mercredi 30 juin 2010

SNPedia, a wiki dedicated to human SNPs

- SNPediais a wiki investigating human genetics. SNPedia shares information about the effects of variations in DNA, citing peer-reviewed scientific publications. It is used by Promethease to analyze and help explain your DNA.

Genome-wide association mapping and rare alleles: from 
population genomics to personalized medicine. Session at PSB 2011

PSB 2011 - Full paper submission deadline: July 12 2010 (let the co-chair know if you need a few days extension)

Genome-wide associations studies (GWAS) have been very 
successful in identifying common genetic variation associated to 
numerous complex diseases.

However, most of the identified 
common genetic variants appear to confer modest risk and few 
causal alleles have been identified. Furthermore, these 
associations account for a small portion of the total 
heritability of inherited disease variation.

This has led to the 
reexamination of the contribution of environment, gene-gene and 
gene-environment interactions, and rare genetic variants in 
complex diseases.

There is strong evidence that rare variants 
play an important role in complex disease etiology and may have 
larger genetic effects than common variants.

Currently, much of 
what we know regarding the contribution of rare genetic variants 
to disease risk is based on a limited number of phenotypes and 
candidate genes.

However, rapid advancement of second 
generation sequencing technologies will invariably lead to 
widespread association studies comparing whole exome and 
eventually whole genome sequencing of cases and controls.

tremendous challenge for enabling these "next generation" 
medical genomic studies is developing statistical approaches for 
correlating rare genetic variants with disease outcome. 

The analysis of rare variants is challenging since methods used 
for common variants are woefully underpowered (e.g., accurately 
estimating allele frequencies in cases vs. controls requires ~10 
observations of the minor allele; however, many of the 
functional rare alleles may be present only once in the 
resequence data).

Therefore, methods that can deal with genetic 
heterogeneity at the trait-associated locus and that can be 
applied to both in cases vs. controls and quantitative trait 
studies are needed.

Currently, these approaches are in their 
infancy and very basic criteria (such as functional annotation, 
sequence conservation, or biological pathway classification) are 

There is tremendous opportunity to apply data mining 
methods outside of the standard statistical toolkit to this 

Additionally, deep sequencing will reveal many variants 
that are not causal, and in order to reduce the problems of 
misclassification, i.e. inclusion of non-causal variants and 
exclusion of causal variants in the analysis, it is beneficial 
to predict their potential functionality.

Thus, methods to 
classify and annotate rare variants for subsequent analysis are 

The session of PSB 2011 would focus on distilling current 
knowledge in assessing rare variant functionality and their 
correlation with complex traits, and more importantly bring 
forth methodological questions that need to be addressed for 
successful analysis of rare variants.

"GWAS by sequencing" 
presents many new challenges and proposed solutions for 
interpreting sequencing data from clinical case/control cohorts 
will be of particular interest to a diverse audience.

session will similarly consider application-specific algorithms, 
analysis methods, or study planning and design tools with 
emphasis in the leveraging rare genetic variation in complex 
trait/disease correlation. 

Deadline for full paper submission: July 12, 2010. Deadline for poster abstracts: November 1, 2010. 


The Pacific Symposium on Biocomputing (PSB 2011) is an 
international, multidisciplinary conference for the presentation 
and discussion of current research in the theory and application 
of computational methods in problems of biological significance. 

PSB 2011 will be held at the Big Island of 
Hawaii on January 4-7, 2011. 

For more information see the official PSB 2011 Web page:

See also

- How to read a genome-wide association study, genomes unzipped, July 18th 2010

jeudi 24 juin 2010

Personalized Therapy at AACR

- Clinical Applications of Genomics and Biomarker Cancer Research

Ari M. VanderWalde, MD, MPH

The paradigm in cancer care is shifting toward individualized therapy. This was the message reiterated by speaker after speaker at the 101st Annual Meeting of the American Association for Cancer Research (AACR), held in Washington DC, April 17-21, 2010.

As Levi Garraway of the Dana-Farber Cancer Institute in Boston, Massachusetts, explained at Monday's plenary session, the hope is that any patient with cancer would have their tumor biopsied and profiled. The profile would then be displayed as a unique genetic signature, which would in turn predict which therapy is most likely to work.

Personalized Therapy

An early example of this approach was described by Edward Kim[2] from the MD Anderson Cancer Center in Houston during Sunday's plenary session when he presented the first results from the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trial in lung cancer.

In this trial, real-time biopsies were performed and an adaptive approach toward enrollment was used that, for the first time, attempted to predict which molecular markers in individual cancers would respond to which agents.

The BATTLE study identified 4 molecular markers: epidermal growth factor receptor (EGFR), Ras-Raf, RXR/cyclin D1, and vascular endothelial growth factor (VEGF). Patients were then randomly assigned to receive to erlotinib (an EGFR inhibitor), sorafenib (a VEGF inhibitor), vandetanib, or a combination of erlotinib and bexarotene.

The investigators found that 8-week disease control as determined by biopsy before and after this period was a good predictor of overall survival. Specifically, patients who had 8-week disease control had overall survival of 11.3 months vs only 7.3 months in those who did not have 8-week disease control.

Total disease response across all groups was 46%. However, response to sorafenib was very good in all non-EGFR groups; response was especially robust in the KRAS mutation group (79% disease control). Erlotinib yielded the best outcomes in the EGFR mutant group, but response to this agent was poor in the other groups.

Developing and Implementing Predictive Therapeutic Markers for Cancer

During Sunday's plenary session, Martine Piccart-Gebhart, founder and chair of the Breast International Group (BIG), presented the structure of the Neo-BIG program, which is being developed by BIG to accelerate drug development and biomarker discovery in early breast cancer.

The plan is to develop several concurrent clinical trials in the neoadjuvant setting that will evaluate genomics to determine predictive models of efficacy that can later be validated in the adjuvant setting.

Dr. Piccart-Gebhart explained that attempts to bring various tumor markers into the clinical setting have been unsuccessful owing to subjectivity of interpretation of histology or gene expression, as well as lack of specificity of the marker in predicting outcome or response to treatment. However, she noted that "genomic grade" seems to be a promising tool.

She explained that "early readout" of proliferation or signaling in the genetic signature of the tumor may predict response of the tumor to various agents, particularly in luminal-B cancers, a more aggressive genetic group of breast cancer. These data will be incorporated into the next Neo-BIG trial.

Elucidating the Cancer Genome

Monday's plenary session focused on how to make current research elucidating the cancer genome into something meaningful for clinical practice. Most speakers commented that cancer research is in the midst of a paradigm shift. They stated that the field of oncology is moving away from an anatomy- and histology-based view of cancer toward a genomic view the disease.

Bert Vogelstein of The Johns Hopkins University in Baltimore, Maryland, described the astounding progress scientists have made in identifying cancer-specific mutations since the announcement of the completion of the human genome project in 2003.

Dr. Vogelstein's laboratory studied the genomes of 68 tumors and found that genomic alterations in tumor cells occur at different rates and amounts in different tumors, with mutations accumulating as the tumor ages.

Most mutations are "passengers," meaning that they do not fundamentally determine the behavior of the tumor. However, using genetic mapping techniques, the researchers found that about 15% of a tumor is composed of "drivers": 2 or 3 oncogenes and tumor suppressor genes in each tumor, or about 320 "driver" genes across all human cancers combined, that have activity in 12 key cellular or nuclear pathways.

Using the cancer genome, Dr. Vogelstein identified 2 approaches toward development of targeted agents, which he dubbed the "mutant-gene" and "mutant-pathway" approaches. The benefit of the mutant-pathway approach is that 90% of drivers are tumor suppressor mutations that turn cellular genes off.

Because a therapeutic agent cannot turn a gene back on but can disrupt an overexpressed gene, and because resistance patterns are more likely if only 1 gene is targeted, he advocated using the mutant-pathway approach and suggested that it is likely to be more useful than targeting an individual gene.

He concluded with the inspiring assertion that we may now, for the first time, truly understand cancer. The hope is that what we do know can be used to help people.

The Human Genome and Cancer Risk

Rather than describing genomics of tumors themselves, Stephen Chanock[5] of the National Cancer Institute in Bethesda, Maryland, described progress in the identification of causal and contributory mutations in cancer genetic germ-line syndromes. This is the search for such syndromes as BRCA and Li-Fraumeni syndromes, wherein a mutation that affects every cell in the body predisposes for various types of cancer.

Whereas focus had previously been on looking for candidate genes, it is now shifting toward genome-wide association studies, which identify "soft spots" in the genome that seem to confer susceptibility.

For example, multiple cancers have been mapped to 2 distinct regions: 8q24 and 5p15.33. 8q24 is a 600-megabase region toward the middle of the chromosome from the MYC gene that harbors a series of independent markers associated with chronic lymphocytic leukemia and with breast, colorectal, prostate, and bladder cancer.

5p15.33 harbors the TERT-CLPTM1L locus and contains several variants associated with lung, brain, skin, and pancreatic cancers. Dr. Chanock noted that the success of genome-wide association studies has opened new horizons for exploration, and he expressed hope that common variants will be identified and applied in clinical and public health venues.


At the AACR Annual Meeting, cancer researchers expressed hope that the time to use genomics to create personalized cancer care is coming. The insights from their research and from their future planned studies confirmed this hope and left the audience optimistic and inspired.

mercredi 23 juin 2010

Genome project at Kaiser: From Californians’ DNA, a Giant Genome Project

From Californians’ DNA, a Giant Genome Project, By SABIN RUSSELL. New York Times, May 28, 2010.

Still in fine fettle at the age of 87, Ruth Young, a retired Oakland school nurse, jumped at the chance, she said, to “spit for the cause.”

Mrs. Young is one of more than 130,000 members of Kaiser Permanente in Northern California who have volunteered to have their DNA scanned by robotic, high-speed gene-reading machines as part of the largest human genome study of its kind ever attempted.

The goal of the study they are participating in is to help scientists uncover the genetic roots of chronic disease and, perhaps, to find out why some people live longer than others.

This month, researchers at Kaiser Permanente in Oakland and the University of California, San Francisco began the highly automated, large-scale process of analyzing that DNA, which is being extracted from tens of thousands of saliva samples donated by Kaiser members in Northern California since 2008.

Each sample of ordinary spit is laden with cells containing the volunteer’s entire set of genes, their genomes, which carry in sequences of DNA the coded instructions for building and maintaining life. The hope for this so-called genome-wide association study is that, when the genes of people with diseases like cancer and multiple sclerosis are compared with the genes of those in good health, computer analysis will pinpoint genes responsible for the illnesses.

With a speed that would have seemed preposterous to contemplate a decade ago, the work of collecting, purifying and digitizing billions of discrete bits of chemical information will be finished in less than 18 months, providing a rich resource for scientists to analyze for decades to come.

Winifred K. Rossi, who is managing the project for the National Institute on Aging, said most genome-wide association studies scan between 5,000 and 8,000 participants, although data from multiple, smaller studies can be pooled to form a larger group. What makes the Kaiser study unique is that members of a single, colossal cohort will have their genomes scanned uniformly, then paired with their medical histories. “It is absolutely the largest study of its kind, and it has enormous statistical power.” Ms. Rossi said.

Mrs. Young, a Kaiser member for 63 years, suffers from arthritic knees and Type II diabetes, which took her father’s life at an early age. “I’m conscientious about my diet, but I do love sweets,” she said.

She had originally been one of nearly two million patients asked in 2007 about participating in the Kaiser study. A huge group of volunteers, ranging in age from 18 to 107, filled out questionnaires. Tens of thousands of them, like Mrs. Young, were asked for specimens.

Following instructions found in a kit mailed to her Oakland home, Mrs. Young deposited the requested spit into a special plastic cup. She sealed it with a blue lid fitted with a built-in preservative and sent it back to Kaiser. Along with her saliva, the samples from the other 130,000 people began arriving in Kaiser’s mailbox.

Experiments like this one underscore how quickly gene-scanning technology is moving from the lab to the home. Last week, officials of the University of California, Berkeley, disclosed that 6,000 incoming freshman and transfer students will be asked to swab their cheeks at home for DNA, to participate in a collective lesson in genetics and a preview of the predicted era when medicine will be tailored to each person’s genetic makeup.

Each student who agrees to participate will be able to tap in a security code on a laptop and check whether they carry gene variants that might affect their ability to process lactose, alcohol or folate, a vitamin found in leafy greens. The Kaiser study participants will not have the same option. Their names are scrubbed from their samples, and only researchers — working with codes instead of names — will be able to link the gene scans to medical histories. Their goal is to discern the larger picture, hoping to spot associations between genes and health that would not show up until very large numbers of individuals are compared at once.

Although this vast experiment has been contemplated for years, it was given a boost last year when Kaiser and the university won a $25 million grant from the National Institutes of Health as part of the stimulus package.

However, the study has begun just as some scientists have started to question the value of these experiments, and when private ventures, like 23andMe, are struggling to find a consumer market for gene tests.

David B. Goldstein, a Duke University researcher, said he believed “interesting and valuable information” would come from the Kaiser study, but he questioned whether it was the most efficient way to gather information about the genetic links to disease. “It’s an awfully expensive study,” Dr. Goldstein said in an e-mail message.

He added, “We have literally hundreds of genome-wide association studies for common diseases, and in most cases we are having trouble making much use of them.” While Dr. Goldstein stresses that discoveries are being made using that technique, he believes that a different approach — sequencing the entire genetic code of fewer patients rather than scanning the genome for variations — “is likely to yield more useful returns.”

For Kaiser, the federal grant is just the beginning of a long-term endeavor.

In the coming years, 400,000 more members will be asked to contribute their DNA to the project when they come in for routine blood work. Kaiser is spending $9 million to build a repository for the blood samples.

“It’s an idea whose time has come,” said Dr. Pui-Yan Kwok, an investigator at the Institute for Human Genetics at the University of California, San Francisco, where the genes are being scanned. “The genotyping technology is here, the electronic medical records are here.”

Using high-precision robots to process each sample, the genomes of 2,500 participants are being analyzed each week. The genetic information will be stored in computers for future studies by scientists all over the globe.

At the same time, Elizabeth Blackburn, a Nobel-prize winning biologist at the university, and her lab will be conducting a mass experiment on a separate set of 100,000 samples of DNA from the Kaiser patients. They will be measuring the length of telomeres — wads of DNA at the top and bottom of every chromosome that, like shoelace tips, keep them from unraveling when a cell divides. Telomere length tends to shorten with age, and shorter telomeres tend to be linked with shorter life spans.

“Telomere length is more reflective of things that happen in your life than the genetic hand you are born with,” said Dr. Blackburn.

She said that the Kaiser patients are a valuable resource for science because their detailed medical histories can be matched with the varied measurements of telomere length and matched to the gene scans that will be done for each participant as well. Her targets are the three top diseases that kill the elderly: cancer, cardiovascular disease and diabetes.

At the Kaiser research lab, a production line of robotic equipment has been set up to process the 130,000 cups of saliva that have been mailed by patients and stored, at room temperature, in racks of cardboard “pizza boxes,” 50 cups to a box. Here, the robots draw out a sample of spit, and chemically process it to extract the donor’s DNA.

One set of Mrs. Young’s DNA will be sent to Dr. Blackburn’s lab, where the length of its telomeres will be measured. A second set will arrive at Dr. Kwok’s newly equipped facility, where the genome of each Kaiser participant will be scanned using an array of robots, each costing about a quarter million dollars.

At Dr. Kwok’s ninth-floor lab, three sets of robots prepare the DNA samples shipped from Oakland. The full complement of DNA from each volunteer is washed over a custom-designed silicon chip about this size of small fingernail. Microscopic wells etched into the chip are each engineered to pluck out one of 675,000 possible gene variants.

“Our biggest fear is a power-failure,” said Dr. Kwok. Each array, filled with 96 processed DNA samples, costs $10,000.

mardi 22 juin 2010

Biology 2.0

The Economist, June 17th 2010

A decade after the human-genome project, writes Geoffrey Carr (interviewed here), biological science is poised on the edge of something wonderful.

TEN years ago, on June 26th 2000, a race ended. The result was declared a dead heat and both runners won the prize of shaking the hand of America’s then president, Bill Clinton, at the White House. The runners were J. Craig Venter for the private sector and Francis Collins for the public. The race was to sequence the human genome, all 3 billion genetic letters of it, and thus—as headline writers put it—read the book of life.

It quite caught the public imagination at the time. There was the drama of a maverick upstart, in the form of Dr Venter and his newly created firm, Celera, taking on the medical establishment, in the form of Dr Collins’s International Human Genome Sequencing Consortium. There was the promise of a cornucopia of new drugs as genetic targets previously unknown to biologists succumbed to pharmacological investigation. There was talk of an era of “personalised medicine” in which treatments would be tailored to an individual’s genetic make-up. There was the frisson of fear that a genetic helotry would be created, doomed by its DNA to second-class health care, education and employment. And there was, in some quarters, a hope that a biotech boom based on genomics might pick up the baton that the internet boom had just dropped, and that lots and lots of money would be made.

And then it all went terribly quiet. The drugs did not appear. Nor did personalised medicine. Neither did the genetic underclass. And the money certainly did not materialise. Biotech firms proved to be just as good at consuming cash as dotcom start-ups, and with as little return. The casual observer, then, might be forgiven for thinking the whole thing a damp squib, and the $3 billion spent on the project to be so much wasted money. But the casual observer would be wrong. As The Economist observed at the time, the race Dr Venter and Dr Collins had been engaged in was a race not to the finish but to the starting line. Moreover, compared with the sprint they had been running in the closing years of the 1990s, the new race marked by that starting line was a marathon.

The new race has been dogged by difficulties from the beginning. There was a false start (the announcement at the White House that the sequence was complete relied on a generous definition of that word: a truly complete sequence was not published until 2003). The competitors then ran into numerous obstacles that nature had strewn on the course. They found at first that there were far fewer genes than they had expected, only to discover later that there were far more. These discoveries changed the meaning of the word “gene”. They found the way genes are switched on and off is at least as important, both biologically and medically, as the composition of those genes. They found that their methods for linking genetic variation to disease were inadequate. And they found, above all, that they did not have enough genomes to work on. Each human genome is different, and that matters.

All is revealed

One by one, however, these obstacles are falling away. As they do so, the science of biology is being transformed. It seems quite likely that future historians of science will divide biology into the pre- and post-genomic eras.

In one way, post-genomic biology—biology 2.0, if you like—has finally killed the idea of vitalism, the persistent belief that to explain how living things work, something more is needed than just an understanding of their physics and chemistry. True, no biologist has really believed in vitalism for more than a century. Nevertheless, the promise of genomics, that the parts list of a cell and, by extension, of a living organism, is finite and cataloguable, leaves no room for ghosts in the machine.

Viewed another way, though, biology 2.0 is actually neo-vitalistic. No one thinks that a computer is anything more than the sum of its continually changing physical states, yet those states can be abstracted into concepts and processed by a branch of learning that has come to be known as information science, independently of the shifting pattern of electrical charges inside the computer’s processor.

So it is with the new biology. The chemicals in a cell are the hardware. The information encoded in the DNA is the preloaded software. The interactions between the cellular chemicals are like the constantly changing states of processing and memory chips. Though understanding the genome has proved more complicated than expected, no discovery made so far suggests anything other than that all the information needed to make a cell is squirreled away in the DNA. Yet the whole is somehow greater than the sum of its parts.

Whether the new biology is viewed as rigorously mechanistic or neo-vitalistic, what has become apparent over the past decade is that the process by which the genome regulates itself, both directly by one gene telling another what to do and indirectly by manipulating the other molecules in a cell, is vastly more complicated and sophisticated than anybody expected. Yet it now looks tractable in a way that 20 years ago it did not. Just as a team of engineers, given a rival’s computer, could strip it down and understand it perfectly, so biologists now believe that, in the fullness of time, they will be able to understand perfectly how a cell works.

And if cells can be understood completely in this way, then ultimately it should be possible to understand assemblages of cells such as animals and plants with equal completeness. That is a much more complicated problem, but it is different only in degree, not kind. Moreover, understanding—complete or partial—brings the possibility of manipulation. The past few weeks have seen an announcement that may, in retrospect, turn out to have been as portentous as the sequencing of the human genome: Dr Venter’s construction of an organism with a completely synthetic genome. The ability to write new genomes in this way brings true biological engineering—as opposed to the tinkering that passes for biotechnology at the moment—a step closer.

A second portentous announcement, of the genome of mankind’s closest—albeit extinct—relative, Neanderthal man, shows the power of biology 2.0 in a different way. Putting together some 1.3 billion fragments of 40,000-year-old DNA, contaminated as they were with the fungi and bacteria of millennia of decay and the personal genetic imprints of the dozens of archaeologists who had handled the bones, demonstrates how far the technology of genomics has advanced over the course of the past decade. It also shows that biology 2.0 can solve the other great question besides how life works: how it has evolved and diversified over the course of time.

As is often the way with scientific discovery, technological breakthroughs of the sort that have given science the Neanderthal genome have been as important to the development of genomics as intellectual insights have been. The telescope revolutionised astronomy; the microscope, biology; and the spectroscope, chemistry. The genomic revolution depends on two technological changes. One, in computing power, is generic—though computer-makers are slavering at the amount of data that biology 2.0 will need to process, and the amount of kit that will be needed to do the processing. This torrent of data, however, is the result of the second technological change that is driving genomics, in the power of DNA sequencing.

The new law

Computing has, famously, increased in potency according to Moore’s law. This says that computers double in power roughly every two years—an increase of more than 30 times over the course of a decade, with concomitant reductions in cost.

There is, as yet, no sobriquet for its genomic equivalent, but there should be. Eric Lander, the head of the Broad Institute, in Cambridge, Massachusetts, which is America’s largest DNA-sequencing centre, calculates that the cost of DNA sequencing at the institute has fallen to a hundred-thousandth of what it was a decade ago (see chart 1). The genome sequenced by the International Human Genome Sequencing Consortium (actually a composite from several individuals) took 13 years and cost $3 billion. Now, using the latest sequencers from Illumina, of San Diego, California, a human genome can be read in eight days at a cost of about $10,000. Nor is that the end of the story. Another Californian firm, Pacific Biosciences, of Menlo Park, has a technology that can read genomes from single DNA molecules. It thinks that in three years’ time this will be able to map a human genome in 15 minutes for less than $1,000. And a rival technology being developed in Britain by Oxford Nanopore Technologies aspires to similar speeds and cost.

This increase in speed and reduction in cost is turning the business of biology upside down. Up until now, firms that claim to read individual genomes (see article) have been using a shortcut. They have employed arrays of DNA probes, known as gene chips, to look for pre-identified variations in their clients’ DNA. Those variations have been discovered by scientific collaborations such as the International HapMap Project, which search for mutations of the genetic code called single-nucleotide polymorphisms, or SNPs, in blocks of DNA called haplotypes. A SNP (pronounced “snip”) is a place where a lone genetic letter varies from person to person. Some 10m SNPs are now known, but in the forest of 3 billion genetic letters there is reason to believe they are but a smattering of the total variation. Proper sequencing will reveal the lot.

Finding the sequence—even the full range of sequences—is, though, just the beginning. You then have to do something useful with the result. This is where the computing comes in. Computers allow individual genomes—all 3 billion base pairs of them—to be compared. And not only human genomes. Cross-species comparisons are enormously valuable. Laboratory experiments on creatures ranging from yeast to mice can reveal the functions of genes in these species. Computer comparison then shows which human genes correspond in DNA sequence and thus, presumably, in function, to the genes in these “model” organisms.

Cross-species comparison also shows how species differ, and thus how they have diverged. Comparing DNA from populations within a species can show how that species is evolving. Comparing DNA from individuals within a population can explain why those individuals differ from one another. And comparing the DNA from cells within an individual can show how tissues develop and become differentiated from one another, and what goes wrong in diseases like cancer.

Even before cheap sequencing became available, huge databases were being built up. In alliance with pathology samples, doctors’ notes and—most valuable of all—long-term studies of particular groups of individuals, genetic information can be linked to what biologists refer to as the phenotype. This is an organism’s outward expression: its anatomy, physiology and behaviour, whether healthy or pathological. The goal of the new biology is to tie these things together reliably and to understand how the phenotype emerges from the genotype.

That will lead to better medical diagnosis and treatment. It will result in the ability to manipulate animals, plants, fungi and bacteria to human ends. It will explain the history of life. And it will reveal, in pitiless detail, exactly what it is to be human.

The next advances in genomics may happen in China

China: The dragon's DNA, The Economist, June 17th, 2010

IN AN old printing works on an obscure industrial estate in Hong Kong’s New Territories a little bit of history is being made. Most of the five-storey building is dusty and derelict. One floor, however, is state-of-the-art. The paintwork shines. The metal gleams. And in the largest room the electrical sockets in the floor sit in serried ranks awaiting contact.

That contact will shortly be made with the delivery of 120 spanking new top-of-the-range Illumina sequencing machines. When they have all been installed the building will, so it is claimed, have more DNA-sequencing capacity than the whole of the United States. And that is just the start. According to Alex Wong, who runs the facility, the other four floors will also soon be refurbished and the whole building will become a powerhouse ready to generate information for biology 2.0.

The building belongs to the BGI, once known as the Beijing Genomics Institute. Mr Wong manages the institute’s Hong Kong operation, but the institute itself is based over the border in the People’s Republic proper, in Shenzhen. The BGI itself is one part—arguably the leading one—of China’s effort to show that it can be the scientific peer of the West.

Its boss, Yang Huangming, is certainly the peer of people like Dr Venter, Dr Lander and Dr Collins. He is a man on a mission to make the BGI the first global genomics operation. Part of the reason for building his newest sequencing centre in Hong Kong is to reassure researchers from other countries that the facility will operate inside a reliable legal framework. If all goes well, laboratories in North America and Europe will follow.

The BGI began in 1999, when Dr Yang muscled his way into the human-genome project, cornering part of the tip of chromosome three (about 1% of the total human genome) as the Chinese contribution to that international project. From this humble beginning it now plans to sequence 200 full human genomes as part of an international collaboration called the 1,000-genome project. Half these genomes will be Chinese, but the institute’s researchers intend to sample the full geographical range of humanity. And not only human genomes. The BGI has already solved the genomes of rice, cucumbers, soyabeans and sorghum, honeybees, water fleas, pandas, lizards and silkworms, and some 40 other species of plant and animal, along with over 1,000 bacteria.

And it, too, is interested in cancer. According to Dr Yang the institute will not merely compare healthy and tumorous tissue from the same individuals, as the International Cancer Genome Consortium (of which it is a part) plans to do, it will actually be able to follow the pattern of mutation, in the order that it happened, within an individual that has led to his cancer. That may allow pre-emptive treatment to be developed for people whose tumours are not yet malignant. Indeed, as the price of sequencing drops, this “internal phylogenetics”, as Dr Yang calls it, might be extended to trace the pattern of mutation that develops in even an apparently healthy body as cells proliferate within it. That may yield nothing interesting. On the other hand it might help explain patterns of disease associated with ageing as cells whose ancestors were genetically identical slowly diverge from one another.

A better balsa

The BGI also has non-medical ambitions. Its researchers are examining fast-growing plants with interesting structural properties, such as balsa, a lightweight South American wood familiar to generations of schoolboy model-makers, and bamboo, a traditional construction material in China. They are experimenting, too, with animal cloning. The BGI was the first outfit to clone pigs, and it has developed a new and more effective way of cloning mammals that might ultimately be applied to humans, if that were ever permitted.

But the organisation is involved in even more controversial projects. It is about to embark on a search for the genetic underpinning of intelligence. Two thousand Chinese schoolchildren will have 2,000 of their protein-coding genes sampled, and the results correlated with their test scores at school. Though it will cover less than a tenth of the total number of protein-coding genes, it will be the largest-scale examination to date of the idea that differences between individuals’ intelligence scores are partly due to differences in their DNA.

Dr Yang is also candid about the possibility of the 1,000-genome project revealing systematic geographical differences in human genetics—or, to put it politically incorrectly, racial differences. The differences that have come to light so far are not in sensitive areas such as intelligence. But if his study of schoolchildren does find genes that help control intelligence, a comparison with the results of the 1,000-genome project will be only a mouse-click away.

At the moment this frenetic activity is paid for mostly by regional development grants and loans from state-owned Chinese banks, but Dr Yang hopes to go properly commercial. The Hong Kong operation will work partly as a contractor, and Mr Wong hopes to persuade biologists around the world to send their samples in and have them sequenced there rather than relying on their own universities to do the sequencing. Whether the BGI’s researchers can turn their mass-produced DNA sequences into new scientific insights and bankable products remains to be seen, but the world is watching.

Special reports

dimanche 20 juin 2010

No predicting value of 100 genetic variants linked to heart disease

- One recent study found that some 100 genetic variants that had been statistically linked to heart disease had no value in predicting who would get the disease among 19,000 women who had been followed for 12 years.


- The Genome, 10 Years Later, NYT, June 20, 2010

mardi 15 juin 2010

Geneticist George Church: Sequencing human genome ‘high priority’ for China, By Boonsri Dickinson | Jun 10, 2010

Long before he could grow his signature beard, geneticist George Church fantasized about sequencing the genomes of mankind. Today, that dream is a reality. Three years before anyone else thought to sequence genomes — 1987, to be precise — Church was in his Harvard University laboratory unraveling the DNA data code.

Hype is mounting for the 10-year anniversary of the announcement of the first draft of the human genome, officially this June. But Church admits that he’s not at all impressed — despite $3 billion already invested, humanity is far from completely decoding the human genome.

Perhaps no one has seen genomics as up-and-close as Church, who became his own guinea pig in the Personal Genome Project, or PGP. To date, the project counts more than 16,000 volunteers — but only a select dozen has made their genetic and medical history public. Eventually, 100,000 people will be sequenced through the project.

This week, Church is in Steamboat Springs, Colorado, where he’ll be speaking at the FASEB Summer Research Conference on Genome Engineering. I spoke with him yesterday about why genetic engineering is about selective application — and why the U.S. needs to defend its lead in genomic technology.

BD: Now, how exactly are you going to program biology to do what you want?

GC: There are two sides to my research: reading and writing biology.

The genome engineering is on the writing side. It’s not so much about changing every part of a genome at once, but cost-effectively engineering many parts of genomes that matter — for example, engineering them for resistance to all viruses.

On the other side, we are reading genomes for personal genomics. But there are many ways that reading and writing interact. We need to read the genomes of nature to get ideas then re-write these in novel combinations, and then re-read them to see that we made what we intended or see how lab evolution has made our constructs even better.

BD: Did you learn anything from having your genome sequenced?

GC: We are writing software for everyone to use. We have 32 public genomes already on which we are testing this software. We stare at the output from 32 genomes. Mine is probably among the most boring.

For example, PGP number 6 had the allele of hypertrophic cardiomyopathy. It’s a condition, where one day you are shooting a basketball and then suddenly drop dead. It’s not part of standard medical care to look out for this. We recommended that PGP 6, get an endocardiogram.

It’s a perfect example that can happen to you late in life. You can look at the many highly predictable and highly actionable gene variants like fire insurance. Everybody is at risk. You can’t say that you aren’t at risk until you look at your genome.

BD: Can you tell me more about how you were among the first to start sequencing the human genome?

GC: As a teenage researcher in 1974, I typed in all the DNA into a computer. At the time, almost no biologists used computers. I thought it would be nice to take these strings of [the letters of DNA] A, C, G , T, and fold them up and see if they looked like each other when they were folded. This was exciting and I wondered what about folding up these strings from many humans . So I went to Harvard where Wally Gilbert was interested in sequencing.

At the time, very few molecular biologists were working full-time on new technology. It was considered not a suitable occupation. They said to me, you should be studying science instead of developing technology. It didn’t earn you respect. They would say things like, “well this is taking a long time, why don’t you just do an experiment, and learn about the real biology.” And they would ask, “are you just playing games or do you care about the answer?”

In 1984, I published a paper called “Genomic Sequencing”. That year, the US Dept of Energy had a very small meeting - about a dozen of us were there and we said we could sequence a human genome. One of the administrators at DOE saw the report and encouraged us to apply for a grant. So I did.

BD: You must have gotten your hands dirty early on in the sequencing game.

GC: Up until 1984, I was a grad student at Harvard. I was a post doc from 1984 to 1986 at the University of California at San Francisco. Then I went back to Harvard as a professor in 1986. As a starting professor, did a lot of experiments myself - and began to get help from students.

I was pretty sure that sequencing many human genomes would work. I was considered optimistic by my colleagues, but now I realize how I underestimated how fast sequencing would change. The last five years it has been meteoric. Even fast technologies like computers advance by a factor of 1.5 per year, according to Moore’s Law. But genomics has improved by 10-fold per year for the last 5 years. I thought it would follow the same curve as computing. But it hasn’t.

The field of genetics depends on computers. But even though computers are moving more slowly, they are adequate.

Computers handle the sequencing information, processing trillions of bits of information, and those images are compressed and analyzed. Interpreting the genome involves more than computers. It involves new studies on many people to see how variations in genome plus environments produce our distinctive traits .

BD: Are you excited about the 10-year anniversary?

GC: It’s kind of an arbitrary number. For one thing, no one even sequenced an entire human genome. They made an announcement, saying it was over. They sequenced 93 percent of one genome. [People have two genomes]. They completely disregarded the issue of traits. It wasn’t even from one person. The other 7 percent is so hard, we still haven’t done it.

I’m excited that we can now actually get enough genomes and trait data from volunteers so that we can work together to add value to the 10 year-old crude genome sequence that we celebrate today.

BD: Are other countries trying to get in on this genetic race?

GC: Beijing was a minor player in human genome 10 years ago and is a major player today. I’m working with them through my company, Knome, to sequence personal genomes of early adopters. The Chinese government has set this as a high priority.

It’s like in the 60s, the U.S. decided to put a man on the moon. The U.S. was a leader in the human genome project and is now leading in genomic technology. The U.S. could launch another project, but maybe we’ve been waiting for the cost of sequencing to drop.

BD: So how much does an entire genome cost these days?

GC: The price of a genome is a little less than $10,000. The cost is $1,000. There is a gap between the price and the cost.

The gap is shrinking and the costs are still dropping.

We are going to start hearing stories about people getting their entire genome sequenced. What might these stories miss?

One thing that they might do, is try to interpret the data the same way they did for companies like 23andMe and focus on common variants.

The real story is in the rare alleles. One in ten percent of us are very affected by these, and the sequencing tests reveal them as long as we are looking for them.

Almost all common diseases have a rare allele component to it. What happened before is that we went through a fad. Scientists were looking where the light was in the common variants and they mostly ignored rare alleles.

My company, Knome, can test for all 1,800 genes that have known medically actionable rare alleles. While every gene has rare alleles, a lot don’t have an impact.

Clinical geneticists order these tests of rare alleles that have large and well-known impacts all the time, but just one or two tests at a time because it is so expensive. That’s going to change.

BD: Do you think you’ll accomplish your dream soon?

GC: I suspect everyone who wants to have their genome sequenced could have it done in the next few years. It depends on the complexity of the social interactions. Even if the price is right, it depends on who else is getting their genome sequenced. If celebrities do it, then it will become a fad and will be accepted more quickly.

Susceptibility loci for Alzheimer disease

While we have understood the bases for mendelian, early-onset Alzheimer disease for nearly 2 decades, elucidation of the genetic risks for late-onset disease beyond the apolipoprotein E locus, discovered in 1993, had been painfully slow until the last year.

From 1993 to 2009, thousands of genetic association studies on Alzheimer disease had been published without any becoming generally accepted as true risk loci for the disease.

With the benefit of hindsight, we now have some indication of why no other risk loci were found during this period; simply, there are no other loci with similar effect sizes to apolipoprotein E to be found.

Now, however, with the advent of whole-genome associations, we are beginning to find the weaker risk loci for the disease.

Whole-genome associations rely on the observation that, within a certain population, genetic variability at 1 point predicts (tags), with reasonable accuracy, the other genetic variability within approximately 20 kilobases (kb).

This means that assessment of variability across the whole genome can be achieved by assessment of these tagging single-nucleotide polymorphisms.

In practice, this means that genetic variability across the genome can be systematically tested for association with disease by genotyping about 400 000 evenly spaced tagging single-nucleotide polymorphisms in large numbers of cases and controls. The larger the series of cases and controls, the smaller the effect that can be detected.

Through the application of this technology and the use of approximately 2000 Alzheimer cases and a greater number of controls, 2 recent studies have identified 3 loci as being clearly implicated in Alzheimer disease6-7: CLU, CRI, and PICALM, with other loci, including BIN1 and CNTN5, almost reaching significance.


- Identification of Alzheimer Risk Factors Through Whole-Genome Analysis. John Hardy, PhD; Julie Williams, PhD. Arch Neurol. 2010;67(6):663-664.

What Five FDA Letters Mean for the Future of DTC Genetic Testing

A interesting post from Dan Vorhaus at

lundi 14 juin 2010

Genetic Testing Companies in San Diego, Boston, & San Francisco Studying FDA Letters

Bruce V. Bigelow 6/14/10,

Five companies that provide genetic testing services—including San Diego’s Illumina (NASDAQ: ILMN), 23andMe and Navigenics in the San Francisco Bay Area, and Knome in Cambridge, MA—no doubt spent the weekend parsing letters issued Friday by the FDA.

The letters, which were posted on the FDA website and signed by Alberto Gutierrez of the FDA’s office of In Vitro Diagnostic Device Evaluation and Safety, notify the companies that genome-sequencing tests they offer to consumers are medical devices that require the agency’s approval. The Food and Drug Administration says it wants to make sure that direct-to-consumer (DTC) genome test kits are “analytically and clinically accurate so that individuals are not misled by incorrect test results or unsupported clinical interpretations.”

The FDA challenge, which also was sent to deCODE Genetics, which is headquartered in Iceland, follows the agency’s move last month to prevent San Diego-based Pathway Genomics from selling its personal genome test kit through Walgreens stores. The letters sent by the FDA do not order the companies to stop selling the tests, but suggests that some genetic testing services they offer may not be marketed legally.

The San Diego Union-Tribune says the FDA letters prompted Escondido, CA-based Palomar Pomerado Health to suspend sales of DNA kits from 23andMe of Mountain View, CA. Palomar Pomerado spokesman Andy Hoang told the newspaper, “we believe the future of medicine is genomics and that personalized medicine, driven by a deeper understanding of the patient’s own unique genetic profile, represents the way medicine will be practiced in the future.

The letters likely were a surprise, as Illumina CEO Jay Flatley said nothing about it when we discussed the FDA’s regulation of personal genome testing the previous day. Illumina declined to comment to the Union-Tribune Friday, except to say the company is studying the content of the letter the FDA sent to Flatley concerning Illumina’s Infinium HumanHap550 array. Illumina doesn’t sell its services directly to consumers, but provides its HumanHap550 array to 23andMe and deCODE Genetics.

Other news accounts explaining the FDA challenge are available at The New York Times and Washington Post, but I found an excellent analysis of the issue by attorney Dan Vorhaus of Charlotte, N.C., here at the Genomics Law Report.

Bruce V. Bigelow is the editor of Xconomy San Diego. You can e-mail him at or call 858-202-0492

samedi 12 juin 2010

A Decade Later, Genetic Map Yields Few New Cures

By NICHOLAS WADE, NYT, Published: June 12, 2010

Ten years after President Bill Clinton announced that the first draft of the human genome was complete, medicine has yet to see any large part of the promised benefits.

For biologists, the genome has yielded one insightful surprise after another. But the primary goal of the $3 billion Human Genome Project — to ferret out the genetic roots of common diseases like cancer and Alzheimer’s and then generate treatments — remains largely elusive. Indeed, after 10 years of effort, geneticists are almost back to square one in knowing where to look for the roots of common disease.

One sign of the genome’s limited use for medicine so far was a recent test of genetic predictions for heart disease. A medical team led by Nina P. Paynter of Brigham and Women’s Hospital in Boston collected 101 genetic variants that had been statistically linked to heart disease in various genome-scanning studies. But the variants turned out to have no value in forecasting disease among 19,000 women who had been followed for 12 years.

The old-fashioned method of taking a family history was a better guide, Dr. Paynter reported this February in The Journal of the American Medical Association.

In announcing on June 26, 2000, that the first draft of the human genome had been achieved, Mr. Clinton said it would “revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases.”

At a news conference, Francis Collins, then the director of the genome agency at the National Institutes of Health, said that genetic diagnosis of diseases would be accomplished in 10 years and that treatments would start to roll out perhaps five years after that.

“Over the longer term, perhaps in another 15 or 20 years,” he added, “you will see a complete transformation in therapeutic medicine.”

The pharmaceutical industry has spent billions of dollars to reap genomic secrets and is starting to bring several genome-guided drugs to market. While drug companies continue to pour huge amounts of money into genome research, it has become clear that the genetics of most diseases are more complex than anticipated and that it will take many more years before new treatments may be able to transform medicine.

“Genomics is a way to do science, not medicine,” said Harold Varmus, president of the Memorial Sloan-Kettering Cancer Center in New York, who in July will become the director of the National Cancer Institute.

The last decade has brought a flood of discoveries of disease-causing mutations in the human genome. But with most diseases, the findings have explained only a small part of the risk of getting the disease. And many of the genetic variants linked to diseases, some scientists have begun to fear, could be statistical illusions.

The Human Genome Project was started in 1989 with the goal of sequencing, or identifying, all three billion chemical units in the human genetic instruction set, finding the genetic roots of disease and then developing treatments. With the sequence in hand, the next step was to identify the genetic variants that increase the risk for common diseases like cancer and diabetes.

It was far too expensive at that time to think of sequencing patients’ whole genomes. So the National Institutes of Health embraced the idea for a clever shortcut, that of looking just at sites on the genome where many people have a variant DNA unit. But that shortcut appears to have been less than successful.

The theory behind the shortcut was that since the major diseases are common, so too would be the genetic variants that caused them. Natural selection keeps the human genome free of variants that damage health before children are grown, the theory held, but fails against variants that strike later in life, allowing them to become quite common. In 2002 the National Institutes of Health started a $138 million project called the HapMap to catalog the common variants in European, East Asian and African genomes.

With the catalog in hand, the second stage was to see if any of the variants were more common in the patients with a given disease than in healthy people. These studies required large numbers of patients and cost several million dollars apiece. Nearly 400 of them had been completed by 2009. The upshot is that hundreds of common genetic variants have now been statistically linked with various diseases.

But with most diseases, the common variants have turned out to explain just a fraction of the genetic risk. It now seems more likely that each common disease is mostly caused by large numbers of rare variants, ones too rare to have been cataloged by the HapMap.

Defenders of the HapMap and genome-wide association studies say that the approach made sense because it is only now becoming cheap enough to look for rare variants, and that many common variants do have roles in diseases.

At this point, some 850 sites on the genome, most of them near genes, have been implicated in common diseases, said Eric S. Lander, director of the Broad Institute in Cambridge, Mass., and a leader of the HapMap project. “So I feel strongly that the hypothesis has been vindicated,” he said.

But most of the sites linked with diseases are not in genes — the stretches of DNA that tell the cell to make proteins — and have no known biological function, leading some geneticists to suspect that the associations are spurious.

Many of them may “stem from factors other than a true association with disease risk,” wrote Jon McClellan and Mary-Claire King, geneticists at the University of Washington, Seattle, in the April 16 issue of the journal Cell. The new switch among geneticists to seeing rare variants as the major cause of common disease is “a major paradigm shift in human genetics,” they wrote.

The only way to find rare genetic variations is to sequence a person’s whole genome, or at least all of its gene-coding regions. That approach is now becoming feasible because the cost of sequencing has plummeted, from about $500 million for the first human genome completed in 2003 to costs of $5,000 to $10,000 that are expected next year.

But while 10 years of the genome may have produced little for medicine, the story for basic science has been quite different. Research on the genome has transformed biology, producing a steady string of surprises. First was the discovery that the number of human genes is astonishingly small compared with those of lower animals like the laboratory roundworm and fruit fly. The barely visible roundworm needs 20,000 genes that make proteins, the working parts of cells, whereas humans, apparently so much higher on the evolutionary scale, seem to have only 21,000 protein-coding genes.

The slowly emerging explanation is that humans and other animals have much the same set of protein-coding genes, but the human set is regulated in a much more complicated way, through elaborate use of DNA’s companion molecule, RNA.

Little, if any, of this research could have been done without having the human genome sequence available. Every gene and control element can now be mapped to its correct site on the genome, enabling all the working parts of the system to be related to one another.

“Having a common scaffold on which one can put all the information has dramatically accelerated progress,” Dr. Lander said.

The genome sequence has also inspired many powerful new techniques for exploring its meaning. One is chip sequencing, which gives researchers access to the mysterious and essential chromatin, the complex protein machinery that both packages the DNA of the genome and controls access to it.

The data from the HapMap has also enabled population geneticists to reconstruct human population history since the dispersal from Africa some 50,000 years ago. They can pinpoint which genes bear the fingerprints of recent natural selection, which in turn reveals the particular challenges to which the populations on different continents have had to adapt.

As more people have their entire genomes decoded, the roots of genetic disease may eventually be understood, but at this point there is no guarantee that treatments will follow. If each common disease is caused by a host of rare genetic variants, it may not be susceptible to drugs.

“The only intellectually honest answer is that there’s no way to know,” Dr. Lander said. “One can prefer to be an optimist or a pessimist, but the best approach is to be an empiricist.”

Next: Drug companies stick with genomics but struggle with information overload.

F.D.A. Faults Companies on Unapproved Genetic Tests

By ANDREW POLLACK, NYT, Published: June 11, 2010

The Food and Drug Administration is cracking down on 23andMe and other companies that sell genetic tests directly to consumers.

The F.D.A. sent letters this week to five companies involved in that business, saying their tests are medical devices that must receive regulatory approval before they can be marketed.

“Premarket review allows for an independent and unbiased assessment of a diagnostic test’s ability to generate test results that can reliably be used to support good health care decisions,” Alberto Gutierrez, who leads diagnostic test regulation at the F.D.A., wrote in the letters.

The letters, posted on the F.D.A. Web site on Friday, say the companies must apply for approval or discuss with the agency why certain test claims do not require such approval.

But the letters stop short of saying the tests must be taken off the market until they are approved. Dr. Gutierrez said in an interview that it would be unfair to remove the tests from the market because the agency had not clearly told the companies that the devices needed approval.

23andMe and two other recipients of the letters, Navigenics and DeCode Genetics, sell tests that scan a person’s DNA, looking at genetic variations that can suggest whether a person is at a higher or lower risk of getting diseases like cancer or diabetes. The most prominent of the companies, 23andMe, is backed by Google and run by Anne Wojcicki, the wife of Google’s co-founder, Sergey Brin.

Illumina, which also received a letter, sells so-called DNA chips that are used by some companies to do the DNA scans. The fifth recipient, Knome, offers consumers a complete sequence of their DNA, which can be used to glean disease risk information.

The F.D.A. action is the latest salvo in a long-running debate about whether and how such tests should be regulated.

On one side are some doctors, geneticists and state regulators who say the tests should be regulated because the results might be used to make medical decisions. Some also say a doctor should be involved in ordering the tests and interpreting results.

On the other side are those, especially 23andMe executives, who argue that the services merely provide information, not medical diagnosis, and that consumers have a right to the information contained in their genes. At a time when consumers are taking more control of their health care, denying them such information would be, as one director of 23andMe recently put it, “appallingly paternalistic.”

The companies have also said that their tests do not require F.D.A. approval because they have been developed and are offered by a single laboratory. The F.D.A. has typically refrained from regulating such tests, as opposed to test kits that are widely sold to laboratories, hospitals and doctor’s offices.

The F.D.A. is now clearly deciding in favor of regulation, saying the tests of disease risk can have medical consequences.

“It is not unknown for women to take out their ovaries if they are at high risk of ovarian cancer,” Dr. Gutierrez said. Some of the services are also offering consumers information that could be used to determine the doses they should get of particular drugs, like the blood thinners, warfarin and Plavix.

But Dr. Gutierrez denied that the agency was being paternalistic. “We really don’t have any issues with denying people information,” he said. “We just want to make sure the information they are given is correct.”

In a statement Friday, 23andMe said it disagreed with the F.D.A.’s conclusion but was open to discussion on ways to regulate the personal genetics industry. “We are sensitive to the F.D.A.’s concerns, but we believe that people have the right to know as much about their genes and their bodies as they choose.”

By contrast, Kari Stefansson, head of research at DeCode, said the interest by the F.D.A. was “timely, appropriate and welcome” because the company wanted its test to become part of standard medical care. A spokesman for Knome said the company would cooperate with the F.D.A.

The F.D.A. recently sent a similar letter to another company, Pathway Genomics, which had planned to sell its test through Walgreen drugstores and other chains. Walgreen dropped its plans to sell the test, though Pathway still offers it online.

The House Energy and Commerce Committee is also looking into these tests and sent letters last month to 23andMe, Navigenics and Pathway Genomics requesting extensive information.

Concern about the tests was also raised this week when 23andMe said that because of a laboratory mix-up, up to 96 customers might have received information on someone else.

Daniel Vorhaus, a lawyer specializing in regulation of genetic testing and author of the blog Genomics Law Report, said some of his clients were holding back tests because it was unclear which would be regulated.

“No one has a clear understanding of where the F.D.A. is drawing the line at this point,” said Mr. Vorhaus, who does not represent any of the five companies that received the letters. He said the F.D.A. was “trying to keep up with a commercial space that is moving way faster than they are capable of.”


- Three Ways FDA Can Lift 'Barriers' to MDx Development, GenomeWeb, June 28, 2010

jeudi 10 juin 2010

Autism Genome Project Consortium Implicates Rare CNVs in Autism

June 09, 2010

Members of the Autism Genome Project Consortium reported online today in Nature that they have identified a host of rare copy number variants (CNVs) that appear to contribute to autism susceptibility.

The team, which includes more than 100 researchers from centers around the world, used high-density microarrays to assess CNV profiles in about 1,000 families affected by autism and nearly 2,000 control individuals.

Their results suggest that while individuals with autism don't necessarily have more CNVs overall than unaffected individuals, they tend to carry more CNVs that affect genes — particularly those involved in processes such as brain cell communication and cellular proliferation.

The results substantiate the importance of genes in autism susceptibility, corresponding author Stephen Scherer, a molecular genetics researcher at the University of Toronto and director of the Hospital for Sick Children's Centre for Applied Genomics, said during a telephone briefing with reporters this week.

Those involved in the study also emphasized the potential of the new findings for helping to diagnose autism earlier and for finding pathways that might serve as targets for improved autism treatments.

Although a fraction of autism cases correspond to conditions — such as fragile X syndrome — resulting from changes to a single gene, most cases appear to be a consequence of much more complex and heterogeneous genetic patterns.

In an effort to uncover new autism risk genes and gain insights into commonly affected molecular pathways, consortium members used the Illumina Infinium 1M SNP microarray to evaluate CNV patterns in 1,275 individuals with autism spectrum disorders and their parents as well as 1,981 unaffected control individuals.

After their quality control steps, the team was left with data for 876 family trios, including 996 individuals with ASD, and 1,287 controls. The CNVs they identified were larger than 30,000 bases and present at less than one percent frequency overall.

Although the team did not find more CNVs overall in individuals with ASD, they found that more of these CNVs — especially deletions — affected gene coding regions in the ASD group than in unaffected individuals.

On average, individuals with ASD had about 19 percent more genic CNVs than control individuals. In addition, some 5.7 percent of children with ASD carried de novo CNVs not present in either of the child's parents.

Some, but not all, of the affected genes have been implicated in autism previously. Among the genes not found in past studies of autism: SHANK2, SYNGAP1, DLGAP2, and the DDX53-PTCHD1 locus.

"Most individuals with autism are probably quite unique," Scherer said, noting that even the most common CNVs detected turn up in less than one percent of the ASD cases tested.

Now that researchers have a catalog of genes affected by rare CNVs, Scherer added, it's possible to begin tying these genes together in pathways and looking at effects on brain function. For example, the researchers reported that the CNVs they detected often impacted genes involved in cellular motility, proliferation, and communication pathways.

By further characterizing these pathways, the team hopes to find clues to detecting autism earlier. Early detection and intervention, in turn, are expected to improve autistic children's social, intellectual, and language outcomes, noted co-author Geraldine Dawson, chief scientific officer for Autism Speaks and a member of the National Institutes of Health's inter-agency autism coordinating committee.

Such analyses are also expected to highlight biological pathways that might be targeted by new or existing drug treatments.

The current findings "give us an idea of what the picture [of autism genetics] may look like," Anthony Monaco, a researcher with the University of Oxford's Wellcome Trust Centre for Human Genetics and study co-author, told reporters.

Nevertheless, the researchers explained, since the rare CNVs found so far account for just 10 to 15 percent of autism risk, more research is needed to understand autism genetics and the interplay between autism susceptibility genes and environmental risk factors.

That will likely require studies using high-throughput sequencing of autism families to find additional genetic changes in genes and genomes, Monaco said, along with studies aimed at finding the best ways of translating genetic research into the clinic.

In an effort to get a better handle on the predictive statistics available from microarray data, Scherer and his colleagues in Ontario plan to use arrays to assess some 5,000 newly diagnosed autism cases in that province over the next few years.

Researchers in Oxford reportedly hope to do a similar pilot study involving at least 1,000 children with autism.

"By identifying the genetic causes of autism, we hope in the future to be able to improve the diagnosis and treatment of this condition which can affect children and their families so severely," Monaco said in a statement.

"[K]nowing about these genetic changes can help the families involved come to terms with why their child has autism, but it can also be important where there are siblings too in determining future risk."

mercredi 9 juin 2010

Illumina Slashes Cost of Individual Genome Sequencing Service

Denise Gellene 6/9/10,

The cost of getting your genome sequenced continues to drop. San Diego’s Illumina (NASDAQ: ILMN) has lowered the cost of its individual sequencing service to $19,500 from $48,000.

The company is offering a discounted price of $9,500 for people with serious medical conditions who could potentially benefit from having their genomes decoded.

Last year, doctors at Yale University reported using whole-genome sequencing to diagnose the mutation responsible for an infant’s persistent diarrhea. The information allowed doctors to tailor their treatment.

Illumina also is offering a discounted price of $14,500 to groups of five or more from the same physician.

“It’s very clear as the price comes down that we’ve been able to open broad new markets,” says Illumina CEO Jay Flatley.

Illumina’s announcement last week came on the heels of Pathway Genomics’ aborted plans to market its genetic test kits in Walgreen drug stores. The retail chain reversed plans to carry the kits after the FDA questioned the company’s decision to market the test without the agency’s approval.

Pathway Genomics, which is based in San Diego, has maintained it is in compliance with “currently applicable” regulations. Now a Congressional committee is looking into genetic tests marketed on the Internet by Pathway and competitors 23andMe and Navigenics.

The service Pathway Genomics intended to offer was cheaper than Illumina’s and far from the comprehensive genome sequence that Illumina provides.

Pathway Genomics planned to sell the kits at $20 to $30 each and charge $79 to $249 to analyze customers’ saliva for relatively few specific genetic characteristics, such as links to certain diseases or how their bodies respond to caffeine or certain prescription drugs.

Illumina’s Flatley says he sees huge opportunities for using the information that can be gleaned from a patient’s genome, adding that he thinks FDA regulators “are as excited to the possibilities as we are. I think they’re just trying to figure out the best way to make that happen, and their concerns are about the process.”

Illumina formed an internal ethics committee to study its handling of the process, and Flatley says it took roughly a year to develop internal protocols that require customers to obtain a doctor’s prescription for the genomic sequencing.

The company’s protocols require that a doctor takes a patient’s sample and that results of Illumina’s genetic analysis are returned to the doctor—not the patient.

“Illumina is taking the high road to make sure it’s done right,” Flatley says.

In its press release, Illumina says its process requires individuals to undergo pre-service consultation, consent and a seven-day cooling-off period.

How useful is all that information to a healthy consumer? My guess is not very, since a great deal of genetic information remains to be discovered.

To Flatley, the really important stake in the ground is the special $9,500 pricing for patients with very serious, life-threatening diseases.

In such cases, Flatley says sequencing a patient’s genome could be beneficial to making a diagnosis or a path for treating the disease.

Denise Gellene is a former Los Angeles Times science writer and regular contributor to Xconomy. You can reach her at

mardi 8 juin 2010

On a Mission to Sequence the Genomes of 100,000 People

New York Times, June 7, 2010

Traditionally, biology is about taking apart things like cells to better understand them. For the geneticist George M. Church, the main objective is to put the pieces back together.

Strolling through his laboratory, one of the larger ones at Harvard Medical School, Dr. Church, 56, points out benches where students and colleagues work on everything from basic genetics, proteomics and biocomputing to synthetic biology and the impact of the millions of microbes that inhabit our guts.

“I’m a polyglot who believes in integration,” he said. “That’s my specialty.”

Dr. Church — a tall man with a long graying beard and rumpled clothes — oversees 45 students in his lab and has co-founded or advises some 22 businesses, many of them startups that focus on things like synthetic biology, genetic sequencing and companies that provide genetic testing to consumers.

His most visible work is the Personal Genome Project, which has 16,000 volunteers, 12 of whom have had their genomes sequenced and made publicly available. These include science and technology celebrities like the Internet pioneer Esther Dyson and the Harvard psychologist and best-selling author Steven Pinker.

Eventually Dr. Church wants to sequence the entire genomes of 100,000 people — nearly every one of the six billion As, Cs, Gs and Ts that occur in a human.

“The goal of getting your genome done is not to tell you what you will die from,” he said, “but it’s how to learn how to take action to prevent disease.”

So far, the science of predicting a person’s health future using genetic markers has not produced much useful information for common diseases, although Dr. Church believes that this will change.

“We need full genome sequences to understand what is really going on genetically,” he said. “Until recently, this wasn’t feasible.”

The project is becoming possible as the speed and efficiency of sequencing increase dramatically, and the once-prohibitive costs drop from millions of dollars for a genome two years ago to under $10,000 today.

Ultra-low sequencing costs will also allow researchers to study interactions between genes and environmental components — microbes, allergens, viruses, toxins, autoimmunity.

Typically, Dr. Church has been at the center of the development of the technologies that are making this possible. He advises or has licensed technology to most of the companies active in this field. This makes his potential conflicts of interests almost byzantine, since many are rivals, particularly in the hotly competitive field of genetic sequencing.

But he is undisturbed and open about his various commercial and scientific involvements — and seems to be like Teflon in avoiding the sort of criticism that other scientists often face for such entanglements.

Indeed, he starts his frequent lectures with a disclosure slide packed with the logos of companies he is involved with — among them LS9 (biofuels), Knome (personal genomes), Alacris Pharmaceuticals (cancer) and Joule Unlimited (photosynthesis).

“I want to move the science into application,” Dr. Church explains, “and I’ll support anything that gets it there. I won’t support one over the other. If they tell me something secret, I can’t tell anyone until it comes into the public domain.”

Dr. Edward R. B. McCabe, a geneticist and physician at the University of California, Los Angeles, said: “George has been an important figure in molecular genetics and its evolution, including genomics and bioinformatics. If we are to understand the complexity of biological systems, then integration on the scale George recommends will be essential.”

A leader in the Human Genome Project during the 1980s and ’90s, Dr. Church first came to prominence while still a graduate student, for developing some of the earliest genetic sequencers. These machines and processes combined a love of computers, engineering and science that began in high school.

“I always loved computers — it’s something inside you,” he said in an interview. But as a boy growing up in Clearwater, Fla., Dr. Church did not have access to computers. “So I made one myself,” he said. Later, when his mother married a physician, he became interested in biology.

As an undergraduate at Duke University, he majored in zoology and chemistry and worked in a lab that used sophisticated X-rays to identify the shapes of crystallized proteins.

“I got to use math, physics, chemistry and computers,” he said. “This was also one of the few areas of biology at the time that used robots.”

As scientists go, Dr. Church is an active public figure who gets more than his share of news media attention, which he clearly enjoys and takes in stride. In fact, little seems to disrupt his equilibrium.

“I’m pathologically calm,” he said — which may be one reason he has ruffled so few feathers in the hypercompetitive world of high-stakes science.

His lab includes cold rooms filled with tissue samples, machine shops with clamps and drills, and benches overflowing with electronics equipment. He points out where teams are studying antibiotic drug resistance, microbial fuels, metabolic engineering and epigenetics (the turning on and off of genes, usually by environmental influences).

He presides over his bio-empire with a tiny Sony laptop that he carries like someone else might cradle a baby, or a poodle. Shuffling from bench to meeting to lecture, he mostly listens to students and colleagues, asking a few pointed questions while multitasking on his computer.

Sometimes, Dr. Church seems to veer into science fiction. At a dinner a few months ago, he sat with colleagues discussing a project that involves “mirror biology” — the creation of DNA, cells and organisms that are exact opposites of the natural versions.

He explained that this was like building a replica of an old-fashioned clock by looking only at its reflection. “The copy will predictably tell time, but the numerals will be flipped and the hands will rotate counterclockwise,” he said.

“While mirror life may look identical to current life,” he said, “it is radically different in terms of resistance to viruses, pathogens and enzyme digestion, among other things, because molecular interactions of life are very sensitive to the mirror arrangement of the atoms.”

Dr. Church expects to have a proof of concept — a functioning mirror cell that serves some useful purpose — in two years. “The mirror project is challenging because it requires building an entire cell from parts,” he said.

He added that this was more complicated than creating, say, the entire genome of a microbial organism and inserting it into a living cell — a feat recently announced by the geneticist J. Craig Venter.

When a student stopped by his small office to chat about a just-published study in Science about the genetic sequencing of a Neanderthal, he said playfully, “Maybe one day we’ll make Neanderthals.”

Maybe so. He prizes imagination in his students and associates.

“I like to keep the median age in my lab low because they will indulge me in my dreams,” Dr. Church said. “They don’t yet think things are impossible.”

lundi 7 juin 2010

The Genome 10K project

The Genome 10K project aims to assemble a genomic zoo—a collection of DNA sequences representing the genomes of 10,000 vertebrate species, approximately one for every vertebrate genus.

The Genome 10K project aims to assemble a genomic zoo—a collection of DNA sequences representing the genomes of 10,000 vertebrate species, approximately one for every vertebrate genus. The trajectory of cost reduction in DNA sequencing suggests that this project will be feasible within a few years. Capturing the genetic diversity of vertebrate species would create an unprecedented resource for the life sciences and for worldwide conservation efforts.

The growing Genome 10K Community of Scientists (G10KCOS), made up of leading scientists representing major zoos, museums, research centers, and universities around the world, is dedicated to coordinating efforts in tissue specimen collection that will lay the groundwork for a large-scale sequencing and analysis project.

The Personal genome project

Personal genome project wants to sequence and compare 100 000 people.



100 genetic risks by genome

In the April 30, 2010 online issue of The Lancet, Ashley Caplan, PhD, director of the Center for Bioethics at the University of Pennsylvania and several of his colleagues note in an article that the average person will discover he or she has about 100 genetic risks.

"Even if [counseling on] that information averaged only three minutes per disorder, this process would take more than five hours of direct patient contact, after many hours of background research," they calculate.

And there are only about 2,500 trained genetic counselors and 1,100 clinical geneticists in North America, all now busy with other work.


The Personal genome project (PGP) wants to sequence and compare 100 thousand people.

The Genome 10K project aims to assemble a genomic zoo—a collection of DNA sequences representing the genomes of 10,000 vertebrate species, approximately one for every vertebrate genus.

The trajectory of cost reduction in DNA sequencing suggests that this project will be feasible within a few years. Capturing the genetic diversity of vertebrate species would create an unprecedented resource for the life sciences and for worldwide conservation efforts (


- $1,000 Personal Genome Coming: Are We Ready?,, April 29, 2010

- Clinical assessment incorporating a personal genome. Ashley EA, Butte AJ, Wheeler MT, Chen R, Klein TE, Dewey FE, Dudley JT, Ormond KE, Pavlovic A, Morgan AA, Pushkarev D, Neff NF, Hudgins L, Gong L, Hodges LM, Berlin DS, Thorn CF, Sangkuhl K, Hebert JM, Woon M, Sagreiya H, Whaley R, Knowles JW, Chou MF, Thakuria JV, Rosenbaum AM, Zaranek AW, Church GM, Greely HT, Quake SR, Altman RB. Lancet. 2010 May 1;375(9725):1525-35. PMID: 20435227

- The personal genome--the future of personalised medicine? Samani NJ, Tomaszewski M, Schunkert H. Lancet. 2010 May 1;375(9725):1497-8. PMID: 20435212

- Challenges in the clinical application of whole-genome sequencing. Ormond KE, Wheeler MT, Hudgins L, Klein TE, Butte AJ, Altman RB, Ashley EA, Greely HT. Lancet. 2010 May 15;375(9727):1749-51. PMID: 20434765

vendredi 4 juin 2010

What is the Cost of Human Genome Sequencing?

Two groups tied in first sequencing a human genome, the Human Genome Project, funded by the US Department of Energy, and Celera Genomics, a private company.

The Human Genome Project took 10 years and cost $3 billion USD (US Dollars), while the Celera genome sequencing project took two years and cost just $300 million USD. Both projects concluded in 2000 or 2001, depending on what is considered a "complete" human genome sequencing.

Gene sequencing costs have been dropped exponentially since the sequencing of the human genome in 2000.

In 2007, the genome sequencing of James Watson, a co-discoverer of the structure of DNA, was completed at a cost of $2 million USD.

In 2008, the first full genome sequencing services were sold commercially to customers for a cost of $100,000 USD.

By March 2008, one company, Applied Biosystems, completed a human genome sequencing in two weeks for $60,000 USD, the best cost yet.

Another company, Intelligent Bio-systems, has developed a system that can sequence a full human genome in 24 hours for $5,000 USD.

A price has been offered for the first to sequence 100 human genomes for $10,000 USD each in ten days or less. The $10 million USD prize, donated by diamond prospector Steward Blusson, will continue to be available until the deadline of 4 October 2013.

If the cost of genome sequencing falls below $1,000 USD, or better yet, $500 USD, many futurists have predicted qualitative changes in the way we do medicine.

1000$ genome is coming

In the April 30 online issue of The Lancet, Ashley Caplan, PhD, director of the Center for Bioethics at the University of Pennsylvania and several of his colleagues note that the average person will discover he or she has about 100 genetic risks.

"Even if [counseling on] that information averaged only three minutes per disorder, this process would take more than five hours of direct patient contact, after many hours of background research," they calculate.

And there are only about 2,500 trained genetic counselors and 1,100 clinical geneticists in North America, all now busy with other work.

Personal genome project wants to sequence and compare 100 thousand people. The Genome 10K project aims to assemble a genomic zoo—a collection of DNA sequences representing the genomes of 10,000 vertebrate species, approximately one for every vertebrate genus.

The trajectory of cost reduction in DNA sequencing suggests that this project will be feasible within a few years. Capturing the genetic diversity of vertebrate species would create an unprecedented resource for the life sciences and for worldwide conservation efforts (

30$ genome

According to, a Harvard University physicist is promising an even cheaper price, the ability to sequence a human genome for just $30.

David Weitz and his team are adapting microfluidics technology that uses tiny droplets, a strategy developed in his lab, to DNA sequencing.

While the researchers have not yet sequenced DNA, they have successfully demonstrated parts of the process and formed a startup, GnuBio, to commercialize the technology.

Weitz's team had previously developed a way to create picoliter droplets of water, which act as tiny test tubes. The droplets can be precisely moved around on a microfluidics chip, injected with chemicals and sorted based on color.

Smaller drops means smaller volumes of the chemicals used in the sequencing reaction.

These reagents comprise the major cost of sequencing, and most estimates of the cost to sequence a human genome with a particular technology are calculated using the cost of the chemicals.

Based solely on reagents, Weitz estimates that they will be able to sequence a human genome 30 times for $30.

In Weitz's approach, droplets are injected with short strands of DNA of a known sequence, and these strands are labeled with an optical bar code.

Pieces of the sample with an unknown sequence are also injected into the droplets--if the sample has a stretch of sequence complementary to the known strand, the two pieces will bind, triggering a change in color. Repeat this 1,000 times with 1,000 different known strands and you can generate the sequence of 1,000 letters of DNA, says Weitz.

Both the optical bar code and the color change are detected using a microscope and camera with automated detection software. Weitz says they can produce and process a million drops per second.


- 2000: $3 billion USD (The Human Genome Project)
- 2000: $300 million USD (Celera genome sequencing project)
- 2007: $2 million USD (genome sequencing of James Watson)
-2008: $100,000 USD (first full genome sequencing services sold commercially)
- March 2008: $60,000 USD (Applied Biosystems, two weeks)
- August 2009: $50,000 (Illumina)
- 2009: $50,000 (Helicos Biosciences)
- 2010: $10 000 (Illumina HiSeq 2000)

jeudi 3 juin 2010

New susceptibility loci for nasopharyngeal carcinoma

Researchers identify three new susceptibility loci for nasopharyngeal carcinoma in the genome-wide association study they've published in Nature Genetics. The team examined 464,328 autosomal SNPs in 1,583 cases and 1,894 controls, and found that TNFRSF19, MDS1-EVI1, and the CDKN2A-CDKN2B gene cluster were associated with NPC. "Our findings provide new insights into the pathogenesis of NPC," the authors write.


- A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Jin-Xin Bei, Yi Li, Wei-Hua Jia, Bing-Jian Feng, Gangqiao Zhou, Li-Zhen Chen,Qi-Sheng Feng, Hui-Qi Low, Hongxing Zhang, Fuchu He, E Shyong Tai, Tiebang Kang, Edison T Liu, Jianjun Liu & Yi-Xin Zeng. [Nature Genetics->] (2010)

mercredi 2 juin 2010

New Genetic Associations Revealed for Nasopharyngeal Carcinoma

Source: spittoon

Nasopharyngeal cancer (NPC) arises in the upper part of the throat, behind the nose. It is rare in most areas of the world—affecting only about 1 in every 100,000 people—but about 25 times more common in southern China, earning it the name “Cantonese Cancer.” NPC rates are also high in southeastern Asia, northern Africa and the Arctic.

Environmental factors play a very large role in NPC. Smoking increases risk, as does infection with the Epstein-Barr virus. Diets high in salt cured food, which are common in many of the areas where increased rates of NPC are seen, have also been shown to increase risk. These foods can be very high in nitrates and nitrites, which react with protein to form DNA-damaging chemicals.

It’s also been known for quite some time, however, that genetics contribute to NPC susceptibility. In 1970s, certain immune markers were associated with increased risk. Now a large genomewide association study has revealed three more immune related areas of the genome that are associated with risk for NPC. These results, published online this week in the journal Nature Genetics, could eventually help develop models for prediction and screening, which in turn would help with early diagnosis.

Researchers from Singapore, China and the United States studied about 5,000 people with NPC and 5,000 controls, as well as more than 250 families, all of southern Chinese descent. As expected, a strong genetic effect was seen in areas of the genome that encode the previously identified immune markers. But variants in three other regions were also associated with NPC risk. Two of these associations were statistically significant. The third SNP did not make the cut off, but was highly suggestive.

(23andMe Complete Edition customers can check their data for these SNPs using the links in the table at the end of this post.)

The statistically significant genetic associations variants were in the TNFRSF19 and MDS1-EVI1 genes. Previous research has shown that these genes encode proteins that may be involved in the body’s response to Epstein-Barr virus infection, possibly providing a neat connection between the new findings and a known environmental risk factor for NPC.

The third association was with a variant near the CDKN2A and CDKN2B genes. This gene cluster is deleted in about 40% of NPC tumors, suggesting that they are crucial for preventing cancerous growth. Additionally, this same SNP CDKN2A/CDKN2B SNP associated with NPC risk has been linked to glioma in European populations.

All of the genes identified in this study—TNFRSF19, MDS1-EVI1 and CDKN2A/CDKN2B—have previously been shown to be involved in leukemia. This suggests that there might be common disease mechanisms between that disease and NPC. Significantly, leukemia is found at higher than average rates in people with NPC.

According to the authors, the next step for research is to investigate the interactions between the genetic susceptibility factors identified by them and others with the environmental risk factors known to influence NPC.

SNP Gene Less Common Version Effect on Odds of NPC of Less Common Version
rs9510787 TNFRSF19 G 1.2
rs6774494 MDS1-EVI1 G 0.84
rs1412829* CDNK2A/CDNK2B G 0.78

* The association of this SNP with NPC was not statistically significant, but was highly suggestive.

What is the number of genes in the human genome ?

The number of genes in the human genome was found to be 20,000-25,000, smaller than predicted.