The prospect of being able to identify genetic problems in the genome of an individual and then link that to a specific disease or disability – that’s been on scientists’ minds for a long time. Since the completion of the Human Genome Project in 2003 the prospects have become even better. The sequencing technology is improving by leaps and bounds in a very competitive market. The price of full genome sequencing has dropped from $1,000,000,000 circa 2000 to about $25,000 now. Within a few years a complete personal genome sequence will not cost much more than some medical tests – say about $500. Because of the growing availability of genome sequencing, we’re starting to see the payoff from the Human Genome Project. Part of that payoff is a new field of medicine: clinical genetics.

As the cost of full genome sequencing drops, it becomes practical to study and eventually treat genetically caused illnesses on both a per individual basis and including families for genetic comparison. Comparison of genomes and the identification of disease causing genetic mutations is the core of clinical genetics. Two cases involving genome sequencing illustrate the potential of clinical genetics.

Case 1: A family of four

The Institute for Systems Biology (Seattle, USA) published March 11 in Science Express a study that included the sequencing of genomes from a family of four where the children were afflicted with a combination of Miller Syndrome (a rare disfigurement of face and limbs) and primary ciliary dyskenesia (PCD – a lung disease). By sequencing the entire family and comparing the genomes the researchers were able to reduce the number of candidate genes for the Miller’s Syndrome to four. One gene was subsequently identified as a cause of the syndrome. Mutations in a second of the genes were previously shown to be a cause of PCD.

One of the important parallel discoveries in this study was that the parents passed 30 mutations each, 60 in total, to their children. This was surprising, as most scientific models had predicted the number would be 75. There are about three billion base pairs in the human genome. Sixty mutations to those base pairs in a generation is not a bad ratio and few of these have any (known) physical significance. This shows that the genetic mechanisms are robust and accounts for the relatively low incidence of mutation caused diseases. It also is a clue as to why another line of genomic research failed to identify genetic causes of disease.

It was thought that common diseases should have common mutations. One project, called the HapMap (costing about $100 million), compared patients genomes with those of healthy genomes, however the comparisons were done by taking selected segments of the genome (called SNP “snip” chips). Unfortunately, while 2,000 sites on the human genome were statistically linked with diseases – most of them were outside of the genes included in the SNP chips. The conclusion was that common diseases were, in fact, caused by rare mutations. To find these mutations full genome comparisons would be necessary.

[Source: EurekAlert, Institute for Systems Biology]
[Source: EurekAlert, University of Utah]

Case 2: Dr. James Lupski

James Lupski is a medical geneticist and molecular biologist afflicted with Charcot-Marie-Tooth disease, which disrupts the normal action of sensory and motor nerves leading to weakness of foot and leg muscles. The disease is known to be genetic, and Lupski had been doing his own research for 25 years to find the responsible genes. In 1990 he found the first mutation linked to Charcot-Marie-Tooth, a duplication of a gene on chromosome 17 that links to several other genes in producing the fatty insulation that covers nerve fibers. Overall, 29 genes and 9 genetic regions have been linked to the disease – but Lupski’s own genome sequence revealed no mutation responsible for his case.

In 2007 Lupski’s full genome was sequenced using technology from Applied Biosystems (Foster City, California, USA) and compared the results with the reference sequence from the Human Genome Project. This comparison eventually revealed two different mutations, which were tied to the disorder. The team working with Lupski then sequenced the genome from his siblings, parents, and (deceased) grandparents. The same gene mutation was found in his brothers and sisters, while the parents and grandparents carried either none or one. His mother had none of the mutations. His father had one, and showed mild symptoms of the disease. The results of this research were published March 10 in the New England Journal of Medicine.

[Source: New York Times]
[Source: Science Blogs]

Such research is what scientists expected after the Human Genome Project. More and more genomes are becoming available. Comparative databases are developing. There is no doubt that readily available genome sequencing will have a major impact on the identification of disease and disablement causing mutations. Not cures, but a kind of diagnosis.

We may be on the road to cures, but there is an important caveat: Although we are increasing our ability to link specific genes to illness or disability, in almost all cases we know little about how this works, and even less about why. In a way, it’s similar to the work with fMRI to isolate regions of the brain associated with various things like seeing, feeling, walking. fMRI can show us where the brain is active, but it can’t show how it’s working or explain why the brain functions the way it does. In short, our tools like the fMRI and genome sequencers are sophisticated as equipment but relatively superficial in what they show us.

Another way of looking at both clinical genetics and fMRI studies is that they lack a molecular foundation. In almost all cases, scientists don’t know the fundamental organic chemistry that is active in the processes at the molecular level. They know the genes, but they don’t know how gene expression works for each case. They know the region for brain activities, but they don’t know what specific cells are involved, much less the molecular chemistry. This kind of research is always interesting, but is subject to huge errors of interpretation – simply because science doesn’t really know what’s happening.

For the most part current clinical genetics is in the hands of researchers and highly qualified professionals. It won’t stay that way. Claims will be made that not only can mutations be identified, but measures can be taken. Probably not, in truth; not for a long while yet in most cases. That won’t stop the charlatans.

And when it is possible to ‘cure’ many genetic disorders, counteract the effect of mutations, and remove genes (of any kind)…what then? That’s another question for the new age of clinical genetics.