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linkage disequilibrium

Sunday 23 November 2003

Patterns of linkage disequilibrium (LD) reveal the action of evolutionary processes and provide crucial information for association mapping of disease genes.

A complete description of human genetic variation requires more than just properties of isolated genes, microsatellites or SNPs.

How these vary simultaneously within a part or whole chromosome requires statistics of correlation between the variation at different positions, and these are usually described by patterns of linkage disequilibrium (LD).

The stronger the LD, the more likely that alleles at each of two positions will be found in association with one another.

Using studies of protein variants in the 1970s and 1980s it was rare to identify strong LD in populations of outcrossing diploids.

However, as more details become available on variation in human DNA across populations, LD between polymorphic DNA sites is increasingly being detected.

Standard population genetic theory suggests that LD between pairs of genetic markers should decrease as the recombination between them increases. But early studies of short segments of DNA did not show this relationship for SNPs.

Because the pattern of LD is expected to vary both with local effects, such as the extent of selection, the degree to which pairs of sites interact in response to selection (epistasis), and with population-scale forces, such as drift, migration and non-random mating, genomic patterns of LD can be expected to be fairly complex.

Recent studies of relatively long (200−500 kb) stretches of DNA, however, have produced a picture of blocks of high LD interspersed by short intervals of low LD.

Within the blocks of high LD there is evidence of lack of recombination, whereas the regions between the blocks seem to be ’hot spots’ in which recombination occurs frequently.

It has been therefore suggested that the next phase of research into human variation should focus on these blocks of high LD, for which haplotypes, rather than single markers, will become the unit of variation.

Although it has been known for many years that the extent of LD among specific sets of genes shows great variation around the world-for example, it is usually much weaker in African than in European populations-genome-wide studies covering representative worldwide populations remain to be done.


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