New Era for Human Genetics Begins

1000 Genomes Project focuses on genetic differences which could lead to greater understanding of disease, evolution

Art Chimes | St. Louis, Missouri 27 October 2010

An international effort to build a detailed map of human genetic variation has completed its pilot phase and could shape a new understanding of human evolution and may help in fighting disease.

The 1000 Genomes Project aims to sequence the genetic code of 2,500 people.

A decade ago, scientists made worldwide headlines when they announced they had sequenced the human genome - made a kind of map, in other words, of DNA, the inherited molecule that makes us human. But that was only one genome. Everyone on Earth has a unique genetic makeup, and researchers have now sequenced thousands of individuals' DNA.

The first effort to sequence the human genome came in under budget and ahead of schedule, and the process has gotten progressively cheaper and faster.

"In the last 10 years," said Richard Durbin, co-chair of the 1000 Genomes Project. "DNA sequencing technology has advanced dramatically so it has become feasible to systematically sequence many people to find genetic variants, and build a catalog which we can use as a basis for investigations into disease, genetics, and which variants may be functional."

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Genetic variations are the way your genes differ from other people's. Some variations relate to differences we can see, like eye color. Others may put us at greater risk for disease. Some variations are inherited. Others can be caused by toxic chemicals or radiation or simply by mistakes in copying DNA.

Most genetic variations are found in lots of unrelated people. Scientists have started to investigate possible links between disease and some of these variations, called single nucleotide polymorphisms, or SNPs. The researchers aim to probe deeper.

"The 1000 Genomes Project makes this approach much more complete and much more powerful," said David Altschuler, 1000 Genomes co-chair, "by going down to much lower frequencies, and also broader range of populations and more complete data in each frequency range and each population."

At the University of Washington in Seattle, meanwhile, Evan Eichler and his colleagues have been using a technique to identify pieces of the genome that duplicate other parts of the DNA code. Writing in the journal Science, the researchers describe how they identified more than four million places where they found these duplicates, called copy-number variants.

Eichler says these variants could help identify genes that may be associated with disease that are what he called "inaccessible" using other techniques. He also said it can help improve the understanding of human evolution.

"We think the veil has been lifted for us in terms of a whole new level of genetic diversity. And when we compare these roughly 159 humans that we've analyzed to date, and compared variations they've found in their genomes to that of the great apes, we have the ability, I think pretty clearly, to identify the genes and the gene families which have expanded specifically in our lineage of evolution since we separated from that of chimpanzee and gorilla," Eichler said.

Back at the 1000 Genomes project, co-chair David Altshuler says the organization's work will provide data so scientists can answer questions about the role genes play in health based on facts, not guesswork. "And so rather than speculate," he said, "I think we'd say we are helping to create the foundation to answer that question, and anyone who does speculate, I think is speculating."

By the way, the goal of the 1000 Genomes project isn't to sequence the genetic code of exactly 1,000 people. Instead, the aim is to identify genetic variations that occur in at least one out of every 100 people or one percent. In particular, that will require using genetic material from many thousands of people from all over the world. And it will need to include a lot more geographic diversity. Only a handful of genomes from Latin America and Africa have been sequenced so far.

Researchers May Some Day Treat Depression with Gene Therapy

Jessica Berman 21 October 2010

Doctors may some day treat patients suffering from major depression with gene therapy. So say scientists who report they are encouraged by human and animal research.

Scientists have identified a protein called p11 in a small region of the brain that plays a role in major depression. The brain region, known as the nucleus accumbens, is responsible for feelings of pleasure and reward.

Researcher Michael Kaplitt of the department of neurological surgery at Presbyterian / Weill Cornell Medical Center in New York, says mice bred without the p11 gene showed signs of severe depression, including passivity when dangled by their tails instead of trying to get away and a disinterest in sugar water, which he says is like candy to mice who normally drink a lot of it.

Kaplitt also says autopsy studies of tissue taken from the brains of people with severe depression showed extremely low levels of p11 in the nucleus accumbens compared to the brains of individuals without depression.

"So if human beings have lower levels of p11 in this area of the brain, if they have depression, and if animals when they have low p11 levels in this area show depression-like behaviors, then that suggests that this might be a very important component of depression; not the only component but it may be a very important component," said Kaplitt.

Using so-called knock-out mice that completely lacked the p11, Kaplitt says researchers inserted a normal copy of the protein into a harmless virus and infused it into the nucleus accumbens of the depressed rodents.

"Now when we restored it to these adult mice, it completely normalized their behaviors; it reversed these depression-like behaviors so that they were back to normal," he said. "So that suggested that if you have low p11 levels in that area, and if that is a cause of depression, that we could potentially reverse it with gene therapy."

Kaplitt and colleagues have also been conducting promising therapy trials with Parkinson's disease patients.

The researchers hope to soon begin gene therapy experiments in patients with major depression who do not respond to anti-depressant medications.

An article on gene therapy for major depression is published in the journal Science Translational Medicine.

Scientists Discover Pain Genes

Jessica Berman | Washington 11 November 2010

Scientists have discovered hundreds of genes that appear to play a role in determining pain sensitivity. Researchers say slight variations in one pain gene in particular seem to affect how intensely pain is felt.

Under normal circumstances, scientists say pain serves an important biological function; a sharp poke with a needle or knifepoint, or slight burn, causes most people to recoil, protecting them from further harm.

Then there is another type of pain, according to Clifford Woolf a neurobiologist at Children's Hospital in Boston, Massachusetts.

"The other kind of pain is when the fire alarm system is on all the time, and these would be patients who have chronic persistent pain," Woolf explained. "And that is a situation where pain has become a disease in its own right. It's no longer warning of damage; the fire alarm is on all the time and there's no fire."

Scientists say studies of twins show that the degree to which an individual feels pain is largely inherited.

In an effort to identify genes involved in pain, an international team of researchers led by Woolf identified some 600 potential genes in fruit flies which are similar in humans.

Scientists focused on one gene in particular called "Alpha 2 Delta 3."

In a study of 189 healthy volunteers, researchers found reduced sensitivity to heat among participants who had slight alphabet variations to the DNA code within or close to the location of the Alpha 2 Delta 3 gene.

Researchers also found in another study that back pain patients who had the rarer genetic variants were less likely to experience persisting pain after surgery.

By learning the genetic underpinnings of pain, Woolf says it will someday be possible to develop medications to treat a variety of pain syndromes.

"There's pain associated with damage to the nervous system. Pain associated with the inflammatory diseases," neurobiologist Woolf noted. "There's post-operative pain. And each of them operates in slightly different ways, and so there will be different targets and different analgesics required for these different kinds of pain."

Researchers say it may one day be possible to develop genetic risk profiles to determine who is at greatest risk of chronic pain following surgery. Such information could be useful in helping patients decide whether to go forward with an operation.

An article describing the pain genes is published in the journal Cell.

Stem Cell Therapy Gaining Ground in Asia

Heda Bayron | Hong Kong 25 November 2010

Asians are beginning to warm up to the idea of using their own stem cells to treat a host of illnesses such as heart disease, cystic fibrosis or leukemia. Some parents are preserving their babies' umbilical cords, hoping that as technology advances their children can use the umbilical blood to cure future illnesses.

It is a nightmare for parents to hear their child has developed a disease that requires a bone marrow transplant. For instance, patients with leukemia, a type of blood cancer, sometimes have a hard time finding a bone marrow match.

Scientists say the umbilical cord that attaches a baby to its mother is a rich source of stem cells, which can treat diseases like leukemia. They can be collected immediately after birth and stored in freezers by companies such as Cordlife, which operates cord blood banks in Hong Kong, Singapore, Indonesia, India and the Philippines. If a child needs it, doctors can retrieve cord blood for treatment.

"We're seeing an explosion umbilical cord blood banking as a source of biological insurance for parents in Asia and their children," said Andrew Wu, Cordlife's technical and laboratory director.

Scientists around the world are finding new ways to use cord blood stem cells to treat problems such as spinal cord damage, diabetes, cerebral palsy and heart disease.

At Cordlife, parents pay about $4,000 to keep their children's cord blood for 18 years.

"I'm most excited to see the use of stem cell in therapy becoming a standard of care, where clinicians when they look at a disease would ask, 'What's my stem cell option in terms of therapy? How I can look to stem cells to treat this disease or regenerate this organ or to combat this tumor?'" Wu said.

Asia appears striding toward the use of stem cells for treatment.

Dr. Supachai Chaithiraphan, a professor emeritus of Thailand's Mahidol University and director of the cardiac center at Chao Phya hospital in Bangkok, conducted a clinical trial in 2004 that injected stem cells derived from human blood to treat people with end-stage heart disease.

"Eighty percent showed improvement in terms of New York Heart Association classification and also the Canadian [Cardiac Society] angina classification. So we feel that this group of patients can derive benefit from their own stem cell therapy," Supachai said.

In Asia, there are fewer regulations regarding the use of stem cells than in the United States, which encourages research and clinical uses.

In the U.S., the use of stem cells has been controversial because of ethical concerns over the use of embryonic stem cells - derived from early-stage embryos that develop from human eggs fertilized in a laboratory. Under President Bush, the government limited funding to a few batches of stem cell lines. But the Obama administration has since relaxed those rules.

However, cord blood storage appears to be increasing in the U.S. A new national cord blood bank has been established at Duke University in the state of North Carolina.

Some practitioners, such as Wu worry that Asia's lax regulations may lead to inflated expectations and false promises.

"A lot still needs to go into building this understanding and building appropriate regulations around the use of these stem cells so that the industry as a whole can develop within a legal framework that not only benefits the companies but most importantly benefits the clinicians and the patients at the end of the day," Wu said.

Poor medical facilities in some developing Asian nations also hold back use of stem cells.

But Supachai says in time, stem cell therapy will be more accessible.

"I would foresee that in the near future more doctors would come to realize that this cell therapy is really of help to certain number of patients with certain diseases, in particular heart disease," Supachai said.

The World Health Organization estimates that about 20 million people worldwide will die from cardiovascular disease annually by 2015. The number of people in developing nations suffering from heart disease is expected to rise as incomes increase.

Scientists say DNA provides 'historical archive'

Edinburgh scientists say they have developed a genetic test that can tell if people's ancestors were from a large populated area or a rural village.

The team found that a person's DNA records provide a "historical archive" of where they are from.

The test can also detect if a person's ancestors were related, such as if they are from a community where marriage between cousins was commonplace.

It could help identify people who are more prone to genetic illnesses.

Gene pool

A team at Edinburgh University analysed the DNA of more than 1,000 people across 51 different ethnic groups, ranging from Europeans to Amazonian tribes, during the study.

They identified those who had inherited the same genetic material from both parents The study found that native South Americans had the highest amount of shared DNA, suggesting that those communities were small and isolated over many generations.

By contrast, African communities had the lowest degree of genetic similarity, indicating a more diverse population over time.

The team believe this could be explained by the fact that humans originated in Africa and so have had the most time to develop a diverse gene pool.

Dr Jim Wilson, Royal Society research fellow at Edinburgh University, said: "The exciting thing about these results is that it shows our genes are recording the history of movements in our population.

"It's like an archive being written in genetic code, so that we can understand the way our populations have developed from the distant past.

"The findings are also important because it highlights those areas of the world where genetic similarity is common and this can be a risk factor for some diseases like cystic fibrosis, which can be caused when you inherit a faulty gene from both parents."

The scientists said DNA records provided a "historical archive" of where people are from

(source: BBC)

Genes Predict Who Will Live Longer

Technique may also help predict disease

Art Chimes | St. Louis, Missouri

Researchers at Boston University have identified a kind of genetic signature in people who are likely to live to age 100 or older. The technique may also help doctors predict whether you're likely to get a disease, decades before the symptoms show up.

Living a long, healthy life tends to run in families. If your grandparents and parents lived into their 90s and remained relatively healthy until the end, there's a pretty good chance you will, too.

So it's pretty clear genetics plays some role in longevity.

In this study, the research team developed a new statistical way of analyzing the genetic code of people who had reached age 100 as compared with people who had a more typical lifespan. Tom Perls, who heads the New England Centenarian Study, explains what they found.

"We discovered 150 or so genetic markers that can highly predict whether or not a person has the genetic propensity to live to extreme old age."

Using just that large number of genetic markers, the team was able to predict in almost four out of five cases whether a person would live to be 100.

Perls says the key to successfully predicting long life was the sophisticated statistical analysis of many different gene variations that each played some role.

"And that's what this method does - it captures the complexity of the puzzle and the interaction of all these genes together to produce exceptional longevity."
Perls and his colleagues publish their study in the online edition of the journal Science.

The Boston University researcher says this kind of analysis could play a role, not just in predicting who will live longest, but in actually helping people live longer and healthier lives.

In an interview via Skype, Tom Perls said the same technique used to predict long life may also be used to predict whether a person might eventually develop certain diseases. He gave the example of Alzheimer's Disease as one in which genetics plays a role.

"And we think that this methodology can very much be used to capture the bunch of genes that are playing an important role in one's susceptibility to that disease," he said. "And the same can be true, perhaps, for looking at adult-onset diabetes, or cardiovascular disease, or stroke. Again, where I think there is at least a moderate impact from genetic variation."

As the cost of the needed genetic tests continues to decline, he predicts doctors will be able to screen patients for diseases they may not develop until later in life, and recommend ways to avoid them.

Gene Abnormality Found To Predict Childhood Leukemia Relapse

Scientists have identified mutations in a gene that predict a high likelihood of relapse in children with acute lymphoblastic leukemia (ALL). Although the researchers caution that further research is needed to determine how changes in the gene, called IKZF1 or IKAROS, lead to leukemia relapse, the findings are likely to provide the basis for future diagnostic tests to assess the risk of treatment failure. By using a molecular test to identify this genetic marker in ALL patients, physicians should be better able to assign patients to appropriate therapies.

The findings of the Children Oncology Group (COG) study, led by scientists from St. Jude Children Research Hospital, Memphis, Tenn., the University of New Mexico Cancer Research and Treatment Center, Albuquerque, N.M., and the National Cancer Institute (NCI), part of the National Institutes of Health, appear online Jan. 7, 2009, in the New England Journal of Medicine, and in print on Jan. 29, 2009.

ALL, a cancer of white blood cells, is the most common childhood cancer, in that it is diagnosed in about one in 29,000 children annually. Using currently available therapies, cure rates for ALL are now upwards of 80 percent. However, those therapies carry with them substantial side effects, and even with treatment, only 30 percent of children who experience a relapse of ALL will survive five years. Determining the risk of relapse faced by an individual patient would help physicians tailor treatment intensity appropriately, but until now there has been no good marker for predicting outcome.

"Great progress has been made in recent years in improving the cure rate of childhood ALL," said Stephen Hunger, M.D., chairman of the COG ALL committee and the lead COG investigator on this study. "The findings of this study help us further subdivide those patients who are unlikely to be cured, and identify patients in whom different therapies should be tested."

In the study, researchers analyzed genetic data on leukemia cells obtained at diagnosis from 221 children with high-risk leukemia (i.e., a high chance of relapse) who had been treated in an existing COG study. They conducted their analysis using microarrays and DNA sequencing � technologies which allow researchers to quickly and efficiently identify and analyze multiple genes simultaneously in the same cell. Using these technologies to identify genetic abnormalities in leukemia cells, the investigators examined the DNA of the leukemia cells at the time of diagnosis and then determined if any of the identified genetic changes predicted relapse. To confirm that specific genetic changes were associated with relapse, the scientists also examined a second group of 258 children with ALL who were treated at St. Jude.

"We looked across the genome in an unbiased fashion in an attempt to pull out any genes that were significantly associated with outcome," said Charles Mullighan, M.D., Ph.D., assistant member in the St. Jude Department of Pathology and the paper抯 first author. "From these findings, we identified a group of genetic abnormalities that together predicted poor outcome."

The most significant association was with the deletions or changes in the IKAROS gene. Mutations of IKAROS were shown to identify a subgroup of patients who were treated in the COG study that had a very poor prognosis. The prognostic significance of these genetic alterations was validated in the independent St. Jude patient group, a finding of particular importance since different types of therapies were used in these two groups of patients.

Previous research has shown that the IKAROS gene serves as the blueprint for production of the IKAROS protein, which regulates the activity of many other genes. The IKAROS protein plays an essential role in the development of lymphocytes, the white blood cells that, when changed, give rise to pediatric ALL. The way in which IKAROS abnormalities contribute to the development of relapse remains to be determined.

The study also examined gene expression in the leukemia cells using microarray chips, and found that leukemia cells from patients with IKAROS alterations expressed primitive, stem cell-like genes, suggesting that the cells are less mature and possibly more resistant to the effects of drugs used to treat ALL. "These findings show how detailed analysis of leukemic cells using complementary techniques can enhance our understanding of the genetic basis of leukemia," said co-author Cheryl Willman, M.D., director and CEO, University of New Mexico Cancer Research and Treatment Center.

The researchers also tested whether the presence of IKAROS alterations was associated with levels of minimal residual disease, another measure of treatment response in ALL.

"Measurement of levels of minimal residual disease is widely used to monitor treatment responsiveness and also to alter patients� therapy if they have a very poor response to treatment," said James Downing, M.D., St. Jude scientific director and the paper抯 senior author. "An important analysis we conducted was to see whether identifying the association of IKAROS alterations with poor outcome added anything to just measuring levels of minimal residual disease. And, indeed, it did."

The researchers� analysis indicated that identifying IKAROS alterations may be clinically useful and will complement existing diagnostic tests and measurement of minimal residual disease levels.

While a clinical test for alterations of IKAROS could prove valuable for predicting poor outcomes in children with ALL, complexities remain. There are different types of deletions in the gene, some that involve the entire IKAROS gene and others that involve only parts of the gene. Because the genetic alterations in IKAROS in ALL are not uniform or limited to a single mutation or deletion, it may be necessary to develop a panel of different tests to detect IKAROS lesions and identify which patients are at highest risk for relapse.

This research was done as part of the NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, which seeks to utilize the study of genomics to identify therapeutic targets in order to develop more effective treatments for childhood cancers. The first two cancers being studied in the program are ALL and neuroblastoma, a cancer that arises in immature nerve cells and affects mostly infants and children. Combined, these two cancers account for 3,000 new cases each year, and in both cancers, there are some children who have a very favorable prognosis and others who are at high risk for treatment failure. By determining the genetic factors that distinguish these groups, the hope is that researchers can use this information to improve patient outcomes and develop better treatments, particularly for those in the high-risk group.

"In the long term, our goal is to develop effective therapeutic interventions, directed toward vulnerabilities that leukemia cells acquire as a result of the genomic abnormalities identified through the TARGET initiative," said Malcolm Smith, M.D., Ph.D., of NCI抯 Cancer Therapy Evaluation Program. These are the first results to come out of this initiative. For more information about TARGET, please visithttp://target.cancer.gov

St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. For more information, please visit www.stjude.org.

The Children抯 Oncology Group/CureSearch
Children抯 Oncology Group (COG), the world抯 largest cooperative pediatric cancer research organization, which includes every recognized pediatric cancer program in North America, comprises a network of more than 5,000 physician, nurse, and other clinical and laboratory investigators whose collaboration in clinical and translational research has turned childhood cancer from a virtually incurable disease to one with an overall cure rate approaching 80 percent. COG is committed to conquering childhood cancer through scientific discovery and compassionate care. For more information, please visit www.childrensoncologygroup.org

The University of New Mexico Cancer Research and Treatment Center
The UNM Cancer Center is New Mexico抯 only National Cancer Institute-designated cancer center, and is home to the state抯 largest and most experienced team of cancer experts with 81 board-certified oncology physicians and more than 120 research scientists, supported by more than $50 million in grants annually. As the Official Cancer Center of the State of New Mexico, the Center served 7,600 new patients last year in 84,000 patient visits, treating nearly half of all adults with cancer in the state and virtually all the children.

The National Cancer Institute

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The National Institutes of Health

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Reference: Mullighan CG, Su X, Zhang J, Radtke I, Phillips LAA, Miller CB, Ma J, Liu W, Cheng C, Schulman BA, Harvey RC, Chen I, Clifford RJ, Carroll WL, Reaman G, Bowman WP, Devidas M, Gerhard DS, Yang W, Relling MV, Shurtleff SA, Campana D, Borowitz MJ, Pui C, Smith M, Hunger SP, Willman CL, Downing JR, and the Children's Oncology Group. Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia. NEJM. Vol. 360, No.