Linkage Disequilibrium

Linkage disequilibrium is the phenomenon in which certain alleles at different loci appear more frequently together in the population, than is suggested by their individual frequencies. Examples of linkage disequilibrium in HLA include HLA-B*07 being often found with HLA-C*07 and HLA-DRB1*03:01 being often found with HLA-DQB1*02:01.

In a randomly mating population, there is an assumption that given sufficient evolutionary time, random recombination events should result in an equilibrium distribution of alleles at each locus. The frequency of a particular allele at a given locus should be independent of alleles at other loci. When this is not the case, the alleles are said to be in linkage disequilibrium. Factors that can affect linkage disequilibrium include:

• System of Mating – A non-randomly mating population can cause certain alleles within the mating groups to be found more frequently together
• Selection pressures – Certain alleles may be protective for certain diseases and therefore carry an evolutionary advantage
• Genetic recombination – The generation of new traits in offspring that differ from those found in either parent
• Mutation rates – Certain alleles may be as a result of recent mutations and will not therefore not yet reached equilibrium
• Population structure – Systematic difference in allele frequencies between subpopulations in a population, possibly due to different ancestry
• Genetic drift – Changes in the frequency of an existing allele in a population due to random sampling of parents to form offspring can lead to two alleles being associated together more frequently
• Admixture – When two or more previously isolated populations begin interbreeding
• Genetic linkage – Two allele that are physically near to each other may be inherited together due to their physical closeness
• Gene conversion – The process by which one DNA sequence replaces a homologous sequence such that the sequences become identical after the conversion event

Study of HLA and disease – Linkage disequilibrium influences the study of HLA and disease as it can potentially mask the true genetic association. A disease which is thought to be in association with one HLA allele may in fact be in association with a different allele which happens to be in linkage disequilibrium. For example Iron overload was once thought to be associated with HLA-A3 until the association with HFE was discovered

Anthropological studies – Genetic anthropological meta-analyses can potentially allow for comprehensive evaluation of the relationships within and between given populations. Analysis of the HLA profiles of two adjacent tribes for instance can potentially yield insights into how those tribes have historically migrated from where they originated to where they find themselves today as well as give insights into historical intermingling of the tribes.

Stem cell donor selection – Stem cell donor identification can be tricky for patients who do not have a standard HLA-B Cw or HLA-DR DQ association. Many donors on the registry do not have HLA-Cw or HLA-DQ types. Calling such a donor for a patient who has an uncommon association is often futile.

Interpretation of HLA antibody results – HLA antibody screening by CDC is complicated by linkage disequilibrium which means that HLA-Cw7 for instance could not be readily identified in isolation from HLA-B8 s these are in LD. This problem is largely resolved by the use of SAB technology however wherever there is a clinical need for CDC screening the issue remains.

Interpretation of HLA typing results – Knowledge of the common HLA associations often serves as a valuable internal quality control check when reviewing HLA typing results.

Hardy Weinberger Equilibrum (HWE)

The Hardy Weinberg Equilibrium (HWE) states that in a randomly mating population, allele and genotype frequencies will remain constant from generation to generation unless there is an evolutionary force influencing change.

Factors that can disrupt HWE include:

• Mutation: rate of gene mutation under normal conditions is very low (~1×10^-7/gamete/locus/generation)
• Migration: gene frequencies vary among generations. Migration means populations intermate and leads to gene flow – changes gene frequency of original group
• Genetic heterogeneity: individuals with similar phenotypes or identical clinical symptoms of specific disease may have different genotypes.
• Random genetic drift: random fluctuation of gene frequency in small separated section of population
• Founder effect: form of genetic drift and refers to new group founded by minor individuals with some alleles of parent group. Population of this new group may increase but its gene variation is small due to reduced intermating between this group and other populations.
• Selection: either reproductive fitness or heterozygote dominance (in some recessive hereditary diseases and under certain conditions the heterozygote state may be more favourable to survival and progeny reproduction in contrast to homozygotes)