Should we sequence everyone’s genome? YesBMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f3133 (Published 21 May 2013) Cite this as: BMJ 2013;346:f3133
- John Burn, professor
We should all have our genomes sequenced. In 1986 our 5 year old son planted a conker in our back yard. He explained that he wanted a tree house so needed a tree. The tree is now ready to receive boarders, though they will be from our family’s next generation. The Human Genome Project began at about the same time with similar high aspirations: to deliver personalised medicine to generations to come.
That time is now upon us. The cost of gene sequencing has fallen 10 000-fold in a decade, with another drop by an order of magnitude expected soon. Setting aside the considerable but surmountable challenges associated with large segments being duplicated or deleted and stretches of hard to sequence repeats, we can have a whole genome for the price of a family package holiday. Even now, bulk sequencing all 20 000 “genes,” the exome, costs less than £500 (€590; $770).
The Human Genome Project depended on British discovery, particularly the work of the Wellcome Trust’s Sanger Institute. No one can match our capacity to do “genetic medicine” in a coordinated healthcare system at scale. This is why the UK government has committed £100m to pump prime sequencing of 100 000 whole genomes in the NHS. Only by analysing sequence data and phenotypes across large patient populations will we understand which bits of genetic information are clinically relevant. We can and should lead the world in showing how to put genetic knowledge into patient care safely and effectively.
Genetic predisposition plays a central role in most common diseases. It is the primary cause of most of the rare diseases that collectively afflict 1 in 17 people.1 Clinically relevant discoveries are entering practice at a rate of more than 30 a month.
And the provisos? First do no harm. Our capacity for interpretation is still rudimentary so we must have explicit consent to retain sequence data linked to patients’ records. Our population trusts the health service to deliver healthcare to all in need, regardless of their genetic predispositions. We must keep that principle safe along with the sequence data. That doesn’t preclude partnership with the pharmaceutical and biotechnology industries: we need them to expand the exciting list of drugs that can target genetic subgroups and give us the gadgets and biomarker algorithms to find them.
As we leave the high ground of “single gene disease,” such as hereditary cancers and cardiomyopathies, we risk drowning in data and doing harm. Offering volunteers at risk of monogenic disorders an effective service in return for them allowing their genomes to be pooled and data mined is straightforward. Systematic gathering of genomic information where there has been no request, and any sequence variation discovered lacks clinical use, is more challenging if consent and follow-up counselling are to be effective.
Each one of us carries, perhaps, three million sequence variants, of which about 400 contribute to disease predisposition,2 and one or two would cause a severe recessive disease if both partners pass them to a child. The bioinformaticians need to know it all to develop robust diagnostic algorithms.
But patients do not. We must not dump heaps of molecular uncertainty on patients, families, and their carers. In Nijmegen, the Netherlands, teams of geneticists try to interpret exomes of patients provided by clinicians, passing on (with explicit consent) only information about variants of known relevance plus “incidental” findings of obvious importance (H G Brunner, personal communication).
Genomics is not just about rare syndromes and predisposition to disease. It underpins huge variation in our capacity to metabolise drugs, often leading to serious adverse events, but this is ignored. At the moment everybody gets the same size shoes and they are asked to hobble back next week if they don’t fit. We have known for decades many of the simple genetic variants responsible for such adverse events. We write more than half a million prescriptions for warfarin each year, knowing that three genetic variants can help quickly to reach the individual dose, cutting attendances and adverse events; yet still we just guess.3 Widespread sequencing linked to outcomes will expand such knowledge considerably.
I remain sceptical of an early transition to providing our genome as part of our electronic medical records. The sequences we can provide now are not sufficiently complete, and safe storage and access present challenges.
When it costs only £100 we can run the sequencers more than once, extracting necessary information and discarding the rest. In some situations we will be able to reduce the question to a genetic test at the point of care.
I am part of a team that’s been working for five years on using nanowires to analyse nucleic acids.4 We are about to test disposable cassettes that will extract, amplify, and perform specific tests such as drug sensitivity in under 15 minutes for under £20. The next step will be to provide whole genomes. Others are also innovating in this field. Whoever wins the race, the strong probability is a mixed economy of stored whole genomes, disposable sequencing in hospitals, and cheap, fast genotype panels in some frontline care settings. The net result will be accurately targeted diagnosis, treatment, and prevention.
Genomics extends beyond identifying predisposition to disease. Linking whole genome sequencing to clinical outcomes will influence drug discovery and development—for example, the BRAF gene inhibitor vemurafenib to treat melanoma was developed only a decade after the cancer genome project identified the target.5 And the tools developed from human genomics will transform another battlefront—routine high speed sequencing of pathogens will expose their weaknesses within hours, revolutionising response to epidemics worldwide.
Meanwhile “point of care” technology will allow drug resistance of infective agents causing diseases such as malaria to be studied in real time in the swamp. Whole genome sequencing is a technical, clinical, and societal challenge. But as Goethe said, “Whatever you do, or dream you can, begin it. Boldness has genius and power and magic in it.”
Cite this as: BMJ 2013;346:f3133
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare the following interests: I am chair of the British Society for Genetic Medicine and genetics lead for the National Institute of Health Research. I am a shareholder and director of QuantuMDx Group, which is involved in nanowire based genotyping and sequencing.
Read Frances Flinter’s side of the debate at doi:10.1136/bmj.f3132.
Provenance and peer review: Commissioned; not externally peer reviewed.