The tiny exome: secrets within our genome’s mighty protein maker

Every one of us comes with an instruction manual – a step-by-step guide to building us, called a genome – that is 3 billion letters. It's a long read.

But there is another hidden manual within our genomes that many of us haven’t heard of, called the exome. To understand the exome we must to go back to 2003, when scientists first mapped the human genome - a decade long mission that gave the first full map of human DNA.

Not all DNA is the same. In fact, only about 2 percent of DNA is used to help make things our bodies need. These rare bits of code are called genes, and together all our genes make up the exome.

Medical researchers focus on the exome because it includes all the DNA code necessary to make large, complex molecules called proteins. Proteins play a critical role in the body, doing everything from building the structure of our cells, to sending messages around our body and attacking viruses and bacteria that might make us ill. As a result, many diseases can be attributed to problems with poorly-made proteins. Many medical treatments work by trying to overcome these problems.

In a way, exome sequencing is the human body’s CliffsNotes. By reading a fraction of the DNA, exome sequencing is quicker to do than whole genome sequencing. The data is much simpler to store, understand and compare to other medical information given our current level of scientific knowledge – making it a kind of genetic researcher’s cheat sheet.

Now, a pioneering project in Britain called the UK BioBank is seeking to provide researchers with the tools to find even more answers. AbbVie is one of six pharmaceutical companies who are pooling resources to fund exome sequencing of 500,000 people and make the data available to researchers around the world.

“With genetics, the focus in the past has been on ‘case control’ studies - where you examine genetics of people with a particular disease and then compare against a reference genotype and work out how they are different,” says professor Rory Collins of Oxford University, who leads the UK BioBank. “This only works when the genetic cause of a disease is obvious. But if you are interested in the combination of how genetics interact with environmental triggers for disease, measuring and following a very large group of people without the disease is the way to go.”

By 2010, half a million volunteers provided blood and urine samples, completed lifestyle and health surveys and granted researchers access to their past and future medical records. All 500,000 of their exomes are being sequenced in a project that will finish in 2019, the results of which will be made available to academic and industrial scientists all across the world. Researchers hope to tease out previously undiscovered roots of a wide range of diseases by comparing the genetic information of so many people, and being able to cross reference it with other health information now and in the future.

Exome sequencing is an important step, but large scale whole genome sequencing is needed to comprehensively uncover the causes of illness for the benefit of us all.

When it comes to understanding the complex nature of human disease, there is no short cut, says Steven Elmore, Ph.D., vice president, target enabling science and technology, AbbVie.

“With whole exome sequencing, scientists can get insights into how changes in protein structure impact disease and clues as to how we might make treatments to target these proteins. However, exome sequencings doesn’t give us the whole story, it’s more like a low-res photo,” Elmore says.

“To get the high-res version, we need whole genome sequencing to show us the parts of the genome outside of the exome – the other 98 percent of our DNA – that controls if, when and in what order genes are turned on and off, orchestrating the complex biology of life,” he says. “Understanding how and why genes are regulated will deliver far deeper understanding of disease biology and may lead to entirely new approaches to treating disease.”