Genetic mutations can be passed down from parent to child – with sometimes devastating consequences, as evidenced by the case of British baby Charlie Gard. But the importance of one’s genetic makeup should not be overstated. Though our genes will define our height, hair, skin, or even whether or not we’re at risk of heart disease, the majority of our identity comes from our environment.

Studies have shown that when two people have similar genetic risks of heart disease, the one that exercises regularly will likely stave off any problems until old age. And the likes of coloured contacts and hair dye allow us to circumvent our genetic make-up at will. But what is a genetic mutation, and how does a doctor go about finding out if their patient has one?

When a technique called Sanger sequencing was discovered twenty seven years ago, it became possible to ‘read’ the letters that make up our DNA. The four fundamental letters – A, T, C, and G – each represent a unique molecule, called a nucleotide. Added one after the other, a long sequence (a very, very long sequence of over 3.3 billion) of these four nucleotides is how all our genetic information is encoded – the human genome. In 1990, a collection of governments and universities decided they would launch the Human Genome Project, with the goal of reading (‘sequencing’ in the scientific jargon) the entire human genome. The project had an expected cost of several billion dollars and duration of 15 years.

The Human Genome Project finished ahead of time. Some discoveries made were real surprises: the previous consensus was that the human genome encoded at least 50,000 genes, possibly up to 150,000. It turns out there are about 20,000. What’s more, genes only make up about 1.5% of our DNA. We have in recent years started to understand the function of the remaining 98.5%, but a large chunk of that is still a mystery. With more reading came more shockers: Human beings share 40% of our DNA with worms, 98% with chimpanzees, and two different human beings have on average 99.9% of their DNA in common.

And advances in computing and human genomics have allowed large population studies. One of the big players in the field of genomics is Illumina, Inc., a biotech company which produces what are probably the most widely-used sequencers (machines that sequence DNA). These machines essentially complete Sanger sequencing on a massive scale; the genome is shredded, small segments are amplified, and sequenced independently. A computer then processes the billions of small reads to recreate the whole sequence of the human genome. Sequencing the first genome cost several billion dollars, but scientists today sequence whole genomes routinely, usually for $1,000 or less. Private companies have also popped up, inviting private individuals to sequence their own genomes.

But back to mutations. Firstly, it’s important to know the difference between an ‘allele’ and a ‘mutation’. For example, the genes for eyes have different alleles to define their colour (e.g. brown, green, blue alleles), which creates natural variation between human beings. Mutations are different. Some can have a dramatic impact, while others seem to have no impact at all. Some of the main types of mutations are called Single Nucleotide Variants (SNV), Single Nucleotide Polymorphisms (SNP), and Insertions or Deletions (Indel). While SNVs and SNPs are a single change of nucleotide (say, an A to a G), Indel means sequences of nucleotide are either removed or added – which usually has a disproportionate effect on the gene.

The only difference between SNPs and SNVs is the fact that SNPs are common (identified in at least 0.1% of the population) and largely harmless. The biggest database for human SNPs (dbSNP) displays several hundred millions, and counting. The current thinking in the field is that dozens of SNPs (each independently having undetectable consequences) come together to have a small effect, either for good or bad. On the other hand, multiple studies have shown that select SNVs can be disproportionately harmful. They are often found in cancer, including Lymphoma.

Next-generation sequencing

The distinction between SNP and SNV has only been made possible by the fact that we have sequenced enough genomes to determine which mutations are common or rare, as well as which mutations are deleterious (scientific speak for bad). This torrent of data has mostly come from successors to the Human Genome Project, such as the 1000 Genome Project, which aimed to sequence 1000 human genomes across several continents.

Today’s projects are much more ambitious. England’s National Health Service (NHS) has announced the 100,000 Genome Project with the stated aim of bringing clinicians into a new era of genomic-driven medicine. The project has almost collected a third of its stated goal, and it could even link genomic data to clinical data over a patient’s entire lifetime.

A new piece of technology, Oxford Nanopore’s MinION, promises to revolutionize genomics in a clinical setting. Similarly to Illumina, Oxford Nanopore has uploaded instructional videos about their technology. Though initially presented as unpublished, non-peer-reviewed claims, MinION is increasingly mentioned in highly respected journals, such as in Nature Biotechnology and Nature Methods. The technology is very different from any other sequence technique used today: the strands of DNA are passed through a nanopore, across a membrane, and the disruption in electrical current is measured as the strand is threaded through.

The beauty of the technology is the fact that very long strands can be sequenced, as opposed to the current Illumina gold standard which only allows at most a couple of hundred base pairs. This does away with a lot of labour-intensive sample preparation, and is much faster than anything else currently available. The Nanopore technology is not yet perfect – the company has not managed to reach the level of accuracy that Illumina sequencing typically yields. But if it does, chances are it will become the next generation of sequencing technology.

The small-sized technology would make it possible to sequence DNA at your doctor’s office, within a couple of hours. Imagine you go to your doctor’s office, and the nurse at the reception takes a prick of your blood, putting it into a box the size of a large USB stick. You come back in the afternoon, and in the meantime your DNA has been sequenced and analysed. You doctor informs you that, though you are healthy, in your old age you will be at risk of disease A and B – all according to correlation with the 100,000 Genomes Project. For the first, your doctor will recommend you start using a treadmill more regularly, while for the second they will put you on a mild course of prophylactics. All for a total cost of $100.

But do you want to know what diseases you’re at risk of developing? The scenario certainly raises some ethical questions, not to mention issues around data protection. Either way, no one could argue that this wouldn’t be a revolution of modern medicine.

About the author

HUGO LAROSE is a Ph.D student at the University of Cambridge. In his research, he uses next-generation sequencing in the hopes of finding new insights into pediatric tumors (lymphomas).