Mary Ann Robinson, Laboratory of Immunogenetics, National Institutes of Health, Maryland, USA
Linkage disequilibrium is an important concept in genetic studies that aims to identify and/or localize genes related to disease susceptibility. The term linkage disequilibrium is commonly used to indicate that two genes are physically linked, however, the strict definition of the term does not specify close genetic linkage. Linkage disequilibrium is defined as the difference between the observed frequency of a particular combination of alleles at two loci and the frequency expected for random association. This is based on the assumption that, given sufficient evol utionary time, the occurrence of random recombination events will result in an equilibrium distribution of alleles at each locus. Thus, the frequency of a particular allele at a given locus will be independent of alleles at other linked loci.
In immunology, the term linkage disequilibrium is often encountered in studies of the HLA complex. The HLA gene complex consists of multiple highly polymorphic loci. Linkage disequilibrium (A) is most simply calculated using the equation:
where p is the frequency of allele 'a' at locus 1, q is the frequency of allele 'b' at locus 2, and Fohs is the observed frequency of alleles 'a' and 'b' occurring together.
Taking a sample population where the gene frequencies of HLA-B8 and HLA-DR3 are 9 and 10% respectively, random recombination of HLA-B8 and HLA-DR3 would result in their presence in the same haplotype at a frequency of 0.9%. However, the observed frequency of HLA-B8/DR3 positive haplo-types is "7%, giving a linkage disequilibrium of 6.1%. Thus HLA-B8 and HLA-DR3 occur together in a haplotype in this population far more frequently than expected. Similar examples of linkage disequilibrium have been observed for alleles of HLA genes in every population studied; the specific alleles involved vary in different populations.
Many diseases have been associated with, or linked to, genes encoded within the HLA gene complex; however, the association between an HLA allele and a given disease is rarely absolute. Therefore, the observed association between a given HLA allele and a particular disease or functional characteristic may reflect some property of a gene closely linked to the tested locus, rather than a property of the locus itself.
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