By Sharon Kingman
BioWorld International Correspondent
LONDON ¿ The sequence of chromosome 20, which has just been published, will allow medical researchers to ¿zoom in¿ on the genetic causes of diseases as diverse as Creutzfeld-Jakob disease, obesity, eczema and Type II diabetes, the scientists who carried out its sequencing predict.
Panos Deloukas, senior group leader in the department of human genetics at the Wellcome Trust Sanger Institute in Hinxton, UK, told BioWorld International, ¿The sequence of chromosome 20 will prove to be a very useful tool for everybody who wants to dissect out the genetic causes of many of these common diseases.¿ He predicted that scientists will want to put together a map identifying the commonest blocks of the chromosome that have been passed down over thousands of generations, and which are shared by many people. This would, he said, simplify the task of identifying where crucial mutations or variations, implicated in common complex diseases, lie in the sequence.
Now that the sequencing of chromosome 20 is finished, he forecasted, it will become a good target for systematic analysis of its encoded proteins. Once mutant or variant genes have been identified, it may be possible to design new drugs to treat diseases with a genetic component. ¿Once you know the structure of the protein molecule,¿ Deloukas said, ¿you can envisage ways of designing new drugs to modify its function.¿
Francis Collins, director of the U.S. National Human Genome Research Institute in Bethesda, Md., who leads the American arm of the Human Genome Project, said: ¿My diabetes research team has benefited enormously from the chromosome 20 sequence. We used the mapped draft sequence as it became available ¿ and now the finished sequence ¿ and have been able to close in on the likely gene on chromosome 20 that is altered in Type II diabetes.¿ He congratulated the Wellcome Trust Sanger Institute for ¿this contribution to humanity.¿
Deloukas and his colleagues at the institute report their findings in a paper in Nature titled: ¿The DNA sequence and comparative analysis of human chromosome 20.¿
Chromosome 20 is the largest human chromosome to be sequenced so far, comprising about 2 percent of the human genome. It has nearly 60 million bases, and the Sanger team has sequenced about 99.5 percent of its genetically active regions. The researchers have annotated, or labeled, 720 genes.
A novel approach taken in the analysis of the sequence information for chromosome 20 was to compare the data with that for the mouse, Mus musculus, and the puffer fish, Tetraodon nigroviridis.
Deloukas explained: ¿We did this as an independent evaluation of our analysis of the human chromosome. The comparison indicates that, in the present study, we have annotated more than 95 percent of coding exons. Interestingly, when you compare the human to the mouse, you observe conservation not only in the coding blocks or exons, but also in the noncoding regions ¿ whether the latter are within genes or between genes. But when you add the third genome, of an organism which is more distantly related, then the coding regions start popping up more clearly, because there doesn¿t seem to be any conservation in the non-coding parts of the genome between humans and puffer fish.¿
One surprising discovery, Deloukas said, was that some people have an extra chunk of DNA in chromosome 20. This inserted segment is about 40,000 bases long and seems to have a gene within it. ¿It will be very interesting to find out if this gene is expressed and therefore functional and, if so, what sort of benefits it may confer on those who have it.¿
Initial studies carried out following the discovery of the insertion suggest that it is carried by about 37 percent of the Caucasian population. The gene is similar to others in a gene family in the same locality and its structure suggests that it may encode a molecule resembling an immunoglobulin. Some researchers have speculated that it may have a role in cell-cell adhesion, Deloukas said.
Part of the chromosome 20 project involved pinpointing the positions of single nucleotide polymorphisms (SNPs), places where single nucleotides frequently vary. Deloukas said the team had identified 32,000 of these SNPs.
Analysis of the genes on chromosome 20 known to be involved in the inheritance of monogenic diseases such as Creutzfeld-Jakob disease and severe combined immunodeficiency would shed light on both the familial and sporadic forms of these diseases, Deloukas said.
¿There are also a handful of other monogenic diseases encoded by genes on chromosome 20, which are rare but very important to those families affected by them,¿ he added. ¿My own group is collaborating with researchers at the Institute of Ophthalmology in London, investigating two diseases ¿ congenital hereditary endothelial dystrophy and posterior polymorphous dystrophy ¿ that affect the cornea, causing severely impaired vision and blindness. We now know the regions concerned, we have all the genes, and we are going through them systematically to find out which gene is responsible for this disease.¿