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Full genome sequencing

Full genome sequencing (FGS), also known as whole genome sequencing, complete genome sequencing, or entire genome sequencing, is a laboratory process that determines the complete DNA sequence of an organism's genome at a single time. This entails sequencing all of an organism's chromosomal DNA as well as DNA contained in the mitochondria and for plants the chloroplast as well. Almost any biological sample—even a very small amount of DNA or ancient DNA—can provide the genetic material necessary for full genome sequencing. Such samples may include saliva, epithelial cells, bone marrow, hair (as long as the hair contains a hair follicle), seeds, plant leaves, or anything else that has DNA-containing cells. Because the sequence data that is produced can be quite large (for example, there are approximately six billion base pairs in each human diploid genome), genomic data is stored electronically and requires a large amount of computing power and storage capacity. Full genome sequencing would have been nearly impossible before the advent of the microprocessor, computers, and the Information Age.

Full genome sequencing should thus not be confused with DNA profiling. The latter only determines the likelihood that genetic material came from a particular individual or group and does not contain additional information on genetic relationships, origin or suspectability on specific diseases.[1]. It is also distinct from SNP genotyping which covers less than 0.1% of the genome. Almost all truly complete genomes are of microbes; the term "full genome" is thus sometimes used loosely to mean "greater than 95%". The remainder of this article focuses on nearly complete human genomes.

In general, knowing the complete DNA sequence of an individual's genome does not, on its own, provide useful clinical information, but this may change over time as a large number of scientific studies continue to be published detailing clear associations between specific genetic variants and disease.[2][3]

The first nearly complete human genomes sequenced were J. Craig Venter's (Caucasian at 7.5-fold average coverage) [4][5][6] and James Watson's (Caucasian male at 7.4-fold).[7][8][9], a Han Chinese (YH at 36-fold) [10], a Yoruban from Nigeria (at 30-fold) [11], a female leukemia patient (at 33 and 14-fold coverage for tumor and normal tissues)[12], and Seong-Jin Kim (Korean at 29-fold) [13]. Other full genomes have been sequenced but not published, and as of June 2009, commercialization of full genome sequencing is in an early stage and growing rapidly.

New techniques
An ABI PRISM 3100 Genetic Analyzer. Sequencers automate the process of sequencing the genome.

One possible way to accomplish the cost-effective high-throughput sequencing necessary to accomplish full genome sequencing is by using Nanopore technology, which is a patented technology held by Harvard University and Oxford Nanopore Technologies and licensed to biotechnology companies.[14] To facilitate their full genome sequencing initiatives, Illumina licensed nanopore sequencing technology from Oxford Nanopore Technologies and Sequenom licensed the technology from Harvard University.[15][16] Another possible way to accomplish cost-effective high-throughput sequencing is by utilizing fluorophore technology. Pacific Biosciences is currently using this approach in their SMRT (single molecule real time) DNA sequencing technology.[17] Complete Genomics is developing DNA Nanoball (DNB) technology that are arranged on self-assembling arrays.[18] Pyrosequencing is a method of DNA sequencing based on the sequencing by synthesis principle.[19] The technique was developed by Pål Nyrén and his student Mostafa Ronaghi at the Royal Institute of Technology in Stockholm in 1996,[20][21][22] and is currently being used by 454 Life Sciences in their effort to deliver an affordable, fast and highly accurate full genome sequencing platform.[23]

Older techniques

Sequencing of the entire human genome was first accomplished in 2000 partly through the use of shotgun sequencing technology. While full genome shotgun sequencing for small (4000–7000 base pair) genomes was already in use in 1979,[24] broader application benefited from pairwise end sequencing, known colloquially as double-barrel shotgun sequencing. As sequencing projects began to take on longer and more complicated genomes, multiple groups began to realize that useful information could be obtained by sequencing both ends of a fragment of DNA. Although sequencing both ends of the same fragment and keeping track of the paired data was more cumbersome than sequencing a single end of two distinct fragments, the knowledge that the two sequences were oriented in opposite directions and were about the length of a fragment apart from each other was valuable in reconstructing the sequence of the original target fragment.

The first published description of the use of paired ends was in 1990 as part of the sequencing of the human HPRT locus,[25] although the use of paired ends was limited to closing gaps after the application of a traditional shotgun sequencing approach. The first theoretical description of a pure pairwise end sequencing strategy, assuming fragments of constant length, was in 1991.[26] In 1995 Roach et al.introduced the innovation of using fragments of varying sizes,[27] and demonstrated that a pure pairwise end-sequencing strategy would be possible on large targets. The strategy was subsequently adopted by The Institute for Genomic Research (TIGR) to sequence the entire genome of the bacterium Haemophilus influenzae in 1995,[28] and then by Celera Genomics to sequence the entire fruit fly genome in 2000,[29] and subsequently the entire human genome. Applied Biosystems, now called Life Technologies, manufactured the shotgun sequencers utilized by both Celera Genomics and The Human Genome Project.

While shotgun sequencing was one of the first approaches utilized to successfully sequence the full genome of a human, it is too expensive and requires too long of a turn-around-time to be utilized for commercial purposes. Because of this, shotgun sequencing technology, even though it is still relatively 'new', is being displaced by technologies like pyrosequencing, SMRT sequencing, and nanopore technology.[30]
[edit] Race to commercialization

In October 2006, the X Prize Foundation, working in collaboration with the J. Craig Venter Science Foundation, established the Archon X Prize for Genomics,[31] intending to award US$10 million to "the first Team that can build a device and use it to sequence 100 human genomes within 10 days or less, with an accuracy of no more than one error in every 100,000 bases sequenced, with sequences accurately covering at least 98% of the genome, and at a recurring cost of no more than $10,000 per genome."[32] However, higher accuracy rates (or confirmatory methods) are desirable for some clinical applications. An error rate of 1 in 100,000 bases, out of a total of six billion bases in the human diploid genome, would mean about 60,000 errors per genome, which is a significant number of false positives and negatives. For the latter it is not known where the errors occur . The error rates required for widespread clinical use, such as Predictive Medicine[33] is currently set by over 1400 clinical single gene sequencing tests [34] (for example, errors in BRCA1 gene for breast cancer risk analysis). As of May 2010, the Archon X Prize for Genomics remains unclaimed.

In 2007, Applied Biosystems started selling a new type of sequencer called SOLiD System in 2008.[35] Current SOLiD chemistries enable users to sequence 60 gigabases per run.[36]

In 2008 and 2009, both public and private companies have emerged that are now in a competitive race to be the first mover to provide a full genome sequencing platform that is commercially robust for both research and clinical use,[37] including Illumina,[38] Sequenom,[39] 454 Life Sciences,[40] Pacific Biosciences,[41] Complete Genomics,[42] Intelligent Bio-Systems,[43] Genome Corp.,[44] ION Torrent Systems,[45] and Helicos Biosciences[46]. These companies are heavily financed and backed by venture capitalists, hedge funds, investment banks and, in the case of Illumina, Sequenom and 454, heavy re-investment of revenue into research and development, mergers and acquisitions, and licensing initiatives.[47][48][49]

In the race to commercialize full genome sequencing, companies have made claims about being able to offer a service at a specific time for a specific price that have turned out to not be true. Intelligent Bio-Systems stated in November 2007 that by the end of 2008 they would release a platform capable of a providing a $5,000 full genome sequence, but, as of May 2010, no such platform has yet to be released.[50]

Pacific Biosciences stated that they would start selling their full genome sequencers in early 2010. While they didn't disclose the cost to sequence a single genome, they did state they may not release their second-generation machine capable of a $1,000 genome until 2013.[51] Complete Genomics, however, stated that they'll be able to provide a $5,000 full genome sequencing service by the summer of 2009.[52] The accuracy, precision, and reproducibility of both Pacific Biosciences and Complete Genomics technology, however, is still unknown.

Knome currently provides genome sequencing services but the cost is about $99,500 per genome (down from $350,000 per genome initially),[53] the turn-around time is unknown, the accuracy is unknown, and the number of people was limited to 20 for the first year, and is still considered early stage commercialization of full genome sequencing, focusing on wealthy customers.[54]

As of January 2009, there are no indications that any of these companies have been hindered by the global recession. And thus, the race appears to be proceeding forward at full speed.[55]

At the end of February 2009, Complete Genomics released a full sequence of a human genome that was sequenced using their service. The data indicates that Complete Genomics' full genome sequencing service accuracy is just under 99.99%, meaning that there is an error in one out of every ten thousand base pairs. This means that their full sequence of the human genome will contain approximately 80,000-100,000 false positive errors in each genome. However, this accuracy rate was based on Complete Genomics' sequence that was completed utilizing a 90x depth of coverage (each base in the genome was sequenced 90 times) while their commercialized sequence is reported to be only 40x, so the accuracy may be substantially lower unless they can find some way to improve it before their first service release planned for the summer 2009. This accuracy rate may be acceptable for research purposes, and clinical use would require confirmation by other methods of any reportable alleles.[56][57] In March 2009, it was announced that Complete Genomics has signed a deal with the Broad Institute to sequence cancer patient's genomes and will be sequencing five full genomes to start.[58] In April 2009, Complete Genomics announced that it plans to sequence 1,000 full genomes between June 2009 and the end of the year and that they plan to be able to sequence one million full genomes per year by 2013.[59] Complete Genomics plans to officially launch in June 2009, although it is unknown if their lab will have received CLIA-certification by that time.

In June 2009, Illumina announced that they were launching their own Personal Full Genome Sequencing Service at a depth of 30X for $48,000 per genome.[60] This is still expensive for widespread consumer use, but the price may decrease substantially over the next few years as they realize economies of scale and given the competition with other companies such as Complete Genomics.[61][62] Jay Flatley, Illumina's President & CEO, stated that "during the next five years, perhaps markedly sooner," the price point for full genome sequencing will fall from $48,000 to under $1,000.[63] Illumina has already signed agreements to supply full genome sequencing services to multiple direct-to-consumer personal genomics companies.

In August 2009, the founder of Helicos Biosciences, Dr. Stephen Quake, stated that using the company's Heliscope Single Molecule Sequencer he sequenced his own full genome for less than $50,000. He stated that he expects the cost to decrease to the $1,000 range within the next two to three years.[64]

In August 2009, Pacific Biosciences secured an additional $68 million in new financing, bringing their total capitalization to $188 million.[65] Pacific Biosciences said they are going to use this additional investment in-order to prepare for the upcoming launch of their full genome sequencing service in 2010.[66] Complete Genomics followed by securing another $45 million in a fourth round venture funding during the same month.[67] Complete Genomics has also made the claim that it will sequence 10,000 full genomes by the end of 2010.[68]

GE Global Research is also now in the race to commercialize full genome sequencing as they are currently working on creating a service that will deliver a full genome for $1,000 or less.[69]

In September 2009, the President of Halcyon Molecular announced that they will be able to provide full genome sequencing in under 10 minutes for less than $100 per genome.[70] This is, to date, the most ambitious promise of any full genome sequencing company.

In October 2009, IBM announced that they were also in the heated race to provide full genome sequencing for under $1,000, with their ultimate goal being able to provide their service for $100 per genome.[71] IBM's full genome sequencing technology, which uses nanopores, is known as the "DNA Transistor."[72]

In November 2009, Complete Genomics announced that they are now able to sequence a full genome for $1,700.[73] If true, this would mean the cost of full genome sequencing has come down exponentially within just a single year from around $100,000 to $50,000 and now to $1,700. However, it should be noted that Complete Genomics has previously released statements that it was unable to follow through on. For example, the company stated it would officially launch and release its service during the "summer of 2009," provide a "$5,000" full genome sequencing service by the "summer of 2009," and that it would "sequence 1,000 genomes between June 2009 and the end of 2009" - all of which, as of November 2009, have not yet occurred.[52][57][59][59]

In March 2010, Pacific Biosciences said they have raised more than $256 million USD in venture capital money and that they will be shipping their first 10 full genome sequencing machines by the end of 2010. The company reported that the market initially will be researchers and academic institutions and then will rapidly turn into clinical applications that will be applicable to every single person in the world. Pacific Biosciences also stated that their second generation machine, which is scheduled for release in 2015, will be capable of providing a full genome sequence for a person in just 15 minutes for less than $100 USD. Therefore, within five years we may see full genome sequencing revolutionize medicine by providing clinicians with a full genome for each one of his or her patients. However, the medical community has shown some push-back to this, stating that even if they are supplied with a full genome sequence of a patient, they wouldn't know how to analyze or make use of that data.[74]

In June 2010, Illumina 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.

Helicos Biosciences, Pacific Biosciences, Complete Genomics, Illumina, Sequenom, ION Torrent Systems, Halcyon Molecular, IBM, and GE Global appear to all be going head to head in the race to commercialize full genome sequencing.

Disruptive technology

Full genome sequencing provides information on a genome that is orders of magnitude larger than that provided by the current leader in sequencing technology, DNA arrays. For humans, DNA arrays currently provides genotypic information on up to one million genetic variants,[75][76][77] while full genome sequencing will provide information on all six billion bases in the human genome, or 3,000 times more data. Because of this, full genome sequencing is considered disruptive to the DNA array markets as the accuracy of both range from 99.98% to 99.999% (in non-repetitive DNA regions) and their cost of $5000 per 6 billion base pairs is competitive (for some applications) with DNA arrays ($500 per 1 million basepairs).[40] Agilent, another established DNA array manufacturer, is working on targeted (selective region) genome sequencing technologies[78]. It is thought that Affymetrix, the pioneer of array technology in the 1990s, has fallen behind due to significant corporate and stock turbulence and is currently not working on any known full genome sequencing approach.[79][80][81] It is unknown what will happen to the DNA array market once full genome sequencing becomes commercially widespread, especially as companies and laboratories providing this disruptive technology start to realize economies of scale. It is postulated, however, that this new technology may significantly diminish the total market size for arrays and any other sequencing technology once it becomes commonplace for individuals and newborns to have their full genomes sequenced.[82]

Sequencing versus Analysis

Full genome sequencing provides raw data on all six billion letters in an individual's DNA. However, it does not provide an analysis of what that data means or how that data can be utilized in various clinical applications, such as in medicine to help prevent disease. As of now, the companies that are working on providing full genome sequencing do not provide clinical analytical services for the interpretation of the raw genetic data. Therefore, in-order for this data to be useful, researchers or companies first need to find a way to analyze it on a clinical level and make it useful to physicians and patients.[74]

Societal impact
Further information: Personal genomics - predictive medicine services already available

Inexpensive, time-efficient full genome sequencing will be a major accomplishment not only for the field of Genomics, but for the entire human civilization because, for the first time, individuals will be able to have their entire genome sequenced. Utilizing this information, it is speculated that health care professionals, such as physicians and genetic counselors, will eventually be able to use genomic information to predict what diseases a person may get in the future and attempt to either minimize the impact of that disease or avoid it altogether through the implementation of personalized, preventive medicine. Full genome sequencing will allow health care professionals to analyze the entire human genome of an individual and therefore detect all disease-related genetic variants, regardless of the genetic variant's prevalence or frequency. This will enable the rapidly emerging medical fields of Predictive Medicine and Personalized Medicine and will mark a significant leap forward for the clinical genetic revolution. Full genome sequencing is clearly of great importance for research into the basis of genetic disease. However, it should be recognized that despite advancements in genome sequencing technology, incomplete understanding of the significance of individual variants or combinations of variants will limit the widespread usefulness of full genome sequencing in medicine until its clinical utility can be demonstrated.

Illumina's CEO, Jay Flatley, stated in February 2009 that "A complete DNA read-out for every newborn will be technically feasible and affordable in less than five years, promising a revolution in healthcare" and that "by 2019 it will have become routine to map infants' genes when they are born."[83] This potential use of genome sequencing is highly controversial, as it runs counter to established ethical norms for predictive genetic testing of asymptomatic minors that have been well established in the fields of medical genetics and genetic counseling.[84][85][86][87] The traditional guidelines for genetic testing have been developed over the course of several decades since it first became possible to test for genetic markers associated with disease, prior to the advent of cost-effective, comprehensive genetic screening. It is established that norms, such as in the sciences and the field of genetics, are subject to change and evolve over time.[88][89] It is unknown whether traditional norms practiced in medical genetics today will be altered by new technological advancements such as full genome sequencing.

Today, parents have the legal authority to obtain testing of any kind for their children. Currently available newborn screening for childhood diseases allows detection of rare disorders that can be prevented or better treated by early detection and intervention. Specific genetic tests are also available to determine an etiology when a child's symptoms appear to have a genetic basis. Full genome sequencing, however, reveals a large amount of information (such as carrier status for autosomal recessive disorders, genetic risk factors for complex adult-onset diseases, and other predictive medical and non-medical information) that is currently not completely understood, not clinically useful during childhood, and may not necessarily be wanted by the individual upon reaching adulthood. Despite the theoretical (and currently unproven) benefits of predicting disease risk in childhood, genetic testing also introduces potential harms (such as discovery of non-paternity, genetic discrimination, and psychological impacts). The established ethical guidelines for predictive genetic testing of asymptomatic minors thus has more to do with protecting this vulnerable population and preserving the individual's privacy and autonomy to know or not to know their genetic information, than with the technology that makes this possible. While parents may have legal authority to obtain such testing, the mainstream opinion of professional medical genetics societies is that presymptomatic testing should be offered to minors only when they are competent to understand the relevancy of genetic screening so as to allow them to participate in the decision about whether or not it is appropriate for them.[90][91]

See also

* DNA microarray
* DNA profiling
* Medical genetics
* Human Genome Project
* Personal Genome Project
* List of sequenced eukaryotic genomes
* List of sequenced bacterial genomes
* List of sequenced archaeal genomes
* Predictive medicine
* Personalized medicine
* Stratified medicine


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External links

* Archon X Prize for Genomics
* James Watson's Personal Genome Sequence
* AAAS/Science: Genome Sequencing Poster
* Outsmart Your Genes: Book that discusses full genome sequencing and its impact upon health care and society


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