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DNA Helix

Posts Tagged ‘genetics’

OpenPCR: DNA amplification for anyone

OpenPCR is a cool new project dedicated to building plans for an open source PCR machine. There’s not much inherently complicated about a PCR machine and it’s about time — a PCR machine built with $300 in parts using a modern software controller will likely be as powerful as any non-realtime PCR out there. Of course, the reagent pricing is what gets you.

Josh and Tito are raising money for this project using Kickstarter. $1024 gets them to build you a PCR machine, which is a reasonably good deal in the scheme of scientific equipment. I gave them $8, because I like stickers and already have a PCR machine that doesn’t exactly get a lot of use.

The issue of gene patents [update]

Hospitals in Australia are stuck in a bad position when it comes to genetic testing. The Sidney Morning Herald has a piece discussing the patented gene SCN1A, which is used to diagnose a particular type of epilepsy in infants. The company that has the test patented, Genetic Technologies, won’t let hospitals do in house testing. Instead, they must resort to sending samples to Scotland to be tested…a process that takes a lot of time and costs much more than necessary. This results in worse care for the infants.

Babies with a severe form of epilepsy risk having their diagnosis delayed and their treatment compromised because of a company’s patent on a key gene.

It is the first evidence that private intellectual property rights over human DNA are adversely affecting medical care.

This is only the beginning of genetic testing. What role are patents going to play in this, especially considering that they seem to do more harm than good from the patent’s perspective. I wonder if there is some legal loophole that hospitals can use to get around this, at least in the United States. Perhaps it may work if the hospital conducted the test for internal research purposes only and then used the results after it had them, though I don’t know if this argument would hold up in court.

What do Think Gene readers think about this? Let’s hear your thoughts!

Personal Genetics Education Project: Lesson 1

(update: what do teachers think of the PGEP?)

Dana Waring and colleagues at the Personal Genetics Education Project have put together an excellent set of resources for teachers and professors. The first few lesson plans are freely available for download at http://genepath.med.harvard.edu/WuLab/pgEd/curricula.html.

For example, the first lesson plan is geared toward a general discussion of ethical questions regarding genetic testing and possible consequences. Discussion centers on the story of a young girl who, after watching her grandfather’s decline due to Huntington’s, decided to get herself tested and the fallout that ensued upon learning she tested positive.

There has been much media hype lately about genetic tests and genome wide SNP tests from companies such as 23andme and Navigenics, yet, many do not have a working understanding genetic testing and its implications. Waring does a good job discussing the possible negative outcomes of having a genetic test, and she demonstrates why it’s so important to consult with a physician or genetic counselor before getting a high penetrance genetic test such as the one for Huntington’s. Students are forced to think about the issues at hand and how genetic testing will play a large role in not only their medical futures, but also their day to day lives.

I’m looking forward to reviewing more of Dana and her team’s material, and I hope professors and teachers who read Think Gene will consider taking advantage of this educational resource and integrate it into their curriculum. This generation of students will be the first to have to make decisions about genetic tests, and I feel it’s our duty to properly educate them so they are prepared.

Andrew says:

UPDATE: What do secondary education teachers think about Waring’s Personal Genetics Education Project?

Jane Yates, a veteran teacher (and my mother) writes:

The Personal Genomes 101 summary is a great quick resource. The lesson plans could be helpful to a teacher, but they should list which national and state standards to which it relates. Teachers probably would not use the PowerPoint slides. I don’t think that the lessons would be used much by High School teachers, however, it is a great resource for a student who would be assigned a biology research paper or an English position paper.

Accumulated bits of a cell’s own DNA can trigger autoimmune disease

Josh: I never would have thought that an autoimmune disease could be triggered by a mutation such as this. I suppose many things in biology and medicine are unexpected and don’t work as you would initially expect. Take, for example, the view of how the heart worked before William Harvey published On the Motion of the Heart and Blood in Animals; Galen‘s works stated that blood was a nutritive substance that did not flow in a circuit through the body, and that the purpose of the lungs was to cool the blood. Like Harvey’s discovery, I think unexpected causes such as this will be taken much more seriously in the future and lead to a re-writing of text books. It’s unfortunately a common trend for unexpected results or data to be discarded since it doesn’t fit the accepted theory or view.

A security system wired within every cell to detect the presence of rogue viral DNA can sometimes go awry, triggering an autoimmune response to single-stranded bits of the cell’s own DNA, according to a report in the August 22nd issue of the journal Cell, a Cell Press publication. The source of that single-stranded DNA is so-called endogenous retroelements—genetic elements accounting for a substantial portion of the genome that can move to new locations using a “copy and paste” mechanism, according to the researchers.

The new findings help to explain the cause of a rare autoimmune disorder known as Aicardi-Goutieres Syndrome in which infants appear to suffer from an acute viral infection, despite the fact that no virus had ever been found.

“We and others had demonstrated the existence of a DNA detection pathway within cells, but we are still early in our understanding,” said Daniel Stetson of the Howard Hughes Medical Institute and the University of Washington, Seattle. “Our findings offer an important piece of evidence that this pathway is not only very relevant, but it can be the cause of severe autoimmune disease.”

Detection of foreign nucleic acids is an ancient form of host defense, the researchers explained. In vertebrates, nucleic acid detection activates a program of antiviral defense designed to neutralize the spread of infection. This antiviral program is coordinated by type I interferons (IFNs), which direct a multifaceted response to restrict viral replication within infected cells, alert neighboring cells to the presence of infection, and expand white blood cells to provide long-term and specific protection against the virus.

The defense mechanism includes two systems: one consisting of “Toll-like receptors” on specialized, sentinel immune cells that monitor for infection and another that detects viral nucleic acids within the infected cell itself. That internal system includes one arm for detecting RNA and another for detecting DNA.

The biological relevance of those internal DNA sensors remained somewhat mysterious, according to Stetson, because the “nuts and bolts” of the system hadn’t been worked out.

In a screen for proteins relevant to this pathway they call the interferon-stimulatory DNA (ISD) response, the researchers now identify an enzyme known as 3′ repair exonuclease, aka Trex1. In studies of mice, the researchers showed that single-stranded DNA fragments derived from endogenous retroelements accumulate in Trex1-deficient hearts. Those fragments are produced through a process known as reverse transcription in which specialized enzymes copy RNA back into single-stranded DNA. Trex1 usually breaks down reverse-transcribed DNA of those endogenous retroelements, keeping the ISD response in check.

Mutations in the human Trex1 gene were already known to cause Aicardi-Goutieres Syndrome, although the mechanism remained uncertain. The new findings suggest that the syndrome is triggered by an accumulation of reverse-transcribed DNA. “In a sense, it’s an enemy from within,” Stetson said.

A similar mechanism may underlie other immune disorders as well, he added. In fact, other mutations in Trex1 have been linked to an autoimmune disorder called chilblain lupus and are found more frequently in people with systemic lupus erythematosus than in healthy individuals.

The findings also suggest an unanticipated contribution of endogenous retroelements to autoimmunity.

“Just as commensal bacteria outnumber our own cells by four or five orders of magnitude, endogenous retroelements outnumber our genes by at least 100-fold,” the researchers concluded. “Both have the potential to be detected by the immune system and cause autoimmune disease. Therefore, specific mechanisms evolved to prevent this, and Trex1 represents the first example of a mechanism to prevent autoimmunity caused by endogenous retroelements.”

Source: Cell Press

Trex1 Prevents Cell-Intrinsic Initiation of Autoimmunity. Daniel B. Stetson, Joan S. Ko, Thierry Heidmann, and Ruslan Medzhitov. Cell. August 22, 2008: 134 (4)

Largest study of its kind implicates gene abnormalities in bipolar disorder

The largest genetic analysis of its kind to date for bipolar disorder has implicated machinery involved in the balance of sodium and calcium in brain cells. Researchers supported in part by the National Institute of Mental Health, part of the National Institutes of Health, found an association between the disorder and variation in two genes that make components of channels that manage the flow of the elements into and out of cells, including neurons.

“A neuron’s excitability – whether it will fire – hinges on this delicate equilibrium,” explained Pamela Sklar, M.D., Ph.D., of Massachusetts General Hospital (MGH) and the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, who led the research. “Finding statistically robust associations linked to two proteins that may be involved in regulating such ion channels – and that are also thought to be targets of drugs used to clinically to treat bipolar disorder – is astonishing.”

Although it’s not yet known if or how the suspect genetic variation might affect the balance machinery, the results point to the possibility that bipolar disorder might stem, at least in part, from malfunction of ion channels.

Sklar, Shaun Purcell, Ph.D., also of MGH and the Stanley Center, and Nick Craddock, M.D., Ph.D., of Cardiff University and the Wellcome Trust Case Control Consortiuum in the United Kingdom and a large group of international collaborators report on their findings online Aug. 17, 2008 in Nature Genetics.

“Faced with little agreement among previous studies searching for the genomic hot spots in bipolar disorder, these researchers pooled their data for maximal statistical power and unearthed surprising results,” said NIMH Director Thomas R. Insel, M.D. “Improved understanding of these abnormalities could lead to new hope for the millions of Americans affected by bipolar disorder.”

In the first such genome-wide association study for bipolar disorder, NIMH researchers last fall reported the strongest signal associated with the illness in a gene that makes an enzyme involved the action of the anti-manic medication lithium. However, other chromosomal locations were most strongly associated with the disorder in two subsequent studies.

Since bipolar disorder is thought to involve many different gene variants, each exerting relatively small effects, researchers need large samples to detect relatively weak signals of illness association.

To boost their odds, Sklar and colleagues pooled data from the latter two previously published and one new study of their own. They also added additional samples from the STEP-BD study and Scottish and Irish families, and controls from the NIMH Genetics Repository. After examining about 1.8 million sites of genetic variation in 10,596 people – including 4,387 with bipolar disorder – the researchers found the two genes showing the strongest association among 14 disorder-associated chromosomal regions.

Variation in a gene called Ankyrin 3 (ANK3) showed the strongest association with bipolar disorder. The ANK3 protein is strategically located in the first part of neuronal extensions called axons and is part of the cellular machinery that decides whether a neuron will fire. Co-authors of the paper had shown last year in mouse brain that lithium, the most common medication for preventing bipolar disorder episodes, reduces expression of ANK3.

Variation in a calcium channel gene found in the brain showed the second strongest association with bipolar disorder. This CACNA1C protein similarly regulates the influx and outflow of calcium and is the site of interaction for a hypertension medication that has also been used in the treatment of bipolar disorder.

Source: NIH/National Institute of Mental Health

Scientists discover major genetic cause of colorectal cancer

Josh: This is an extremely high penetrance mutation. More doctors and physicians need to be trained to order genetic tests for mutations such as this for their patients, especially those with a family history of colorectal cancer. If someone has this mutation, chances are they are going to get colorectal cancer, so routine screenings may be enough to save their life…preventative medicine at its best.

About one-third of colorectal cancers are inherited, but the genetic cause of most of these cancers is unknown. The genes linked to colorectal cancer account for less than 5 percent of all cases.

Scientists at Northwestern University’s Feinberg School of Medicine and colleagues have discovered a genetic trait that is present in 10 to 20 percent of patients with colorectal cancer. The findings strongly suggest that the trait is a major contributor to colorectal cancer risk and likely the most common cause of colorectal cancer to date.

If a person inherits this trait — which is dominant and clusters in families — the study found the lifetime risk of developing colorectal cancer is 50 percent, compared to 6 percent for the general population. The study will be published August 14 in an advanced on-line report in the journal Science.

“This probably accounts for more colorectal cancers than all other gene mutations discovered thus far,” said Boris Pasche, M.D., a lead author of the paper and director of the Cancer Genetics Program at the Feinberg School and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Pasche also is a physician at Northwestern Memorial Hospital.

“The reasonable expectation is this finding will save some lives,” Pasche said. “We will be able to identify a larger number of individuals that are at risk of colorectal cancer and, in the long term, maybe decrease the cases of colorectal cancer and of people dying from it by being able to screen them more frequently.”

Colorectal cancer is the second leading cause of cancer death in the U.S.

The trait, which has been named TGFBR1 ASE, results in decreased production of a key receptor for TGF-beta, the most potent inhibitor of cell growth. With less of this vital protective substance to inhibit cell growth, colon cancer can more easily develop.

In 1998, Pasche and colleagues discovered the first mutation of this gene and in 1999 they showed that it was linked to a higher risk of colorectal cancer.

The results presented in this new study are the first to show that decreased production of this receptor for TGF-beta was present in 10 to 20 percent of patients with colorectal cancer. Decreased production of the same receptor was present in only 1 to 3 percent in healthy control groups.

The findings, which are based on a Caucasian population, need to be confirmed in other studies and may show strong variation between ethnic groups, Pasche said.

Pasche expects that a clinical test will soon be developed that could be offered to families with a history of colorectal cancer and other individuals to determine whether they carry this mutation.

Source: Northwestern University

Germline Allele-specific Expression of TGFBR1 Confers an Increased Risk of Colorectal Cancer. Laura Valle, Tarsicio Serena-Acedo, Sandya Liyanarachchi, Heather Hampel, Ilene Comeras, Zhongyuan Li, Qinghua Zeng, Hong-Tao Zhang, Michael J. Pennison, Maureen Sadim, Boris Pasche, Stephan M. Tanner, and Albert de la Chapelle. Science. Published online August 14 2008; 10.1126/science.1159397 (Science Express Reports)

Inherited form of hearing loss stems from gene mutation

Josh: More people need to recognize that role that genetics play in their health and what happens to him. Most people really do attribute hearing loss to environmental factors, and there are definitely many cases where this is true, but certainly if a family all begin losing their hearing, especially earlier in their lives, the cause should be recognized as being genetic. I’m glad that at least in this case, someone investigated it.

Pat Phalin learned she had hearing loss at 30, when she volunteered to give hearing tests at her local school. The pupils heard sounds she could not hear.

Her husband Larry, a genealogy enthusiast, saw a pattern in his wife’s family history. Her mother, grandfather and great-grandfather had severe hearing loss as adults. One of the Phalins’ children had hearing problems before he reached school age. … Continue Reading »

Genetic variant increases triglyceride levels in Asian-Americans

Josh: While this is certainly an important genetic variation to find, I’m wondering if doctors would be able to use this information if they tested their patients. What could be done differently in treating high levels of triglycerides? This would be much more useful if a drug existed to treat this specific cause of elevated plasma TG levels.

A genetic variant found almost exclusively in individuals of Asian descent increases the risk of elevated triglycerides over four-fold, reports a comprehensive study in the August Journal of Lipid Research. In fact, all 11 subjects who carried both copies of this rare variant for apolipoprotein A-V had extremely high and dangerous triglyceride levels in their blood.

Apolipoprotein A-V is a recently discovered lipid-binding protein that likely plays an important role in metabolizing triglycerides. Some population studies with groups in China and Taiwan indicate that a polymorphism in the APOA5 gene (553 G>T shift) is associated with elevated plasma TG levels, which like cholesterol, increase the risk of heart disease. … Continue Reading »