads to the fact that schizophrenia is most likely caused by a disruption of the neurological signals; prohibiting the brain from functioning properly. Reelin is a protein in the brain, if you cannot produce reelin in the brain, your brain will not be able to function properly (Roddie, 2016).
- What is the enzyme responsible for methylating DNA? How does a drug like doxorubicin affect DNA methylation?
The enzyme that is responsible for methylating DNA is called methyltransferase. Doxorubicin affects DNA methylation by becoming an inhibitor for the methyltransferase enzyme. Without the methyltransferase enzyme functioning properly it constricts the methylation of DNA.
- In reference to Figure 7, what is the effect of doxorubicin on the expression of reelin in NT-2 cells? How does increasing amounts of doxorubicin affect reelin expression in these cells?
The doxorubicin enzyme will allow the reelin amounts to increase because the doxorubicin constricts DNA methylation. This allows the genome to not become affected by environmental factors. This means, increasing doxorubicin will increase the reelin count in the brain. This will lead to an increase in proper brain development and functions.
- Based on these data, might a drug like doxorubicin be a potential treatment for schizophrenia? Why or why not? What additional experiments should be performed before a drug like doxorubicin goes into clinical trials?
- Sores in the mouth and throat.
- loss of appetite (and weight loss)
- Weight gain.
- Stomach pain.
- Increased thirst.
Side effects of doxorubicin.
Doxorubicin drugs could be an exceptional treatment option for schizophrenia. This is because it inhibits DNA methylation, and increases the reelin count in the brain.
The Additional experiment should firstly consist of tests on animals that share similar DNA to humans such as rats; this is because it is safer to do tests on rats than humans. The drug should also be tested in an environment with a pH corresponding to the human body. Moreover, they should test the drugs with human patients that volunteer as tribute. Humans share 99% of DNA with rats; this would make them a good model to do the experiment because they will share similar results with humans. A good test would be to give a rat with schizophrenia the doxorubicin drugs. The observations could be recorded to see if the doxorubicin drug is effective.
Bird, A. (2003). Epigenetic regulation. Retrieved January 12, 2016, from Hickerson, T. (n.d.). Nature
Et al, R. (n.d.). Environmental Influences on Gene Structure May Be Transmitted to Offspring. Retrieved April 26, 2016, from http://bipolarnews.org/?p=316
How Does DNA Transcription Work? (2016, February). Retrieved April 26, 2016, from http://biology.about.com/od/cellularprocesses/ss/Dna-Transcription.htm
Journal of DNA. Retrieved April 26, 2016, from Thomas
Somanna A. (2012, March). Histone Modification: Acetylation n Methylation. Retrieved April 26, 2016, from http://www.slideshare.net/somannaan/histone-modification-acetylation-n-methylation
Torrey, E. F. (2001). Surviving schizophrenia: A manual for families, consumers, and providers. New York: Quill.
Preidt, R., Dr. (2016, April 22\). National Library of Medicine – National Institutes of Health. Retrieved April 28, 2016, from https://www.nlm.nih.gov/
Roddie, B. (Writer). (2016, April 26-28). Live performance in Canada, Hamilton.