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Personal safaris into the genome
Dr Valerie Corfield
Medical Research Centre for Molecular and Cellular Biology, University of Stellenbosch Medical School,
South Africa
Dr Corfield is actively engaged in research into the human genome. Here she
gives us an overview of the research she and her team of postgraduate students
has undertaken in collaboration with Prof Brink from the University's Dept of
Internal Medicine and with collaborators elsewhere.
Using many of the resources available through the Human Genome Project (HGP), we are studying the molecular basis of a number of inherited diseases that occur in South Africa. Although these are not the more common infectious diseases that plague our nation, they cause considerable stress and suffering in the families in which they do occur. An immediate "spinoff" of our research is to offer a molecular-based diagnosis for many of the conditions. We are often the only centre offering such a service on this continent. In addition, the data adds to international efforts to understand the underlying molecular mechanisms of disease.
Getting to the heart of the matter
The genes that cause some forms of inherited disease can be mapped to specific chromosomal regions using a combination of approaches, often referred to as reverse genetics. Thus, we have shown that the gene causing a rare condition (abbreviated to PFHBI), in which the electrical impulses that control the heart's contraction are disrupted, resides on a particular region of chromosome 19, while the gene causing a subtly different condition (PFHBII) lies on chromosome 1.
However, there are many different genes in either search area. In a collaboration with Ms Zainu Arieff (PhD student) and Messrs Fahgri February and Morne du Plessis (Msc students), all at the University of the Western Cape, we are carefully trawling the PFHBI target region to look for the causative gene. This work has been facilitated by a collaboration with the South African National Bioinformatics Institute (SANBI) (Director, Dr Win Hide), and the genome database mining done by Mr Alan Christoffels (SANBI).
Similarly, Mr Pedro Fernandez (PhD student) in our laboratory is fine-combing a region on chromosome 1, using a combination of
wet-bench and in silico genome-based data techniques to find the PFHBII II gene.
The work of Dr Hanlie Moolman-Smook, Mr Toy de Lange (PhD student) and Ms Lundi Korkie in our group utilises a range of genome data-dependent methods to understand why genetic defects in a battery of different muscle protein-encoding genes cause an inherited disease known as hypertrophic cardiomyopathy. This work forms part of a collaboration with Professor Hugh Watkins (Oxford University).
We are also looking for the molecular causes of a condition known as long QT syndrome, in which cardiac rhythm disturbances predispose affected people to sudden unexpected death (Ms Glenda Durrheim). We have found that many of our patients carry a mutation that they have inherited from a common ancestor (a founder effect), which increases the success rate of molecular diagnosis.
A new project seeks to find the molecular causes of inherited adult cystic kidney disease (Ms Zola Makubalo).
Badly behaved genes
Even behavioural disorders, such as obsessive compulsive disorder (brilliantly portrayed by Jack Nicholson in "As good as it gets"), can now be investigated, using knowledge gleaned from the HGP. In a collaboration with Dr Dana Niehaus (Department of Psychiatry), Mr Craig Kinnear and Ms Sian Hemmings (MSc students) are searching for normally occurring gene variants that predispose people to developing obsessive compulsive disorder.
Give and take
In addition to using HGP resources, our studies have also contributed data to the suite of complementary HGP databases. Currently, there are still inconsistencies in
the draft sequence and many of the estimated 27 000-40 000 have not been identified ("annotated"). Thus, SANBI (Alan Christoffels) has been adding annotation to the sequence data on chromosome 19, by identifying gene-coding regions, as well as sequence gaps in the target area.
We have deposited sequence information and characterised a potassium channel gene on chromosome 19 (Dr Soraya Bardien-Kruger, post-doc) in collaboration with Dr George
Chandy (University of California). In many of our studies, we have identified normally occurring sequence variants (known as single nucleotide polymorphisms -or SNPs- pronounced "snips"). These SNPs have been deposited in the SNP database, where they may eventually help pinpoint areas of the genome that predispose people to developing particular diseases.
Beyond 2001?
Research often raises questions, even as it provides answers. Our research, like that of many others, is showing that DNA (or at least a single defective gene) alone is not destiny. We continually see family members who carry a mutation that can cause as many as half of their similarly afflicted relatives to die suddenly and unexpectedly. We anticipate that the detailed mapping and annotation of the human genome will provide a rich resource to mine for other genetic factors that modulate disease susceptibility.
Eventually, it is anticipated that the accumulated knowledge gained from a range of studies, that will benefit enormously from HGP database resources, will lead to new treatments and prevention strategies for many of the diseases that afflict mankind.
Image on this page courtesy of the DOE Human Genome Program Web-site
Back to Dr Corfield's article: "Bringing the
human genome home to Africa"
on this article
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