Accurate detection and genotyping of SNPs utilizing population sequencing data.

Next generation sequencing technologies have made it possible to sequence targeted regions of the human genome in hundreds of individuals. Deep sequencing represents a powerful approach for the discovery of the complete spectrum of DNA sequence variants in functionally important genomic intervals. Current methods for SNP detection are designed to detect SNPs from single individual sequence datasets. Here we describe a novel method SNIP-Seq (Single Nucleotide polymorphism Identification from Population Sequence data) that leverages sequence data from a population of individuals to detect SNPs and assign genotypes to individuals. To evaluate our method, we utilized sequence data from a 200 kilobase region on chromosome 9p21 of the human genome. This region was sequenced in 48 individuals (5 sequenced in duplicate) using the Illumina GA platform. Using this dataset, we demonstrate that our method is highly accurate for detecting variants and can filter out false SNPs that are attributable to sequencing errors. The concordance of sequencing based genotype assignments between duplicate samples was 98.8%. The 200 kb region was independently sequenced to a high depth of coverage using two sequence pools containing the 48 individuals. Many of the novel SNPs identified by SNIP-Seq from the individual sequencing were validated by the pooled sequencing data and were subsequently confirmed by Sanger sequencing. We estimate that SNIP-Seq achieves a low false positive rate of ~2% improving upon the higher false positive rate for existing methods that do not utilize population sequence data. Collectively, these results suggest that analysis of population sequencing data is a powerful approach for the accurate detection of SNPs and the assignment of genotypes to individual samples.

from The Scripps Institute

Cheap DNA sequencing will drive a revolution in health care

The dream of personalized medicine was one of the driving forces behind the 13-year, $3 billion Human Genome Project. Researchers hoped that once the genetic blueprint was revealed, they could create DNA tests to gauge individuals' risk for conditions like diabetes and cancer, allowing for targeted screening or preëmptive intervention. Genetic information would help doctors select the right drugs to treat disease in a given patient. Such advances would dramatically improve medicine and simultaneously lower costs by eliminating pointless treatments and reducing adverse drug reactions.

Delivering on these promises has been an uphill struggle. Some diseases, like Huntington's, are caused by mutations in a single gene. But for the most part, when our risk of developing a given condition depends on multiple genes, identifying them is difficult. Even when the genes linked to a condition are identified, using that knowledge to select treatments has proved tough (see "Drowning in Data"). We now have the 1.0 version of personalized medicine, in which relatively simple genetic tests can provide information on whether one patient will benefit from a certain cancer drug or how big a dose of blood thinner another should receive. But there are signs that personalized medicine will soon get more sophisticated. Ever cheaper genetic sequencing means that researchers are getting more and more genomic information, from which they can tease out subtle genetic variations that explain why two otherwise similar people can have very different medical destinies. Within the next few years, it will become cheaper to have your genome sequenced than to get an MRI (see "A Moore's Law for Genetics"). Figuring out how to use that information to improve your medical care is personalized medicine's next great challenge.

Can a Genomics Platform Model Work in Diagnostics?

Start-Up -- deCODE Genetics has emerged from bankruptcy with a streamlined, diagnostics-oriented business model. In the near term, the privately held firm expects to offer its genomics discovery capabilities on a service basis, echoing the original genomics platform specialists of the late 1990s, including deCODE itself, which did largely unsuccessful technology deals focused on using genetic insight to generate therapies. The difference? It is now using genetic information to assess disease risk and better manage patient health, a strategy it thinks will succeed as the field of personalized medicine diagnostics continues to gain traction.

By Mark L. Ratner

Elsevier Business Intellingence

First Illumina HiSeq Machines Advertised

News: the Illumina HiSeq can produce 200 gigabases (Gb) of sequence data and 2 billion reads per run. When it was launched we knew that BGI in China had signed an agreement to buy 128 of these machines but no-one has fessed up to owning one just yet.

Things might have changed today.

Two updates to the map of high-throughput sequencers, one hot on the heels of the other are both advertising HiSeq capability in Europe. GATC and DNAvision, both service companies have updated the map to say they have a HiSeq machine ready and waiting to service customers. Their corporate websites are a bit less clear on whether it has actually arrived yet, indicating probably that the HiSeq has just been ordered.

Medco Acquires DNA Direct: A Great Step for Personalized Medicine

Combined capabilities will deliver precision health services designed to improve

clinical and financial outcomes

FRANKLIN LAKES, N.J. and SAN FRANCISCO, Feb. 2, 2010 –– Committed to being at the forefront

of translating personalized medicine from the science to its daily practice in healthcare, Medco Health

Solutions, Inc (NYSE:MHS) today announced the acquisition of DNA Direct, Inc., a leader in providing

guidance and decision support for genomic medicine to patients, providers, payors and employees.

Financial details of the acquisition were not released.

“DNA Direct has been a recognized pioneer in assimilating knowledge about molecular diagnostic testing

and deploying certified genetics professionals to help rationalize the opportunities and implications faced

by many in this new and rapidly evolving field,” said David B. Snow Jr., Medco chairman and chief

executive officer.

By integrating DNA Direct’s physician, client and patient support services and capabilities with Medco’s

growing portfolio of personalized medicine capabilities and extensive customer base, Medco intends to

deliver a broader suite of precision health services, ranging from consumer education to clinical decision

support.

“Medco is simply the most innovative and forward thinking healthcare company in the industry today,”

said Ryan Phelan, DNA Direct founder and CEO. “Having spent the past 25 years as an entrepreneur

translating healthcare information to patients, I can’t think of a better partner to take personalized

medicine to the next level.”

DNA Direct is the first genomics-focused company offering URAC-accredited utilization management

programs to help payors ensure the appropriate use of the more than 2,000 genetic and molecular tests

available today. URAC is a Washington D.C.-based health care accrediting organization that establishes

quality standards for the health care industry. DNA Direct’s national call center of genetic experts,

complemented by online decision support services help physicians and patients determine if genetic tests

are appropriate and how to use genetic test results to guide clinical decisions. Medco’s existing

personalized medicine approach encompasses a robust pipeline of important pharmacogenetic research,

turnkey testing programs for drugs like tamoxifen and warfarin, and warnings on over 50 drug-gene

interactions, which are used by Medco's specialist pharmacists to inform physicians and patients about

potential therapy adjustments to ensure the safety and efficacy of the treatment.

“When a Fortune 50 company like Medco makes a commitment to personalized medicine with an

acquisition like this, it’s proof positive that we are at a turning point in the healthcare industry,” said

Sharon Terry, president and chief executive officer of Genetic Alliance. “Integrating Medco’s

phenomenal capacity to respond to its members, with the innovative and creative patient-focused services

of DNA Direct is a win for all consumers.”

The DNA Direct purchase builds upon Medco’s commitment to advancing pharmacogenomics (PGx), a

cornerstone of which is the company’s Personalized Medicine Research Center. The research center is

dedicated to furthering the understanding of the impact of genetics on patient medication response and

applying that science to clinical practice. As knowledge is gained through the research, applications will

be rolled out to the broader client base within Medco’s precision health services.

“By integrating proven state-of-the-art science into every day care, we are providing patients and

providers with actionable information that drives more personalized care to achieve higher efficacy or

improved safety,” said Dr. Robert Epstein, Medco’s chief medical officer. “We have already started this

today with our existing Personalized Medicine programs. DNA Direct will serve to accelerate our speedto-

market implementation capabilities, transforming research into actionable services to meet the

demands of our clients and patients.”

About Medco

Medco Health Solutions, Inc. (NYSE: MHS) is pioneering the world’s most advanced pharmacy® and its

clinical research and innovations are part of Medco making medicine smarter™ for more than 60 million

members.

With more than 20,000 employees dedicated to improving patient health and reducing costs for a wide

range of public and private sector clients, and 2008 revenue exceeding $51 billion, Medco ranks 45th on

the Fortune 500 list and is named among the world’s most innovative, most admired and most trustworthy

companies.

For more information, go to http://www.medcohealth.com.

About DNA Direct

DNA Direct was founded in 2005 to deliver guidance and decision support for genomic medicine to

patients, providers and payers -- reducing health risks, preventing disease, and better targeting therapies.

The first genomics-focused company to receive full URAC accreditation for utilization management in

the U.S, DNA Direct’s comprehensive clinical programs combine proprietary technology with genetic

expertise including a national call center of genetic experts, web-based applications, and educational

resources and training. The company is based in San Francisco and was backed by Firefly Investments

and Lemhi Ventures. For more information, visit www.dnadirect.com.

Association between Type 2 Diabetes Loci and Measures of Fatness

Type 2 diabetes (T2D) is a metabolic disorder characterized by disturbances of carbohydrate, fat and protein metabolism and insulin resistance.

The majority of T2D patients are obese and obesity by itself may be a cause of insulin resistance. Our aim was to evaluate whether the recently identified T2D risk alleles are associated with human measures of fatness as characterized with Dual Energy X-ray Absorptiometry (DEXA).

Nine single nucleotide polymorphisms (SNPs) in the CDKN2AB, CDKAL1, FTO, HHEX, IGF2BP2,KCNJ11, PPARG, SLC30A8 and TCF7L2 genes were genotyped.

Linear regression was used to study association between individual SNPs and the combined allelic risk score with body mass index (BMI), fat mass index (FMI), fat percentage (FAT), waist circumference (WC) and waist to hip ratio (WHR).

Significant association was observed between rs8050136 (FTO) and BMI (p = 0.003), FMI (p = 0.007) and WC (p = 0.03); fat percentage was borderline significant (p = 0.053). No other SNPs alone or combined in a risk score demonstrated significant association to the measures of fatness.

From the recently identified T2D risk variants only the risk variant of theFTO gene (rs8050136) showed statistically significant association with BMI, FMI, and WC.

Toward reading your own personal 'Book of Life'

What secrets about your risk for diseases are written in your own personal "Book of Life" - the 30,000 or so genes that make you you?

Advances in DNA-sequencing technology are bringing closer the day when it will be more economical for consumers to get an answer to that question, and others, by ordering up the deciphering of their entire genetic endowment - their "personal genome." With their Book of Life in hand, consumers and their physicians could map out strategies for the prevention, early diagnosis, and more effective treatment of diseases ranging from cancer to rare-genetic disorders.

C&EN Senior Editor Celia Henry Arnaud notes that the first human genome sequence cost more than $2 billion and took about a decade to complete. Technological advances now have cut the time to as little as one week, and some companies are charging individuals $48,000 for the service, a cost that experts expect to drop sharply in the coming years, the article notes.

But the technology also raises important ethical and legal issues, including the possibility of discrimination on the basis of genetic information in the areas of employment and insurance coverage. Many believe that personal genomes are inevitable. "In the future, sequencing will be so cheap and so easy to access that everybody could get sequenced if they want. It'll be iPod pricing," says the CEO of a company that specializes in direct-to-consumer genome sequencing.

Genetics Times: New research could advance research field critical to personalized medicine

It's the ultimate goal in the treatment of cancer: tailoring a person's therapy based on his or her genetic makeup.

While a lofty goal, scientists are steadily moving forward, rapidly exploiting new technologies. Researchers at Georgetown Lombardi Comprehensive Cancer Center report a significant advance in this field of research using a new chip that looks for hundreds of mutations in dozen of genes.

The goal of personalized medicine is to determine the best treatment and the optimal dose carrying the fewest side-effect, especially as new drugs are discovered and treatment options increase. Variations in our genes encode proteins, which impact how a drug is metabolized or taken in by the cells. This directly impacts the drug's effectiveness and the kinds of side-effects that may be caused by its toxicity.

"Currently, available genotyping tools test only a few genes at a time," explains John F. Deeken, a pharmacogentic researcher at Lombardi. "With a new chip called DMET, as many as 170 genes can be examined for more than a thousand variations. This type of turn-key testing, if validated, could eventually replace highly-specialized, time-consuming and labor-intensive testing -- thus allowing more institutes the opportunity to pursue genotyping and pharmocogenetic research. That alone would be a significant development for our field and for expediting the research many of us believe is the future of medicine."

Such a development is particularly critical for cancer research, both in terms of drug discovery and treatment. Genetic variability among patients in cancer clinical trials is not commonly taken into account, a factor that could skew dosage amounts and doom an otherwise promising new drug. A more simple and faster test could be readily incorporated into treatment trials.

Deeken serves as a consultant to Sanofi-Aventis, the manufacturer of docetaxel, a drug involved in the current reported study. Three other authors are employees of Affymetrix, the manufacturer of the DMET platform. The study was done in part at the National Cancer Institute and supported by funding from the National Institutes of Health.

Institute for Personalized Medicine

Personalized Therapy for Each Patient

Fox Chase's new Institute for Personalized Medicine is on the forefront of a transformation in cancer care. Unlike the traditional method of delivering care, this approach will base treatment on the genetic makeup of an individual patient's tumor, making the "one-size-fits-all" approach to cancer therapy a thing of the past. Through the Institute for Personalized Medicine, our doctors and researchers are using leading edge technology to expand the understanding of cancer genetics, develop clinical trials of new treatments, and match emerging drug treatments to the unique genetics of individual patient tumors.

The immediate objective of the Institute for Personalized Medicine is to sequence exons from genes known to impact key, targetable, signaling pathways in patients with metastatic disease.

Customized Oncology

"Personalized medicine is truly transformational," says Jeff Boyd, senior vice president and chief scientific officer. "It's impossible to overstate this inflection point that cancer medicine is entering. The whole premise of how cancers are treated becomes not the tissue of origin, or how it looks under a microscope, how it looks to the surgeon, how it looks to the pathologist, but how it looks to the DNA sequencer," Boyd says.

The Institute for Personalized Medicine will build on Fox Chase's already substantialBiosample Repository and Tumor Bank to add an additional layer of new knowledge about the genetic information in individual patient tumors. Fox Chase will also use this information to accelerate the development of new cancer treatments through collaboration with its highly regarded Phase 1 Clinical Trials Program, which tests a broad spectrum of novel cancer therapeutics in patients with advanced cancer.

Vision

Our vision is one in which at the time of diagnosis and again at disease progression, a patient's cancer will be sequenced either for selected genes of interest or the entire genome. The resultant information will be housed in a searchable database, thereby allowing patients to be matched to particular drugs based upon mechanism of action, regardless of the phase of clinical trial. Updated eligibility criteria will no longer state the requirement for a given disease but instead will articulate a far more sophisticated paradigm focusing on pathway activation, gene amplification, gene mutation, or combinations thereof.

Health care and personalized genetics

How does a simple petri dish of DNA constitute the identity of a complex human being—from the way she laughs to her love of Cocoa Krispies? It turns out that the question of how biology determines identity interests not only the philosophically-inclined, but those in the drug and healthcare industry as well.

In a recent study published in Molecular Systems Biology, a computational biology team at Columbia explored the very questions that drive the current research on personalized care: How does a cell take a genotype and translate it into a phenotype? More specifically, how do genes determine our responses to medicine?

“The idea behind personalized care is that each of us is very different - we look different, we behave different, we have clearly different disease susceptibilities. All these things are genetically determined. Genetics also determines our responses to drugs,” Dr. Dana Pe’er, head of that computational biology research team, explained. Like many gadget lovers today, patients are clamoring for one-pill-fits-all cures. Tylenol, for instance, claims to relieve four different types of aches, fever, cold, cramps and arthritis. But with standardization comes the possibility of unpleasant side effects, such as, in the case of Tylenol, liver damage.

Medicines tailored to individuals would reduce the possibility of such side effects. But wouldn’t personalized care be much more expensive than the generic options we have now? “It would be cheaper!” Pe’er exclaims. “It would do away with the trial and error. A cancer patient has to pay $100,000 for chemotherapy. Won’t it be nice to tell them, ‘This won’t work for you because of your genes?’ Instead of getting it right on the third try, you can get it right on the first try.

”She also points out that avoiding all the adverse effects saves “tons of money and pain,” and that the “right meds put you back in the workforce in one day instead of three.”

A genotype scan currently costs a hefty $399, but patients only need it once in a lifetime. So what’s stopping personalized care from becoming an everyday reality? Part of the reason is that the science hasn’t yet come that far. According to Pe’er, the technology developed to investigate the connection between genotype and phenotype in terms of drug-responses is only a few years old, and the task it faces is gargantuan.

Pe’er analogizes: “Imagine there’s this huge cave, maze-like, with lots of passageways and everything’s pitch dark. Trying to do research on humans is like searching in this cave without even knowing what you’re looking for.”

To improve the search for the human genes that are related to drug resistance, Pe’er and her team focused on an easier subject: yeast, the common “workhorse” that scientists use to develop technology to apply to humans. By manipulating and testing 104 strains of yeast, they improved old search methods that traditionally relied on genetics by creating a new method that also harnesses gene expression (RNA), which indicates which genes are actively used. Their RNA-utilizing algorithm accurately predicted strain resistance for 87 of the 94 drugs tested, effectively narrowing down the number of genes related to drug resistance.

The main opponents of personalized care are not health insurers. For them, Pe’er believes, profits will rise with the reduction of the trial-and-error process which forces insurers to pay up with every treatment. Instead, pharmaceutical companies are the real antagonists: in order to maximize profit, they want standardized drugs to serve the whole population and not just a section of it. Recent pressure from the FDA—which has threatened to take drugs with adverse side effects off the shelves—has lead to heavy investment in a new field that combines pharmaceutical research and genetics: pharmocogenics. Pharmeceutical companies like Eli Lilly, who’ve been involved in legal disputes for marketing unapproved drugs, are now increasingly involved in studies on patient responses due to genetic variation.

But even if all pharmaceuticals participate to produce personalized medicine on a large scale, the truth is that we are not yet ready for personalized care. Patients and doctors are not adequately trained to interpret genotypes and translate them into appropriate treatments.

Specialized knowledge needs to be transferred from genetic-researchers to everyday medical practitioners. As Joel Burrill points out in an interview with Wired Science, unless medical schools adapt their training programs, there will be a shortage of DNA interpreters. Web sites like 23andme.com do a good job of explaining what the data means, but a large-scale implementation of personalized care would require more than Web sites.

Perhaps just as importantly, the legal infrastructure to protect the privacy of genetic information isn’t sufficiently established. It would be a veritable disaster if health insurers or workplaces got a hold of their clients’ or employees’ genetic predispositions to illnesses.Despite these obstacles, Pe’er believes that personalized care will be a reality within our lifetimes. Things are moving, even if slowly, in the right direction.

By Sarah Ngu

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Whole-Genome Sequencing: Any Useful Data?

ClinSeq is a pilot project to investigate the use of whole-genome sequencing as a tool for clinical research. By piloting the acquisition of large amounts of DNA sequence data from individual human subjects, we are fostering the development of hypothesis-generating approaches for performing research in genomic medicine, including the exploration of issues related to the genetic architecture of disease, implementation of genomic technology, informed consent, disclosure of genetic information, and archiving, analyzing, and displaying sequence data.

In the initial phase of ClinSeq, we are enrolling roughly 1,000 participants; the evaluation of each includes obtaining a detailed family and medical history as well as a clinical evaluation. The participants are being consented broadly for research on many traits and for whole-genome sequencing. Initially, Sanger-based sequencing of 300-400 genes thought to be relevant to atherosclerosis is being performed, with the resulting data analyzed for rare, high-penetrance variants associated with specific clinical traits.

He also mentioned the 1000$ genome project and the unofficial estimation is that now it’s possible to sequence a person’s genome for under 5000$ and the 1000$ aim can become a reality at the end of this year.

Personalized medicine: The Doctors are OK with this?

Yesterday in "The Times" a nice article was posted about the revolutionary way in which doctors will receive education about CLINICAL genetics, this time it is from NonClinical Scientists......

At the tune of 4.5 Million British Pounds!

This may work with CGCs, oh wait, they don't do much of anything in the UK system.

What about clinical geneticists?
Who?

Ok, scientists it is......

So I can just see it now.

A busy NHS practice, patients out the door, flu shot here, flu shot there and in rolls the "Scientist"

Clinician-"Oh hi, you must be the genetics guy sent from the government. Have a seat, I'll be right with you"

4 hours later

Scientist-Sitting nicely, waiting

Clinician-"Ok, lets chat over lunch"

Scientist-"Glad to be here, Let's talk about what a chromosome is"

Clinician-Scarfing down a sandwich "Ok, that was great, gotta go. I am double booked. See you in a few"

4 hours later

Scientist-Sitting Nicely, waiting

Clinician-"Sorry about that, I had a sickie and then the crazy lady....G-d where did the time go?"

Scientist-"See you tomorrow?"

Clinician-"You bet, I feel better prepared already"

As nice as this one is, I have already tried it with a clinical geneticist who actually can create billable events and see patients........ I am not so certain that going to the doctors will help as much as being on their iPhone or on a hotline.......

Is cancer genetic?

Cancer risk is complex. Cancer is so common that we all probably know someone whose life has been affected by one form of cancer or another. A lot of us probably know people who seem to have cancer "running in the family". Cancer can occur in three main ways:

• Sporadic cancers - these are cancers that occur by chance in individuals who have no known genetic risk factors and no significant family history. Approximately 60% of cancers are sporadic.
  
  
• Familial cancers - these are cancers caused by variants in multiple genes and the environment all working together. In this case, each genetic variant causes a slight increase in risk. The overall risk of developing cancer depends on the number of cancer risk genetic variants that a person inherits and what environmental factors interact with those genes. Although these cancers appear to cluster in families, they don’t follow the typical rules of inheritance.
  
  
• Hereditary cancers - these are cancers that are associated with a change in a single cancer susceptibility gene (like BRCA1 or BRCA2). These genes account for a very small percentage of all cancers. In fact, only 5-10% of breast and colon cancer cases are caused by changes in a single gene. Although everyone who carries a change in a cancer susceptibility gene does not get cancer, the risk is increased greatly, usually to 50% or higher. These types of genetic changes are passed on in an autosomal dominant inheritance pattern in families. This means that each child of an individual that carries a gene change in a hereditary cancer susceptibility gene has a 50% chance of inheriting the gene change.

Many people mistakenly think that the risk of cancer is always passed on through families as a single "cancer gene". However, like other complex diseases, changes in many genes that each plays a role in the development of cancer are much more likely to be the cause of familial cancer than a change in a single gene.

The testing that is provided as part of participation in the Coriell Personalized Medicine Collaborative™ study will look at gene changes that contribute to an individual's risk of cancer but WILL NOT look for single genes, such as BRCA1 or BRCA2, known to cause hereditary breast and ovarian cancers or other genes known to cause other hereditary cancer syndromes. If you believe you are at risk of a hereditary cancer syndrome please discuss this with your doctor or a genetic counselor.

nheriting a "cancer gene" does NOT mean you will get cancer

Having a genetic variant associated with cancer does NOT mean that you will definitely get cancer. A genetic variant associated with cancer is simply another risk factor. Just as non-genetic risk factors like smoking or diet impact your overall cancer risk, genetic variants also influence your risk of developing cancer. Knowing that you have a genetic risk and understanding what it means may motivate you to make preventive lifestyle and behavioral changes. It may also encourage you to ask your doctor about other ways to help lower your risk.

Genetic changes can influence cancer treatment

Treatment for cancer is very complex. Two patients with the same type of cancer may respond very differently to the same treatment. While some genes are involved in the risk to develop cancer, other genes are involved in the way our body responds to medicine. Researchers have found gene changes that are associated with a better or worse response to certain cancer-fighting drugs. The CPMC research study hopes to gain a better understanding of the genetic variants that play a role in drug response so that this information can be used to improve the treatment of cancer and other diseases.

New database for gene variations will help diagnosticians

Genetics researchers have unveiled a reference standard of deletions and duplications of DNA found in the human genome. Drawn from over 2,000 healthy persons, the study provides one of the deepest and broadest sets of copy number variations (CNVs) available to date, along with a new research tool for diagnosing and identifying genetic problems in patients.

A team from The Children's Hospital of Philadelphia published its high-resolution map and analysis of CNVs in the human genome in the July 10 online edition of the journal Genome Research.

In contrast to single base alterations of DNA, which are single nucleotide polymorphisms, or SNPs, often referred to as "snips," CNVs are larger variations in DNA structure. As changes to a single DNA letter, SNPs might be considered misspellings or alternate spellings of a word, while CNVs are losses of whole phrases, paragraphs or even pages (deletions), or are repeated sections (duplications). Some CNVs are inserted stretches of DNA from other parts of the genome. Both SNPs and CNVs contribute to genetic diversity and disease by changing the action of genes for which DNA carries coded instructions.

"We all carry a number of these variations in our own genomes," said study co-leader Peter S. White, Ph.D., a molecular geneticist and director of the Center for Biomedical Informatics at Children's Hospital. "Some CNVs contribute to a disorder, but most of them do not, and it is often challenging to determine which are important. One approach is to compare CNVs in healthy individuals to those in patients with a disease, to find those CNVs that seem to occur primarily in people with a certain disease. Our map provides a large and uniform baseline standard to indicate which CNVs represent normal variation."

The investigators analyzed DNA from blood samples taken from 2,026 subjects. The subjects were healthy children and their parents, all of them drawn from primary care and well-child clinics in the Children's Hospital health care network. Of the samples, 65 percent were from Caucasians and 34 percent from African Americans.

The CNV map has a higher resolution than most previous efforts, say the authors, with over 50,000 CNVs cataloged throughout the genome. Three-quarters of these were "non-unique," occurring in multiple unrelated individuals. A majority (51.5 percent) of these non-unique CNVs were newly discovered. On average, the healthy subjects in the study have approximately 27 CNVs each.

The researchers have posted the full CNV database on the Hospital's website, where it is freely available to gene researchers worldwide. The web browser also enables researchers to compare specific CNVs to those collected in public data repositories from other institutions.

"This resource will be very important in enabling rapid and accurate diagnoses of rare diseases resulting from CNVs," said lead author Tamim H. Shaikh, Ph.D., a molecular geneticist at Children's Hospital. These genetic diseases may be individually rare, but collectively occur at frequencies comparable to disorders such as Down syndrome. "In order to pinpoint the one CNV that is the cause of a disease, it is critical to quickly eliminate those that are part of the spectrum of normal variation that exists in the human genome. That's what this CNV data and other similar resources allow us to do," Shaikh added.

The authors went on to analyze DNA from a child with multiple congenital problems, including developmental delay and brain malformations. They found 35 CNVs, of which 32 were previously detected in healthy controls. Two of the patient's three unique CNVs were relatively small in size, but the third CNV was a deletion in chromosome 17 that encompassed 51 genes, including several that are active in early prenatal development. Unlike most of the other CNVs, it did not occur in the child's parents, strongly supporting the conclusion that the chromosome deletion arose spontaneously in the patient and that it caused the child's disease.

To detect CNVs in the thousands of samples, the investigators used automated gene-analyzing technology at the Center for Applied Genomics at Children's Hospital, directed by Hakon Hakonarson, M.D., Ph.D., a co-leader of this study. "Although these CNVs were detected in healthy children, they may have significant disease implications that may not manifest until later in life," said Hakonarson. Hakonarson and colleagues earlier published studies of CNVs in autistic spectrum disorders and attention-deficit hyperactivity disorder. Both studies found CNVs in gene regions involved in neurological development during early childhood.

The new database has another strength, added Shaikh. Because it analyzed large numbers of samples from both Caucasians and African Americans, it measured CNV levels that differ between the two ethnic groups, and enables clinicians to make more precise diagnoses. Shaikh added that the researchers expect to expand the database with larger sample sizes and data from additional ethnic populations.

In addition to its use in diagnosis, said White, the database may also assist researchers studying molecular evolution. For example, those investigating how genetic variations occurred as human populations spread across continents.

Source: Children's Hospital of Philadelphia

Start-Ups Bring Genetic Tests To The Home

By Brian Gormley

What’s in your DNA? Venture capitalists believe you’ll pay to find out.

A few venture firms are funding start-ups that promise to offer consumers insight into what their DNA says about ancestry or disease risks. While most of these services don’t diagnose disease, they say they can spot warning signs.

The latest company seeking to help consumers decode their genetic risk for disease isPathway Genomics Corp., which recently introduced its service to take on venture-funded companies such as Navigenics Inc. and 23andMe Inc., as well as publicly traded companies like deCODE Genetics Inc.

Pathway, based in San Diego, formed in 2008 and closed its most recent venture round in June, though it is not disclosing how much it raised. Investors include technology firm Founders Fund, Western Technology Investment, and Harry Edelson, who has funded several health care and technology companies through Edelson Technology Partners. Navigenics backers include Kleiner Perkins Caufield & Byers, while 23andMe has raised capital from New Enterprise Associates, Genentech Inc. and others.

Pathway Genomics will charge $249 for a service that provides consumers with their genetic risk to more than 90 health conditions by analyzing their genome for genetic markers. Consumers also can order an ancestry test for $199, or both services for $348.

Consumers can learn their genetic risk for several cancers, including those of the prostate and breast, cardiovascular diseases, rheumatoid arthritis, Type 1 and Type 2 diabetes, and many other diseases.

Its prices are in the range of what others charge: 23andMe offers a service that provides disease risk and ancestral information for $399, for example. Pathway Genomics performs its services at its own research lab, so customers’ DNA - taken from saliva samples that they send in after ordering a test from Pathway’s Web site - never leaves the company’s grounds. Its lab has State of California and Clinical Laboratory Improvement Amendments certifications.

For an additional fee, Pathway Genomics customers can also gain access to genetic counselors. The company hasn’t disclosed what it will charge for these services, but James Plante, founder and CEO, said the fees will only cover its expenses and won’t be a moneymaker.

“We think it’s an important service to have available. We don’t anticipate it being a profit center,” Plante said.

Improved understanding of how genetic variations influence health has combined with technological innovation to make such services possible. But since health insurers aren’t covering these offerings - at least not yet - anyone wanting these services will have to pay up for them. It’s as yet unclear how many people will do so.

A Doctor’s Vision of the Future of Medicine

It's June 2018. Sally picks up a handheld device and holds it to her finger. With a tiny pinprick, it draws off a fraction of a droplet of blood, makes 2,000 different measurements and sends the data wirelessly to a distant computer for analysis. A few minutes later, Sally gets the results via e-mail, and a copy goes to her physician. All of Sally's organs are fine, and her physician advises her to do another home medical checkup in six months.

This is what the not-so-distant future of medicine will look like. Over the next two decades, medicine will change from its current reactive mode, in which doctors wait for people to get sick, to a mode that is far more preventive and rational. I like to call it P4 medicine—predictive, personalized, preventive and participatory. What's driving this change are powerful new measurement technologies and the so-called systems approach to medicine. Whereas medical researchers in the past studied disease by analyzing the effects of one gene at a time, the systems approach will give them the ability to analyze all your genes at once. The average doctor's office visit today might involve blood work and a few measurements, such as blood pressure and temperature; in the near future physicians will collect billions of bytes of information about each individual—genes, blood proteins, cells and historical data. They will use this data to assess whether your cell's biological information-handling circuits have become perturbed by disease, whether from defective genes, exposure to bad things in the environment or both.

Several emerging technologies are making this holistic, molecular approach to disease possible. Nano-size devices will measure thousands of blood elements, and DNA sequencers will decode individual human genomes rapidly, accurately and inexpensively. New computers will sort through huge amounts of data gathered annually on each individual and boil down this information to clear results about health and disease.

Medicine will begin to get more predictive and personalized (the first two aspects of P4 medicine) over the next five to 10 years. First, doctors will be able to sequence the genome of each patient, which together with other data will yield useful predictions about his or her future health; it will be able to tell you, for example, that you have a 30 percent chance of developing ovarian cancer before age 30. Second, a biannual assessment of your blood will make it possible to get an update on the current state of your health for each of your 50 or so organ systems. These steps will place the focus of medicine on individual patients and on assessing the impact that genes and their interactions with the environment have in determining health or disease.

In preventive medicine (the third P), researchers will use systems medicine to develop drugs that help prevent disease. If, say, you have a 50 percent chance of developing prostate cancer by the time you're 50, you may be able to start taking a drug when you're 30 that would reduce substantially reduce that probability. In the next 10 to 20 years the focus of health care will shift from dealing with disease to maintaining wellness.

Participatory medicine acknowledges the unparalleled opportunities that patients will have to take control of their health care. To participate effectively, though, they will have to be educated as to the basic principles of P4 medicine. New companies that can analyze human genome variation, like 23andMe and Navigenics, are already planning to provide patients with genetic information that may be useful in modifying their behavior to avoid future health problems. In the future, patients will need not just genetic data but insight into how the environment is turning genes on and off to cause disease—just as smoking often causes lung cancer and exposure to sunlight can cause skin cancer.

By Leroy Hood (NEWSWEEK)

personal genomics in europe

Following the booming of personalized genetics on the other side of the globe, I'm quite curious about the impact that personal genomic screening services might have, and probably will have, in Europe.

There are at least two considerations to make: first, Europe is less dependent on private health insurance, therefore, less tempted by DIY medical analyses; second, these tests seems to rely on an internet-based service that is not so diffuse in Europe, especially among southern countries. Will these barriers be enough to stop the wave of "trendy" personal genetic testing approaching our continent?