Amniocentesis, Cell, Amyotrophic lateral sclerosis, Chorionic villus sampling, Chromosome, COVID-19, CRISPR-Cas9, Cystic fibrosis, DNA, Duchenne Muscular Dystrophy, Etiology, Familial Hypercholesterolemia, Gene, Genetic Counselling, Genetic Testing, Hemophilia, Leopard syndrome, Mucopolysaccharidosis type I, Noncoding DNA, Parkinson’s disease, Pharmacogenomics, Phenylketonuria, Precision Medicine, Prenatal testing, Severe Combined Immunodeficiency Disorder, Spinal Muscular Atrophy
What is Genomics?
Genomics is the study of genomes. It is becoming an integral part of the healthcare system and revolutionized the future of medicine, making therapeutics more personalized and preventative. To provide some background, a person’s genome consists of all their genetic material or DNA, which is made up of chemicals known as bases. Our DNA is composed of four nitrogenous bases, which are adenine, guanine, thiamine, and cytosine (A, G, T, and C). These bases match up to form base pairs by the process of complementary base pairing (Figure 1).
The vast majority of cells in the human body contain a copy of the approximately 3 billion base pairs that comprise the human genome (1). The DNA in the nucleus of the cell is actually two metres in length. In order for DNA to fit into the nucleus it is coiled and packaged into chromosomes. The structure of DNA itself appears to be like two ladders intertwined which form a shape called the double helix. In 1962, Watson, Crick and Wilkins were awarded a Nobel Prize for their discovery of double helix structure of DNA, helix translating to “spiral” in Latin (2).
In order to study an individual’s genome, the genome is “sequenced”, meaning that the order of the bases within their genome is determined. Many diseases are associated with changes in a person’s DNA. These changes are known as DNA variants or mutations that can be identified via DNA sequencing. For example, mutations within the CFTR gene are associated with the disease cystic fibrosis, a rare genetic disorder that affects the lungs. Many mutations can be identified by comparing a person’s genome with what is known as the “reference genome”, generated based on sequencing the genomes of many individuals. The reference genome was assembled by scientists to represent the DNA of an “idealized” individual, and therefore variation away from this reference genome can indicate susceptibility to disease or can in certain cases, lead to the diagnosis of a genetic condition. The reference genome is often updated and revised in line with new scientific discoveries (3).
The arrival of a technology termed “Next-generation sequencing” (NGS) has transformed the field of genomics (Figure 2). NGS allows for either part or the entirety of an individual’s genome to be sequenced much more quickly and at a lower cost than previously possible. The exome is a collection of all the sequences within a genome that code for genes. Genes contain the instructions for making proteins. The exome can be sequenced separately in an NGS process known as “Whole Exome Sequencing”, which can be a faster approach than sequencing the entire genome via “Whole Genome Sequencing”. Exome sequencing yields less data than whole genome sequencing and can therefore be analyzed more easily. However, with exome sequencing, there is the risk of missing what may be crucial information that may be present within noncoding DNA sequences. More targeted sequencing can be performed if there are known genes that are associated with a particular disease. This type of sequencing is carried out using a “Targeted Gene Panel” and is commonly used for genetic testing within the NHS (4).
Although the human genome was first sequenced in 2003, due to the limitations of genomics technologies at the time, approximately 8% of the genome including five full chromosomal arms, was not sequenced. This missing piece of the puzzle mainly contains highly repetitive sequences, previously referred to as “junk DNA”, that actually play essential roles in the function of cells throughout the body (5). These sequences account for much of the variation that is seen between individuals and therefore understanding the role of these sequences could potentially shed light on why some people are at a greater risk of developing a particular disease. In March of 2022, the Telomere-to-Telomere (T2T) Consortium announced that they had conducted the first sequencing of the complete human genome. They achieved this by using long-read sequencing, which allows large sections of the genome to be sequenced. Using this approach, scientists were able to determine the genetic instructions for the synthesis of every single cell in the human body. This is a significant breakthrough as this knowledge may facilitate the development of treatments for numerous diseases for which no effective treatment is currently available(5).
NGS can be conducted via platforms such as Sequell IIE (Pacific Biosciences (USA)), PromethION (Beta) (Oxford Nanopore Technologies (UK)), and Ion GeneStudioTM S5 system (Thermo Fisher Scientific (USA)) (4,6). In January 2022, doctors from Stanford Hospital California carried out the fastest DNA sequencing technique yet, setting a Guinness World Record. Euan Ashley and the team at Stanford Hospital California managed to sequence the entirety of a patient’s genome in only five hours and twelve minutes. This is astounding given that the first attempt at DNA sequencing by the Human Genome Project took over a decade to conduct. Furthermore, this DNA sequencing allowed Matthew Kunzman, a patient aged 13, to understand that the cause of his heart failure was due to a mutation in a gene crucial to heart function. Matthew was given this diagnosis and immediately put on the transplant list all in just over seven hours. Heart failure at such a young age generally occurs for two reasons, either due to a genetic factor as in Matthew’s case or due to a disease known as myocarditis, which presents as an accumulation of immune cells within the heart. The difference is that myocarditis is reversible and so can be treated, but this is not the case for Matthew’s condition, highlighting the importance of genomics in the diagnosis of diseases that present similar symptoms but are intrinsically distinct (6). Table 1 lists some of the companies that are using NGS technologies for clinical applications.
The value of genomics
Genomics can aid in the diagnosis, treatment, and management of a wide range of medical conditions. When genomics is applied within healthcare and health-related research, it is known as Genomic Medicine. Genomic Medicine facilitates a more preventative and personalized approach to medicine. It allows for an early diagnosis of certain diseases and for treatments to be tailored to the patient’s medical condition in terms of their genetic makeup. The susceptibility of an individual to developing a particular disease can be determined in individuals before they are born, using prenatal genetic tests. Genomics technology offers a non-invasive process by which prenatal testing can be conducted. This is usually done via blood test or ultrasound rather than sampling the chorionic villus or amniocentesis which were the only options available in the pre-genomics era. These invasive techniques have a chance of miscarriage that is avoided by conducting genetic tests from blood samples (7). For example, when screening for blood disorders such as sickle cell anemia a blood test is taken before the mother is 10 weeks pregnant (8).
There is a critical need for the development of genetic tests for a wider range of diseases and particularly those diseases that progress significantly before symptoms arise. For example, in Parkinson’s disease, patients only experience disease-associated symptoms at a stage when they have already lost up to 80% of their dopaminergic neurons. Therefore, if the diagnosis can be made prior to the emergence of initial symptoms, early treatment has the potential to preserve those dopaminergic neurons and thereby slow down the progression of the disease (9). A relatively new field of genomics known as pharmacogenomics uses genomic information to inform drug design. It allows for a patient’s treatment to be tailored to both their genome and their medical condition. This results in the creation of more personalized treatments that have a greater chance of being successful.
Genomic analysis can help doctors predict which treatments may be most effective for a particular patient as well as determine the correct dosage for an individual patient. This approach is known as pharmacogenomics and comes under the umbrella of precision medicine. One of its main aims is to reduce the likelihood of negative side effects by revealing the treatments that are most likely to be effective for an individual patient rather than using a “trial-and-error” approach. Some treatments are only effective if the patient presents a particular DNA variant or mutation within a specific gene. It also allows for doctors to avoid prescribing certain medications to certain patients who are more likely to experience serious side effects associated with particular medical conditions. For example, life-threatening side effects have been observed in some patients following treatment with the antiretroviral drug known as Abacavir. However, these side effects were only seen in a small percentage of patients. Genomics research revealed that this adverse reaction to the drug occurred only in those patients with the genetic variant “HLA-B*5701”. This knowledge has enabled doctors to screen patients for this genetic variant before deciding on which treatment is appropriate (7). This means that patients have an increased chance of their treatment being effective without the risk of those serious drug-related adverse events. Pharmacogenomics can also influence the design of novel drugs or new versions of existing drugs by pharmaceutical companies.
Genomics and Drug Discovery
For the past two decades, genomics has played a significant role in speeding up the process of drug development. It has been instrumental in the identification of drug targets as well as establishing the mechanism of action of particular drugs. Genomics research enables the identification of genes that either cause or protect against a particular disease. These genes or their gene products can then be considered as potential targets for the development of novel therapeutics (11). For example, if either a gene or the protein that it encodes, is implicated in a particular disease, the disease could potentially be treated by disrupting or in certain cases enhancing, the function of that gene or protein. This is the case for drugs such as Evolocumab and Alirocumab, which are inhibitors of the protein PCSK9, which controls the number of low-density lipoprotein receptors. These drugs are used to treat diseases such as familial hypercholesterolemia and prevent heart attacks and strokes(11). Moreover, genomics has enabled diseases to be split into subtypes based on the disease mutation detected in an individual’s DNA. An example of this is the use of genomics to classify different types of Amyotrophic lateral sclerosis (ALS). ALS can be caused by mutations within multiple genes such as SOD1, C9orf72, FUS, and TARDBP. Defining disease subtypes can aid the design and development of therapeutics that have greater specificity and are more likely to be effective against particular disease subtypes.
The role of genomics within the NHS
Genomics is applied both within industry as previously mentioned, as well by healthcare systems such as the NHS. The NHS released its ten-year plan, “The NHS long term plan” in 2019. The plan included initiatives to integrate and expand the routine use of genomics into healthcare in the UK, as well as to increase its accessibility for patients. In this plan, the NHS stated that it aimed to offer NGS to children at risk of rare diseases as well as to both adults and children diagnosed with cancer (4). In the UK, rare diseases affect around 1 in 17 people, with 80% of these cases being due to genetic factors (12). The application of genomics to rare diseases is allowing scientists to identify new DNA variants that can indicate susceptibility to a rare disease or aid in diagnosing a patient with a particular rare disease. Genomics data is also used in the development of novel therapies and to improve the patient management of rare diseases. The development of cancer is normally due to a mutation or an accumulation of multiple mutations in DNA, which leads to cells dividing in an unregulated manner (12). The application of genomics to the field of cancer research allows for a greater understanding of the genetic architecture of primary and secondary cancer. This can help researchers to discover new metabolic pathways that can potentially be targeted for the development of novel cancer therapies. By 2023, the NHS plans to offer more than 100,000 genomic tests to patients with cancer annually (4). The NHS currently offers over 500 different genomics tests for rare and inherited disease including Duchenne muscular dystrophy, a muscle degeneration disorder and Hemophilia, a bleeding disorder that can lead to spontaneous bleeding events following trauma or surgery (13).
The NHS also offers newborn screening. This type of genetic testing was first conducted in the 1960s for phenylketonuria, a disease that can cause irreversible brain damage if not treated at an early stage and presents as an increase of phenylalanine in the blood (14). Since the 1960s, the application of newborn screening has meant that thousands of children have had access to diagnoses and treatment that have either saved their lives or prevented life-long disability. Early diagnosis is vital to avoid, what can be in some cases numerous, often invasive procedures to find a diagnosis. Furthermore, newborn diagnosis facilitates treatment management rather than trying to manage the disease once it has already progressed and is therefore already severely affecting the patient. For example, newborn screening at the University of Alberta Hospital in 2019 was able to diagnose Hudson Cowie as a newborn with a severe combined immunodeficiency disorder (SCID), a disorder in which babies are born practically without an immune system. His father was quoted to say that this screening test saved his son’s life (15).
Despite the pros to newborn screening, there are ethical concerns with regards to screening a child so soon after their birth (16). Some parents are concerned about who may obtain access to their child’s genetic information and the possibility of their child being discriminated against by future employers or insurers. The Genetic Information Non-discrimination Act (GINA) does aim to prevent such discrimination but does not guarantee that discrimination will not occur (17). The process of newborn screening typically consists of the genetic or metabolic analysis of dried blood spots taken from the newborn within the first few days after their birth. This is usually confirmed using NGS to analyze the sequence of particular genes that are associated with certain genetic conditions such as sickle cell anemia, cystic fibrosis, and severe combined immunodeficiency (16). As previously mentioned, ethical issues can also arise with a genomics-based newborn screening approach in terms of false-positive and indeterminate results, this is especially dangerous when the treatment can be as harmful as the disease itself. “Overdiagnosis” can occur in cases where genetic tests lead to a child being diagnosed with a particular disease, despite the child not displaying any clinical symptoms. It is difficult for a doctor to know in such cases, whether or not to recommend treatment for the condition (16).
Genetic counselling is a service that is offered to patients by the NHS and by the healthcare systems of many countries around the world. It involves a discussion between an individual and a clinician who has trained in both genetics and genomics. This service is provided to help people to understand how certain medical conditions arise due to genetic factors and that in certain cases, these conditions may also affect some of their family members, as well as any children that they may choose to have in the future. Genetic counselling helps patients understand the findings derived from genomics studies and access advice based on these findings in terms of what it means for the patient and their family (18). Calculations are made to determine the likelihood of developing a certain genetic condition and then passing it on to any children. For example, some diseases have what is known as an autosomal dominant pattern of inheritance. This means that only one allele of that particular trait is required for that trait to be observed in an individual. Patients who have a genetic disorder that has an autosomal dominant pattern of inheritance have a 50% chance of having a child with that disease. Diseases with autosomal recessive inheritance on the other hand mean that those with this disease have a 25% chance of passing the disease on to any children they have in the future (Figure 3). In the case of recessive traits, this means that two recessive alleles for the particular trait are needed in order for that trait to be observed within the individual. To give an example, let’s say the trait of blue eyes is recessive and the trait of brown eyes is dominant. In this case, you would need both alleles for blue eyes in order to have blue eyes. Whereas, you would only need one allele to be for the brown eyes trait to have brown eyes.
Case Study: 100,000 Genomes Project The 100,000 Genomes project was undertaken by Genomics England. It sequenced the genomes of patients within the NHS with cancer and rare diseases, as well as their family members. This project was completed in 2018 and has enabled the identification of new disease-associated variants, which can be applied to the diagnosis, prognosis, and treatment of these patients as well as their relatives within the UK (19). For example, this project made it possible for Alex, a participant of the study aged 19, to obtain an accurate diagnosis for his condition. Leopard Syndrome (LS). LS is a rare disorder that results from a mutation within the PTPN11 gene. This mutation leads to deleterious effects on the heart, skin, and face (20).
The project has made an enormous impact on Alex as well as his family as they now have a greater understanding of Alex’s condition as well as the treatment and surgical procedures he receives and why (21). On top of clinical benefits, the family also received closure and peace of mind from finally receiving an accurate diagnosis. In addition to the benefit for individual patients, sequencing the genomes of these individuals has led to the development of an enormous database, which can be used to further understand the etiology or cause of the disease and its development. A study in 2021 used data from the 100,000 genomes project to understand mutations seen within the TUBB2A gene and the impact of these mutations on a group of brain diseases known as cerebral cortex dysplasia (22).
The impact of genomics technologies on COVID-19
Genomic technologies have been used extensively during the COVID-19 pandemic. Techniques such as Reverse Transcription Polymerase Chain Reaction (RT-PCR) allow for the identification of viral genes within the RNA isolated from patient samples. This allows for the rapid diagnosis of infectious diseases such as COVID-19 (23). Like humans, each coronavirus particle has a genome. However, the viral genome is made of RNA rather than DNA. The genomes of the different virus particles and strains may vary due to mutations that can arise as the virus multiplies. Scientists have applied genome sequencing to detect and differentiate different strains and this helps them to track the spread of different strains of COVID-19 around the world (24). Genomics techniques such as whole-genome sequencing also make it possible for researchers to analyze the mutations in the different variants of COVID-19. This allows them to better understand how the virus infects, its ability to spread and the speed at which it is able to spread (its transmissibility) (23). Furthermore, genomics has enabled the identification of genes that affect a person’s risk of infection and/or their likelihood of developing severe disease. For example, levels of the protein ACE-2 have been linked to susceptibility to infection. This is because the interaction of SARS-CoV-2 with a protein known as ACE-2 facilitates the entry of the viral particle into the cell (Figure 4) (25).
With the advent of NGS and greater accessibility to genomics within healthcare, medicine is gradually moving towards becoming more predictive and preventative. Genomics has already facilitated research into the etiology of complex diseases such as Parkinson’s and Amyotrophic lateral sclerosis. It has also enabled the development of therapeutics that can treat the cause of the disease rather than only the symptoms a patient may have as a result of the disease. However, genomics does pose a major challenge with regard to the analysis and storage of the vast volumes of data that are generated. Furthermore, understanding the genetic basis of diseases is only part of the story, as environmental factors such as smoking and diet can also have a significant influence on disease development.
How to get involved in Genomics Research
Genomics research can allow for an improved understanding into how genes may lead to or affect the risk of developing a disease. This research enables the development of medical innovations to improve the diagnosis and treatment of a wide range of medical conditions for current and future generations of patients. Although the 100,000 Genomes project has already been completed, there are many genomic research studies currently being carried out by the National Human Genome Institute that are continuing to seek participants.
This website hosts a database of all of the clinical trials that are currently being conducted worldwide, together with contact details for requesting information on how to participate in particular trials. The database allows you to refine your search by entering the name of the condition or disease that you are interested in, as well as the location of the studies that are currently recruiting participants. In early 2022, the database included over fifty genomics studies being conducted in the UK that are actively recruiting participants (26).
Current Clinical Studies (genome.gov):
This website provides information about how to find out whether you may be eligible to participate in a particular trial as well as contact details for requesting further information on the clinical studies listed (26).
Gap-free human genome sequence completed for the first time
National Genomic Testing Directory
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