Variomics seeks to understand what makes us unique

Announcing the completion of the first draft of the human genome in 2000, then-US president Bill Clinton spelt out what this monumental achievement would mean for humankind, “With this profound new knowledge, humankind is on the verge of gaining immense new power to heal. Genome science will have a real impact on all our lives, and even more on the lives of our children.”

The international consortium of scientists involved in the Human Genome Project would go on to complete their final draft just three years later (two years ahead of schedule).

The project provided us with the genetic sequence of the average human. But there’s actually no such thing as an average human. We are all different in one way or another. And these differences play a significant role in our health and quality of life.

Understanding the extent of genetic variation in individuals and what effect these have on their health and well-being is the key to providing quality, personalised health care. Thanks to the Human Genome Project and recent advances in DNA sequencing technology, finding genetic variants is a cheap, straightforward process. But determining the consequences of these variants is a difficult one.

Take the gene known as CFTR for example. Variants found in this gene have been shown to cause the genetic disorder cystic fibrosis. The gene itself is approximately 200,000 base-pairs (or DNA letters) in length. Each one of these base-pairs can be changed in a variety of ways.

A database at the US National Institutes of Health has records of 3,083 variants that have been observed in this gene. But only 235 of them have been proven to cause cystic fibrosis. In fact, we know that 85% of cystic fibrosis cases are caused by the same 20 variations. (All the other variants or mutations implicated in cystic fibrosis are recorded in a separate, gene-specific database, which records 1,938 variants.)

So the presence of any variant in a particular gene is not a guarantee that someone will have a particular disorder. It is the variant itself that’s the determining factor. But even then, the presence of other variants, in that gene and in others, as well as environment and lifestyle factors, can all play a role in the progression and severity of a disorder.

Sifting through this complex interplay of 20,000 genes, their variants, environmental influences and epigenetic factors is the business of the field of variomics. On a spectrum between basic science and clinical delivery, variomics sits in the middle – bridging the gap between knowledge generation and application.

One of the major challenges in the field of variomics is poor and uneven access to knowledge across the world. Discoveries about the functional consequences of newly-discovered gene variants and the disease risks associated with them are made every day in genetic testing laboratories around the world. Unfortunately, in most cases, these discoveries are used only in the diagnosis and treatment of the patient in whom the variant was discovered. This local knowledge remains hidden and, consequently, has limited impact.

But efforts have begun to change this. The Human Variome Project is an international consortium of researchers and health-care professionals working to integrate the free and open sharing of this knowledge into routine clinical practice.

For those of us living in developed countries with robust health systems, the single largest determinant of health is genes. Genes play a role in nine out of the ten top causes of death in Australia, the United States and most other developed countries. And while genetic diseases are commonly associated with diseases of childhood – cystic fibrosis, Down syndrome, phenylketonuria – genes actually play a role in our health at all stages of life.

There are adult onset genetic diseases, such as Huntington’s disease and genetic hyperthyroidism, and we are learning more about the role genes play in more common diseases, such as heart disease, diabetes, obesity and cancer.

Francis Collins, the US director of the Human Genome Project has said of the human genome, “It’s a shop manual, with an incredibly detailed blueprint for building every human cell. And it’s a transformative textbook of medicine, with insights that will give health-care providers immense new powers to treat, prevent and cure disease.”

What the Human Genome Project gave us was the ability to read that shop manual. What the field of variomics is trying to work out is what happens to us when our personal copy of that manual has a mistake.

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