Genetic information, encoded in DNA, is passed down, influencing traits. Genes are specific DNA segments on chromosomes. While genes are inherited, the different versions of these genes, known as alleles, do not always combine randomly. Linkage disequilibrium describes this non-random association of alleles at different positions on a chromosome.
Understanding Linkage Disequilibrium
Linkage refers to the physical proximity of genes on the same chromosome. When genes are located close to each other, they tend to be inherited together because the chromosome is passed on as a unit. Disequilibrium, in this context, signifies a non-random association of alleles at two or more distinct locations, or loci, within a population. This means that specific combinations of alleles appear together more or less frequently than would be expected if their inheritance were independent.
Alleles at different locations on a chromosome can be found together more often than chance alone would predict. For example, if allele ‘A’ at one locus is consistently observed with allele ‘B’ at another, it suggests linkage disequilibrium. This phenomenon is distinct from genetic linkage, which describes genes being physically close on a chromosome. While linked genes can be in linkage disequilibrium, disequilibrium can also occur between unlinked genes due to other factors.
Alleles are in “equilibrium” when their association is random, meaning the frequency of a specific combination of alleles is simply the product of their individual frequencies. Conversely, “disequilibrium” indicates a non-random association, where the observed frequency of an allele combination deviates from this expected random product. Scientists measure this deviation using statistical methods like D’ and r², which quantify the degree of association between alleles at different loci.
How Linkage Disequilibrium Arises
A primary factor contributing to linkage disequilibrium is the lack of recombination between physically close genes on a chromosome. During meiosis, the process of producing reproductive cells, homologous chromosomes can exchange segments through crossing over, or recombination. Genes that are very close together are less likely to be separated by these recombination events, leading to their alleles being inherited as a block across many generations.
Genetic drift, the random fluctuation of allele frequencies, also contributes to linkage disequilibrium, particularly in smaller populations. Chance events can cause certain allele combinations to become more common, even without selective advantage.
Natural selection can further influence linkage disequilibrium by favoring specific combinations of alleles, known as haplotypes, that provide an advantage. If a particular haplotype improves survival or reproduction, its frequency will increase in the population, thereby maintaining the non-random association of those alleles. This selective pressure ensures that beneficial allele combinations are passed on together.
Population bottlenecks and founder effects are additional mechanisms that can generate high levels of linkage disequilibrium. When a population undergoes a drastic reduction in size (bottleneck) or when a new population is established by a small group of individuals (founder effect), the genetic diversity is significantly reduced. The resulting population carries a limited subset of the original genetic variation, leading to increased non-random associations among alleles throughout the genome. A new mutation that arises on a specific chromosomal background will initially be in complete linkage disequilibrium with the surrounding alleles on that particular chromosome segment.
Linkage Disequilibrium in Genetic Studies
Linkage disequilibrium plays a role in identifying genes associated with various diseases, particularly in human genetics. If a specific genetic marker, such as a Single Nucleotide Polymorphism (SNP), is consistently found alongside a disease, it often means that this marker is in linkage disequilibrium with the actual disease-causing genetic variant. Researchers can then use the measurable marker to indirectly pinpoint the location of the unmeasured disease-causing variant.
Genome-Wide Association Studies (GWAS) rely on linkage disequilibrium to efficiently scan the entire genome for common genetic variations linked to diseases or specific traits. Because of linkage disequilibrium, scientists do not need to analyze every single genetic variant. Instead, they can examine a representative set of markers and infer the presence and association of other, unmeasured variants that are in disequilibrium with the tested markers. This approach streamlines the process of disease gene mapping.
The patterns of linkage disequilibrium also provide insights into human population history. Variations in these patterns across different human populations can reveal information about ancient migration routes, past population bottlenecks, and admixture events where previously separated populations interbred. High levels of linkage disequilibrium, for instance, might indicate a recent common ancestry or a more recent population bottleneck.
Understanding linkage disequilibrium can also have implications in pharmacogenomics, which focuses on how an individual’s genetic makeup affects their response to drugs. By analyzing an individual’s genetic profile and the associated linkage disequilibrium patterns, scientists can predict how they might react to certain medications. This application aims to personalize medicine by tailoring drug treatments based on an individual’s unique genetic predispositions.