Explain in detail how meiosis differs from mitosis

25 Jun Explain in detail how meiosis differs from mitosis

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NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE

Identical Twins, Identical Fates?
An Introduction to Epigenetics
by
Sarah A. Wojiski
School of Arts and Sciences
Massachusetts College of Pharmacy and Health Sciences, Boston, MA

Part I – Coming Home
Elise was excited as she boarded the bus. She had just finished her first year at college and was looking
forward to her first night back home since winter break, which would include mom’s spaghetti and meatballs and
catching up with her family. She couldn’t wait to curl up on the couch with her cat Ziggy snuggled next to her, and
she was hopeful that her sister, Shannon, would be willing to join her there, since they had talked very little since
Elise’s last visit home.
As she settled in for the four-hour bus ride home, Elise pulled out her iPhone, put on some music, and started looking
through old photographs. She came across a few of her and her sister taken at Christmas—the last time they had seen
each other. Looking at Shannon was like looking in the mirror. After all, they were identical twins. Elise recalled all
of the pranks that she and Shannon used to pull in school when they were kids. In 5th grade, they once made it all the
way to lunchtime before their teachers realized that they had swapped classes and were impersonating one another!
Shannon and Elise used to have so much fun together, but things had changed. Elise was worried about her sister and
the serious health troubles she had been having over the past year and a half. And she couldn’t help but wonder to
herself, “Are the same troubles heading my way?”

Questions
1. What exactly are twins, and how do they arise? Your response should distinguish between the two different types
of twins.
2. Are identical twins completely identical? Why or why not?
3. What can studying twins tell us about the genetic influence on a particular trait?

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Part II – The Diagnosis
Elise stared out the window of the bus at the rush-hour traffic that had befallen travelers on the other side of the
highway. She recalled that night back in November when her mother called her at school to share the fateful news
about her sister. “Shannon has been diagnosed with schizophrenia,” was what she had said. The words had dropped
into the pit of Elise’s stomach.
She had known that something was going wrong with her sister. The summer before she left for college, Elise noticed
changes in Shannon’s behavior. Despite being an avid swimmer and lifeguard, Shannon quit her highly coveted swim
camp instructor position just two weeks into the summer. She seemed withdrawn and unmotivated, and had also
unexpectedly decided not to attend college in the fall, despite Elise’s and her parent’s efforts to convince her otherwise.
But Elise did not get to see the worst of Shannon’s behavior, when she began having hallucinations and couldn’t seem
to carry on a coherent conversation with her parents.
Elise had done some research about schizophrenia after hearing of her sister’s diagnosis. She did not like what she
found out. Apparently, schizophrenia has a tendency to run in families. In fact, studies indicate that a sibling of a
schizophrenic has a 10-fold higher risk of developing schizophrenia over the general population. Elise began to worry
about her own mental health. She decided she would do some further investigation into the disease once she got home
for summer break.

Questions
You are encouraged to consult reliable sources (such as your textbook and other online and print resources) to answer
some of these questions. The review articles listed below address Question #3.
1. What causes genetic variation? For example, what causes some people to have curly hair and others to not? What
causes some people to have a genetic disease such as cystic fibrosis and others to not?
2. What does it mean when a trait or a disease “runs in families”?
3. What could be some possible genetic and non-genetic causes of Shannon’s schizophrenia?

Review Articles
Gejman, P.V., Sanders, A.R., and Kendler, K.S. (2011). Genetics of schizophrenia: new findings and challenges. The
Annual Review of Genomics and Human Genetics 12: 121–44.
Roth, T.L., Lubin, F.D., Sodhi, M., and Kleinman, J.E. (2009). Epigenetic mechanisms in schizophrenia. Biochim
Biophys Acta 1790(9): 869–877.
Rutten, B.P. and Mill, J. (2009). Epigenetic mediation of environmental influences in major psychotic disorders.
Schizophrenia Bulletin 35(6): 1045–1056.

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Part III – Just How “Identical” Are We?
Elise had been home from college for a week, and she was still preoccupied with Shannon’s diagnosis and her own
potential risk for mental illness. Elise expressed her anxiety and concerns to her mother one night after dinner. “Elise,”
her mother said, “your concerns are perfectly valid, and you have every reason to want to get more information. Why
don’t we make you an appointment to consult with a psychiatrist?” Elise decided to make the appointment the next day.
*****
Elise left Dr. O’Brien’s office feeling that some of the weight had been lifted from her shoulders. On the car ride home,
she thought about the things that Dr. O’Brien had said to her during their consultation.
“It was good of you to come in to see me, Elise. You are absolutely right to have concerns for yourself when your
identical twin has been diagnosed with schizophrenia. Research shows that schizophrenia is almost 50% heritable, and
since you share nearly identical DNA with your sister, that puts you at a higher risk for developing this disease as well.”
“Fifty percent may sound like a scary number, but remember that schizophrenia is a very complex disease, and 50% of
what causes schizophrenia is due to things other than your DNA.”
“Well, like what? What else could be contributing to Shannon’s schizophrenia that wouldn’t necessarily affect me?” Elise
asked.
Dr. O’Brien replied, “There are many, many environmental influences that seem to play a role in the development
of this disease, such as increased stresses and anxiety, or difficult relationships with other people. Interestingly, there
is some groundbreaking research that is going on that suggests that the environment itself might even play a role at
influencing one’s DNA at the molecular level. This concept is called epigenetics. An example of epigenetics in nature is
the calico cat. Each calico cat has a unique orange and black fur color pattern because of alterations, called epigenetic
changes, which occur within the cells that produce coat color during the cat’s development. Research in the field of
epigenetics suggests that individuals with schizophrenia appear to have some of these epigenetic changes to their DNA
that are due to environmental influences, and that these alterations could be contributing to their development of
mental illness.”
“But wouldn’t I also have these ‘epigenetic alterations’ in my DNA?” Elise asked.
“Not necessarily, because you and Shannon have not experienced completely identical environments throughout
your lives. For example, you and Shannon have had different teachers and jobs throughout high school. And I also
understand that you spent many childhood summers with a friend and her family out in the Grand Canyon, while
your sister was off at swim camps. If you are interested, I can give you some literature to read about this subject.”
Elise was definitely interested. She took the articles and headed home.

Questions
1. Briefly describe what you know about the structure of DNA and how DNA is packaged in a cell.
2. At the molecular level, speculate on some ways that the environment might have an influence on DNA and its
packaging.

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Part IV – What Really is “Epigenetics”?
Despite being three weeks into her summer break, Elise felt like she was back in school. The more she read about the
topic of epigenetics, the more fascinated she became, and she found herself spending most of her days on the Internet
doing research. Elise had learned about genetics in her general biology class and thought she had a pretty good idea of
how the Laws of Mendel worked, but this whole field of epigenetics seemed to take the idea of inheritance to another
level. She was particularly fascinated by an article that Dr. O’Brien had given her regarding epigenetic differences
between identical twins. The article suggested that during one’s lifetime epigenetic changes occur to one’s DNA that
can affect gene expression, and therefore whether or not one will express a certain trait. These epigenetic changes are
influenced by one’s environment and behaviors, so despite having identical DNA, identical twins will not always have
the same epigenetic changes, and therefore, will not always express the same traits.
In this article, researchers examined a particular type of epigenetic modification called DNA methylation, whereby a
cytosine base becomes methylated through the action of an enzyme called a DNA methyltransferase. The reaction is
shown below in Figure 1.

Figure 1. Methylation of cytosine to form 5-methylcytosine. SAM
(S-adenosyl methionine) serves as the source of the methyl group, giving
SAH (S-adenosyl-L-homocysteine) as a by-product.

The researchers examined genome-wide methylation patterns in several twin pairs of various ages. Representative data
from their analysis is shown below in Figures 2 and 3:

Figure 2. Differential DNA methylation between two sets of monozygotic twins, one
set at age 3 (left), one set at age 50 (right) using AIMS (amplification of intermethylated sites). Different bands, corresponding to sibling-specific changes of
DNA methylation, are indicated with arrows. (Panel A of Figure 2 in Fraga et al.,
2005. Epigenetic differences arise during the lifetime of monozygotic twins. PNAS
102:10604–10609. Copyright 2005 National Academy of Sciences, USA.)
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Elise read this article several times, and began to feel a little
bit better about her “genetic future.” According to this
article, it seemed that as time went on she and Shannon
would become more and more epigenetically dissimilar,
even though they did carry the same genes. Perhaps she
would not share the same fate as her sister after all.

Questions
You are encouraged to consult reliable sources (such as your
textbook and other online and print resources) to answer
some of these questions. The article by Singh et al. (2003)
referenced below is a useful resource for Question #2.
1. 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) have the most
similar DNA methylation profiles? Provide a brief
explanation of your observations.
2. What types of environmental factors can influence
DNA methylation?
3. Aside from DNA methylation, what other types
of epigenetic modifications can occur within the
genome to influence gene expression?
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?

Reference
Singh, S.M., Murphy, B., and O’Reilly, R.L. (2003).
Involvement of gene-diet/drug interaction in DNA
methylation and its contribution to complex diseases:
from cancer to schizophrenia. Clinical Genetics 64(6):
451–460.

“Identical Twins, Identical Fates?” by Sarah A. Wojiski

Figure 3. Mapping of chromosomal regions with differential
DNA methylation in monozygotic twins using comparative
genomic hybridization for methylated DNA. Four
representative chromosomes pairs are shown. Methylated
DNA from one twin was labeled with a red fluorescent
dye, while methylated DNA from the other twin in the
pair was labeled with a green dye. Both sets of twin DNA
were hybridized to normal metaphase chromosomes. The
yellow color represents equal amounts of red and green
dye hybridizing to the chromosomes, indicative of similar
levels of DNA methylation at those particular chromosomal
locations. (Figure 3 of Fraga et al., 2005. Epigenetic
differences arise during the lifetime of monozygotic twins.
PNAS 102:10604–10609. Copyright 2005 National
Academy of Sciences, USA.)

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Part V – What Does the Research Say?
Dr. O’Brien took off her reading glasses and rubbed her temples. It had been a long day of office visits, rounds at
the hospital, and reviewing the latest literature on schizophrenia at her desk. Her recent office visit with Elise, whose
identical twin sister had been diagnosed with schizophrenia, had prompted her to revisit some studies that had been
conducted showing a link between epigenetic modifications and schizophrenia.
In particular, certain studies demonstrated that the DNA methylation patterns of select genes were abnormal in the
brains of patients with schizophrenia as opposed to non-psychotic control subjects. The abnormal methylation patterns
led to the abnormal expression of these genes. One such gene encodes REELIN, a glycoprotein secreted by GABAergic
interneurons, which activates signaling pathways important for many neurological processes responsible for brain
development and adult brain functioning. Figure 4 shows a schematic diagram of the REELIN signaling pathway.

Figure 4. Schematic diagram of REELIN signaling. Reelin is a secreted glycoprotein
capable of binding to several receptors, including apolipoprotein E receptor 2
(ApoE2) and very low density lipoprotein receptor (VLDLR). Binding of reelin
to these receptors leads to phosphorylation of the intracellular adaptor protein
disabled-1 (Dab-1), which is then capable of activating many downstream signaling
pathways important in neurological function.

It seemed clear to Dr. O’Brien that epigenetics played an important role in the clinical course of schizophrenia. But
what epigenetic modifications were the most critical? And, more importantly, could these epigenetic changes somehow
be reversed pharmalogically as a form of therapy for patients with this disease?
Dr. O’Brien put on her reading glasses again. She decided to review the REELIN papers one more time before finally
heading home.
Figures 5–7 represent some of the data Dr. O’Brien reviewed that evening at her desk:

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Figure 5. Mean number of REELIN (RELN) positive neurons detected by immunohistochemistry
in prefrontal cortex layers I-VI in non-psychiatric control subjects and patients with schizophrenia.
(Figure 3 of Impagnatiello et al., 1998. A decrease of reelin expression as a putative vulnerability factor
in schizophrenia. PNAS 95:15718–15723. Copyright 1998 National Academy of Sciences., USA.)

Figure 6. Levels of methylation of the REELIN promoter in sections of the prefrontal cortex taken
post-mortem from non-psychotic control brains (panel A) or schizophrenic brains (panel B). Levels
of 5-methylcytosine are mapped against specific positions along the REELIN promoter, as shown
in panel C. (Figure 1 of Grayson, et al., 2005. Reelin promoter hypermethylation in schizophrenia.
PNAS 102: 9341–9346. Copyright 2005 National Academy of Sciences, USA.)
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Figure 7. Measurements of REELIN (RELN) expression by RT-PCR analysis. NT-2
neuronal precursor cells were grown for 48 hours in the presence of varying concentrations
(0-250nM) of the DNA methyltransferase inhibitor Doxorubicin (DOXO). G3PDH
expression serves as a control. (Portion of Figure 1A from Marija Kundakovic, Ying
Chen, Erminio Costa, and Dennis R. Grayson, DNA Methyltransferase Inhibitors
Coordinately Induce Expression of the Human Reelin and Glutamic Acid Decarboxylase
67 Genes, Molecular Pharmacology March 2007 71: 644–653. Used with permission.)

Questions
You are encouraged to consult reliable sources (such as your textbook and other online and print resources) to
answer some of these questions. The NCBI’s Online Mendelian Inheritance in Man (OMIM) is a useful resource for
examining the role of reelin in the brain.
1. 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?
2. 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?
3. What is the enzyme responsible for methylating DNA? How does a drug like doxorubicin affect DNA
methylation?
4. In reference to Figure 7, what is the effect of doxorubicin treatment on the expression of reelin in NT-2 cells?
How does increasing amounts of doxorubicin affect reelin expression in these cells?
5. 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?

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References
Fraga, M.F., Ballestar, E., Paz, M.F., Ropero, S., Setien, F., Ballestar, M.L., Heine-Suner, D., Cigudosa, J.C., Urioste,
M., Benitez, J., Boix-Chornet, M., Sanchez-Aguilera, A., Ling, C., Carlsson, E., Poulsen, P., Vaag, A., Stephan,
Z., Spector, T.D., Wu, Y-Z., Plass, C., and Esteller, M. (2005). Epigenetic differences arise during the lifetime of
monozygotic twins. Proceedings of the National Academy of Sciences 102(30): 10604–10609.
Gejman, P.V., Sanders, A.R., and Kendler, K.S. (2011). Genetics of schizophrenia: new findings and challenges. The
Annual Review of Genomics and Human Genetics 12: 121–144.
Grayson, D.R., Kundakovic, M., and Sharma, R.P. (2010). Is there a future for histone deacetylase inhibitors in the
pharmacotherapy of psychiatric disorders? Molecular Pharmacology 77(2): 126–135.
Impagnatiello, F., Guidotti, A.R., Pesold, C., Dwivedi, Y., Caruncho, H., Pisu, M.G., Uzunov, D.P., Smalheiser, N.R.,
Davis, J.M., Pandey, G.N., Pappas, G.D., Tueting, P., Sharma, R.P., and Costa, E. (1998). A decrease of reelin
expression as a putative vulnerability factor in schizophrenia. PNAS. 95: 15718–15723.
Kundakovic, M., Chen, Y., Costa, E., and Grayson, D. (2007). DNA methyltransferase inhibitors coordinately induce
expression of the human reelin and glutamic acid decarboxylase 67 genes. Molecular Pharmacology 71: 644–653.
Maiti, S., Kumar, K.H.B.G., Casetllani, C.A., O’Reilly, R., and Singh, S.M. (2011). Ontogenetic de novo copy
number variations (CNVs) as a course of genetic individuality: studies on two families with MZD twins for
schizophrenia. PLoS One 6(3): e17125.
Roth, T.L., Lubin, F.D., Sodhi, M., and Kleinman, J.E. (2009). Epigenetic mechanisms in schizophrenia. Biochim
Biophys Acta 1790(9): 869–877.
Rutten, B.P. and Mill, J. (2009). Epigenetic mediation of environmental influences in major psychotic disorders.
Schizophrenia Bulletin 35(6): 1045–1056.
Singh, S.M., Murphy, B., and O’Reilly, R.L. (2003). Involvement of gene-diet/drug interaction in DNA methylation
and its contribution to complex diseases: from cancer to schizophrenia. Clinical Genetics 64(6): 451–460.

•
Credit: Licensed image in title block © Hipering | Dreamstime.com, id: 22094413. Case copyright held by the National Center
for Case Study Teaching in Science, University at Buffalo, State University of New York. Originally published October 4, 2012.
Please see our usage guidelines, which outline our policy concerning permissible reproduction of this work.
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