BioWorld International Correspondent

LONDON - Large segments of chromosome 22 are inherited as single blocks that are identical in most people, an analysis of DNA sequence has shown. Companies and researchers trawling the genome for mutant genes that cause disease are likely to focus their efforts on those stretches of DNA first, with a much better chance of success, the team who carried out the work predicts.

Lon Cardon, Wellcome Trust principal fellow at the Wellcome Trust Centre for Human Genetics at the University of Oxford, told BioWorld International: "We looked at chromosome 22 in more than 200 people to try to find out what was similar or different in terms of its DNA sequence, in order to allow us to prioritize our hunt for genes on this chromosome. What we found was that there are these long tracks of the genome that somehow avoid being broken up over time. We want to know why that is, and what biological processes are allowing genes to recombine, or to mutate rapidly, in some areas, but hardly at all in others."

Cardon and his colleagues report their study in a paper in Nature (advance online publication July 10, 2002) titled "A first-generation linkage disequilibrium map of human chromosome 22."

In their paper, Cardon and co-authors describe the chromosomes of present-day humans as being similar to "mosaics of ancestral chromosomes that have arisen through multiple recombination events in the past." The specific sequence of each chromosome comprises an individual "haplotype." When the different parts of the haplotype do not occur in the population at the frequency expected if they freely underwent random recombination events, scientists conclude that they are associated with each other - a phenomenon called linkage disequilibrium.

Cardon, together with collaborators from the Wellcome Trust Sanger Institute in Hinxton; the University of Michigan in Ann Arbor; Third Wave Technologies Inc., of Madison, Wis.; the University of Tartu in Estonia; and the European Bioinformatics Institute in Cambridge, set out to find the areas of linkage disequilibrium on chromosome 22. They chose the chromosome because it was the first to be completely sequenced, an event that took place at the Wellcome Trust Sanger Institute, another bonus.

They focused on single nucleotide polymorphisms (SNPs) - places where single bases varied between people. Some are mutations that alter the protein encoded by the gene in question - possibly producing disease - while others are base changes of no consequence.

Cardon said: "We looked at 1,500 SNPs at intervals of 15,000 bases. We wanted to find tracks of SNPs where the haplotypes - the collections of SNPs - were very similar throughout our samples."

The findings, he said, were "quite surprising." They had expected to find bunches of tiny segments where the DNA sequence was conserved between individuals, separated by tiny segments where everyone's DNA sequence was different.

"But we did not find that at all," Cardon explained. "We found two very long tracks on chromosome 22 - about 40 percent of the chromosome - where all the samples we looked at were very highly similar. For the other 60 percent, individuals' DNA sequences differed quite markedly."

Researchers looking for disease genes in these homogenous regions, he predicted, would have a good chance of success. He expects future studies to compare those areas of high linkage disequilibrium in populations of people with certain diseases to those in normal controls. Because the reference samples used for the study reported in Nature came from people of European ancestry, researchers also would want to know whether the same findings hold true for people of other ethnic origins.

Cardon said the linkage disequilibrium map of chromosome 22 could form part of the proposed genome-wide haplotype map or "hap map." Perlegen Sciences Inc., of Mountain View, Calif., published similar information for chromosome 21, but Cardon said the number of samples Perlegen used was limited. "They looked at more markers but in only 10 people, so their data are not really as generalizable as our [data]," he said.

Cardon is keen to take an even closer look at chromosome 22. "We looked at one SNP every 15,000 base pairs - we would like to look at one SNP every 1,000 base pairs, say, to discover the very minute patterns as well as the very broad ones. Also, this type of work needs to be done for all the other chromosomes, too," he said.