Exome sequencing finds single gene for multiple brain abnormalities

Researchers have found that a single gene can cause several types of developmental brain abnormalities that experts have traditionally considered different disorders. They found those mutations through whole exome sequencing – a new gene scanning technology that cuts the cost and time of searching for rare mutations.

“This is going to change the way we approach single-gene disorders,” said lead investigator Murat Gunel, MD, who is chief of the Neurovascular Surgery Program and co-director of the Program on Neurogenetics at Yale University in New Haven, Connecticut, US. Whole exome sequencing can be applied to dozens of other rare genetic disorders where the culprit genes have so far evaded discovery, he said.

Such information can help couples assess the risk of passing on genetic disorders to their children. It can also offer insights into disease mechanisms and treatments. The study appears in Nature, (REF: Bilguvar K, Ozturk AK et al. “Whole exome sequencing identifies WDR62 mutations in severe brain cortical malformations.” Nature, published online 22 August 2010) and focuses on children with malformations of cortical development (MCD).

Different types of MCD are recognised based on anatomy. They carry names like microcephaly (small brain and head), schizencephaly (fluid filled clefts in the brain), pachygyria (a cortex with thicker, fewer folds) and polymicrogyria (cortex with many small folds). These conditions reflect a failure of brain cells to grow and reach their proper places during development. They can result from prenatal exposure to alcohol, drugs and some viruses. In many cases, the cause is genetic, but the specific genetic lesion is often unknown.

Through whole exome sequencing, the new study found a single gene at the root of seemingly distinct types of MCD in children from multiple families. Rather than scanning a person’s entire genome for mutations, this technique focuses on the protein-coding bits of DNA, or exome, which makes up about 1.5% of the genome.

Genetic forms of MCD occur worldwide and in all kinds of families, but the highest incidence is among children born to parents who are related. Dr Gunel and his colleagues at Yale teamed up with investigators in Turkey to study Turkish families with MCD. The country has a tradition of firstand second-cousin marriages, and thus a relatively high incidence of MCD.

Those results show that a single gene “is required for strikingly diverse aspects of human cortical brain development”, said Dr Gunel.



Third generation HapMap published

An international consortium has recently published a third-generation map of human genetic variation, called the HapMap, which includes data from an additional seven global populations, increasing the total number to 11 populations. The improved resolution will help researchers interpret current genome studies aimed at finding common and rarer genetic variants associated with complex diseases.

Any two humans are more than 99% the same at the genetic level. But, the small fraction of genetic material that varies among people can help explain individual differences in susceptibility to disease, response to drugs or reaction to environmental factors. Variation in the human genome is organised into local neighbourhoods called haplotypes, which usually are inherited as intact blocks of DNA sequence information. Consequently, researchers refer to the map of human genetic variation as a haplotype map, or HapMap.

“The generated HapMap provides an important foundation for studies aiming to find genetic variation related to human diseases. It is now routinely used by researchers as a valuable reference tool in our quest to use genomics for improving human health,” said Eric D. Green, MD, PhD, director of the US National Human Genome Research Institute (NHGRI).

The most common genetic differences among people are SNPs, single-nucleotide polymorphisms. Each SNP reflects a specific position in the genome where the DNA spelling differs by one letter in different people. SNPs serve as landmarks across the genome. The initial version of the HapMap contained approximately 1 million SNPs, and the second-generation map brought that total to more than 3.1 million SNPs. Over the last few years, researchers conducting genome-wide association studies have relied on publicly available data from the HapMap to discover hundreds of common genetic variants associated with complex human diseases, such as cardiovascular disease, diabetes, cancer and many other health conditions.

The first- and second-generation versions of HapMap resulted from the analysis of DNA collected from 270 volunteers from four geographically diverse populations: Yoruba in Ibadan, Nigeria; Japanese in Tokyo; Han Chinese in Beijing; and Utah residents with ancestry from northern and western Europe.

The third-generation HapMap, reported in the 2 September issue of the journal Nature, is the largest survey of human genetic variation performed thus far. It has data on 1,184 people, including the initial HapMap samples. Additional human samples were collected from the original populations and from seven new populations: individuals of African ancestry from the Southwestern United States; Chinese individuals from metropolitan Denver; Gujarati Indians from Houston; Luhya people from Webuye, Kenya; Maasai people from Kinyawa, Kenya; individuals of Mexican ancestry from Los Angeles; and individuals from Tuscany, Italy.

The increased number of samples allows detection of variants that are much rarer than could be found by the earlier HapMaps. Because of human population history, lower-frequency variation is shared less among populations. For instance, 77% of the detected SNPs were new, revealing that many more variants remain to be found, especially rare variants.

Many of the HapMap researchers are part of the 1000 Genomes Project, an international public-private consortium launched in 2008 that is building an even more detailed map of human genetic variation. Project researchers are currently using nextgeneration DNA sequencing technologies to build a public database containing information from the complete genomes of 2,500 people from 27 populations around the world, many of which were studied in the HapMap project. Disease researchers will be able to use the catalogue, which is being developed over the next two years, in their studies of the contribution of common and rarer genetic variation to illness.



The HapMap online http://hapmap.ncbi.nlm.nih.gov

Revolutionary treatment for heart disease

Researchers have identified a process to successfully reprogramme mesenchymal stem cells harvested from the bone marrow of heart failure patients into cardiac precursor cells.

Injected into an animal model of heart disease, these cardiac precursor cells improved heart function by repopulating scar tissue and generating new blood vessels, effectively eliminating the scar and rebuilding the heart with new functional human heart tissue. Treated animals demonstrated improved heart function and were cured from their heart failure.

This revolutionary stem cell treatment for heart failure has been developed by a Belgian company, Cardio3 BioSciences, who have named the pharmaceutical product ‘C-Cure’.

The research – carried out at Mayo Clinic in Rochester, Minnesota, USA, and in collaboration with the Cardiovascular Center in Aalst, Belgium – was published in the Journal of the American College of Cardiology (JACC).

Cardio3 BioSciences has advanced the development of this technology with the recent conclusion of a Phase II clinical trial that recruited 45 heart failure patients in Europe. The company recently announced that its compound C-Cure had an excellent safety profile and observed positive trends in both physiological and clinical heart function, as was anticipated from the animal model data published in JACC.

Dr Christian Homsy, CEO of Cardio3 BioSciences, said: “Publication of this research in a journal as prestigious as JACC highlights the quality of the science underlying our product. This trans-Atlantic effort involving edge science in both the US and Belgium served to dramatically increase the potency of human stem cells to repair heart tissue and provides the basis for C-Cure, a therapy that could revolutionise the treatment of this disease.

“We are now finalising the design of our pivotal clinical programme for C-Cure and look forward to continuing steps needed to bring this much needed treatment to patients.”



Move to sequence human genome for less than $1000

More than US$18 million in grants to spur the development of a third generation of DNA sequencing technologies was announced recently by the US-based National Human Genome Research Institute (NHGRI).

“NHGRI and its grantees have made significant progress toward the goal of developing DNA sequencing technologies to sequence a human genome for $1,000 or less,” said Eric D. Green, MD, PhD, director of NHGRI.

During the past decade, DNA sequencing costs have fallen dramatically fueled in large part by tools, technologies and process improvements developed by the Human Genome Project. NHGRI subsequently launched programmes in 2004 to accelerate improvements in sequencing technologies and to further drive down the cost. Last year, the programme surpassed the goal of producing high-quality genome sequences of 3 billion base pairs – the amount of DNA found in humans and other mammals – for $100,000. The cost to sequence a human genome has now dipped below $40,000. Ultimately, NHGRI’s vision is to cut the cost of whole-genome sequencing of an individual’s genome to $1,000 or less, which will enable sequencing to be a part of routine medical care.

“Next generation sequencing technologies used in laboratories today have allowed significant advances in the scale and scope of biological research,” said Jeffery Schloss, PhD, NHGRI’s programme director for technology development. “Still, there are other improvements that remain to be made before such sequencing tools can be used routinely in the laboratory and clinic.”

The new grants will fund ten investigator teams to develop revolutionary technologies that may make it possible to sequence a genome for $1,000. The collective approaches incorporate many complementary elements that integrate biochemistry, chemistry and physics with engineering to enhance the whole effort to develop the next generation of DNA sequencing and analysis technologies.



Breakthrough in using neural stem cells for spinal cord injury

Researchers have reported a breakthrough in using human neural stem cells to restore motor function in chronic spinal cord injury – showing an expanded time frame following the injury in which the stem cells can be used successfully.

The company funding the research – StemCells Inc. – announced publication of new preclinical data demonstrating that the company’s proprietary human neural stem cells restore lost motor function in mice with chronic spinal cord injury.

The study, entitled “Human Neural Stem Cells Differentiate and Promote Locomotor Recovery in an Early Chronic Spinal Cord Injury NOD-scid Mouse Model,” was led by Dr Aileen Anderson of the Sue and Bill Gross Stem Cell Research Center at the University of California, Irvine (UCI). The paper was published in the journal PLoS ONE. Ref: doi:10.1371/ journal.pone.0012272.

StemCells’ human neural stem cells were transplanted into mice 30 days after a spinal cord injury that results in hind limb paralysis. The transplanted mice demonstrated a significant and persistent recovery of walking ability in two separate tests of motor function when compared to control groups. These results are particularly significant because it is the first time that human neural stem cells have been shown to promote functional recovery in a chronic spinal cord injury setting, which is characterised as a point in time after injury in which inflammation has stabilised and behavioural recovery has reached a plateau. In humans, the chronic phase typically does not set in until several weeks or months following the injury.

“These exciting results demonstrate an expanded window of opportunity for human neural stem cell intervention in spinal cord injury,” explained Stephen Huhn, MD, FACS, FAAP, Vice President and Head of the CNS Program at StemCells.

“The strong preclinical data we have accumulated to date will enable our transition to a clinical trial, which we plan to initiate in 2011.”



A factory for stem cells

A team of scientists have published a paper which shows their discovery of man-made acrylate polymers which allow stem cells to reproduce while maintaining their pluripotency.

Currently, stem cells are cultured using animal derived products that encourage the cells to reproduce without losing their pluripotency – their ability to be turned into any type of adult stem cell.

However, the potential for cross-species contamination and the difficulty in reproducing these cells in large numbers means that while they are useful as a research tool, a synthetic alternative would be essential for the treatment of patients.

Leader of the research team, Professor Morgan Alexander in Nottingham University’s School of Pharmacy (in the UK) said this was an important breakthrough which could have “significant implications for a wide range of stem cell therapies, including cancer, heart failure, muscle damage and a number of neurological disorders such as Parkinson’s and Huntington’s”.

“One of these new manmade materials may translate into an automated method of growing pluripotent stem cells which will be able to keep up with demand from emerging therapies that will require cells on an industrial scale, while being both costeffective and safer for patients.”



Stress hormone affects mood genes

Long-term exposure to a common stress hormone may leave a lasting mark on the genome and influence how genes that control mood and behaviour are expressed, a mouse study led by Johns Hopkins researchers suggests. The finding, published in the September issue of Endocrinology, could eventually lead to new ways to explain and treat depression, bipolar disorder, and other mental illnesses.

Scientists and physicians have long been interested in the cause of depression, a sometimes debilitating disorder that affects about 16% of people at least once over the course of a lifetime. While studies have shown that many other mental illnesses are strongly heritable, studies have shown that the risk of depression is only about 40% genetic. Consequently, environmental factors are thought to play a major role in causing this disease.

Unsurprisingly, previous research has shown that stressful life events can increase the risk of depression. But how these life events play into the biology of this disease is unknown.

James Potash, MD, MPH, an associate professor at the Johns Hopkins University School of Medicine, and colleagues suspected that epigenetic factors might be at work in the disease. Epigenetic, or “above the genome”, factors are so named because they affect how genes are expressed without changing the genetic sequence. One of the most prevalent epigenetic changes, or “marks,” are methyl chemical groups that clip onto DNA, often shutting off the gene that they attach to.

To see if stress might influence epigenetic marks on genes involved in depression, Potash and his colleagues gave some mice corticosterone in their drinking water for four weeks. Corticosterone is the mouse version of cortisol, a hormone produced by the human body during stressful situations. Other mice drank plain water without this hormone.

At the end of the four-week period, the mice who received corticosterone displayed anxious characteristics in behavioural tests. Gene expression tests on these animals showed a marked increase in protein produced by a gene called Fkbp5. This gene’s human form has been linked to mood disorders, including depression and bipolar disease.

When the researchers examined the rodents’ DNA for epigenetic marks on Fkbp5, they found substantially fewer methyl groups attached to this gene in mice that received corticosterone compared with those that didn’t. These differences in epigenetic marks persisted for weeks after the mice stopped receiving the hormone, suggesting long-lasting change.

“This gets at the mechanism through which we think epigenetics is important,” says Potash, who directs Johns Hopkins’ Mood Disorders Research Programs. He explains that epigenetic marks that are added through life experience may prepare an animal for future events. “If you think of the stress system as preparing you for fight or flight, you might imagine that these epigenetic changes might prepare you to fight harder or flee faster the next time you encounter something stressful.”

These behaviours, which were probably advantageous earlier in evolution, aren’t as useful today with modern stressors that we can’t fight or flee, such as work deadlines, Potash adds. Consequently, chronic stress might instead lead to depression or other mood disorders triggered by epigenetic changes.

Potash notes that, eventually, doctors may be able to look for these epigenetic changes in DNA isolated from a patient’s blood to predict or diagnose psychiatric illnesses. Ultimately, researchers may someday be able to target these epigenetic marks with drugs to treat depression and other diseases. 

                                   
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