Daily Archives: March 27, 2014

A group of scientists from Children's Hospital Oakland Research Institute and UC Berkeley report the first mapping of genome methylation in the fruit-fly Drosophila melanogaster in their paper "Genome methylation in D. melanogaster is found at specific short motifs and is independent of DNMT2 activity," published this month in Genome Research.

This paper represents a major advance in the study of DNA methylation in insects. No previous study has succeeded in pinpointing the location of DNA methylation in the fly genome. The common opinion in the field was that the fly does not have genomic methylation. But Drs. Sachiko Takayama and Joseph Dhahbi, co-first authors who carried out the key work, and Drs. David Martin and Dario Boffelli, who led the project, found otherwise. The authors were able to detect genomic methylation in the fly by solving the main technical hurdle: fly methylation is relatively rare, and they developed a sensitive method that allowed them to detect it.

Why is this finding important? Methylation is a stable chemical modification of the genome; in humans and other vertebrates it participates in controlling when and where genes are on and off, but its functions in other organisms are not understood. The finding suggests that genome methylation may have a hitherto uncharacterized function. While the authors still do not know what genome methylation does in the fly, they were able to find that the DNA sequence patterns that associate with methylation are very different from the patterns seen in humans, or in other animal or plant species to date.

Drosophila is one of the classic model organisms, with very well established tools to study its biology. The researchers' description of methylation in the fly will facilitate the use of this powerful experimental system to study methylation. Drosophila has only one known enzyme that could establish DNA methylation, and the researchers show that this enzyme is not responsible for the methylation patterns they detected. The fly genome has been studied very deeply, but the finding suggests that a new enzyme lies undiscovered within it.

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The above story is based on materials provided by Children's Hospital & Research Center Oakland. Note: Materials may be edited for content and length.

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First genome methylation mapping in fruit fly

A large international team of scientists has built the clearest picture yet of how human genes are regulated in the vast array of cell types in the body - work that should help researchers target genes linked to disease.

In two major studies published in the journal Nature, the consortium mapped how a network of switches, built into human DNA, controls where and when genes are turned on and off.

The three-year long project, called FANTOM5 and led by the RIKEN Center for Life Science Technologies in Japan, involved more than 250 scientists across 20 countries and regions.

"Humans are complex multicellular organisms composed of at least 400 distinct cell types. This beautiful diversity of cell types allow us to see, think, hear, move and fight infection - yet all of this is encoded in the same genome," said Alistair Forrest, scientific coordinator of FANTOM5.

He explained that the difference between cell types comes down to which parts of the genome they use - for instance, brain cells use different genes than liver cells, and therefore work very differently.

"In FANTOM5, we have for the first time systematically investigated exactly what genes are used in virtually all cell types across the human body, and the regions which determine where the genes are read from the genome," he said.

The team studied the largest ever set of cell types and tissues from humans and mice so that they could identify the location of switches within the genome that turn individual genes on or off.

They also mapped where and when the switches are active in different cell types and how they interact with each other.

David Hume, director of the Roslin Institute at Britain's Edinburgh University and one of the lead researchers on the project, used the analogy of an airplane:

"We have made a leap in understanding the function of all of the parts. And we have gone well beyond that - to understanding how they are connected and control the structures that enable flight," he said.

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Scientists publish 'navigation maps' for human genome

Should whole-genome sequencing be used in the public-health programs that screen newborns for rare conditions?

That question is likely to stir debate in coming years in many of the more-than-60 countries that provide newborn screening, as whole-genome sequencing (WGS) becomes increasingly affordable and reliable. Newborn screening programs -- which involve drawing a few drops of blood from a newborn's heel -- have been in place since the late 1960s, and are credited with having saved thousands of lives by identifying certain genetic, endocrine or metabolic disorders that can be treated effectively when caught early enough. Advocates of routine WGS for newborns argue that the new technology could help detect and manage a wider array of disorders.

But the possibility of making whole-genome sequencing part of routine screening programs for newborns raises ethical, legal and social issues that should be weighed carefully, according to researchers at McGill University's Department of Human Genetics in Montreal.

In an article published March 26 in the journal Science Translational Medicine, Prof. Bartha M. Knoppers and colleagues lay out key questions and considerations to be addressed. "Any change in newborn screening programs should be guided by what's in the best interests of the child," says Prof. Knoppers, who is Director of the Centre of Genomics and Policy at McGill. "We must also tread carefully in interpreting the scientific validity and clinical usefulness of WGS results."

The researchers outline the following considerations:

What information to report? Using WGS in newborn screening could generate vast amounts of information -- including incidental findings such as paternity information or reproductive risks. What's more, health-related information can include non-validated or poorly predictive results, or may involve adult-onset conditions. One possible solution: perform WGS but have a list of pediatric conditions to be communicated to parents; other results could be retrieved for later disclosure, when they gain scientific validity and clinical usefulness, or when they can be reported to the "mature" child directly.

Impact on health care systems. If WGS in newborn screening is implemented, public health care systems would have to be revamped to handle the massive amount of information generated. The added information could also lead to more false-positive results, imposing a big burden on families and on the resources of a health-care system.

Mandatory vs. voluntary. Most newborn screening programs currently are mandated by law or use presumed parental consent. Should parental consent be required for screening that doesn't stand to directly benefit the infant during childhood?

Educating health professionals and parents. Many doctors have little training in genetics, so health professionals and parents will need more education in genetics and genomics.

Communicating results over time. The validity of tests and the communication and understanding of results over time pose numerous challenges for doctors and families.

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Should whole-genome sequencing become part of newborn screening?

PUBLIC RELEASE DATE:

27-Mar-2014

Contact: Melinda Krigel mkrigel@mail.cho.org 510-428-3069 Children's Hospital & Research Center Oakland

March 27, 2013, Oakland, CA A group of scientists from Children's Hospital Oakland Research Institute and UC Berkeley report the first mapping of genome methylation in the fruit-fly Drosophila melanogaster in their paper "Genome methylation in D. melanogaster is found at specific short motifs and is independent of DNMT2 activity," published this month in Genome Research.

This paper represents a major advance in the study of DNA methylation in insects. No previous study has succeeded in pinpointing the location of DNA methylation in the fly genome. The common opinion in the field was that the fly does not have genomic methylation. But Drs. Sachiko Takayama and Joseph Dhahbi, co-first authors who carried out the key work, and Drs. David Martin and Dario Boffelli, who led the project, found otherwise. The authors were able to detect genomic methylation in the fly by solving the main technical hurdle: fly methylation is relatively rare, and they developed a sensitive method that allowed them to detect it.

Why is this finding important? Methylation is a stable chemical modification of the genome; in humans and other vertebrates it participates in controlling when and where genes are on and off, but its functions in other organisms are not understood. The finding suggests that genome methylation may have a hitherto uncharacterized function. While the authors still do not know what genome methylation does in the fly, they were able to find that the DNA sequence patterns that associate with methylation are very different from the patterns seen in humans, or in other animal or plant species to date.

Drosophila is one of the classic model organisms, with very well established tools to study its biology. The researchers' description of methylation in the fly will facilitate the use of this powerful experimental system to study methylation. Drosophila has only one known enzyme that could establish DNA methylation, and the researchers show that this enzyme is not responsible for the methylation patterns they detected. The fly genome has been studied very deeply, but the finding suggests that a new enzyme lies undiscovered within it.

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The research team also included additional researchers from CHORI and UC Berkeley. For a link to the paper and its authors, please click here.

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Research from CHORI scientists demonstrates first genome methylation in fruit fly

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Newswise March 27, 2013, Oakland, CA A group of scientists from Childrens Hospital Oakland Research Institute and UC Berkeley report the first mapping of genome methylation in the fruit-fly Drosophila melanogaster in their paper Genome methylation in D. melanogaster is found at specific short motifs and is independent of DNMT2 activity, published this month in Genome Research.

This paper represents a major advance in the study of DNA methylation in insects. No previous study has succeeded in pinpointing the location of DNA methylation in the fly genome. The common opinion in the field was that the fly does not have genomic methylation. But Drs. Sachiko Takayama and Joseph Dhahbi, co-first authors who carried out the key work, and Drs. David Martin and Dario Boffelli, who led the project, found otherwise. The authors were able to detect genomic methylation in the fly by solving the main technical hurdle: fly methylation is relatively rare, and they developed a sensitive method that allowed them to detect it.

Why is this finding important? Methylation is a stable chemical modification of the genome; in humans and other vertebrates it participates in controlling when and where genes are on and off, but its functions in other organisms are not understood. The finding suggests that genome methylation may have a hitherto uncharacterized function. While the authors still do not know what genome methylation does in the fly, they were able to find that the DNA sequence patterns that associate with methylation are very different from the patterns seen in humans, or in other animal or plant species to date.

Drosophila is one of the classic model organisms, with very well established tools to study its biology. The researchers description of methylation in the fly will facilitate the use of this powerful experimental system to study methylation. Drosophila has only one known enzyme that could establish DNA methylation, and the researchers show that this enzyme is not responsible for the methylation patterns they detected. The fly genome has been studied very deeply, but the finding suggests that a new enzyme lies undiscovered within it.

The research team also included additional researchers from CHORI and UC Berkeley. For a link to the paper and its authors, please click here.

About Childrens Hospital & Research Center Oakland Childrens Hospital & Research Center Oakland is a premier, not-for-profit medical center for children in Northern California, and is the only hospital in the East Bay 100% devoted to pediatrics. Childrens Oakland affiliated with UCSF Benioff Childrens Hospital on January 1, 2014. Childrens Oakland is a national leader in many pediatric specialties including hematology/oncology, neonatology, cardiology, orthopaedics, sports medicine, and neurosurgery. The hospital is one of only two solely designated California Level 1 pediatric trauma centers in the region, and has one of largest pediatric intensive care units in Northern California. Childrens Oakland has 190 licensed beds, over 500 physicians in 43 specialties, more than 2,600 employees, and a consolidated annual operating budget of more than $500 million. Childrens is also a leading teaching hospital with an outstanding pediatric residency program and a number of unique pediatric subspecialty fellowship programs.

Childrens research arm, Childrens Hospital Oakland Research Institute (CHORI), is internationally known for its basic and clinical research. CHORI is at the forefront of translating research into interventions for treating and preventing human diseases. CHORI has 250 members of its investigative staff, a budget of about $50 million, and is ranked among the nations top ten research centers for National Institutes of Health funding to childrens hospitals. For more information, go to http://www.childrenshospitaloakland.org and http://www.chori.org.

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Research Demonstrates First Genome Methylation in Fruit Fly

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Whole genome sequencing is becoming more popular in medical research. With its falling cost and increasing reliability, some scientists hail the process as being the future of genetic research. But should whole genome sequencing be used as a part of newborn screening programs? This is a question that researchers from McGill University in Canada say should be addressed.

The human genome is made up of over 3 billion genetic letters - A, C, G, and T. These are known as DNA nucleotides and represent pieces of DNA called adenine, cytosine, guanine and thymine. Whole genome sequencing (WGS) involves using advanced technology to determine the order of these nucleotides within the genome.

As well as enabling quicker and simpler gene discovery, scientists say that WGS may reveal previously unknown genes that contribute to diseases and that the process could lead to personalized treatment methods. Furthermore, WGS could lead to identification of lifestyle and environmental factors that affect genetic predisposition.

As a result of these potential benefits, some scientists say WGS should be offered as part of newborn screening programs.

At present, more than 60 countries have newborn screening programs. These include a blood spot test, which involves taking a few drops of blood from a newborn's heel and testing the blood for genetic, endocrine and metabolic disorders, including sickle cell disease and cystic fibrosis.

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Newborn screening: should whole genome sequencing be introduced?

The synthetic chromosome, with the site of every single change marked. Areas denoted in tan were deleted entirely.

Illustration by Lucy Reading-Ikkanda

A few years ago, researchers managed a technical tour-de-force: starting with short DNA sequences that were chemically synthesized in a machine, they built up an artificial bacterial genome and used it to replace the normal copy in living bacteria. But their artificial genome had only minor differences from the original, mostly tags that allowed its presence to be detected.

Today, a large international team of researchers took a major step beyond that. Like the team that worked in bacteria, they started with nothing but short, chemically synthesized pieces of DNA. Using those, they built up an entire chromosome in yeast, eventually replacing the yeast's normal copy. Although this involved less DNA than the bacterial genome, the team made radical changes to the DNA normally found in yeast, deleting most of the sequences that might be considered non-essential. Despite the elimination of 15 percent of the chromosome, the synthetic version worked fine, and the resulting yeast were difficult to distinguish from their normal peers.

In many ways, baker's yeast is a bit like a eukaryotic version of bacteria. Although it's got a collection of linear chromosomes in its nucleus (bacteria lack a nucleus and have a single, circular chromosome), the genome is very compact, with little in the way of the superfluous sequences that seem to make up the majority of the vertebrate genomes. It also has some of the features that make genetics so convenient in bacteria: it can carry extra genes in short, circular pieces of DNA called plasmids, and it's easy to shuffle DNA from these plasmids into the yeast's chromosomes.

No, not Electro Bolt. But human genetic augmentation is a lot closer than you think.

All of those conveniences were called upon to build up the synthetic chromosome. Short pieces of DNA made by chemical synthesis were combined into short pieces called "building blocks," which were 750 base pairs long. Each of these were stuffed into a bacterial plasmid. This work was considered so routine that the researchers relied on undergrads who enrolled in a class called "Build-a-Genome."

These building blocks were then dumped into a yeast cell with a partial yeast plasmid. Partial overlaps among the sequences ensured that the only way a viable yeast plasmid could emerge was if the yeast DNA repair system recombined them all, creating a 2,000- to 4,000-base-long fragment of chromosome called a "minichunk," inserted inside the yeast plasmid. These minichunks were then recombined into the normal chromosome, replacing the yeast's normal sequence. As more and more minichunks were added, the chromosome's normal sequence was gradually replaced by the artificial one.

The researchers targeted yeast chromosome III, which is normally 316,617 bases long. But they engineered their replacement to be significantly different. Some of the chromosome is composed of repetitive DNA and transposons that serve no known function; the researchers deleted that. They also got rid of introns, pieces of DNA that interrupt the normal coding sequence of genes but are spliced out of the mature RNA used to make proteins. Also on the chopping block: extra copies of genes that are found on other chromosomes (primarily tRNA genes). Backup copies of the genes that determine the yeast's mating type (yes, yeast have the equivalent of sexes) were also removed. In essence, the researchers created a junk-free chromosome.

When all was said and done, the chromosome had shrunk to 272,871 bases long, a drop of about 15 percent. (Amazingly, only 10 minor errors were introduced during this entire process. Good going undergrads!) Yeast carrying the synthetic chromosome were mostly indistinguishable from those with the normal one, with the primary exception being slower growth when a specific chemical was present.

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Researchers replace one of yeasts chromosomes with a synthetic one