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Human genome holds dark secrets

An enormous effort has been spent surveying many diseases for a genetic cause over the last decade. Unfortunately we do not like, nor understand what we've found, writes Professor Simon Foote.

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The hope of modern human genetics is to identify the genetic component of common diseases affecting mankind such as hypertension, heart disease, strokes, the dementias and autoimmune diseases.

Mapping of the human genome over the last decade has identified the genetic mutations that cause many simple genetic diseases such as cystic fibrosis and a small percentage of cancers, such as some breast and bowel cancers.

These rare diseases are very often caused by only one mutation in a gene — either you need only one version of the mutated gene to get the disease (dominant disease) or you require two mutated versions of the gene, one inherited from your mother and the other from your father (recessive disease).

Today, most of the mutated genes causing disease in families have been found. In some cases the identification of the disease gene has led, or will shortly lead to treatment of the disease.

But the story is very different for more complex diseases such as heart disease and dementia, which are much more common than those caused by a single mutation. We understand very little about these complex diseases, yet they cause most of the hospital admissions and are the major cause for a trip to see a doctor.

Unlike simple genetic diseases where the genetic component is a very important part of the disease, complex diseases are caused by genetic and environmental factors. For example, we can see the increasing incidence of Type 2 diabetes due to a change in lifestyle. But we know that there is also an important genetic component to this disease — if you have a relative with diabetes, you, yourself have a greater chance of getting disease than someone with no affected relatives.

We can measure the genetic component accurately by measuring the increased risk a relative has of developing diabetes in many hundreds, even thousands of families.

To make sure that we are not measuring some hidden environmental factor, we can measure the risk to siblings that have been separated at birth and raised apart. We can also look at the risk of identical twins developing disease. Identical twins have the same genetic make-up, therefore if there is a strong genetic component to a disease, if one twin gets the disease the other twin is likely to also get it. If the environmental component is more important, then there will be a decreased likelihood of the second twin developing the disease.

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Baffling complexity

Over the past 20 years the human genome project has produced a series of tools for the study of genetic diseases. Originally these tools were imperfect, however they were good enough to find the genes underpinning the simple genetic diseases.

We now have sufficiently powerful biochemical tests to survey over a million sites on the genome simultaneously and, theoretically cover all chromosomal regions of the entire genome. In other words, there is nowhere else for a gene to hide.

Theoretically, we should be able to identify the variants of the genes responsible for these common diseases. But the complexity we've found is baffling.

For just about every disease looked at, we find many regions that contribute to the genetic effect, but when all of these are summed, they represent a very small percentage of the total, estimated genetic contribution to the disease.

Take the example of multiple sclerosis, an autoimmune disease that affects many thousands of Australians. There are now over 50 different regions of the genome that carry versions of genes that contribute to the genetics of this disease. However, each gene contributes only a very tiny increased genetic risk, and when all the risks for all the genes are added, they contribute only a very small percentage of the total genetic risk calculated using the family studies described above.

The story is the same for most of the common diseases from cancers, through to osteoporosis, arthritis, heart and vessel disease and high blood pressure. They are all similar, risk factors are found, but they only contribute a small percentage of the genetic risk expected.

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The missing link

The missing 'genetic risk' or genetic basis for these diseases is popularly known as 'genetic dark matter' in reference to the astronomical, hypothesized dark matter that makes up the missing mass of the universe.

We do not know where the missing genetic risk is hiding. Some researchers now question the original calculations of genetic contributions to these diseases. But there are other possibilities.

To understand the next part of this story, we need to have a basic idea as to how DNA makes up our genome. Our genome has 23 pairs of chromosomes. Each chromosome is a long 'string of beads', but unlike a string of beads it is not joined together at the ends. There are only four different coloured beads representing the four bases, A, G, C and T, and these are all DNA needs to make our entire genome. There are three billion bases in one human genome and each cell in our body has double this number (as we inherit a copy from each parent). It is the order, or sequence of these bases that defines our genes, that lets cells know to turn genes on and off and, in fact, makes us human.

Changes to the sequence of these bases cause genetic disease. These changes can be complex, for example, deletions of large tracts of bases, or simple, just a substitution of one base for another. These 'DNA variants' arising from base substitutions are a normal part of the human genome and if any two genomes were compared, there would be around three million of these changes found. Some base substitutions may be found in 5 - 40 per cent of the population, whereas others are rare.

When we screen populations in our search for the genetic basis of common complex diseases, our biochemical tools can only identify common DNA variants.

But common DNA variants may have rare DNA variants close by that cause the genetic disease. In other words, while many people may have the common variant, only people with both the common and the rare variant may get the disease.

It's currently difficult to identify rare variants, but will become easier once the cost of genetic sequencing plummets. However, even if we could identify the rare variants, we could account for a greater percentage of the risk, but not all.

Another possibility for the lost genetic component comes from the interactions between different DNA variants through a process geneticists call 'epistasis'. For example, if a person has two particular DNA variants, then the chance of disease may increase enormously. But if each is present alone, then there may be no extra chance of disease.

At the moment we cannot identify DNA variants that act in this manner, but we know from studies in other organisms, that this happens frequently. We also know that variants interacting in this manner can account for a very large proportion of the genetic risk. It is also possible that there may be many interacting variants.

A further possibility is that there are hundreds of genes contributing to the genetic risk of these diseases and we just have not looked at enough people with the disease to find them all. This scenario is depressing, because we may never be able to do studies with sufficiently large enough numbers of people to find all the variants.

Probably the genetic dark matter is a mix of all of the above.

As the cost of sequencing the human genome decreases, we will be able to identify more rare variants which will allow us to find the actual DNA variants that cause disease, however, if there are very large numbers of variants, with each variant contributing only modestly to disease, then it is unlikely we will uncover all of these.

So, while we have identified hundreds of new DNA variants that 'cause' the genetic part of common diseases, we're still a long way from describing most of the genetic basis of these diseases. But, as more work is done, hopefully we will begin to understand just where the genetic dark matter has gone.

Professor Simon Foote is the director of the Menzies Research Institute.

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