What Is Whole Genome Sequencing, And Do You Need It?
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What Is Whole Genome Sequencing, And Do You Need It?
Date of Content: November 18, 2023
Written by: Avanthika Nityanand
Reviewed by: Maarit Tiirikainen, PhD
What is Whole Genome Sequencing?
Whole Genome Sequencing (WGS) is a method for analyzing the entire genetic makeup of an organism. WGS uses advanced technology to read the sequence of the four basic building blocks (nucleotides: adenine, thymine, cytosine, and guanine) and their pairs that make up the DNA double helix.
The process involves determining the complete DNA sequence of an organism’s genome at a single time. It includes all the genes—the coding regions (exons) that translate into proteins and the non-coding regions (introns and intergenic sequences) with regulatory and other functions.
The next step after sequencing at a laboratory is employing bioinformatics tools to piece together the sequenced DNA fragments, aligning them to a reference genome and reconstructing the individual’s complete genome.
WGS provides a detailed view of the genetic variations (such as single nucleotide polymorphisms, insertions, deletions, and copy number variations) that can influence the organism’s development, physiology, and health.
WGS differs from other sequencing methods like whole-exome sequencing, which focuses only on the exons, and targeted gene panel testing, which looks at a specific subset of genes.
While all these methods have their optimal uses, WGS offers the most comprehensive genetic analysis, making it a powerful tool for research, medical diagnosis, and personalized medicine.
The Fascinating Evolution Of WGS
WGS has evolved rapidly since its inception, transforming our understanding of genetics and revolutionizing numerous fields. Its history begins in the 1970s and 1980s with foundational developments in DNA sequencing technology. Frederick Sanger’s introduction of the Sanger method in 1977 was pivotal, allowing for the sequencing of longer DNA strands and setting the stage for future advancements.
The most significant milestone in the history of WGS was the Human Genome Project (HGP), an ambitious international effort launched in 1990 to sequence the entire human genome.
This monumental project, completed in 2003, took 13 years and approximately $3 billion, marking the first time a complete human genome was sequenced. The HGP used Sanger sequencing and proved that sequencing an entire genome was possible, albeit time-consuming and expensive. The story of this project makes for a fascinating read.
Following the HGP, the development and refinement of next-generation sequencing (NGS) technologies in the mid-2000s drastically changed the landscape of genome sequencing.
NGS techniques, such as those developed by Illumina and 454 Life Sciences, significantly reduced the time and cost required for sequencing while increasing accuracy and throughput. These advances made WGS more accessible and practical for various applications.
By the early 2010s, the cost of sequencing a human genome had dropped to around $1,000, a fraction of the original cost during the HGP. This dramatic reduction in cost and time, coupled with improvements in computational methods for data analysis, opened new doors in research, diagnostics, and personalized medicine.
Today, WGS is used not only in academic and medical research but also in clinical settings for diagnosing rare genetic disorders, understanding the genetic basis of diseases, and guiding treatment decisions in fields such as oncology. It has also become a tool in public health for tracking disease outbreaks and understanding microbial genomes.
How Long Does Whole Genome Sequencing Take?
The timeframe for completing whole genome sequencing (WGS) can vary depending on several factors, including the sequencing technology used, the quality and quantity of the DNA sample, and the depth of coverage required.
With modern NGS technologies, the sequencing process can be completed in a day. NGS platforms have significantly accelerated the sequencing step, allowing for the simultaneous processing of multiple samples.
However, sequencing is just one part of the WGS process. Sample preparation, which includes DNA extraction and library preparation, can take additional time. Following sequencing, the raw data requires extensive bioinformatics analysis to assemble the sequences and identify genetic variants.
This data analysis phase can take several days to weeks, depending on the complexity of the genome and the level of detail required in the analysis.
For clinical applications, where time is often critical, rapid WGS methods have been developed that can provide results in as little as one to two days. These quick approaches are particularly valuable in acute care settings, such as neonatal intensive care units, where timely genetic information can be crucial for diagnosis and treatment decisions.
In a research context, where the focus may be more on comprehensive analysis than on speed, the entire process, from sample collection to final report, can take several weeks or even months.
What Can Whole Genome Sequencing Detect?
WGS can detect genetic variations and abnormalities affecting an individual’s health, traits, and ancestry. The following are crucial types of genetic information that WGS can uncover:
- Single Nucleotide Variants (SNVs): These are the most common type of genetic variation, where a single nucleotide (A, T, C, or G) in the genome is altered
- Insertions and Deletions (Indels): Small insertions or deletions of a few nucleotides in the DNA sequence
- Copy Number Variations (CNVs): Variations in the number of copies of a particular gene or region of the genome
- Structural Variations: Large rearrangements in the genome including inversions, translocations, or large insertions and deletions
- Chromosomal Abnormalities: Changes in the number or structure of chromosomes, such as trisomies or monosomies
- Mitochondrial DNA Variations: Mutations in the mitochondrial DNA can be relevant for certain inherited diseases
- Epigenetic Changes: While WGS primarily focuses on the DNA sequence, it can indirectly provide insights into epigenetic modifications by analyzing certain genomic features.
WGS is particularly valuable in identifying rare genetic disorders, characterizing cancers, and understanding complex diseases involving multiple genetic factors. WGS is useful for pharmacogenomics, which studies how genes affect one’s drug response, and for personal genome analysis to understand ancestry and inherited traits.
What is Whole Genome Sequencing Used For?
Whole genome sequencing (WGS) is employed in a variety of fields, reflecting its comprehensive nature and ability to provide detailed genetic information:
- Medical Diagnosis: WGS is instrumental in diagnosing genetic disorders, especially rare or unknown diseases. It can identify mutations that cause or predispose individuals to diseases, allowing for personalized treatment plans.
- Cancer Research: In oncology, WGS helps identify specific mutations and structural changes in cancer cells, facilitating targeted therapy and understanding drug resistance mechanisms
- Pharmacogenomics: WGS informs how genetic variations affect individual responses to medications, enabling personalized medicine and reducing the risk of adverse drug reactions
- Research and Discovery: Scientists use WGS to study genetic diversity, understand evolutionary biology, and discover new genes associated with diseases or traits
- Public Health and Epidemiology: In infectious disease outbreaks, sequencing the genomes of pathogens like viruses and bacteria can track their spread and evolution
- Prenatal and Newborn Screening: WGS is increasingly used in prenatal testing and newborn screening to detect genetic disorders early in life
As WGS technology continues to evolve and become more accessible, its applications are likely to expand further, offering even more insights into human health, disease, and history.
How Much Does Whole Genome Sequencing Cost?
The cost of WGS has witnessed a dramatic reduction since the completion of the Human Genome Project in 2003, where sequencing an entire human genome cost about $3 billion. The price can vary widely depending on the context and purpose of the sequencing.
This 2018 systematic review analyzed 36 studies that explored the application of whole exome sequencing (WES) and WGS in clinical settings, primarily for neurological and neurodevelopmental disorders. These studies showed significant variation in the cost of testing ($555 to $5,169 for WES and $1,906 to $24,810 for WGS).
The cost can be higher in a research or clinical setting due to the need for more rigorous data analysis, interpretation, and potentially more extensive coverage or deeper sequencing. Institutional projects may include overhead costs like equipment, labor, and infrastructure.
It’s important to note that the cost of sequencing alone is just one part of the equation. The subsequent data analysis, which can be complex and labor-intensive, contributes significantly to the overall cost.
Fortunately, as technology advances and becomes more accessible, prices are expected to decrease, making WGS more available to a broader population.
Recent Research Developments In WGS
Drug-Resistant Tuberculosis
A 2022 review discusses the role of NGS in predicting resistance for Mycobacterium tuberculosis isolates. The review presents descriptive analysis research describing the potential of WGS to accelerate the delivery of individualized care and the role of targeted sequencing for resistance detection.
It highlights challenges in the widespread introduction of new drugs without standardized drug susceptibility testing, leading to the rapid emergence of drug resistance. It also suggests combining genotypic and phenotypic techniques to monitor treatment response and curb emerging resistance. Read the full article here.
Advancements in NGS Technology
A review published in July this year (2023) provides an overview of the evolution of NGS technologies and their impact on genomics research. The study also delves into the challenges and future directions of NGS technology. It includes efforts to enhance the accuracy and sensitivity of sequencing data. It further showcases the development of more efficient, scalable, and cost-effective solutions. Read the full article here.
Do You Need To Get Your Genome Sequenced?
WGS is optional. Its relevance and utility depend on specific personal, medical, and research contexts. Here’s a breakdown to better understand when WGS is a necessity and when it’s not:
When WGS Might Be Necessary
Diagnosing Complex Genetic Conditions
In cases where patients present with complex, undiagnosed symptoms that suggest a genetic origin, WGS can be essential for identifying rare genetic disorders.
Cancer Treatment and Research
For certain types of cancer, WGS can provide crucial insights into the genetic mutations driving the cancer, which can guide targeted therapy decisions.
Pharmacogenetics
When understanding an individual’s genetic makeup can significantly influence the choice and dosage of medications, WGS can be necessary to prevent adverse drug reactions or ensure efficacy.
Rare Disease Research
In the context of research, particularly for rare diseases, WGS is often necessary to understand the genetic underpinnings of these conditions.
When WGS Is Not Necessarily Required
Routine Medical Care
For standard medical care and check-ups, WGS is not a routine necessity. Most common conditions and diseases are diagnosed and treated without needing WGS.
General Health Information
Less comprehensive or targeted genetic testing might be sufficient for individuals seeking general health information or minor genetic insights (like trait analysis).
Ancestry and Genealogy
Specific ancestry-focused genetic tests, less comprehensive and costly than WGS, are usually adequate for those interested in ancestry and family history.
References
- https://www.sciencedirect.com/topics/neuroscience/whole-genome-sequencing
- https://pubmed.ncbi.nlm.nih.gov/36655445/
- https://embryo.asu.edu/pages/human-genome-project-1990-2003
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926122/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841808/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283791/
- https://www.bbc.com/future/article/20230210-the-man-whose-genome-you-can-read-end-to-end
- https://www.nature.com/articles/gim2017247
- https://pubmed.ncbi.nlm.nih.gov/35401475/
- https://pubmed.ncbi.nlm.nih.gov/37508427/
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