DNA Mutation in c-Myb Gene linked to Leukaemia

thglobalherald.com

Australian researchers have uncovered a novel DNA mutation in the c-Myb gene that may be linked to the development of leukaemia, breast and colon cancer.

A team led by Dr Peter Papathanasiou from the John Curtin School of Medical Research at The Australian National University and Associate Professor Andrew Perkins from the Institute for Molecular Bioscience at The University of Queensland completed a three-year screening project to find the genes that control the development and turnover of stem cells.

“We’ve shown that blood stem cells with this genetic mutation behave the same way as those present in human bone marrow diseases, including diseases that can evolve into leukaemia,” said Dr Papathanasiou, who is also affiliated with the Australian Phenomics Facility at ANU.

“By understanding more about the genetic blueprint of these kinds of disorders, we can start to develop new ways of targeting diseases,” Dr Perkins said.

“Currently, there is no treatment for this group of blood diseases, but the discovery of this mutation provides new avenues for investigation.”

As a result of the screening project, the researchers have also identified five other abnormal blood stem cell profiles, adding to understanding of the genetic diversity of blood cells. The project has also led to a better understanding of how blood cells develop and how this process becomes corrupted.

“Given that the same genes that operate in stem cells also function in cancer cells – albeit with genetic mutation – this research also has potential implications for regenerative medicine, by understanding how to stimulate the growth of new blood cells,” Dr Papathanasiou said.

The project was the first in the world to mutate the mammalian genome in a specific search for novel genetic regulators of stem cells.

The following is taken from the research paper’s abstract:

Here we demonstrate that chemical mutagenesis of mice combined with advances in hematopoietic stem cell reagents and genome resources can efficiently recover recessive mutations and identify genes essential for generation and proliferation of definitive hematopoietic stem cells and/or their progeny.

We employed high-throughput FACS to analyze nine subsets of blood stem cells, progenitor cells, circulating red cells and platelets in >1,300 mouse embryos at embryonic day (E) 14.5. From 45 pedigrees we recovered six strains with defects in definitive hematopoiesis.

We demonstrate rapid identification of a novel mutation in the c-Myb transcription factor that results in thrombocythemia and myelofibrosis as proof-of-principal of the utility of our FACS-based screen.

The work was made possible by grants from the National Health & Medical Research Council, the Leukaemia Foundation, and by the Australian Government’s National Collaborative Research Infrastructure Strategy to establish the Australian Phenomics Network.

Get the full paper by visiting: http://bloodjournal.hematologylibrary.org/cgi/content/abstract/blood-2010-04-269951v1

DNAWellnessinfo.com Resource:  http://theglobalherald.com/science-dna-mutation-in-c-myb-gene-linked-to-leukaemia/5384/

DNA Test May Speed Colon Cancer Diagnosis

NICHOLAS WADE
Published: August 9, 2010
nytimes.com

A new generation of DNA tests for colon cancer seems likely to improve the detection both of cancers and of the precancerous polyps that precede them. The tests, if validated, could reduce the burden of disease substantially by detecting tumors at an early stage, including those not picked up by a colonoscopy.

Colorectal cancers tend to grow slowly and are easily removed if caught early. But many people over 50 do not comply with the recommendation to have a colonoscopy — a time-consuming procedure in which a tube is threaded up the intestine — and even colonoscopies do not catch everything. Colorectal cancer has become the second most common cancer in the United States; each year it causes more than 50,000 deaths and costs about $14 billion to treat.

Colon tumors provide considerable evidence of their presence by shedding blood and cells that are detectable in the stool. Tests for blood have reduced deaths from colorectal cancer only modestly, because they are not very sensitive to precancerous polyps, the stage at which cancer is best prevented.

Researchers turned to measuring mutations in DNA after Dr. Bert Vogelstein of Johns Hopkins University discovered the series of mutations by which a colon polyp advances to full cancer. But no single mutation predicts a patient’s risk, and the mutation tests, though more accurate than the blood tests, have not been a decisive improvement.

By 2004 it was clear that looking for the Vogelstein mutations was “neat biology but not a home run,” said Dr. David Ransohoff, an expert on colon cancer screening at the University of North Carolina.

A new generation of tests being developed depends on a different process in cancer cells. All cells switch off the genes they do not need by attaching small chemicals called methyl groups to certain sites along their DNA. In cancer cells, there is generally less methylation than usual, except for certain regions of DNA where the methylation process is taken to excess, perhaps because the cells need to shut down tumor suppressor genes. These and other genes are highly methylated in colon tumors and other kinds of cancer.

Exact Sciences, a company based in Madison, Wis., is developing a colon cancer test based on highly methylated DNA. Its researchers reported last month that by testing for methylated DNA at four markers, pieces of DNA drawn from specific genes, they could detect colon tumors and polyps, distinguishing them from normal tissue with 100 percent sensitivity and with no false positives.

The tests of methylated DNA were performed directly on tumors and are expected to be less accurate in the real world, in which they would have to work in stool samples. Almost all of the DNA in stool is from bacteria, and the methylated DNA is a fraction of the 0.01 percent that is human DNA.

Still, Kevin T. Conroy, chief executive of Exact Sciences, said he expected that the four-marker test, when applied to stool samples, would detect at least half of all precancerous polyps and 85 percent of actual cancers. Results of a trial now under way in 1,600 patients will be reported in October, he said.

The test would cost less than $300, and samples could be collected at home. Patients would be advised to take the test every three years. People with a positive result would then have a colonoscopy to verify and remove any polyps, with the result that colonoscopies could be focused on high-risk patients instead of the population at large.

Exact Sciences’ test is based on work by Dr. Vogelstein, Dr. Sanford Markowitz at Case Western Reserve University and Dr. David A. Ahlquist of the Mayo Clinic. Dr. Ahlquist, who is a scientific adviser to the company, identified some of the highly methylated genes the company is testing as markers for colon cancer.

Dr. Ahlquist said that if the test worked as well as hoped on stool samples, “this will be the first noninvasive test that will reliably detect malignant lesions.” Cervical cancer has been virtually eliminated by the Pap test, he said, and “we feel that colon cancer could be eliminated to the same extent.”

The four-marker test can pick up a kind of precancerous tissue called a serrated polyp which is often missed by colonoscopies, Dr. Ahlquist said. It also ignores most innocuous small polyps.

Using different sets of four markers, other kinds of cancer can be detected. “We can detect all of the cancers above the colon — pancreas, esophagus, stomach, bile duct,” Dr. Ahlquist said. Thus in principle, all the cancers of the gastrointestinal tract, which account for nearly a quarter of all cancer deaths in the United States, should be detectable from stool samples.

Dr. Vogelstein said tests for DNA mutations would be better in theory than tests for DNA methylation because “mutations are entirely specific and they are what is driving the tumor”; the methylation is less causative and increases naturally with age.

But the DNA methylation tests are promising in principle, he said, and it seems feasible for Exact Sciences to get a sensitivity of better than 90 percent and a false positive rate of only 5 to 10 percent. “We can tolerate 5 to 10 percent false positives because those people will just get colonoscopies,” he said.

For cancers above the colon, there are many enzymes that digest DNA, so whether such cancers can be detected efficiently can be answered only with experiments, Dr. Vogelstein said. And false positives would be more of a problem, since for these cancers there is no easy verification method like colonoscopy. “That’s when these false positives really start to be the devil,” he said.

Dr. Ransohoff said the Exact Sciences test was still at a preliminary point. “This is neat and it’s promising,” he said. “But we’ve been down this road before and we need to be hopeful without being carried away.”

DNAWellnessinfo.com Resource:  http://www.nytimes.com/2010/08/10/health/10cancer.html?_r=1

Smokeless tobacco may hurt DNA, enzymes

CHANDIGARH, India, June 18 (UPI) — A researcher in India warns smokeless tobacco use may damage the body’s DNA and key enzymes.

Krishan Khanduja of the Postgraduate Institute of Medical Education and Research in Chandigarh, India, suggests smokeless tobacco not only may damage DNA, but may also affect the normal functioning of a key family of enzymes found in almost every organ.

Khanduja and colleagues found laboratory rats exposed to extracts of smokeless tobacco had altered DNA material in the liver, kidney and lungs — as well as changed function of the CYP-450 family of enzymes. This enzyme group affects many functions including the production of hormones such as estrogen and testosterone, the processing of cholesterol and vitamin D and the breaking down of prescription drugs and possibly toxic substances.

The study, published in Chemical Research in Toxicology, noted use of smokeless products is increasing not only among men but also among children, teenagers and women.

“These products are used around the world but are most common in Northern Africa, Southeast Asia, and the Mediterranean region,” the study authors said in a statement. “Most of the users seem to be unaware of the harmful health effects and, therefore, use smokeless tobacco to ‘treat’ toothaches, headaches, and stomachaches.”

DNAWellnessinfo.com Resource: http://www.upi.com/Health_News/2010/06/18/Smokeless-tobacco-may-hurt-DNA-enzymes/UPI-41481276902848/

UPDATE 1-Benefits trump risks of rotavirus vaccine-US panel

By Lisa Richwine

GAITHERSBURG, Md., May 7 (Reuters) – Benefits from rotavirus vaccines made by GlaxoSmithKline Plc (GSK.L) and Merck & Co Inc (MRK.N) outweigh any risk from recently discovered contamination with a pig virus, members of a U.S. advisory panel said on Friday.

Pieces of DNA from porcine circovirus (PCV) have been detected in Glaxo’s Rotarix and Merck’s Rotateq. The U.S. Food and Drug Administration said there was no evidence the virus harms people.

Several members of a Food and Drug Administration advisory panel said the vaccines carried impressive benefits from preventing rotavirus, which can cause fatal diarrhea, and agreed there was no sign so far of illness in people from PCV.
Any risks “are at best theoretical,” said Dr. Melinda Wharton, a panelist and deputy director of the Center for Disease Control and Prevention’s National Center for Immunization and Respiratory Diseases.

“Based on where we are with current knowledge, to me the known benefits clearly outweigh the risks,” she said.

The panel did not take any votes on formal recommendations to the agency.

In March the FDA advised doctors to stop using Rotarix after PCV-1 was found in the vaccine. Merck then tested its vaccine and the FDA announced on Thursday the company found pieces of DNA from PCV-1 and a related virus, PCV-2.

The FDA said it wanted the advisory panel’s input before making new recommendations on either vaccine. The agency will issue its latest advice “in the very near future,” said Karen Midthun, acting head of the FDA unit that reviews vaccines. “We need to consider this very expeditiously,” she told reporters.

Both PCV1 and PCV2 are common in pigs but neither is known to cause illness in humans, the FDA said. PCV2 is believed to cause postweaning multisystemic wasting syndrome in young piglets, marked by diarrhea and an inability to gain weight.

Advisory panel members urged further study to check for any long-term effects from PCV. Some also said parents needed to be told about the PCV finding.
“The fact that it poses no risk in the short term is certainly comforting. I don’t think that necessarily says it’s risk-free in the long term,” said panelist Stephen Hughes, head of the HIV drug resistance program at the National Cancer Institute.

Some panelists said they wanted to know more about PCV2. The committee heard less about that type as Merck’s finding was so recent. The meeting was originally scheduled just to discuss the Glaxo vaccine.

PCV1 apparently has been in Glaxo’s vaccine since it was first developed, the company said. Testing found DNA from the virus in master cells used to make the product.

The material may have come from a pig-derived enzyme called trypsin used early in development, Glaxo officials said.

“All available data support this is a manufacturing quality issue and not a safety issue. PCV1 does not pose a risk for infants vaccinated with Rotarix,” said Dr. Barbara Howe, a Glaxo vice president.

Glaxo said it planned to develop a rotavirus vaccine free from PCV1 but the process would take time.

Merck was not scheduled to speak at the meeting, but the company said on Thursday the levels of DNA from PCV were low in Rotateq and there was no sign it was harmful to people.

Vaccines against rotavirus have a troubled history. Wyeth’s Rotashield was pulled off the market in 1999 after it was linked with a rare but deadly bowel obstruction.

Rotavirus kills more than 500,000 infants each year, mostly in low- and middle-income countries. In the United States, deaths from the virus are rare but it caused more than 50,000 U.S. hospitalizations annually before Merck’s vaccine won FDA approval in 2006.

The World Health Organization and the European Medicines Agency have not recommended any changes in rotavirus vaccine use in Europe or developing countries.

In 2009, sales of Merck’s vaccine totaled $522 million, including $468 million from the United States.

Most of Glaxo’s rotavirus vaccine sales occur outside the United States. Worldwide sales in 2009 were $440 million, including $118 million from the United States. Glaxo’s vaccine won U.S. approval in 2008. (Reporting by Lisa Richwine, editing by Gerald E. McCormick and Carol Bishopric)

DNAWellnessinfo.com Resource: http://www.reuters.com/article/idUSN0712973220100507

DNA referees

By Amber Dance, Special to the Los Angeles Times

May 3, 2010

Your life story depends upon a combination of the DNA you’re stuck with plus your environment, including all the little choices and events that happen over that lifetime.

But in recent years, researchers have discovered that, while DNA lays out the options, many of those life experiences — the foods you eat, the stresses you endure, the toxins you’re exposed to — physically affect the DNA and tell it more precisely what to do.

The cause: a kind of secondary code carried along with the DNA. Called the “epigenome,” this code is a set of chemical marks, attached to genes, that act like DNA referees. They turn off some genes and let others do their thing. And although the epigenome is pretty stable, it can change — meaning lifestyle choices such as diet and drug use could have lasting effects on how the body works.

“The thing I love about epigenetics is that you have the potential to alter your destiny,” says Randy Jirtle, who studies epigenetics at Duke University Medical Center in Durham, N.C.

Twins provide an example of how environment can affect the actions of our DNA. Identical twins have identical genes, but sometimes one twin has autism or cancer while the other remains healthy. Studies show that as twins age, their epigenomes become less and less alike, probably causing a lot of those differences in fate.

Another provocative study: In 2009, researchers at Duke University Medical Center published a study in the journal BMC Medicine on epigenetics and autism. They found that some children with autism had extra DNA referees turning off a gene needed to respond to oxytocin, a hormone important in social interaction. The study was small, including only 40 children, but it suggests that turning off that one gene could cause the social problems people with autism have.

Many pharmaceutical companies are exploring the potential of epigenome-altering medicines: There are already a few cancer drugs that turn off cancer-promoting genes or turn on cancer-fighting ones. But since altering the epigenome could have far-reaching, unintended consequences, many scientists are wary of drugs targeted at less life-threatening conditions.

In short, the study of epigenetics is “booming,” says Dana Dolinoy, a toxicologist at the University of Michigan School of Public Health in Ann Arbor.

Pick and choose

The regular DNA genome carries the code for every recipe involved in making a human (or antelope, or philodendron or whatever) — it’s like “The Joy of Cooking.” But just as some chefs never crack, say, the veggies chapter, while they dog-ear every page on desserts, different parts of the body pick and choose the genes they need.

The epigenome is part of what tells different cells in the body which DNA recipes to read and which to ignore. The small chemicals that attach to the DNA may cover up or restrict access to genes that aren’t needed and keep others wide open and readable.

Jirtle compares the system to a computer: The DNA is the hardware — set and unchanging — and the epigenome is the software that tells it when, where and how to work.

Epigenetics might be especially important for pregnant women and infants, because much of the epigenetic code is laid down early in development. Dolinoy speculates that the time before puberty might also be important, since the genome and epigenome are gearing up to launch new genetic programs.

The chemicals that make up epigenetic codes ultimately come from diet. Folic acid, for example, is needed to produce epigenetic molecules that turn off many unwanted genes. Broccoli and garlic are good sources of other types of chemical tags that are part of the epigenome.

In a classic experiment published in 2003 in the journal Molecular and Cellular Biology, Jirtle showed how diet can affect these DNA referees. He studied certain mice that can have either brown or yellow pups. He showed that when pregnant mice eat lots of folic acid and other vitamins, they have mostly lean, brown pups. If those mothers instead eat a diet without the epigenome-enhancing supplements, they have more fat, yellow pups, which are prone to diabetes.

The DNA of the pups is the same — but mom’s diet determined how they used those genes.

Dolinoy used the same types of mice to examine how bisphenol A, a toxin common in hard plastics, affects the epigenome of unborn mice. In a 2007 paper in the Proceedings of the National Academy of Sciences, she reported that mice whose diet included bisphenol A produced more fat, yellow pups. But eating folic acid counteracted those negative effects.

Human mothers, not just rodent ones, affect their children’s epigenomes. In a study published last year in the American Journal of Respiratory and Critical Care Medicine, scientists at USC’s Keck School of Medicine found that if the mother smoked during pregnancy, there were long-lasting changes in her children’s epigenomes. The authors speculated that these changes could affect how the body turns on genes for cancer and development.

Dolinoy, who is expecting her second child in May, cautions that women concerned about epigenome changes in their kids should not base health decisions on this still-immature science. For example, she advises not to overdo it with prenatal supplements. While some folic acid is certainly good — it prevents birth defects — too much might alter the epigenome in unknown, undesirable ways.

“My philosophy is, everything in moderation,” she says.

The epigenome can also be altered after a person is born. For example, researchers from McGill University and the Douglas Mental Health University Institute in Montreal found that child abuse can affect DNA referees. In a 2009 paper in the journal Nature Neuroscience, the authors report that 12 people who were abused as children, and later committed suicide, had different DNA referees on a gene needed to cope with stress, compared with 24 people who were not abused. The research implies, although in no way proves, that diminished ability to cope with stress might have been a factor in the suicides.

Adult epigenomes are still somewhat malleable, but they are stable compared with those of developing fetuses and infants. So there’s no need to worry that every little action will alter it.

But there are also short-term referees that jump on or off the DNA at a moment’s notice. Many scientists consider these refs to be outside the classical definition of “epigenetics,” but those chemical changes do affect genes in similar ways. They may change in response to what you had for breakfast today, or the stress you feel after a tough day.

Genes are not just “on” or “off.” They can be on just a little bit, on a lot and everything in between. So referees, both the short-term and long-term types, tune genes up or down, rather like the dimmer switch for a lamp.

And many genes can be turned up or down by changes in behavior and environment. For example, researchers at the Preventive Medicine Research Institute in Sausalito, Calif., studied 30 men with prostate cancer. These men declined traditional medical treatment and instead underwent a three-month program that included a healthy diet, moderate exercise and daily stress management.

When the researchers examined gene activity in the men’s prostate biopsy samples, they found that 48 genes were turned up and 453 were turned down, compared with gene activity at the beginning of the study. The authors noted that the study, published in the Proceedings of the National Academy of Sciences in 2008, was small and needs to be repeated to be sure of the effects. They also suggested that similar changes might happen in healthy people too, when they alter their behavior.

Though the science of epigenetics is young, scientists think there’s good reason to think about how lifestyle choices may affect the epigenome.

It’s known already that some referees can be inherited from human parent to child. Praeder-Willi syndrome, for example, is caused when some of Dad’s DNA referees or genes are missing. Among other symptoms, people with the syndrome have an overactive appetite that can easily lead to obesity.

And though it hasn’t been proved, some scientists suspect that DNA referees laid down generations ago — in your grandparents, for example — are still active in your body today. That is, the epigenome may “remember” the environment Grandpa grew up in and set your genes to match it, even if you have different foods and activities than he did.

Such control over one’s DNA is a double-edged sword, Jirtle says. Healthy choices, such as eating right, could lead to helpful referees, but unhealthy activities, such as smoking, could have a negative effect on you — and your descendants.

“You now have a major responsibility … to optimize your epigenome,” he says.

health@latimes.com

DNAWellnessinfo.com Resource: http://www.latimes.com/news/health/la-he-epigenetics-20100503,0,5900529.story?page=1&utm_medium=twitter&utm_source=twitterfeed

DNA Swap Between Eggs May Curb Inherited Disorders, Study Finds

April 14, 2010, 4:59 PM EDT  BusinessWeek

By Kristen Hallam

April 14 (Bloomberg) — Scientists discovered a way to transfer DNA from one fertilized human egg to another in a pioneering effort to avert the spread of a host of genetic disorders such as learning disabilities and diabetes.

The researchers at Newcastle University in northern England extracted the genetic material contributed by the egg and sperm and implanted it into a donor egg, according to the study published today by the journal Nature. It’s the first time DNA has been transferred between two fertilized human eggs.

The approach discards almost all the defective DNA inherited from the mother that disrupts the tiny energy generators inside cells, and may prevent related disorders such as blindness and liver failure, the researchers said. They are planning further experiments to see whether the technique could help people who carry mutated genes to have healthy babies — an end result that may still be a decade away.

“We have no way of curing these diseases at the moment, but this technique could allow us to prevent the diseases occurring in the first place,” said Doug Turnbull, the lead researcher and a professor at the university’s medical school, in a statement. “It is important that we do all we can to help these families and give them the chance to have healthy children, something most of us take for granted.”

Parents contribute a total of 23,000 genes to a child. In a fertilized egg, this genetic material is housed in two pronuclei, one from the egg and one from the sperm. The egg also contains mitochondria, tiny structures found in every cell that produce the chemical fuel needed for life. Mutations in the mitochondrial DNA, which are passed on from the mother, can disrupt the functioning of these energy generators.

‘Changing the Batteries’

The Newcastle scientists were able to extract both pronuclei and implant the material that makes each child unique into a donor egg with healthy mitochondria. They created 80 fertilized eggs using the technique and grew them in a laboratory for six to eight days. That showed for the first time that eggs produced in this way could reach the stage at which they each had divided into about 100 cells.

“It’s like changing the batteries,” Turnbull said today at a news conference in London. “These are diseases where there is battery failure. Because mitochondria are everywhere, these diseases can affect all parts of the body. None of my patients is exactly the same.”

About 1 out of every 200 children is born each year with mutations in mitochondrial DNA that cause no symptoms or only mild conditions. One in every 6,500 children is born with a more serious mitochondrial disease, ranging from muscular weakness to fatal heart failure. Some disorders lead to death in early infancy.

The research was funded by the Muscular Dystrophy Campaign, the U.K. Medical Research Council and the London-based Wellcome Trust, the world’s second-biggest medical research charity.

–Editors: Phil Serafino, Angela Cullen

To contact the reporter on this story: Kristen Hallam in London at khallam@bloomberg.net

To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net

DNAWellnessinfo.com Resource:  http://www.businessweek.com/news/2010-04-14/dna-swap-between-eggs-may-curb-inherited-disorders-study-finds.html

DNA Test Misses Virus That Causes Hearing Loss

April 13, 2010, 16:00 EST

DNAWellnessinfo.com Resource:  http://www.businessweek.com/lifestyle/content/healthday/637947.html

Additional genes associated with age-related macular degeneration identified

April 12, 2010

A large genetic study of age-related macular degeneration (AMD) has identified three new genes associated with this blinding eye disease—two involved in the cholesterol pathway. Results of this large-scale collaborative study, supported by the National Eye Institute (NEI), part of the National Institutes of Health, were published online April 12 in the Proceedings of the National Academy of Sciences.

“Genome-wide association studies require large numbers of patients to discover significant genetic associations. The success of this effort was made possible by a community-wide scientific collaboration of sharing DNA samples and analyzing the genomes of more than 18,000 people,” said Paul A. Sieving, M.D., Ph.D., NEI director. “This study increases our understanding of DNA variations that predict individual risks of AMD and provides clues for developing effective therapies.”

AMD is a leading cause of visual impairment and blindness in older Americans. Researchers have previously discovered genes that account for a significant portion of AMD risk through genome-wide association studies (GWAS), which scan the entire DNA of individuals to uncover genetic variations related to certain diseases.

The recent large GWAS was led by Anand Swaroop, Ph.D., currently chief of the NEI Neurobiology-Neurodegeneration and Repair Laboratory, and Goncalo Abecasis, D.Phil., professor of biostatistics at the University of Michigan, Ann Arbor.

The strongest AMD genetic association found in the study was in a region on chromosome 22, near a gene called metalloproteinase inhibitor 3 (TIMP3). Mutations in the TIMP3 gene were previously found to cause Sorsby’s fundus dystrophy, a rare inherited early-onset form of macular degeneration. Although further research is needed, it is likely that the genetic region pinpointed influences the expression of TIMP3.

Provided by National Institutes of Health

DNAWellnessinfo.com Resource:  http://www.physorg.com/news190294287.html

Key protein aids in DNA repair

April 11, 2010- physorg.com

Scientists have shown in multiple contexts that DNA damage over our lifetimes is a key mechanism behind the development of cancer and other age-related diseases. Not everyone gets these diseases, because the body has multiple mechanisms for repairing the damage caused to DNA by aging, the environment and other human behaviors – but the mechanisms behind certain kinds of DNA repair have not been well-understood.

In a paper published today in the journal Nature, researchers at the University of North Carolina at Chapel Hill’s Lineberger Comprehensive Cancer Center have shown that a particular protein – called Ku – is particularly adept at healing damaged strands of DNA.

According to Dale Ramsden, PhD, associate professor in the department of biochemistry and biophysics and a member of the curriculum in genetics and molecular biology, Ku is a very exciting protein because it employs a unique mechanism to repair a particularly drastic form of DNA damage.

“Damage to DNA in the form of a broken chromosome, or double strand break, can be very difficult to repair – it is not a clean break and areas along the strand may be damaged at the level of the fundamental building blocks of DNA – called nucleotides,” he notes.

Broken chromosomes can be compared to a break in a strand of yarn made up of several different threads or plies. Unless scissors are used to cut the yarn, the strand frays and may break or be damaged at several different places up and down the length of the yarn. These rough ends get “dirty” – making them harder to repair.

Provided by University of North Carolina

DNAWellnessinfo.com Resource:  http://www.physorg.com/news190207556.html

Disease Cause Is Pinpointed With Genome

Article by Nicholas Wade – New York Times
Published: March 10, 2010

Two research teams have independently decoded the entire genome of patients to find the exact genetic cause of their diseases. The approach may offer a new start in the so far disappointing effort to identify the genetic roots of major killers like heart disease, diabetes and Alzheimer’s.

In the decade since the first full genetic code of a human was sequenced for some $500 million, less than a dozen genomes had been decoded, all of healthy people.

Geneticists said the new research showed it was now possible to sequence the entire genome of a patient at reasonable cost and with sufficient accuracy to be of practical use to medical researchers. One subject’s genome cost just $50,000 to decode.

“We are finally about to turn the corner, and I suspect that in the next few years human genetics will finally begin to systematically deliver clinically meaningful findings,” said David B. Goldstein, a Duke University geneticist who has criticized the current approach to identifying genetic causes of common diseases.

Besides identifying disease genes, one team, in Seattle, was able to make the first direct estimate of the number of mutations, or changes in DNA, that are passed on from parent to child. They calculate that of the three billion units in the human genome, 60 per generation are changed by random mutation — considerably less than previously thought.

The three diseases analyzed in the two reports, published online Wednesday, are caused by single, rare mutations in a gene.

In one case, Richard A. Gibbs of the Baylor College of Medicine sequenced the whole genome of his colleague Dr. James R. Lupski, a prominent medical geneticist who has a nerve disease, Charcot-Marie-Tooth neuropathy.

In the second, Leroy Hood and David J. Galas of the Institute for Systems Biology in Seattle have decoded the genomes of two children with two rare genetic diseases, and their parents.

More common diseases, like cancer, are thought to be caused by mutations in several genes, and finding the causes was the principal goal of the $3 billion human genome project. To that end, medical geneticists have invested heavily over the last eight years in an alluring shortcut.

But the shortcut was based on a premise that is turning out to be incorrect. Scientists thought the mutations that caused common diseases would themselves be common. So they first identified the common mutations in the human population in a $100 million project called the HapMap. Then they compared patients’ genomes with those of healthy genomes. The comparisons relied on ingenious devices called SNP chips, which scan just a tiny portion of the genome. (SNP, pronounced “snip,” stands for single nucleotide polymorphism.) These projects, called genome-wide association studies, each cost around $10 million or more.

The results of this costly international exercise have been disappointing. About 2,000 sites on the human genome have been statistically linked with various diseases, but in many cases the sites are not inside working genes, suggesting there may be some conceptual flaw in the statistics. And in most diseases the culprit DNA was linked to only a small portion of all the cases of the disease. It seemed that natural selection has weeded out any disease-causing mutation before it becomes common.

The finding implies that common diseases, surprisingly, are caused by rare, not common, mutations. In the last few months, researchers have begun to conclude that a new approach is needed, one based on decoding the entire genome of patients.

The new reports, though involving only single-gene diseases, suggest that the whole-genome approach can be developed into a way of exploring the roots of the common multigene diseases.

“We need a way of assessing rare variants better than the genomewide association studies can do, and whole-genome sequencing is the only way to do that,” Dr. Lupski said.

With 10 genomes of healthy humans sequenced, Dr. Gibbs, a specialist in DNA sequencing, decided it was time to decode the genome of someone with a genetic disease and asked his colleague Dr. Lupski to volunteer.

Mutations in any of 39 genes can cause Charcot-Marie-Tooth, a disease that impairs nerves to the hands and feet and causes muscle weakness.

Fifty thousand dollars later, Dr. Lupski turned out to have mutations in an obscure gene called SH3TC2. The copy of the gene he inherited from his father is mutated in one place, and the copy from his mother in a second.

Both his parents had one good copy of the gene in addition to the mutated one. A single good copy can generate enough, or nearly enough, of the gene’s product for the nerves to work properly. Dr. Lupski’s mother was free of the disease and his father had only mild symptoms.

In the genetic lottery that is human procreation, two of their eight children inherited good copies of SH3TC2 from each parent; two inherited the mother’s mutation but the father’s good copy and are free of the disease; and four siblings including Dr. Lupski inherited mutated copies from both parents. These four all have Charcot-Marie-Tooth disease. The results are reported in The New England Journal of Medicine.

In Seattle, Dr. Hood and Dr. Galas have also applied whole-genome sequencing to disease. They analyzed the genome of a family of four, in which the two children each have two single-gene diseases, called Miller syndrome and ciliary dyskinesia. With four related genomes available, the researchers could identify the causative genes. They also improved the accuracy of the sequencing because DNA changes that did not obey Mendel’s rules of inheritance could be classed as errors in the decoding process.

The Seattle team believes whole-genome sequencing can be applied to the study of the common multigene diseases and plans to sequence more than 100 genomes next year, starting with multigenerational families.

The family whose genomes they report in Science were sequenced by a company with a new DNA sequencing method, Complete Genomics of Mountain View, Calif., at a cost of $25,000 each. Clifford Reid, the chief executive, said that the company was scaling up to sequence 500 genomes a month and that for large projects the price per genome would soon drop below $10,000. “We are on our way to the $5,000 genome,” he said.

Dr. Reid said the HapMap and genomewide association studies were not a mistake but “the best we could do at the time.” But they have not yet revolutionized medicine, “which we are on the verge of doing,” he said.

Dr. Goldstein, of Duke University, said the whole-genome sequencing approach that was now possible should allow rapid progress. “I think we are finally headed where we have long wanted to go,” he said.

DNAWellnessinfo.com Resource:  http://www.nytimes.com/2010/03/11/health/research/11gene.html