Category Archives: Genome

Prof Eric Lander has trained his focus on identifying disease genes

Chennai, February 25:

Eric S Lander, one of the principal leaders of the Human Genome Project, a massive international research exercise that mapped the entire human genetic code in 2003, said on Wednesday that the real genome project is about studying huge samples of genomic data to identify disease genes.

While phenomenal technological advances have helped reduce the cost of genome sequencing by a million-fold over the last decade, allowing researchers to map thousands of human genomes, the future of genomic medicine depends on sharing information between organisations and countries including India said Prof Lander. In order for therapy to emerge from genetic research, health systems around the world need to turn into learning systems that share information, said Lander, delivering a lecture on The Human Genome and Beyond: A 35 year Journey of Genomic Medicine as part of the three-city Cell Press-TNQ Distinguished Lectureship Series.

Lander envisaged a DNA library where genes can be cross-reference to detect spelling differences and disease genes. The goal before the scientific community now is to find targets for therapeutic intervention, he said to a packed auditorium comprising medical students. There is much to be learnt in the course of clinical care, said Lander who is the founding director of the Broad Institute of MIT and Harvard.

While the breathless hype created around the Human Genome Project suggested that it would cure all disease in a couple of years, he said that much progress has indeed been made over the last decade with the discovery of several genes responsible for diabetes, schizophrenia and heart attacks.

Lander will be speaking next on Friday at JN Tata Auditorium in Bengaluru as part of the lectureship series.

(This article was published on February 25, 2015)

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The real genome project needs countries to share information

IMAGE:This is professor Andrew Biankin. view more

Credit: Garvan Institute of Medical Research

Scientists from Australia and the UK have done the most in-depth analysis yet of 100 pancreatic cancer genomes and highlighted 4 subtypes that may help guide future patient treatment. The study is published in Nature today.

Using whole genome sequencing, the team revealed broad patterns of 'structural variation', or change, previously invisible when it was feasible to sequence only protein-coding genes (around 1% of the genome).

Just as satellite images allow us to see the Earth as a whole, and zoom into the detail when we choose, whole genome sequencing allows us to view global and local DNA damage equally effectively.

Like landmasses or ice shelves, entire chromosomes can shatter and rearrange themselves. Slabs of DNA can break away from one chromosome and join another. Genes can be inverted, deleted or multiplied.

With the benefit of a global view, four kinds of genomic rearrangement were detected in the new study, including 'stable', 'locally rearranged', 'scattered' and 'unstable'. In some cases - notably 'unstable' genomes, which show defective DNA repair mechanisms - effective treatments suggested themselves.

Professors Andrew Biankin and Sean Grimmond, laboratory heads at Sydney's Garvan Institute of Medical Research and the University of Queensland's Institute for Molecular Bioscience (IMB) respectively, led the study, arising out of a much larger ongoing project. Both are now based at the Wolfson Wohl Cancer Research Centre, part of the University of Glasgow in Scotland. They collaborated with bioinformatician Dr Nicola Waddell from IMB, who interpreted the sequencing results.

A prior study by the same group, which examined only the 'exomes' - protein-coding genes - within the same cohort of 100 patients, showed a complex mutational landscape, as well as enormous heterogeneity among the tumours. Thousands of mutated genes were present, and "a long tail of infrequently mutated genes dominated", said Professor Biankin.

"The bottom line is that we really have to start thinking about moving to whole genome sequencing as a diagnostic imperative.

More:
How the landscape of the pancreatic cancer genome is coming into view

Researchers have pinpointed a region in the human genome associated with peanut allergy in U.S. children, offering strong evidence that genes can play a role in the development of food allergies.

But in an additional finding that suggests genes are not the only players in food allergies, the Johns Hopkins Bloomberg School of Public Health-led research team found there may be other molecular mechanisms that may contribute to whether those who are genetically predisposed to peanut allergies actually develop them.

The findings are published online Feb. 24 in the journal Nature Communications.

"We always suspected it, but this is the first genome-wide association study (GWAS) that identified a genetic link to well-defined peanut allergy," says the study's principal investigator, Xiaobin Wang, MD, ScD, MPH, the Zanvyl Krieger Professor and director of the Center on the Early Life Origins of Disease at the Johns Hopkins Bloomberg School of Public Health.

Food allergies have been rising rapidly around the world over the past 20 years and now affect an estimated 2 to 10 percent of children in the United States. Food allergies have become a major clinical and public health problem due to their increasing prevalence, their potential to be life-threatening and their enormous medical and economic impact. Peanut allergy is among the most fatal food allergies and is often a lifelong allergy, unlike the milk or egg allergies that most children will grow out of.

There is currently no effective prevention or treatment approved by the U.S. Food and Drug Administration, except for emergency treatment given after accidental exposure. The only effective prevention strategy is to avoid the food that triggers a reaction. This can be a challenging task given the three most common allergies in American children are to peanuts, eggs and milk, items that are widely found in processed foods.

In their study, Wang and her colleagues analyzed DNA samples from 2,759 participants (1,315 children and 1,444 of their biological parents) enrolled in the Chicago Food Allergy Study. Most of the children had some kind of food allergy. They scanned approximately 1 million genetic markers across the human genome, searching for clues to which genes might contribute to increased risk of developing food allergies, including peanut. They found that a genomic region harboring genes such as HLA-DB and HLA-DR and located on chromosome six is linked to peanut allergy. This study suggests that the HLA-DR and -DQ gene region probably poses significant genetic risk for peanut allergy as it accounted for about 20 percent of peanut allergy in the study population.

Not everyone with these mutations, however, develops peanut allergy, and researchers wondered why. One possible reason, they determined, was that epigenetic changes may also play a role. Epigenetic changes, in which a methyl group attaches itself to the DNA, alter the expression of a gene without altering its underlying code. The levels of DNA methylation regulate whether people with genetic susceptibility to the peanut allergy actually developed it.

While the study represents a "good first step," more research is needed. For example, a better understanding of genetic susceptibility will allow for early risk assessment and prediction of food allergies, perhaps as early as in utero, Wang says.

Unlike genes themselves, DNA methylation levels can change in response to environmental exposures (in particular, in-utero and during the first few years of life), and the changes are potentially reversible. By identifying what environmental factors can alter DNA methylation levels in people with genes that make them susceptible to peanut allergy, researchers could potentially open a new avenue for prevention and treatment of peanut allergy.

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Do genes play a role in peanut allergies? New study suggests yes

According to the public databases, there are currently approximately 1,900 locations in the human genome that produce microRNAs (miRNAs), the small and powerful non-coding molecules that regulate numerous cellular processes by reducing the abundance of their targets. New research published in the Proceedings of the National Academy of Sciences (PNAS) this week adds another roughly 3,400 such locations to that list. Many of the miRNA molecules that are produced from these newly discovered locations are tissue-specific and also human-specific. The finding has big implications for research into how miRNAs drive disease.

"By analyzing human deep-sequencing data, we discovered many new locations in the human genome that produce miRNAs. Our findings effectively triple the number of miRNA-generating loci that are now known" says Isidore Rigoutsos, Ph.D., Director of the Computational Medicine Center at Thomas Jefferson University, who led the study. "This new collection will help researchers gain insights into the multiple roles that miRNAs play in various tissues and diseases."

For nearly three years, the team collected and sequenced RNA from dozens of healthy and diseased individuals. The samples came from pancreas, breast, platelets, blood, prostate, and brain. To their collection they also added publicly available data eventually reaching more than 1,300 analyzed samples representing 13 human tissue types. Their analyses uncovered 3,356 new locations in the human genome that generate over 3,700 previously undescribed miRNAs.

For a handful of the 13 tissues they studied, the team also had access to information describing miRNA association with Argonaute, an essential protein member of the regulatory complex that enables miRNA to interact with their targets. They found that 45 percent of the newly discovered miRNAs were in fact associated with Argonaute, a further indication that these molecules are involved in gene regulation. "We anticipate that many more of the newly discovered miRNAs will be found loaded on Argonaute as additional such data become available for the other tissues," says Eric Londin, Ph.D., an Assistant Professor and co-first author together with Phillipe Loher, M.S., a computational biologist and software engineer, both members of Jefferson's Computational Medicine Center.

One of the key design choices that the team made was to not limit their search to conserved genomic sequences, i.e. to only those sequences that are shared across multiple organisms. Instead the researchers scanned the genome much more broadly. "Advances in sequencing technology of the last several years made it easier to generate more data, from more tissues, and do so faster," says Dr. Rigoutsos who is also a researcher at the Sidney Kimmel Cancer Center at Jefferson. "Investigating the alluring possibility that miRNAs with important roles might exist only in humans was within reach. And this is what we set out to do."

Of the new molecules, 56.7 are specific to humans and most of them (94.4 percent) are found only in primates. Because of this organism-specificity these RNA molecules are involved in regulatory events that are absent from model organisms such as mouse and the fruit fly.

Tissue-specificity is another important characteristic of these new miRNAs. It means that these molecules are behind molecular events that are present in a single tissue, or in only a few tissues. Some of these molecules could potentially prove useful as novel tissue-specific disease biomarkers.

The tissue- and primate-specificity of the new molecules are expected to have important implications for the community's attempts to understand the causes of diseases. A first step in that direction requires the identification and validation of the targets for each of these 3,707 new miRNAs. To assist in these efforts, the team generated computational predictions of each miRNA's putative targets that are available from the Computational Medicine Center's website.

Story Source:

The above story is based on materials provided by Thomas Jefferson University. Note: Materials may be edited for content and length.

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Study nearly triples locations in human genome that harbor microRNAs

Great, wonderful, wacky things can come in small genomic packages.

That's one lesson to be learned from the carnivorous bladderwort, a plant whose tiny genome turns out to be a jewel box full of evolutionary treasures.

Called Utricularia gibba by scientists, the bladderwort is a marvel of nature. It lives in an aquatic environment. It has no recognizable roots. It boasts floating, thread-like branches, along with miniature traps that use vacuum pressure to capture prey.

A new study in the scientific journal Molecular Biology and Evolution breaks down the plant's genetic makeup, and finds a fascinating story.

According to the research, the bladderwort houses more genes than several well-known plant species, such as grape, coffee or papaya -- despite having a much smaller genome.

This incredibly compact architecture results from a history of "rampant" DNA deletion in which the plant added and then eliminated genetic material at a very fast pace, says University at Buffalo Professor of Biological Sciences Victor Albert, who led the study.

"The story is that we can see that throughout its history, the bladderwort has habitually gained and shed oodles of DNA," he says.

"With a shrunken genome," he adds, "we might expect to see what I would call a minimal DNA complement: a plant that has relatively few genes -- only the ones needed to make a simple plant. But that's not what we see."

A unique and elaborate genetic architecture

In contrast to the minimalist plant theory, Albert and his colleagues found that U. gibba has more genes than some plants with larger genomes, including grape, as already noted, and Arabidopsis, a commonly studied flower.

Go here to read the rest:
Carnivorous plant packs big wonders into tiny genome

Geneticist Eric S. Lander, one of the principal leaders of the Human Genome Project that mapped the entire human genome in 2003, offered a rare glimpse into the genetic library of life being created by a global community of scientists. This veritable catalogue has already begun to help decode the genetic basis of certain cancers, heart disease and schizophrenia.

A packed audience of students, scientists and medical practitioners heard Prof Lander speak on The Human Genome and Beyond: A 35 year Journey of Genomic Medicine at the fifth edition of the Cell Press-TNQ Distinguished Lectureship Series at the All India Institute of Medical Sciences here on Monday.

Over the last decade, genetic research has been revolutionised and the costs of genome sequencing have dropped drastically. While mapping a single human genome (as part of the Human Genome Project 1990-2003) costs $3 billion, today it costs less than $ 3,000.

This breakthrough opens up enormous opportunities to understand diseases, he said. Today, for instance, over 108 genes can be associated with schizophrenia, and particular genetic mutations can be linked to heart attacks early in life.

And yet, we have only scratched the surface, Prof Lander said. Discoveries require studying huge samples for every major disease. And for that our healthcare systems have to turn into learning systems.

The Global Alliance for Genomics and Health comprising 246 organisations in 28 countries -- including India -- is one such endeavour to create a critical mass of data.

It is imperative, however that the data remains shareable, said Prof Lander, who is the Founding Director of the Broad Institute (linking MIT, Harvard University and hospitals).

But genetic data must belong to patients, who have the right to share it with their privacy protected.

India, with the extraordinary size of its population is, from the genetic point of view, the single most interesting population in the world.

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From the first human genome, to a great library of life

A study that examined 17 million mutations in the genomes of 650 cancer patients concludes that large differences in mutation rates across the human genome are caused by the DNA repair machinery.

'DNA spellchecker' is preferentially directed towards more important parts of chromosomes that contain key genes.

The study illustrates how data from medical sequencing projects can answer basic questions about how cells work.

The work, performed by two scientists from the EMBL-CRG Systems Biology Unit in Barcelona, will be published online in Nature on 23rd February. Copying the large book that it is our genome without mistakes every time a cell divides is a difficult job. Luckily, our cells are well-equipped to proof-read and repair DNA mistakes. Now, two scientists at the Centre for Genomic Regulation in Barcelona have published a study showing that mistakes in different parts of our genome are not equally well corrected. This means that some of our genes are more likely to mutate and so contribute to disease than others.

The scientists analysed 17 million 'single nucleotide variants' -- mutations in just one nucleotide (letter) of the DNA sequence -- by examining 650 human tumours from different tissues. These were 'somatic' mutations, meaning they are not inherited from parents or passed down to children, but accumulate in our bodies as we age. Such somatic mutations are the main cause of cancer. Many result from mutagens, such as tobacco smoke or ultraviolet radiation, and others come from naturally occurring mistakes in copying DNA as our tissues renew.

Ben Lehner and his team had previously described that somatic mutations are much more likely in some parts of the human genome, thus damaging genes that may cause cancer. In a new paper published on 23rd February in Nature, they show that this is because genetic mistakes are better repaired in some parts of the genome than in others. This variation was generated by a particular DNA repair mechanism called "mismatch repair" -- a sort of a spellchecker that helps fix the errors in the genome after copying. Lehner and Supek show that the efficiency of this 'DNA spellchecker' varies depending on the region of the genome, with some parts of chromosomes getting more attention than others.

Turning the tables on mutation rates

The work presented by Lehner and Supek sheds new light on a process that was unexplored -- what makes some parts of the human genome more vulnerable to damage? "We found that regions with genes switched on had lower mutation rates. This is not because less mistakes are happening in these regions but because the mechanism to repair them is more efficient," explains Ben Lehner, group leader, ICREA and AXA professor of risk prediction in age-related diseases at the EMBL-CRG Systems Biology unit in Barcelona. The 'mismatch repair' cellular machinery is extremely accurate when copying important regions containing genes that are key for cell functioning, but becomes more relaxed when copying less important parts. In other words, there appears to be a limited capacity for DNA repair in our cells, which is directed where it matters most.

The CRG researchers also found that the rate of mutation differs for around 10% of the human genome in cells originating from different tissues. In particular, liver, colorectal and lymphocyte malignancies present more mutations in some parts of our chromosomes, while breast, ovarian and lung cancers accumulate more mutations in other places. They found that genes that are important and switched on (expressed) in a particular tissue also exhibit less mutations in tumours of that tissue; the effect extends into the surrounding DNA. But what gives the important genes a higher resilience to damage?

"The difference is not in the number of new mutations but in the mechanism that keeps these mutations under control," comments Fran Supek, CRG postdoctoral researcher and first author of the paper. "By studying cancer cells, we now know more about maintaining DNA integrity, which is really important for healthy cells as well," he adds. Once the 'genomic spellchecker' has been disabled in a cell, the scientists observed that genetic information started decaying not only very rapidly, but also equally in all parts of the genome -- neither the important nor the less important parts can were repaired well anymore. DNA mismatch repair is known to be switched off in some tumours from the colon, stomach and uterus, producing 'hypermutator' cancer in those organs.

Originally posted here:
'DNA spellchecker' means that genes aren't all equally likely to mutate

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Newswise (PHILADELPHIA) According to the public databases, there are currently approximately 1,900 locations in the human genome that produce microRNAs (miRNAs), the small and powerful non-coding molecules that regulate numerous cellular processes by reducing the abundance of their targets. New research published in the Proceedings of the National Academy of Sciences (PNAS) this week adds another roughly 3,400 such locations to that list. Many of the miRNA molecules that are produced from these newly discovered locations are tissue-specific and also human-specific. The finding has big implications for research into how miRNAs drive disease.

By analyzing human deep-sequencing data, we discovered many new locations in the human genome that produce miRNAs. Our findings effectively triple the number of miRNA-generating loci that are now known says Isidore Rigoutsos, Ph.D., Director of the Computational Medicine Center at Thomas Jefferson University, who led the study. This new collection will help researchers gain insights into the multiple roles that miRNAs play in various tissues and diseases.

For nearly three years, the team collected and sequenced RNA from dozens of healthy and diseased individuals. The samples came from pancreas, breast, platelets, blood, prostate, and brain. To their collection they also added publicly available data eventually reaching more than 1,300 analyzed samples representing 13 human tissue types. Their analyses uncovered 3,356 new locations in the human genome that generate over 3,700 previously undescribed miRNAs.

For a handful of the 13 tissues they studied, the team also had access to information describing miRNA association with Argonaute, an essential protein member of the regulatory complex that enables miRNA to interact with their targets. They found that 45 percent of the newly discovered miRNAs were in fact associated with Argonaute, a further indication that these molecules are involved in gene regulation. We anticipate that many more of the newly discovered miRNAs will be found loaded on Argonaute as additional such data become available for the other tissues, says Eric Londin, Ph.D., an Assistant Professor and co-first author together with Phillipe Loher, M.S., a computational biologist and software engineer, both members of Jeffersons Computational Medicine Center.

One of the key design choices that the team made was to not limit their search to conserved genomic sequences, i.e. to only those sequences that are shared across multiple organisms. Instead the researchers scanned the genome much more broadly. Advances in sequencing technology of the last several years made it easier to generate more data, from more tissues, and do so faster, says Dr. Rigoutsos who is also a researcher at the Sidney Kimmel Cancer Center at Jefferson. Investigating the alluring possibility that miRNAs with important roles might exist only in humans was within reach. And this is what we set out to do.

Of the new molecules, 56.7 are specific to humans and most of them (94.4 percent) are found only in primates. Because of this organism-specificity these RNA molecules are involved in regulatory events that are absent from model organisms such as mouse and the fruit fly.

Tissue-specificity is another important characteristic of these new miRNAs. It means that these molecules are behind molecular events that are present in a single tissue, or in only a few tissues. Some of these molecules could potentially prove useful as novel tissue-specific disease biomarkers.

The tissue- and primate-specificity of the new molecules are expected to have important implications for the communitys attempts to understand the causes of diseases. A first step in that direction requires the identification and validation of the targets for each of these 3,707 new miRNAs. To assist in these efforts, the team generated computational predictions of each miRNAs putative targets that are available from the Computational Medicine Centers website.

Read this article:
Study Nearly Triples the Locations in the Human Genome That Harbor MicroRNAs

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