Nav: Home

Successful precision medicine will require more accurate genome sequencing

March 01, 2016

Large areas of medically important genes fall within troublesome regions of the human genome, where it is currently difficult to obtain accurate sequence information, according to research published in the open access journal Genome Medicine. On average, one fifth of each of these medically important genes is challenging for today's gene sequencing methods to decipher, and the information in these gene regions may be key to a patient's diagnosis or treatment plan.

To optimize medical care, an accurate account of each patient's genetic code is needed to predict risk for disease and to select appropriate medication. The study by researchers from Stanford University highlights the medical consequences of sequencing errors.

Such errors include false positives (identifying genetic mutations that aren't really there) as well as false negatives (failing to detect legitimate disease-causing mutations). Both can have profound consequences for patient care. For example, a false positive mutation in BRCA2, a well-known gene associated with hereditary breast and ovarian cancer, could lead to risk-reducing surgeries, such as double mastectomy and oophorectomy. Thus, a wrongly identified mutation could potentially lead to radical and unnecessary surgeries.

The Stanford team used a gold-standard genome sequence, provided by the US National Institute of Standards and Technology (NIST). This genome, belonging to a female of European ancestry, had been previously sequenced with five different sequencing technologies. The NIST team combined the results from all five technologies to develop a reliable consensus sequence in regions of the genome where the technologies agreed. A reliable consensus was achieved for just 77% of this donor's genome.

Looking at how these "high confidence" areas of the donor's genome overlap with 3,300 genes known to cause human disease, the researchers found that for 593 of these genes, less than half of the crucial protein-coding regions are in areas that can reliably be sequenced.

There is a group of 56 disease genes regarded as most medically "actionable" by the American College of Medical Genetics and Genomics (ACMG), including BRCA2. ACMG guidelines now require clinical genetic testing labs to screen all patients undergoing exome or genome sequencing for disease-causing mutations in these 56 genes, which are involved in treatable conditions ranging from hereditary cancer to life-threatening cardiac arrhythmias. A patient might initially undergo sequencing to identify the cause of their autism, for example, yet would also be informed of an incidental finding in BRCA2, with the goal of predicting or even preventing disease.

Yet for these medically-important genes, the Stanford researchers found that only 80% of each gene's protein-coding regions, on average, can be sequenced with confidence.

This study also shows that the majority of disease-causing mutations identified to date fall within easy-to-sequence areas. Specifically, among disease-causing mutations catalogued in the database ClinVar, more than 80% fall within high-confidence regions of the NIST genome. Furthermore, the overwhelming majority of these ClinVar mutations (greater than 98%) are in stretches of unique DNA sequence, long known to be easier to sequence.

These findings highlight the need for sequencing methods that better penetrate hard-to-sequence regions of the genome, accurately revealing disease-causing mutations there that may currently be obscured.

Lead author Rachel Goldfeder, from Stanford University, says, "As this technology moves from the research lab to the clinic, we need to be able to accurately and reliably sequence entire genomes, because incorrect sequence information can lead to inappropriate medical care. The good news is that, in this case, 77% of the donor's genome was reliably sequenced using current methods. The challenge now is to focus our efforts on the other 23%--namely, on regions of the genome that remain elusive. Only then can we realize the full potential of precision medicine."
Media Contact

Alanna Orpen
PR Assistant
BioMed Central
T: +44 (0)20 3192 2054

Notes to editor:

1. Medical implications of technical accuracy in genome sequencing

Rachel L. Goldfeder, James R. Priest, Justin M. Zook, Megan Grove, Daryl Waggott, Matthew Wheeler, Marc Salit, Euan Ashley

Genome Medicine 2016

During the embargo period, please contact Alanna Orpen for a copy of the article.

After the embargo lifts, the article will be available at the journal website here:

Please name the journal in any story you write. If you are writing for the web, please link to the article. All articles are available free of charge, according to BioMed Central's open access policy.

2. An open access journal at the cutting edge of genomic and high-throughput technologies, medical discovery, and clinical application, Genome Medicine publishes high quality peer-reviewed articles of broad interest. Current areas of focus include precision medicine, novel methods and software, disease genomics and epigenomics, immunogenomics, infectious disease, microbiome, and systems medicine.

3. BioMed Central is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Nature, a major new force in scientific, scholarly, professional and educational publishing, created in May 2015 through the combination of Nature Publishing Group, Palgrave Macmillan, Macmillan Education and Springer Science+Business Media.

BioMed Central

Related Genome Articles:

Genome evolution goes digital
Dr. Alan Herbert from InsideOutBio describes ground-breaking research in a paper published online by Royal Society Open Science.
Breakthrough in genome visualization
Kadir Dede and Dr. Enno Ohlebusch at Ulm University in Germany have devised a method for constructing pan-genome subgraphs at different granularities without having to wait hours and days on end for the software to process the entire genome.
Sturgeon genome sequenced
Sturgeons lived on earth already 300 million years ago and yet their external appearance seems to have undergone very little change.
A sea monster's genome
The giant squid is an elusive giant, but its secrets are about to be revealed.
Deciphering the walnut genome
New research could provide a major boost to the state's growing $1.6 billion walnut industry by making it easier to breed walnut trees better equipped to combat the soil-borne pathogens that now plague many of California's 4,800 growers.
Illuminating the genome
Development of a new molecular visualisation method, RNA-guided endonuclease -- in situ labelling (RGEN-ISL) for the CRISPR/Cas9-mediated labelling of genomic sequences in nuclei and chromosomes.
A genome under influence
References form the basis of our comprehension of the world: they enable us to measure the height of our children or the efficiency of a drug.
How a virus destabilizes the genome
New insights into how Kaposi's sarcoma-associated herpesvirus (KSHV) induces genome instability and promotes cell proliferation could lead to the development of novel antiviral therapies for KSHV-associated cancers, according to a study published Sept.
Better genome editing
Reich Group researchers develop a more efficient and precise method of in-cell genome editing.
Unlocking the genome
A team led by Prof. Stein Aerts (VIB-KU Leuven) uncovers how access to relevant DNA regions is orchestrated in epithelial cells.
More Genome News and Genome Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at     You can read The Transition Integrity Project's report here.