Why are we so complicated?

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Genetics of climate change; new vaccines; how plants flower; the personal genome and other stories from the gene revolution.

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Fifty five years after Watson and Crick discovered DNA’s double helix and ten years after Australia’s national genome facility opened, how are genetics and genomics changing our lives? What will the next decade bring?

Australia’s leading genome scientists are meeting in Melbourne today to discuss the first ten years of the Australian Genome Research Facility (AGRF), and to speculate on what the next ten years of genome science will bring.

Ten years ago a small worm had its genome sequenced. The human genome was still billions of dollars away. Today’s gene sequencing robots can map three human genomes a week. The next generation will be ten times faster. The thousand dollar human genome is on the horizon.

And now over four hundred animals, plants and fungi have had their genome mapped.

‘We have about as many genes as a worm. It turns out that conventional genes aren’t everything,’ says John Mattick, founding director of the AGRF.

‘That was the biggest surprise of the human genome project. We only have about 20,000 genes coding for proteins, the building blocks of life. That’s not much more than that of a simple nematode worm. But the human genome project also found that most of our DNA—about 98.5%—doesn’t make proteins. It was originally described as junk.’

Recent evidence suggests that so-called ‘junk DNA’ guides our development. It interacts with RNA and proteins to turn genes on and off. This ‘epigenetic’ information can even respond to the environment and influence future generations.

‘Our understanding of how genomes work is rapidly changing. This new knowledge, and the dramatic drop in the cost of gene sequencing give Australia unique opportunities,’ says current AGRF director Sue Forrest.

Amongst the Australian projects to be presented at the conference:

  • Genomics is revealing the secrets of wine yeasts and how they contribute to the flavour and complexity of a wine according to the Australian Wine Research Institute’s managing director Sakkie Pretorius.
  • Genome analysis has confirmed that vaccines don’t cause a certain form of epilepsy. It is also helping in the search for the genes underlying many complex and rare genetic diseases says Melbourne epilepsy specialist Sam Berkovic.
  • An animal or plant genome may reveal how well it can adapt to climate change, according to Ary Hoffmann of the University of Melbourne.
  • It could be possible to identify the unique signature of a cancer cell using epigenetics – the complex mix of proteins that control how a gene is expressed. Susan Clark from the Garvan Institute of Medical Research hopes to create a new generation of cancer tests.
  • Australia’s Chief Scientist Jim Peacock says that what makes plants flower isn’t in the genes. He and his colleagues say that understanding the control of flowering may lead to agricultural innovations, such as precise control of flowering in a variety of crops.
  • Genomics is helping Monash University’s Ben Adler to fast track a vaccine to protect farmers and cattle against leptospirosis, a bacterial infection that causes production losses in many domestic animal species
  • ANU’s Jenny Graves, is using the almost complete wallaby genome map to pinpoint important human genes

Why are we so complicated: background information


Redefining cancer genetics

Later this year a new prostate cancer test will go on the market in Europe. It’s based on a biomarker in prostate cancer cells developed by Susan Clark and at the Garvan Institute for Medical Research and Peter Molloy from CSIRO.

Until now, prostate cancer has been diagnosed and monitored by looking at levels of prostate specific antigen, a protein found only on prostate cells. The trouble is, PSA is found on both normal prostate cells and prostate tumour cells, and at best it is an inefficient marker for the disease.

The new test will look at a specific gene in prostate cells that is altered by DNA methylation early in the development of the cancer.

These changes occur in the epigenome – the complex combination of DNA and proteins that make up a chromosome and affects how genes act. Changes in the epigenome can be inherited – without the genetic code changing. These epigenetic changes play a critical role in determining how our genetic code is expressed.

Clark has found that many genes are modified in this way in cancer cells. She hopes to map these changes to obtain epigenetic signatures of normal versus cancer cells.

And because epigenetic changes don’t result in permanent changes to the DNA sequence, they may also be reversible, leading to new therapeutic opportunities.

Clark says the systematic study of the epigenome is just getting started, with an international Human Epigenome Project in the early stages. Australian research has underpinned this initiative with the development of a novel method developed in the Clark lab in the early 90s, that is now being used to to map in detail the DNA methylation changes in the DNA across the genome.

“Epigenetics provides a whole new layer of information on the genome,” Clark says. “But it’s not without its challenges—the interpretation of the data is still in its infancy and is a bioinformatics dream!”

The genomics of good wine

Yeast is central to winemaking. Not only does it convert sugar to alcohol, it produces trace compounds that add to the flavour and complexity of the wine.

Now, says Sakkie Pretorius, the managing director of the Australian Wine Research Institute (AWRI), wine scientists are turning to genomics to understand what makes wine yeast strains good at their job.

By comparing the genome sequences of wine yeasts to a common laboratory strain of yeast, Pretorius and his colleagues hope to identify the genes and metabolic pathways behind desirable traits. Already they have identified a significant amount of variation between the wine yeasts and their laboratory counterparts, including several regions of DNA that are only found in the wine yeasts.

The aim, says Pretorius, is to predict how specific yeast strains will interact with specific grapes. And they also plan to develop yeasts tailored toward emerging markets, such as a yeast that produces a sweeter wine with lower alcohol content for the burgeoning Asian market.

And, to maintain the traditions associated with winemaking, this will be done without using genetic modification in the wineries of Australia. Pretorius says genetically modified yeasts can be produced to prove a concept while traditional methods are used to produce yeasts with the same genetic traits of interest* for actual use in wine production.

The genetics of climate change: can a genome predict extinction?

It may soon be possible to predict whether a particular plant or animal species will cope with climate change or whether it will struggle to adapt, says Ary Hoffmann of the University of Melbourne.

Hoffman says that the flexibility of a species’ genome may hold the key to identifying its ability to change along with the changing environment.  A trait underlain by genes with lots of variability between individuals may be more easily modified and adaptable.

On the other hand, genes can show signs of decay—the accumulation of non-functional mutations means little room to move if conditions change and adaptation is needed. Too much gene decay can limit an organism to a particular environmental niche, which can lead to disaster if that environment suddenly changes.

Hoffmann is interested in how natural selection is reflected in the genes, and whether particular genes or groups of genes form a “signature” that can be monitored to keep track of adaptive changes in natural populations.

And it’s getting easier to look for these kinds of genetic characteristics—modern methods means that genes and genomes can be rapidly compared between individual plants or animals, populations, or even between species.

“The big surprise to us has been the speed at which genes change,” says Hoffmann. “It’s astonishing how quickly genes appear and disappear. There is much more flexibility in the genome than we had appreciated.”

When should a flower flower?

What tells a plant to flower? Research by Australia’s Chief Scientist Jim Peacock and his CSIRO colleagues over the last couple of decades has shown that the answer lies on the genes, not in them.

The mechanisms his team discovered may lead to agricultural innovations such as precise control of flowering in a variety of crops.

In 1992 Peacock and colleagues showed that reducing the amount of DNA methylation—a form of chemical modification of the DNA—could induce flowering in cereal crops and other plants in the absence of the normal environmental trigger. Since then, a more complete picture has emerged of a complex interaction between the flowering master switch genes and the spool-like histone proteins around which the cell’s DNA is wrapped.

At the heart of it again is epigenetics – changes in gene expression retained over rounds of cell division or even sometimes from generation to generation that do not involve changes to the actual gene sequence. Instead, chemical modifications to the DNA or to the chromatin proteins that provide the scaffolding to the chromosomes allow the cell to precisely control activation and repression of gene expression.

And it turns out to be a critical form of regulating gene expression in all organisms, not just plants. It appears to be particularly important in controlling developmental processes, says Peacock.

“It’s a precision way to activate particular sets of genes,” he says.

Fast track to a vaccine

Monash University’s Ben Adler is fast-tracking the development of a vaccine against leptospirosis with the help of genome analysis. He and his team have identified more than 250 proteins with vaccine potential

Leptospirosis is a major disease of many domestic animal species such as cattle and pigs, resulting in substantial economic losses. The disease is spread to humans through direct or environmental contact with animal urine and causes either mild influenza-like illness or severe leptospirosis with a high mortality rate, particularly in developing countries where rodents are the main carriers.

Access to the recently generated genome sequences of several Leptospira species has changed the way he works.

In the past, genome sequences were expensive and slow to generate, and the pathway to identifying a gene of interest was onerous.

Now a bacterial genome can be generated in a matter of months, and computer analysis can quickly look for genes producing proteins with the characteristics required for a successful vaccine.

“The genome sequence doesn’t tell you what to do, but it tells you where to look,” says Adler.

Tracking the cause of epilepsy

Until recently a severe form of epilepsy that emerges in previously normal infants at around six months of age, was incorrectly attributed to the whooping cough vaccine.

But Melbourne clinician and researcher Sam Berkovic has absolved the vaccine and identified a genetic cause—the infants have mutations in genes encoding the sodium channels that play a key role in neuronal excitability.

It’s a great example of how genomics is transforming clinical science, says Berkovic. He has been using the new wealth of genetic information to get to the bottom of rare and complex forms of epilepsy.

In the past, searching for the gene responsible for recessive genetic diseases could take years and require genetic analysis of ten or more affected individuals and their relatives. But new technology means that as few as three affected individuals can be enough to find the gene responsible, as Berkovic found when he went looking for the source of another rare form of epilepsy.

“What used to take a year now just takes a couple of weeks,” he says. “We can solve problems a lot more quickly.”

The case of the missing gene

How have human genes evolved to do the things they do? One way of finding the answers is to compare them to other organisms, says Jenny Graves, from ANU’s Centre for Kangaroo Genomics. Using the almost complete wallaby genome map, she is now able to pinpoint which genes are shared between wallabies and humans and which are not.

“We can put any characteristic we like—even if we don’t know the genetic basis—on the map,” says Graves. “Then we can look at what genes might be involved and compare between species.”

It’s helping her solve a mystery surrounding the regulation of the human X chromosome. In women and female mice, a gene called XIST switches off one of the X chromosomes in females. Graves has been looking for the wallaby equivalent for 18 years to no avail.

“Now we know for sure that it is not there,” she says. “That sheds new light on the complex regulatory system of X chromosome inactivation, suggesting that an ancient system has been refined and expanded in humans.