With the race to find cures for some of the world’s most prolific diseases gathering pace, University of Southampton medical researchers are using new chromosome mapping techniques to fight disease at the genetic level.
Professor Andrew Collins is a medical researcher in the Human Genetics Division of the School of Medicine. His role is to develop maps of human chromosomes in order to find genes which cause diseases. As part of the human genome mapping project, which started in the 1980s, his team’s work has focused on specific sections of chromosomes in the hope that particular genes or small clusters of genes can be isolated and identified as those that cause disease.
The team’s research is at a critical phase because the potential now exists to locate all of the important genes underlying such common diseases as asthma, heart disease and diabetes. The ultimate goal of gene mapping is to clone genes, especially disease genes. Once a gene is cloned, it is possible to determine its DNA sequence and the mutations which disrupt its protein product.
The gene that causes cystic fibrosis (CF) is a good example. In 1985, the gene for CF was mapped to chromosome 7q31-q32 by linkage analysis. Four years later, it was cloned. We now know that the disease is caused by a defect in a chloride channel – the protein product of this gene. ‘Identifying these genes has enormous implications for public health,’ says Andrew. ‘It means we can work towards cures and therapies that were previously impossible.’
Creating the maps
‘Gene mapping’ refers to the locating of genes to specific positions on chromosomes. As a critical step in the understanding of genetic diseases, mapping provides researchers with the route to identifying a specific faulty gene on a chromosome. Andrew and the genetics team have been using a new method for human chromosome mapping in order to isolate these genes. ‘Linkage disequilibrium (allelic association) mapping’ is the next step on from ‘linkage mapping’ and has been heralded as an exciting new avenue in genetics.
‘To find the position of a disease gene on a chromosome we need some form of breakage to reduce the size of the target region,’ explains Andrew. ‘There are many thousands of points of variation along a chromosome between any two individual genes. These are called polymorphisms. Whilst a tiny fraction of these are actually the disease genes we wish to find, the majority are used only as “markers” for a chromosome position. Linkage mapping determines the relative position of a set of markers and a possible disease-causing gene on a chromosome.’
To reduce the target area on the chromosome, linkage mapping looks at sections of chromosome inherited as a unit. The process of meiosis, which leads to the production of egg cells and sperm cells, involves mixing (recombination) of chromosomal material derived from that person’s parents.
If a mother has a faulty gene it will be passed to her children if they inherit the fragment of chromosome containing the faulty form of the gene. She in turn would have received the gene from one of her parents.
Tracing these genes forms the basis of linkage mapping. ‘We use markers to designate where a chromosome has broken (meiotic breaks) and look to see if a particular chromosome segment is inherited along with the disease in a family.’ says Andrew. ‘The idea is to prove beyond reasonable doubt that the fault is occurring in the same genomic region for all samples and to ultimately locate the gene in question.’
Such analysis seems simple when put in these terms, but the amount of information is vast. ‘There are around three billion bases in the human genome and approximately 25,000 genes. At best, linkage analysis may give us sections of one million (a megabase), with several tens of genes present,’ says Andrew.
