Category Archives: Genome

Scientists who sequenced the entire genomes of 2,636 people in Iceland have produced a trove of information about the nature, location, and frequency of human genetic variations.

The new research not only sheds light on the range of human genetic variability; it helps equip researchers to draw more direct lines between genes and diseases.

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FOR THE RECORD

A previous version of this story said the director of the Genetic Variation Program at the National Human Genome Research Institute was Linda D. Brooks. She is Lisa D. Brooks.

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In a package of articles published Wednesday in the journal Nature Genetics, a private consortium of researchers found genetic abnormalities long thought to doom their host to early death to be more common than has been believed. They also discovered new genetic contributors to such varied afflictions as Alzheimer's disease, liver disease and atrial fibrillation.

The effort, underwritten by Amgen's DeCode Genetics, a biopharmaceutical company based in Reykjavik, Iceland, offers scientists insight to the human genome that will expand their ability to investigate the genetic bases of human diseases.

By sequencing the full genomes of more than 2,500 Icelanders and comparing the results with less extensive genotype data from more than 104,000 other Icelanders, the teams identified more than 20 million genetic variants in the Icelandic population.

They then cross-checked that information against Iceland's extensive genealogical and healthcare information records, which would document diagnoses, chronicle treatment response and allow researchers to see how a single disease might run through generations of a given family.

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Icelandic genome offers clues to human diversity, gene-disease links

Large genome databases are starting to reveal critical health informationeven about people who have not contributed their DNA.

Maps show how common certain risk-causing DNA mutations are around Iceland.

The CEO of an Icelandic gene-hunting company says he is able to identify everyone from that country who has a deadly cancer risk, but has been unable to warn people of the danger because of ethics rules governing DNA research.

The company, DeCode Genetics, based in Reykjavk, says it has collected full DNA sequences on 10,000 individuals. And because people on the island are closely related, DeCode says it can now also extrapolate to accurately guess the DNA makeup of nearly all other 320,000 citizens of that country, including those who never participated in its studies.

Thats raising complex medical and ethical issues about whether DeCode, which is owned by the U.S. biotechnology company Amgen, will be able to inform members of the public if they are at risk for fatal diseases.

Kri Stefnsson, the doctor who is founder and CEO of DeCode, says he is worried about mutations in a gene called BRCA2 that convey a sharply increased risk of breast and ovarian cancers. DeCodes data can now identify about 2,000 people with the gene mutation across Icelands population, and Stefnsson saidthat the company has been in negotiations with health authorities about whether to alert them.

We could save these people from dying prematurely, but we are not, because we as a society havent agreed on that, says Stefnsson. I personally think that not saving people with these mutations is a crime. This is an enormous risk to a large number of people.

The Icelandic Ministry of Welfare said a special committee had been formed to regulate such incidental findings and would propose regulations by the end of the year.

Kri Stefnsson

The technique used by DeCode to predict peoples genes offers clues to the future of so-called precision medicine in other countries, including the U.S., where this year President Barack Obama called for researchers to assemble a giant database of one million people (see U.S to Develop DNA Study of One Million People). A large enough U.S. database could also be used to infer genes of people whether or not they had joined it, says Stefnsson, and could raise similar questions about whether and how to report health hazards to the public.

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Genome Study Predicts DNA of the Whole of Iceland

Photo: Chris Lund The blood of a thousand Icelanders.

When the first Viking explorers began settling Iceland, none could have imagined that theirdescendants would pioneer thefuture of modern medicine by surveying the human genome. Fast forward 1000 years to today, whenanIcelandic company has revealedits success insequencing the largest-ever set of human genomes from a single population. The new wealth of genetic data has already begunchanging our understanding of human evolutionary history. It also sets the stage for a new era of preventive medicinebased on individual genetic risks fordiseases such as cancer and Alzheimers disease.

Themilestone in genome sequencing comesfromdeCODE Genetics, a biopharmaceutical company inReykjavk, Iceland. Theirwork, published as four papers in the 25 March 2015 issue of the journalNature Genetics,has yielded new insights aboutthecommon human ancestor for the male Y chromosomenarrowed tosomewhere between 174,000 and 321,000 years agobased on their latest calculation of human mutation rates. Another part of their work discovered thatabout 7.7 percent of the modern-day population has rare knockout genesgenes that have beendisabled by mutations. Early research has also revealed a mutation in theABCA7gene,whichdoubles the risk of Alzheimers disease in Iceland and other populations dominated by European ancestry.

These are just a handful of observations that have come out of the ability to look at the sequence of the genome of an entire nation,saidKari Stefansson, founder of deCODE Genetics, during a press briefing onMonday, 23 March.What is more, we are now sitting in Iceland with the possibility of taking advantage of these insights when it comes to the Icelandic healthcare system.

The company sequenced thewhole genomes of 2636 Icelanders and used those genomes as the basis for calculatingthe genetic variances for the entire Icelandic population.Iceland represents a unique laboratory for genetics researchers because much of the modern population traces its lineage to a relatively small number of founders; a fact that makes it easier to trace genealogies and pedigrees.

Myles Axton, chief editor ofNature Genetics, introduced the Monday press briefingbydescribing how the genetic sequencing strategy in Iceland could also work for other countries:

This strategy of sequencing the DNA of about 1 in 100 of the population, a total of 2,636 Icelanders, and then using shared sets of common genetic variance to predict the full spectrum of genetic variance carried by the whole population, is a great model for the future of human genetics. This technique can be applied to any population and is all the more accurate when there are pedigrees available for much of the population.

Genome sequencing has alloweddeCODE Genetics to begin data-mining information about how certain genes function and their relationship to a broad array of diseases. Past findings from such research included additional insights about gene variants associated with Alzheimers disease and schizophrenia.

The growing database on knockout genes may prove particularly helpful when matched against the phenotypes of individualsthe physical traits or characteristics that can be observed. Perhaps unsurprisingly, the researchers found that knockouts are least common among genes expressed in the brain, given that organs importance.

Basically what we hope to get out of phenotyping the carriers of these knockouts is to figure out which biochemical pathways are necessary for which physiological functions, Stefansson explained.Then the question is whetherthere is redundancy in some of these physiological functions;are there alternative biochemical pathways that can compensate for the loss of one?

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Iceland's Giant Genome Project Points to Future of Medicine

Human Genome Editing Banned By Scientists Over Safety Concerns
A prominent group of scientists has called for a global moratorium on the use of a controversial new genome-editing system. In a paper published in Science magazine, the group argues that changing...

By: TheLipTV

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Human Genome Editing Banned By Scientists Over Safety Concerns - Video

CRISPR-Cas9 is a powerful new tool for editing the genome. For researchers around the world, the CRISPR-Cas9 technique is an exciting innovation because it is faster and cheaper than previous methods. Now, using a molecular trick, Dr. Van Trung Chu and Professor Klaus Rajewsky of the Max Delbrck Center for Molecular Medicine (MDC) Berlin-Buch and Dr. Ralf Khn, MDC and Berlin Institute of Health (BIH), have found a solution to considerably increase the efficiency of precise genetic modifications by up to eightfold (Nature Biotechnology: doi:10.1038/nbt.3198)**.

"What we used to do in years, we can now achieve in months," said gene researcher and immunologist Klaus Rajewsky, indicating the power of this new genome-editing technology. CRISPR-Cas9 not only speeds up research considerably - at the same time it is much more efficient, cheaper and also easier to handle than the methods used so far.

The CRISPR-Cas9 technology allows researchers to transiently introduce DNA double-strand breaks into the genome of cells or model organisms at genes of choice. In these artificially produced strand breaks, they can insert or cut out genes and change the genetic coding according to their needs.

Mammalian cells are able to repair DNA damage in their cells using two different repair mechanisms. The homology-directed repair (HDR) pathway enables the insertion of preplanned genetic modifications using engineered DNA molecules that share identical sequence regions with the targeted gene and which are recognized as a repair template. Thus, HDR repair is very precise but occurs only at low frequency in mammalian cells.

The other repair system, called non-homologous end-joining (NHEJ) is more efficient in nature but less precise, since it readily reconnects free DNA ends without repair template, thereby frequently deleting short sequences from the genome. Therefore, NHEJ repair can only be used to create short genomic deletions, but does not support precise gene modification or the insertion and replacement of gene segments.

Many researchers, including Van Trung Chu, Klaus Rajewsky and Ralf Khn, are seeking to promote the HDR repair pathway to make gene modification in the laboratory more precise in order to avoid editing errors and to increase efficiency. The MDC researchers succeeded in increasing the efficiency of the more precisely working HDR repair system by temporarily inhibiting the most dominant repair protein of NHEJ, the enzyme DNA Ligase IV. In their approach they used various inhibitors such as proteins and small molecules.

"But we also used a trick of nature and blocked Ligase IV with the proteins of adeno viruses. Thus we were able to increase the efficiency of the CRISPR-Cas9 technology up to eightfold," Ralf Khn explained. For example, they succeeded in inserting a gene into a predefined position in the genome (knock-in) in more than 60 per cent of all manipulated mouse cells. Khn has just recently joined the MDC and is head of the research group for "iPS cell based disease modeling". Before coming to the MDC, he was on the research staff of Helmholtz Zentrum Mnchen. "The expertise of Ralf Khn is very important for gene research at MDC and especially for my research group," Klaus Rajewsky said.

Concurrent with the publication of the article by the MDC researchers, Nature Biotechnology published another, related paper on CRISPR-Cas9 technology. It comes from the laboratory of Hidde Ploegh of the Whitehead Institute in Cambridge, MA, USA.

Somatic gene therapy with CRISPR-Cas9 is a goal

The new CRISPR-Cas9 technology, developed in 2012, is already used in the laboratory to correct genetic defects in mice. Researchers also plan to modify the genetic set up of induced pluripotent stem cells (iPS), which can be differentiated into specialized cell types or tissues. That is, researchers are able to use the new tool to introduce patient-derived mutations into the genome of iPS cells for studying the onset of human diseases. "Another future goal, however, is to use CRISPR-Cas9 for somatic gene therapy in humans with severe diseases," Klaus Rajewsky pointed out.

Continued here:
MDC researchers greatly increase precision of new genome editing tool

CRISPR-Cas9 is a powerful new tool for editing the genome. For researchers around the world, the CRISPR-Cas9 technique is an exciting innovation because it is faster and cheaper than previous methods. Now, using a molecular trick, Dr. Van Trung Chu and Professor Klaus Rajewsky of the Max Delbrck Center for Molecular Medicine (MDC) Berlin-Buch and Dr. Ralf Khn, MDC and Berlin Institute of Health (BIH), have found a solution to considerably increase the efficiency of precise genetic modifications by up to eightfold.

"What we used to do in years, we can now achieve in months," said gene researcher and immunologist Klaus Rajewsky, indicating the power of this new genome-editing technology. CRISPR-Cas9 not only speeds up research considerably - at the same time it is much more efficient, cheaper and also easier to handle than the methods used so far.

The CRISPR-Cas9 technology allows researchers to transiently introduce DNA double-strand breaks into the genome of cells or model organisms at genes of choice. In these artificially produced strand breaks, they can insert or cut out genes and change the genetic coding according to their needs.

Mammalian cells are able to repair DNA damage in their cells using two different repair mechanisms. The homology-directed repair (HDR) pathway enables the insertion of preplanned genetic modifications using engineered DNA molecules that share identical sequence regions with the targeted gene and which are recognized as a repair template. Thus, HDR repair is very precise but occurs only at low frequency in mammalian cells.

The other repair system, called non-homologous end-joining (NHEJ) is more efficient in nature but less precise, since it readily reconnects free DNA ends without repair template, thereby frequently deleting short sequences from the genome. Therefore, NHEJ repair can only be used to create short genomic deletions, but does not support precise gene modification or the insertion and replacement of gene segments.

Many researchers, including Van Trung Chu, Klaus Rajewsky and Ralf Khn, are seeking to promote the HDR repair pathway to make gene modification in the laboratory more precise in order to avoid editing errors and to increase efficiency. The MDC researchers succeeded in increasing the efficiency of the more precisely working HDR repair system by temporarily inhibiting the most dominant repair protein of NHEJ, the enzyme DNA Ligase IV. In their approach they used various inhibitors such as proteins and small molecules.

"But we also used a trick of nature and blocked Ligase IV with the proteins of adeno viruses. Thus we were able to increase the efficiency of the CRISPR-Cas9 technology up to eightfold," Ralf Khn explained. For example, they succeeded in inserting a gene into a predefined position in the genome (knock-in) in more than 60 per cent of all manipulated mouse cells. Khn has just recently joined the MDC and is head of the research group for "iPS cell based disease modeling." Before coming to the MDC, he was on the research staff of Helmholtz Zentrum Mnchen. "The expertise of Ralf Khn is very important for gene research at MDC and especially for my research group," Klaus Rajewsky said.

Concurrent with the publication of the article by the MDC researchers, Nature Biotechnology published another, related paper on CRISPR-Cas9 technology. It comes from the laboratory of Hidde Ploegh of the Whitehead Institute in Cambridge, MA, USA.

Somatic gene therapy with CRISPR-Cas9 is a goal

The new CRISPR-Cas9 technology, developed in 2012, is already used in the laboratory to correct genetic defects in mice. Researchers also plan to modify the genetic set up of induced pluripotent stem cells (iPS), which can be differentiated into specialized cell types or tissues. That is, researchers are able to use the new tool to introduce patient-derived mutations into the genome of iPS cells for studying the onset of human diseases. "Another future goal, however, is to use CRISPR-Cas9 for somatic gene therapy in humans with severe diseases," Klaus Rajewsky pointed out.

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Researchers greatly increase precision of new genome editing tool

REYKJAVIK, Iceland, March 25, 2015 /PRNewswire/ --

The largest studies of whole-genome data ever published reveal the power of the sequencing revolution for understanding the roots of disease, diversity and evolution:

deCODE genetics, a global leader in analyzing and understanding the human genome, today published four landmark papers built on whole-genome sequence data from more than 100,000 people from across Iceland. The studies, written by a team of deCODE scientists and which appear in the online edition of Nature Genetics, together present the most detailed portrait of a population yet assembled using the latest technology for reading DNA.

"This work is a demonstration of the unique power sequencing gives us for learning more about the history of our species and for contributing to new means of diagnosing, treating and preventing disease," said Kari Stefansson, founder and CEO of deCODE and lead author on the papers.

"It also shows how a small population such as ours, with the generous participation of the majority of its citizens, can advance science and medicine worldwide. In that sense this is very much more than a molecular national selfie. We're contributing to important tools for making more accurate diagnostics for rare diseases; finding new risk factors and potential drug targets for diseases like Alzheimer's; and even showing how the Y chromosome, a loner in the paired world of our genome, repairs itself as it passes from father to son. Other countries are now preparing to undertake their own large-scale sequencing projects, and I would tell them the rewards are great," Dr Stefansson concluded.

The papers and their highlights:

"Large-scale whole-genome sequencing of the Icelandic population" demonstrates how deCODE is able to use comprehensive national genealogies to accurately impute even increasingly rare sequence data throughout the population, yielding new discoveries and key data for improving diagnostics.

"Identification of a large set of rare complete human knockouts." For decades, genes have been knocked out or switched off in mice, as a model system for studying what genes do and how they might affect human health. But what if we could find people in whom genes had been switched off due to rare mutations? The scale and detail of deCODE's data was used to identify more than a thousand knocked out genes, with nearly 8% of the 104,000 people studied having at least one gene knocked out in this way. The examination of health and other traits in these individuals should provide a unique way to study directly the effect of specific genes on human biology and potentially contribute to the development of new drugs and diagnostics.

"The Y-chromosome point mutation rate in humans" uses more than 50,000 years of male lineage to provide a much more detailed and accurate estimate of the mutation rate in the male sex chromosome. This rate can be used as a kind of evolutionary clock for dating events in the history and evolution of our species and its civilizations. It places the most recent common ancestor of all Y chromosomes in the world today as living some 239,000 years ago - nearly 100,000 years more recent than other estimates and much closer to that of the most recent common ancestor for all mitochondrial DNA, which is passed from mothers to offspring.

"Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease" presents a rare but powerful new risk factor that is also replicated in several European countries and the US.

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The Genomic Portrait of a Nation

Genome Function circa 2016: Updates from Related Projects - Daniel Gilchrist (Moderator)
March 10-11, 2015 - From Genome Function to Biomedical Insight: ENCODE and Beyond More: http://www.genome.gov/27560819.

By: GenomeTV

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Genome Function circa 2016: Updates from Related Projects - Daniel Gilchrist (Moderator) - Video

The Cancer Genome Atlas - Dr Seth P. Lerner, Baylor College of Medicine
EAU TV hear all the latest from Baylor #39;s Dr. Lerner about the Cancer Genome Atlas project, mapping the many cancer genomes, and making leaps and bounds in our understanding of the many forms...

By: WebsEdgeHealth

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The Cancer Genome Atlas - Dr Seth P. Lerner, Baylor College of Medicine - Video

A group of leading biologists hascalled for a worldwide moratorium on the use of a new genome-editing technique that would alter human DNA in a way that can be inherited.

The biologists fear that the new technique is so effective and easy to use that some physicians may push ahead with it before its safety can be assessed. They also want the public to understand the ethical issues surrounding the technique, which could be used to cure genetic diseases, but also to enhance qualities like beauty or intelligence. The latter is a path that many ethicists believe should never be taken.

"You could exert control over human heredity with this technique, and that is why we are raising the issue," said David Baltimore, a former president of the California Institute of Technology and a member of the group whose paper on the topic was published in the journal Science on Thursday.

Ethicists have been concerned for decades about the dangers of altering the human germline, which involves changes to human sperm, eggs or embryos that will last through the life of the individual and be passed on to future generations.

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Until now, these worries have been theoretical, but a technique invented in 2012 makes it possible to edit the genome precisely and with much greater ease. The technique has already been used to edit the genomes of mice, rats and monkeys, and few doubt that it would work the same way in people.

The technique holds the power to repair or enhance any human gene. "It raises the most fundamental of issues about how we are going to view our humanity in the future and whether we are going to take the dramatic step of modifying our own germline and in a sense take control of our genetic destiny, which raises enormous peril for humanity," said George Daley, a stem cell expert at Boston Children's Hospital and a member of the group.

The biologists writing in Science support continuing laboratory research with the technique, and few if any scientists believe it is ready for clinical use. Any such use is tightly regulated in the United States and Europe. American scientists, for instance, would have to present a plan to treat genetic diseases in the human germline to the Food and Drug Administration.

However, the paper's authorsare concerned about countries that have less regulation in science. They urge scientists to"avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans" until the full implications "are discussed among scientific and governmental organisations".

Though such a moratorium would not be legally enforceable and might seem unlikely to exert global influence, there is a precedent. In 1975, scientists worldwide were asked to refrain from using a method for manipulating genes, the recombinant DNA technique, until rules had been established.

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Biologists seek moratorium on method of editing the human genome