Epigenetics in Action: Methylation profiling in medicine

One of the ultimate goals of genetic research is the eventual application of medicine and medical techniques resulting from advances in the basic sciences. One such aspect of this application involves the use of PCR methylation assays as a diagnostic for genetic disease. The study performed by Peñaherrera et al. at the University of British Colombia looks into the feasibility of using a quantitative analysis of methylation levels on chromosome 7 as a means of diagnosing patients with the rare genetic disorder, Russell Silver Syndrome. Wikipedia defines Russell Silver Syndrome (RSS) as a type of dwarfism, effecting between 1 in 100,000 to 1 in 3,000 births. Its cause is unclear, but is believed to be a genetic defect, possibly due to an unnecessary X inactivation.

This case is a good example of the potential for epigenetics in medicine. While the genetic code is pretty much set in stone after cellular differentiation, epigenetic factors however, could be altered. Although this study only looks as methylation as a new medical diagnostic tool to screen for RSS, and admittedly there are still issues regarding consistency, it is exciting to see more practical applications for our understanding genetics.

As a personal note; while I am excited about the potential for epigenetics I feel that we are still a long way away from reaching what I feel is the holy grail of applied genetics, or in this case epigenetics, and that is the use of epigenetic techniques such as methylation, acetylation, etc. to cure diseases such as RSS. If we could somehow control epigenetic expression, we would have far more power over many inherent chronic diseases. As someone afflicted with tourette's Syndrome the field of epigenetic medicine is certainly appealing. Tourette's is believed to be an inherited disorder so there is little in the way of hope to cure it as the genetic level without epigenetic tools.

Citation: Penaherrera MS, Weindler S, Van Allen MI, Yong S-L, Metzger DL, McGillivray B, Boerkoel C, Langlois S, Robinson WP. 2010. Methylation profiling in individuals with Russell–Silver syndrome. Am J Med Genet Part A 152A:347–355.

UC Davis researchers develop new test for fragile X syndrome

Fragile X syndrome is the number one cause of inherited mental retardation in humans. People with Fragile X syndrome experience deficits in learning, behavior, motor skills, sensory systems, and speech. The extent to which each individual will be affected depends largely on how extensive the mutation is on their X chromosome and the affected person’s gender. Additionally, most individuals with the syndrome are screened for whether or not they also have autism as the two disorders are commonly found to be comorbid.

Fragile X syndrome is caused by the slipped mispairing of three nucleotides CGG in the FMR1 gene. This mutation leads to a deficit in the FMR1 Protein as the expanded mutation silences the gene. Lacking this protein, normal communication between nerve cells cannot occur and people with the syndrome often have substantial cognitive delays as a result. Because the FMR1 gene is on the X chromosome, boys are more likely to be affected than girls as a result of inheriting a mother’s affected X chromosome. Likewise, because these mothers pass on the affected X chromosome to their sons, the mothers themselves are often mildly affected with increased anxiety and slight behavioral abnormalities. Girls who inherit one affected X chromosome from either parent will often have mild effects as the other X chromosome can make up for some of the deficit.

At UC Davis, both the MIND Institute and the Center for the Mind and Brain do research on the behavioral and molecular abnormalities associated with the syndrome. A new genetic test, developed by Paul Hagerman at the MIND Institute, is called ELISA and was created to measure the level of FMR1 protein expressed in individuals who carry the gene mutation. This test will better allow individuals to be diagnosed with the syndrome so they may therefore receive earlier treatment for the disorder. Decreased FMRP levels have already been associated with other disorders in development, behavior, anxiety, Fragile-X associated tremor/ataxia syndrome, ovarian deficiencies, and ADHD. It is being discussed whether testing for Fragile X syndrome would be beneficial to add to the standard neonatal tests which are already administered at birth.

The fact that UC Davis is associated with the MIND institute is invaluable to students who are interested in genetic disorders. People come from all over the world to visit Drs. Paul and Randi Hagerman as they are experts in the study of Fragile X syndrome and are directors of the Fragile X Syndrome Treatment and Research Center. I have personally been involved in research on fragile X syndrome as a research assistant at the Center for the Mind and Brain and have been able to apply a lot of what I have learned in genetics and psychology to the internship.

References:

Brown, Phyllis. UC Davis researchers develop new test for fragile X syndrome. Insciences Organisation. 2009 [8 June 2010]. <http://insciences.org/article.php?article_id=5897>

Iwahashi, C., Tassone, F., Hagerman, R.J., Yasui, D., Parrott, G., Nguyen, D., Mayeur, G., Hagerman, P.J. A Quantitative ELISA Assay for the Fragile X Mental Retardation 1 Protein. The Journal of Molecular Diagnostics. 2009 [8 June 2010] Vol. 11(4). <http://jmd.amjpathol.org/cgi/content/short/11/4/281>

THE IMPACT OUR GENES HAVE IN LOSING WEIGHT

Are people overweight because they lack the will-power to go through an effective workout at the gym? Do some people have a much harder struggle while trying to lose wieght because of the information encoded in their genes? To answer these questions we explore, "The Truth about Genetics and Weight Loss," by Caroline J. Cederquist.
For starters, it is important to take into account the myriad of other features such as height and eye-color that is already controlled by genes. Moreover, according to Cederquist, "researchers have identified specific combinations of genes that appear to correlate very strongly with fat retention even in spite of, exercise."
In a study, a group involving post-menopausal females were divided into a control and excercise-intervention group. In this particular group, the women were asked to workout for five days a week for forty-five minutes, and eat whatever they usually ate. At the conclusion of the study, the researchers found that the fat-loss of severalindividuals were not backed up by the amount of time that they spent in the gym compared to other individuals.
After examining the genetic data of the individuals, researchers found two genes, CYP19 and COMT that stood-out.The researchers found that even one CYP19 gene along with its variants did not associate with abdominal fat, but having two did correlate to a higher decrease in the BMI (Body Mass Index) of the individual.Also, atleast one of these CYP19 genes along with a certain strain of COMT correlated to an even larger decrease in BMI.
However, the researchers also found out that while those with this particular CYP19 combination lost more fat in shorter time periods, they also gained more fat in shorter amounts of time. The detailed mechanisms of theseprocesses are not fully understood for there to be made any other conclusions.
So whats the bottom line? Calorie input= Calorie output, you are what you eat... are explanations that do not take into accountthe detailed aspects of human genetics. People simply need to be able to learn about how they react to certain foodsand excercise, and adapt their behaviors to that knowledge. In the end, it is harder for some people to lose weight,but that does not mean that they can't make it atleast just a little easier on themselves.

News Article Website:
http://newsblaze.com/story/20051207150658nnnn.nb/topstory.html

Research Article: http://biblioteca.sp.san.gva.es/biblioteca/publicaciones/MATERIAL/METABUSQUEDAS/MUJER/15229337.PDF

to test or not to test? ...that is the question

A great deal of research is being done on the decision making process as to whether or not mothers should undergo prenatal testing. The answer seemed quite obvious to me, why wouldn’t you want to make sure your child was healthy…right?

First it’s important to distinguish that there are two types of prenatal testing: invasive and non-invasive. A non-invasive prenatal test, for example, is an ultrasound. An ultrasound is a procedure that uses high-frequency sound waves to examine a woman's abdomen and pelvic cavity, creating a picture (known as a sonogram) of the baby and placenta. Invasive procedures, which include amniocentesis or chorionic villus sampling (CVS), tend to be diagnostic tests to determine if specific genetic disorders may be present in the baby. An amniocentesis, for instance, is a procedure where a sample of amniotic fluid is collected through a needle from the amniotic sac. The amniotic fluid contains cells shed by the fetus, and is sent to the laboratory for analysis. Prenatal testing, depending on the particular test, occurs throughout the three trimesters of pregnancy. The American Pregnancy Association website provides detailed profiles on the major prenatal tests, divided into trimester-specific tests. For more information you can visit: http://www.americanpregnancy.org/prenataltesting/.

So, why did I choose this topic? Well, my future aspirations are to become a genetic counselor. A genetic counselor is a healthcare professional that provides information and support to families who have members with birth defects/genetic disorders or to families who may be at risk for a variety of inherited conditions. They identify at risk families, investigate the problem, interpret information about the disorder, analyze inheritance patterns and risks of recurrence, and finally, they assess available options with the family. They also serve as educators and a resource for other healthcare professionals and for the general public[1]. This, of course, all applies to helping pregnant women make informed decisions based on test results, and hopefully reduce any decisional conflict they might have.

However, it is important to consider all of the medical, ethical and social concerns that come with prenatal screening/diagnostic testing. All aspects have to be taken into account because this is an extremely touchy subject. Examples include:

-It is important to be sensitive to their beliefs as well as respect their wishes, remaining unbiased in the process.

-It is imperative the mother has a chance to voice her opinion, but if both parents do not see eye to eye it can complicate the situation.

-Certain ethical decisions may have to be made concerning the life of the baby and/or the life of the mother.

Researchers at the University of California San Francisco conducted a study exploring the decision making process involved with invasive prenatal testing after infertility[2]. Researchers found that a history of infertility affects the decision making process about whether or not to undergo invasive prenatal testing. The results of the study would reveal valuable information for heath care providers and genetic counselors and could help in how they should approach apprehensive patients conflicted with the decision, minimizing conflict and thereby enhance informed choices. After questioning 180 pregnant women (who had a history of infertility) results revealed: 69% of the women declined testing; 42% of the women declined prenatal testing on the grounds that infertility had made them unwilling to take the risk of potentially having a miscarriage as a result of the test; 26% reported that testing was unnecessary because they would accept any baby regardless; only approximately 6% of the women felt medically informed enough to weigh their options clearly and opted for the testing. Several variables, both social and ethical, went into their decision making process.

Given that this study focused solely on women with fertility issues we can hardly conclude that these results reflect the decisions of the majority of women in the US, nor do they reflect the general opinion on prenatal testing. Still the process of prenatal screening/diagnostic testing is controversial and raises many ethical issues. This is a very touchy subject, especially when considering the ethical and social aspects. I think that in the scientific and medical community there is a constant battle between science and faith/belief/emotion, etc…. How do you set your own beliefs aside and acknowledge or go along with those of others? As a future genetic counselor I look forward to exploring this dichotomy and helping families through such a process. Personally I’m an advocate of prenatal testing. I’d prefer to know that my child is healthy and safe rather than have to face potentially losing it early in life or having it grow up and live with difficulties the rest of their life. One thing is for certain, it is important that we educate the public and keep families aware so that they may make informed decisions.

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[1] http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genecounseling.shtml

[2] Caleshu, Colleen; Shiloh, Shoshana; Price, Cristofer; Sapp, Julie; Biesecker, Barbara. “Invasive prenatal testing decisions in pregnancy after infertility”. Prenatal Diagnosis. Volume 30, Issue 6. June 2010, Pages: 575-581

Is Addiction wired to our Genes?

Is Addiction wired into our Genes?

According to the Genetics of Addiction, provided by Addiction and Recovery.org, “addiction is due 50 percent to genetic predisposition and 50 percent to poor coping skills.” In one study comparing the likelihood of becoming addicted between identical and non-identical twins, the study shows if one identical twin was addicted to alcohol, the other has a higher chance of becoming addicted as well; however, one non-identical twin was addicted to alcohol, the other twin does not show increased probability of addiction. Three similar papers based on studies of more than 140,000 people have been published online in the journal Nature Genetics. "These variances in the sequence that we have discovered do not have impact on whether you begin to smoke or not," Lead author Kari Stefansson said.


In human population, only 1% of the genes are different from person to person. Researchers identified 11 chromosomes as the probable locations of genes prone to drug abuse and alcohol addiction. Dr. George Uhl and colleagues at NIDA's Intramural Research Program (IRP) in Baltimore, Maryland identified 89 genes to drug abuse and dependence. We have gene variations between drug addicts and non-addicts; however, their research is inconclusive, and there is no clear indication of a certain gene causing a person to become addictive.We all has the genetic predisposition for addiction because there is an evolutionary advantage to that. Some people have certain genes which are more prone to alcohol abuse, cigarette or drugs, but those people are not necessarily addicts. People who have good coping skills and self-control understand the damages of addictions and can stay away from harmful substances. On the other hand, even though some people start with a low genetic predisposition for addiction, repeated moderate use of substances can permanently rewire their brain and make them prone to addiction. Study shows children of alcoholic parents are eight times more likely to become addicted alcohol themselves, but it’s not clear whether it’s due to genetic predisposition or simply environmental effects.


All three articles conclude genes do not necessarily result in addiction. The two on smoking suggest certain genes might increase the change of becoming addicted; the article about drug abuse suggest there are unknown varations between drug-addicts and non-addicts, but the effects are unknown. So it goes back to the beginning, genetic factors only contribute partially to addiction, there are many other factors, such as environmental, family history, life style, and copping skills, etc. I would say we do not have to get ourselves tested for those addiction genes, if we don’t want to become an addict, stay away from alcohol, drugs, and cigarettes in the first place.


links:


The Genetics of Addiction
http://www.addictionsandrecovery.org/is-addiction-a-disease.htm


Can't quit smoking? Blame your genes
By Ashley Hall
http://www.abc.net.au/news/stories/2010/04/26/2882621.htm

Addiction – Blame It on Genes
http://www.ygoy.com/index.php/addiction-blame-it-on-genes/

Proof that the UK > US

Cancer Research UK, the leading cancer charity in the United Kingdom, has begun a project to analyze tumors of cancer patients to cover a wide array of genetic defects. In doing so, they hope to provide individualized therapy for the patients, especially when it comes to medication. By implementing breakthrough discoveries in the field of pharmacogenetics, the centers around the country hope to catalog and classify the tumor according to specific genetic mutations that it carries. Then, using new-age cancer drugs that target specific genetic mutations in cancerous cells, the doctors can avoid expensive treatments that will provide little benefit. The major difference between cancer knowledge ten years ago and cancer knowledge now is that enough genetic markers and drugs have been discovered so that being tested is much more likely to give useful information. The main goal of this new initiative seems to be to cut cost from the British National Health Service, allow for more effective treatments in patients, and build a database of different types of cancer and how effective certain treatments are against each type.

Honestly, I feel the article is being a little optimistic. While certain drugs like Herceptin are mentioned in the article and are certainly effective, most of them are antibodies and cancers can develop a resistance to them like any other drug. Furthermore, such treatments are expensive and may have trouble dealing with the early stages of breast cancer. Finally, the NHS which is overseeing the program is a government run, publically funded healthcare system, meaning that it is an extension of government bureaucracy and that late stage cancers (which these specially developed drugs are most effective against) may claim the patient’s life while waiting for treatment. Another problem that may arise is that a program like this needs time to show its effectiveness as the staff running the centers may not have a large amount of experience in dealing with the work involved in testing all of these patients; as a pilot scheme, it may only last one or two years until the Department of Health decides that it is not showing enough results and shut it down.

Even still, the benefits of the program are substantial if it is successfully implemented. Pharmacogenetics has been a booming field ever since the human genome was unlocked. Successful application and testing of drugs developed through this principle serves to further enrich the field and may lead to the ultimate goal of cheap, personalized drugs for the average citizen. If such a program were implemented in the United States, it might bring even more benefits as the overall cancer rate in the US is much higher than that in the UK. If future advances in pharmacogenetics and stratified medicines continue at their current pace, it might be plausible to eventually have a cure for most common types of cancers.

Sources Used:

http://news.bbc.co.uk/2/hi/health/10224252.stm

http://en.wikipedia.org/wiki/Trastuzumab

http://en.wikipedia.org/wiki/National_Health_Service_(England)

http://www.nhs.uk/Pages/HomePage.aspx

http://www.cancer.org/docroot/STT/content/STT_1x_Cancer_Facts_Figures_2010.asp

http://info.cancerresearchuk.org/cancerstats/incidence/commoncancers/index.htm

Sea Urchins - A Possible Model Organism?

Related to the model organisms we discuss in class, new evidence has come out within the past couple of years indicating that sea urchins may be used in genetic studies to help understand various human diseases. Indirectly, this article poses the idea that sea urchins could possibly serve as a new model organism. Despite being invertebrates and lacking various organisms such as a nose, eyes, and ears, the sea urchin shares more than 7000 genes with humans. Scientists are hoping that this degree of similarity between humans and sea urchins may help to uncover possible ways to fight—and hopefully someday, prevent—various life-threatening diseases. Due to its simplicity, the sea urchin is proving that it can be an asset to future genetic studies. Its short generation time and capability to produce up to 20 million progeny in its lifetime are some characteristics that indicate just how much potential this small-sized organism can have in the field of genetics.

One of the most interesting characteristics of the sea urchin is its long life span. A single sea urchin can live up to 100 years! This lifespan is far greater than any other model organism currently being studied. What is interesting about the sea urchin is that it has been determined they can live for such a long time because of their strong immune systems. Because of its relatively long lifespan, scientists are hoping that they can study the immune system and possibly uncover various ways in which diseases can be fought. In fact, according to the article, sea urchins have innate immunity, similar to humans. Innate immunity describes the inborn ability of an organism to resist contracting a particular disease (Webster’s Dictionary). The difference between the immune system of humans and the immune system of sea urchins is that humans acquire additional immunities over the course of their lives by being exposed to different pathogens, viruses and other disease-causing agents while sea urchins do not. What is fascinating about the similarity between the innate immunities of both sea urchins and humans is the evolution of both of their immune systems over time. The question boggling the minds of researchers today is how exactly sea urchins are able to live for so long without acquiring any additional immunities over their lifetime. Finding the answer to this question could prove to be a positive step in the right direction towards fighting human diseases.

From this article, there seems to be great potential in the research of the sea urchin genome. From studying the 7000 genes that sea urchins and humans have in common, human medicine could see a potential huge breakthrough in the way medicine is used to fight and prevent many life-threatening human diseases.

Link to article: http://www.sciencedaily.com/videos/2007/0304-sea_urchins_reveal_medical_mysteries.htm