By Dr. Brandon Colby MD, a physician-expert in the fields of Genomics and Personalized Preventive Medicine.
You may have heard terms like whole genome sequencing and genomics and thought that they sound like they’ve come right out of the script for a futuristic movie. But in reality, sequencing technologies are readily available in many parts of the world, and they can be very useful to understand more about human genetics and our own health.
The human genome contains a wealth of information about each of us, from our ancestry to our risk of developing certain genetic diseases or passing them down to our children. As a result, it’s no wonder DNA sequencing is becoming a widely used tool in both research and healthcare.
Put simply, whole genome sequencing (WGS) is a genetic testing technology that allows us to determine how our DNA is confirmed. In order to understand this testing procedure better, let’s take a look at what DNA is, how it’s formed, and what it does.
Deoxyribonucleic acid, more commonly known as DNA, is the molecule that contains all living organisms’ genetic codes. All the living beings that have been identified and examined contain DNA, from complex mammals such as humans to simple organisms like bacteria.
DNA is made up of molecules called nucleotides. These nucleotides act as the basic building blocks of our DNA and are composed of three distinct parts:
- A sugar molecule
- A nitrogenous base
- A phosphate group
The nitrogenous base portion of each nucleotide can be adenine (A), cytosine (C), guanine (G), and thymine (T). These bases are “strung together” during DNA replication. Practically all the cells that exist in our bodies contain DNA, with only a few known exceptions — such as mature hair cells.
The nitrogenous bases are replicated in a specific order, and they form base pairs by binding to a base from a parallel strand — A always binds to T, while C always binds to G —, forming the familiar double helix DNA image that we all know. One of the key features of DNA is that it can replicate itself constantly to create new cells that are identical to their parental cell.
While DNA is formed by two strands of nucleotides that are bound together, a simpler molecule called RNA is formed by a single strand. In humans, RNA molecules act as a messenger and transfer molecules that carry genetic information during the DNA transcription process.
Nitrogenous bases are the portion of our DNA that contains genetic information, and the “patterns” created by these bases in our DNA determine our genetic makeup - specific DNA sequences form genes. Each gene has coding regions that function almost like a blueprint for cells since they contain “instructions” that tell cells in our body how to synthesize amino acids to form different proteins.
There are only 20 amino acids, but they can be combined in different ways to create thousands of different proteins, each with its own structure and function. Proteins carry out a wide range of processes inside our bodies, depending on their type. If there are abnormal variations in our DNA sequence, these instructions could be faulty and lead to various health issues.
However, not all of our DNA is conformed by protein-coding genes — in fact, nearly 99 percent of all our DNA is made up of non-coding DNA, meaning that it doesn’t contain instructions for protein-coding. For a long time, scientists thought that non-coding DNA didn’t have a specific function; however, we’re learning more about the purpose of non-coding DNA every day.
Some parts of our non-coding DNA act as regulatory agents that activate or repress DNA transcription, whereas others contain instructions for the synthesis of RNA, among other functions. Therefore, sequencing our non-coding DNA and RNA can also tell us a lot about human health, since it also plays an important role in genetics.
Chromosomes are long strands of DNA that contain our genes — humans normally have 23 pairs of chromosomes. We each receive two versions of the same gene — one from each of our biological parents. The different versions of a gene are called alleles, and they determine the biological traits that we will express, such as eye or hair color.
Some alleles are dominant (meaning that you only need one copy of the same allele to express its associated characteristic), whereas others are recessive (meaning that you need to inherit two copies of the same allele to express that characteristic). This explains why DNA testing results will be different for everyone, even for full siblings.
The human genome is the compilation of all the genetic information that each person contains, regardless of whether it’s coding or non-coding.
A whole genome sequencing DNA test is a type of genetic test used to determine the order of the nucleotides that form our entire genome — both coding and non-coding —, allowing scientists and physicians to ascertain whether an individual’s DNA sequence contains any abnormalities.
Genetic testing offers a wide array of benefits for scientific research, genetic counseling, individualized medical care, and even public health initiatives.
The original technology used for whole genome sequencing was called Sanger sequencing or chain termination method, and it was invented in 1977. Although this method was revolutionary for its time, it was also very slow and expensive.
When DNA testing was first used, the data analysis required to sequence just one person’s DNA could take years to complete.
The Sanger method was later automated to make the process faster; the automated version of this method was used to complete portions of the Human Sequencing Project, which was a wide-scale, international project that sequenced the base pairs that make up human DNA for the first time.
The Sanger method is still used today to sequence shorter DNA fragments, but newer sequencing methods have made the turnaround time of DNA tests faster while reducing sequencing costs.
These methods also called high-throughput or next-generation sequencing methods have made large-scale DNA testing accessible to a wider audience since they only require a few days to analyze a genome test while still producing high-quality results.
There are several types of DNA tests, and each process genetic information differently and for different purposes. Some types of DNA testing include:
- Whole genome sequencing (WGS)
- As stated above, WGS sequences the entirety of our genome data, including both coding and non-coding DNA. As its name suggests, this type of genetic testing can identify variations in any part of your genome.
- Available from Sequencing.com, Illumina, and Oxford Nanopore.
- Whole exome sequencing (WES)
- Rather than sequencing an individual’s entire genome, this test only sequences the parts of their DNA and RNA that contain coding instructions, which are also known as exons. Many of the genetic mutations that lead to genetic disorders happen in the exome (which is the combination of all our exons), which is why this test can still be very useful despite the fact that it doesn’t analyze your entire genome.
- Available from Illumina, GeneDx, and Ambry Genetics.
- Targeted re-sequencing
- This method isolates specific regions of DNA to analyze them for mutations. This technique can identify variations in specific genes, which can be very useful if you only need to diagnose or rule out distinct variations — for example, when screening for a particular genetic disease.
- Available from Illumina, GeneDx, and Ambry Genetics.
- SNP genotyping (DNA microarrays)
- This test measures the variations of single nucleotide polymorphisms (SNPs) against reference genome fragments from members of the same species. SNPs are variations that occur in a single base pair of your DNA. SNPs are the most common type of genetic variation, and SNP genotyping can determine the set of variants that are present in a person’s DNA. Single SNP annotations can also be used in conjunction with WGS to assess the frequency of rare genetic variants and their consequences.
- Available from Sequencing.com, 23andMe, Ancestry.com, MyHeritage, and FamilyTreeDNA.
Whole genome sequencing and other sequencing methods shouldn’t be confused with DNA profiling, which is simply used to determine the likelihood of a DNA sample coming from a specific source. DNA profiling is widely used to help solve criminal investigations, but it doesn’t provide any further genomic data.
Learn More: What Is 30x Whole Genome Sequencing?
For most of known history, human genetics and the role that genes play in our health were a mystery. In fact, DNA and genes are a relatively modern concept — the molecular structure of DNA was only identified in the 1950s. But thanks to the advent of DNA sequencing, scientists can now analyze raw DNA data to understand human health, how certain diseases work, and what we can do to prevent or treat illnesses more efficiently.
The main objective behind DNA tests, in general, is to identify whether there are any mutations in your DNA that could cause health problems. These tests can also provide information about your genealogy, which can be fascinating on a personal level but also helpful when it comes to determining your risk for certain diseases.
The information provided by genetic testing is also important for public health since it can be used to guide interventions and individualize them according to the genetic characteristics of different population groups.
Learn More: Importance of Whole Genome Sequencing
Whole genome sequencing will play a very big role in the future of personalized medicine. For example, whole genome sequencing provides enough data to personalize therapeutic approaches and treatments to diseases so you’re most likely to receive a treatment that will provide the most benefit with the least risk of side effects.
Instead of using the same treatment on all patients who suffer from the same condition, physicians could use sequencing data to individualize each patient’s management.
These advancements wouldn’t just potentially improve patients’ outcomes — they could also help create a more comfortable patient experience since patients won’t have to test different treatments in order to find the right fit for them. Additionally, it could help lower healthcare costs and improve the workflow at medical facilities by providing a straightforward way to decide between different treatment options.
DNA testing is also used in prenatal genetic counseling, especially for future parents who have a family history of genetic diseases or pregnancy loss. In some cases, genetic testing may be necessary to understand the cause of a patient’s fertility issues. WGS could also be used to detect illnesses and genetic abnormalities in unborn fetuses.
Whole genome sequencing hasn’t been exclusively applied to humans. Sequencing the DNA of bacterial organisms and other pathogens can help scientists understand the disease better, determine the origin of new mutations, synthesize new medications and vaccines, combat drug-resistant pathogens, and even contain outbreaks of contagious diseases around the world.
One of the main reasons why whole genome sequencing tests have become so popular is because they help ascertain your predisposition to certain diseases. Specific variations in your DNA sequence can cause genetic disorders; some of these mutations are inherited from one or both parents, whereas other variations occur de novo — meaning that this is the first time that this variation is present in a member of a family.
But DNA sequencing can also tell us a lot about non-genetic disorders. When we think of genetic testing, our mind immediately goes to inherited rare diseases, but DNA testing can tell you whether you’re at risk of developing more common health conditions, such as high blood pressure or diabetes.
This information can also inform other family members of possible health risks, even if they’re not the ones who took the DNA test.
Some patients may be advised by their physician to take a DNA sequencing test to provide an accurate diagnosis for their symptoms after failing to discover their cause through other methods — WGS has been successfully used to diagnose genetic disorders in gravely-ill children and to modify the therapeutic management they received.
Others may simply choose to take a DNA test to learn more about their ancestry. Since WGS analyzes your entire genome, it may reveal unexpected variations that aren’t currently related to any physical symptoms. These variations are often called “secondary findings”.
Keep in mind that not all genetic variations will automatically generate a disease. Certain genetic changes increase a person’s risk of developing a health condition, such as breast cancer. Depending on the disease, this predisposition can be mitigated through medical treatment or lifestyle changes.
Other genetic variants are benign and don’t affect our health at all. And in other cases, the exact implications of a genetic variant are still unknown — these variants are also known as “variants of uncertain significance”. It’s always important to discuss the results of your sequencing test with a specialist, such as a geneticist.
WGS can also reveal your ancestry with a significant degree of accuracy. To do so, a sequencing service will compare the SNPs in your DNA against reference sequences from specific ethnic populations.
SNPs have been found to be inherited through generations, which is why they’re reliable indicators that can be used to compare your DNA against different populations around the world, thus determining your most likely DNA ancestry. For this reason, SNP sequencing is also valuable in the field of evolutionary biology.
Learn More: Advantages of Whole Genome Sequencing
In the past, genotyping human DNA was a long and expensive process — in fact, the Human Genome Project lasted 13 years —, but now, you can use a DNA kit from the comfort of your own home and get results in a few weeks.
There are several modern DNA sequencing methods, including:
- Illumina dye sequencing
- Single-molecule real-time (SMRT) sequencing
- Nanopore sequencing
In most cases, once you purchase a commercial direct-to-consumer sequencing test, you’ll receive a collection kit that you’ll be able to use at home. You’ll be instructed to swab the inside of your cheek and place the swab inside a labeled container before shipping it back to the provider.
Collecting samples using these DNA testing kits is safe, quick, and painless. In other cases, the sample may be collected at a doctor’s office or lab.
Since the human genome contains so much information, DNA tests can’t analyze it all at once. Instead, these methods use different techniques to break DNA into smaller pieces, and a sequencer is used to determine the order of the nucleotides in each of these DNA fragments. Then, bioinformatic technology is used to put all the pieces back together correctly so that they can be analyzed.
Depending on the type of DNA test that you’ve purchased, you’ll receive your results in a few days or weeks. Whole genome sequencing provides the most comprehensive type of genomic characterization that is currently available. Each whole genome sequencing test generates a colossal amount of data — after all, the human genome contains approximately 3 billion base pairs.
But you won’t be receiving the sequencing results of 3 billion base pairs after mailing your DNA test kit back to the provider, of course. This amount of information would be practically impossible to process, even for a healthcare provider or scientist.
Instead, your results will detail pertinent information regarding your health and genetic makeup. WGS can identify many types of variations in your DNA, such as single nucleotide variants, insertion/deletion (indel) polymorphisms in a specific nucleotide sequence, structural variants, copy number variants, among others.
The results of a DNA testing kit can provide a wide range of information, including:
- Single-gene or Mendelian disorders: as their name suggests, these disorders affect a single gene.
- Your WGS will determine whether you suffer from one of these disorders or are at risk of developing one later on or passing one down to your children.
- Single-gene disorders include sickle cell anemia, Huntington’s disease, cystic fibrosis, or muscular dystrophy.
- Susceptibility to multifactorial disorders: these disorders are caused by mutations in different genes, but they also depend on environmental and/or lifestyle factors.
- As we mentioned earlier, this also means that your risk of developing these diseases can often be mitigated through medical intervention or a healthier lifestyle.
- Some of these conditions include obesity, hypertension, and diabetes.
- Pharmacogenomic profile: this section of your WGS will provide information on how you can be expected to respond to different drugs according to your genetic profile.
- This data can be used to provide individualized medical care, decrease drug toxicity, and adjust medication dosages.
Additionally, whole genome sequencing can also provide information regarding your ethnicity, ancestry, overall health and wellbeing, nutrition and fitness insights, and much more.
Once upon a time — or really, just a few short decades ago — it would have been practically impossible for a private individual to cover the costs of having their DNA sequenced.
But newer high-throughput sequencing methods can handle whole genomes quickly. In fact, certain modern sequencer machines (also called sequencing “platforms”) can even provide same-day results for small DNA fragments.
As the processes involved in DNA sequencing have become faster and easier to access, the costs associated with testing have also gone down.
As recently as 2009, genomic testing could cost approximately $50,000 per individual genome. Now, several companies offer whole genome sequencing for anywhere between $400 to $600, although some companies do charge higher prices.
In recent years, more and more biotechnology companies have started to offer genetic tests. Illumina is one of the biggest stakeholders in the field of genomics, having patented several different sequencer machines and DNA tests. They offer various sequencing platforms to fit different needs, from traditional whole-genome sequencing platforms used in clinics and research labs, to sequencers that can identify specific diseases.
Other major genomics companies include Thermo Fisher Scientific and Oxford Nanopore Technologies — the latter of which created an innovative USB sequencer that can be attached to a desktop computer, opening the possibility of portable and convenient DNA sequencing tests.
Pacific Biosciences is another important biotechnology company. They have introduced a type of real-time sequencing technology that is able to provide the longest DNA reads to date — 10,000 base pairs at once, compared to approximately 150 base pairs at once through other sequencing platforms. If perfected, this new approach could make DNA testing even faster and more accessible than ever before.
Other companies that provide DNA sequencing include Knome, Sequenom, 454 Life Sciences, Life Sciences, BGI, Helicos Biosciences, Veritas Genetics, Complete Genomics, Affymetrix, and IBM, among others. Not surprisingly, the advent of new whole genomic sequencing technologies has generated public discussion surrounding their ethical implications, and the need to ensure the privacy of individuals who choose to take one of these DNA tests.
We can’t stress how important it is to research your chosen provider before taking a genome test in order to understand their privacy and data protection policies.
If you want to learn more about whole genome sequencing, head over to our education center to discover more in-depth articles on this innovative technique.
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Dr. Brandon Colby MD is a US physician specializing in the personalized prevention of disease through the use of genomic technologies. He’s an expert in genetic testing, genetic analysis, and precision medicine. Dr. Colby is also the Founder of Sequencing.com and the author of Outsmart Your Genes.
Dr. Colby holds an MD from the Mount Sinai School of Medicine, an MBA from Stanford University’s Graduate School of Business, and a degree in Genetics with Honors from the University of Michigan. He is an Affiliate Specialist of the American College of Medical Genetics and Genomics (ACMG), an Associate of the American College of Preventive Medicine (ACPM), and a member of the National Society of Genetic Counselors (NSGC)