Analysing genes that are associated with specific diseases is becoming an increasingly important diagnostic tool in personalised and preventive healthcare, but it’s only the beginning of the genetic revolution medicine is currently undergoing. Scientific developments are promising to reveal not just the secrets held by isolated genes of individual patients but those of their complete genetic signature as well.
Until quite recently, isolating and deciphering a person’s genome – all of their genetic material, comprising several billion DNA base pairs and more than 20,000 genes – was an immensely complex, costly and time-consuming endeavour.
When the now famous Human Genome Project was completed in 2003, the sequences of all of the chemical components that make up the human DNA in its entirety were determined from material collected from a variety of people, producing an average or reference human genome.
By 2007, the first complete genomes of individual humans – those of James Watson, co-discoverer of the double helix structure of DNA and American biotechnology pioneer Craig Venter – were published.
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Now we are on the threshold of whole genome sequencing at a cost that makes it accessible as a tool for personalised healthcare, a development many experts consider to be a game-changer in the field.
According to Professor Peter Donnelly of Oxford University: "While the first human genome sequence took ten years to complete, cost billions and involved thousands of scientists, we can now look forward to the prospect of genome sequencing being provided for about R22,000 and in a few days."
Many potential benefits
Each person’s genome contains features that set them apart from others, even members of their immediate family. The specific sets of genes that make up your personal DNA are responsible for all of the traits and physical characteristics that make you a truly one-of-a-kind individual.
By analysing a person’s entire genome and comparing it to published data, doctors may be able to identify certain variations in their genetic material that increase the chances that they will develop an associated illness later in life.
“Genome analysis has great potential in helping us understand the genetic basis of several diseases, including diseases of lifestyle, such as diabetes and hypertension (high blood pressure) that arise due to a mix of genetic and environmental factors,” says Shelley Macaulay, Genetic Counselling Manager at the Division of Human Genetics of the National Health Laboratory Service.
“Through this greater understanding a more personalised and directed approach to treatment and management can be designed. The idea is that medical treatment could be tailored to one’s unique genetic makeup.”
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The data provided by genome analysis can aid doctors in identifying rare, undiagnosed or misdiagnosed genetic conditions and allow them to prescribe the most appropriate treatments and medications. It may also help couples in making pregnancy decisions, for example by determining if either of them is a carrier of a disorder and whether this increases the chances that their child will have the disease.
Are we there yet?
Last year, a study showed that genome sequencing offered a definitive diagnosis for as many as 60% of people who had genetic conditions that were not previously identified by conventional genetic testing. This spurred on efforts to make the technology more widely available in the USA and Europe.
According to Macaulay, whole genome sequencing is not currently available in South African laboratories on a diagnostic basis, but is being investigated in the hope of implementing a local platform for testing in the future. For now, the technique remains very costly and there is an enormous amount of technology, software and expertise that is required before a laboratory can set up and offer such tests.
Some local healthcare service providers are starting to offer genome analysis by using overseas laboratories. In 2015, for instance, Discovery Health announced a range of personalised healthcare products, including genome analysis which will be conducted in partnership with Venter’s company Human Longevity.
One of the hurdles that stand in the way of whole genome analysis becoming more widely used in private and public healthcare is the sheer quantity of information the technique generates. “Bringing together the statistical, computational and clinical knowledge needed to analyse and interpret such vast and complex data in real-time is an exciting, but substantial challenge,” explains Oxford University’s Gil McVean.
One possible way around this problem is to focus only on the so-called exome instead of the entire genome. “The human genome is a long strand of DNA that is made up of coding and non-coding regions,” says Macaulay. “The coding areas are called exons and they consist of genes that code for certain proteins, each of which has a specific function in the body. The exome refers to all of the coding regions (i.e. all of the exons) and is thought to represent only 1.5% of our entire genome”.
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Whole exome sequencing (WES) involves looking at all of the coding regions of the genome. In other words, it targets the areas of our DNA that code for proteins. This is useful because the majority of genetic conditions arise from problems in these protein-coding areas. Whole genome sequencing (WGS) on the other hand involves analysing the entire genome and therefore includes both the coding and non-coding areas.
In contrast, conventional genetic testing usually involves testing for one specific gene at a time. For example, if a doctor suspects cystic fibrosis as a diagnosis in a patient they would only request a test for the gene involved in cystic fibrosis as opposed to testing the patient’s entire exome or genome.
Macaulay points out that while whole exome/genome analysis has great potential, it should not be seen as a replacement for conventional genetic tests. “It may still be far more worthwhile and clinically relevant to test for a single gene than for the whole exome or genome. Medical geneticists and genetic counsellors are specialists who would be able to advise patients on the most appropriate genetic test for them.”
Another concern about genome analysis is that we still only have a relatively limited scientific understanding of the exact influence many variations in the genome have on illnesses. Interpreting whole genome data can therefore be quite tricky.
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According to Macaulay, far more research into variations in the human DNA and whether or not these variations are associated with disease risk needs to be explored. ”Right now, at the most, we can predict approximately 5 to10% of the genetic risks associated with lifestyle diseases, the remaining 90 to 95% of genetic risk factors are undefined,” she explains, emphasising that in terms of lifestyle disease risk (such as the risk for cardiovascular disease or diabetes), no matter what one’s exome or genome analysis reveals, leading a healthy lifestyle is still paramount.
“In addition, undergoing genome analysis may reveal unwanted results such as the diagnosis of conditions for which there are no treatments available. Furthermore, a genetic result often has implications not only for the individual but also for his or her family. Genetic counselling is therefore essential in helping individuals understand the pros, cons, limitations and possible outcomes of the testing”.
In an editorial published in the South African Medical Journal in February, a group of scientists, Macaulay among them, point out that evaluating whole exome data “in individuals from previously understudied populations (such as black African populations) further complicates interpretation”. They also highlight the need for adequate pre- and post-test support from qualified genetic counsellors and medical geneticists of which there are currently insufficient numbers in South Africa.
The authors draw attention to various legal and ethical questions regarding whole-exome analysis when it is offered directly to consumers, as well as the potential for the exploitation of local DNA resources by international companies if there isn’t sufficient oversight and local capacity development in this field.
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Factors influencing success of clinical genome sequencing across a broad spectrum of disorders, Nature Genetics, http://www.nature.com/ng/journal/v47/n7/full/ng.3304.html
Implications of direct-to-consumer whole-exome sequencing in South Africa. The South African Medical Journal, http://www.samj.org.za/index.php/samj/article/view/10534