Good news is that sequencing costs and storage requirements have decreased, making WGS increasingly feasible. But is it worthwhile?<\/p>\n
Yale Medicine is among a few hospitals providing whole genome sequencing (WGS). WGS works by translating 3 billion DNA base pairs into letters that doctors can read using tools and software.<\/p>\n
Genome sequencing used to be an expensive endeavor; even with recent decreases in cost, its implementation remains prohibitively expensive for many patients and healthcare systems.<\/p>\n
However, technological advancements in sequencing are driving costs down further. For instance, Ultima Genomics UG100 platform can sequence seven human genomes at 30x coverage in just an hour! Although this represents an historic achievement in genomics, rapidly declining costs associated with sequencing technology don’t translate to reduced costs of other aspects – since more data is produced faster, robust infrastructure and effective data protection principles become ever more essential to ensure integrity of production and preservation of privacy are key considerations.<\/p>\n
Whole genome sequencing can be an effective way of diagnosing rare and inherited diseases, particularly rare genetic variants that lead to protein-coding genes and examine whether these mutations cause disease. Furthermore, whole genome sequencing helps clinicians locate causes for unexplained symptoms as well as guide treatment decisions.<\/p>\n
Apart from diagnostic purposes, whole genome sequencing can also be used to uncover risk factors associated with certain diseases. This information can be used to inform lifestyle choices and preventive strategies; furthermore it may even help improve medical treatments or create personalized medicine.<\/p>\n
WGS can be especially advantageous for newborns, as it can detect potential causes for conditions before symptoms appear. WGS’ results can often have profound implications for children and their families – in fact, Yale Medicine currently offers WGS to newborns in its neonatal intensive care unit (NICU) and pediatric intensive care unit (PICU).<\/p>\n
WGS testing may also be undertaken for personal reasons; James Watson, who won a Nobel Prize for his research into DNA structure in 1953, had his genome sequenced at 79 years old to assess genetic risks for Late-Onset Alzheimer’s Disease that had already claimed his grandmother.<\/p>\n
No matter your reason for testing, it’s essential to keep in mind that Whole Genome Sequencing (WGS) is still in its early stages of development. While companies like 23andMe, which offers SNP testing services such as 23andMe can provide useful takeaways such as cousin matches and trait predictions from this technology, WGS databases with millions of members don’t yet exist yet.<\/p>\n
Costs associated with genome sequencing continue to drop steadily. Although its accessibility remains limited, genomic sequencing now is within reach for many. Sequencing requires expensive specialized equipment and expert scientists as well as raw materials that have their own associated fees.<\/p>\n
At the start of HGP, costs associated with producing the initial draft sequence were estimated at $300 million; of this sum 50-60% were provided by NIH and this only covers sequencing costs (ie: sequencing the 3 billion base pairs that make up human genome); not including costs related to physical mapping efforts or related efforts under HGP umbrella.<\/p>\n
After the HGP, revolutionary DNA sequencing technologies emerged that greatly reduced genomic sequencing costs. NHGRI collected information on these costs from its funded genome-sequencing groups, and by 2015 the cost to sequence a whole genome had dropped below $4,000.<\/p>\n
Targeted genome sequencing techniques that skip over parts that correspond to genes can be even cheaper. Techniques have been developed to experimentally capture exons, or protein-coding regions of the genome which represent 1.5% of its total DNA. Exomes captured using this approach can then be sequenced without incurring the ‘overhead’ costs associated with sequencing the rest of the genome – pricing of targeted exome sequencing tests has consistently fallen below $1,000 since late 2015.<\/p>\n
However, these tests don’t offer all of the benefits that WGS does; targeted exome sequencing only reveals disease-causing mutations rather than their causes; for a complete genetic profile it takes both sequencing of all genomes as well as analysis of this information.<\/p>\n
Numerous new companies are striving to produce DNA sequencing tests at costs under $1,000. Illumina, an industry giant known for their sequencing machines, recently unveiled the NovaSeq X series that they expect will reach $100 genome sequencing capability; their sale should start within the year.<\/p>\n
WGS poses several significant risks, with its most obvious one being price. Ancestry tests that utilize SNPs provide useful takeaways such as cousin matches and trait predictions; WGS on the other hand produces raw DNA data – for instance Yale Medicine’s WGS test creates 200GB worth of raw data which must then be processed, annotated and interpreted before interpreting – unfortunately there hasn’t been sufficient development of public databases that support WGS interpretations; consequently there exists the possibility that patients might discover secondary findings (such as increased risk for Alzheimer’s) with no treatment available;<\/p>\n
Whole exome sequencing (WES), an economical alternative to WGS, sequences only the portion of your genome that contains genes; however, this approach reveals only 1 to 2% of mutations that might cause diseases; due to this uncertainty some have chosen not to receive WGS testing, including Nobel Prize winner James Watson who did not wish to know whether his gene variant for late-onset Alzheimer’s had caused his grandmother’s death.<\/p>\n
Once a patient has been diagnosed with a genetic disease, it’s critical that they gain as much information about it as possible in order to make informed decisions about treatment. Whole genome sequencing provides invaluable data regarding potential new mutations as well as providing more insight into their impact on health.<\/p>\n
WGS does have some limitations. Interpretation requires more storage and processing power compared to WES and generates twelve times more variants; as well as being more expensive due to handling more samples; but WGS remains an invaluable tool for researchers investigating rare diseases.<\/p>\n
WGS may miss certain mutations because their signatures don’t register with PCR amplification and target enrichment processes, making RNAseq an ideal way to detect more pathogenic variants and increase diagnostic yield.<\/p>\n
Artificial intelligence is being leveraged to improve our ability to predict variation’s impact. One such AI model developed by 3billion, known as 3Cnet, has demonstrated excellent predictive abilities when predicting pathogenicity of variants using clinical information from ClinVar, GnomAD variant data, and conservation data from UniRet – making accurate predictions with each prediction run.<\/p>\n