Genetic linkage occurs when particular alleles are inherited together. Typically, an organism can pass on an allele without regard to which allele was passed on for a different gene. This is because chromosomes are sorted randomly during meiosis?. However, alleles that are on the same chromosome are more likely to be inherited together, and are said to be linked.
Because there is some crossing over of DNA when the chromosomes segregate, alleles on the same chromosome can be separated and go to different cells. There is much more chance of this happening if the alleles are far apart on the chromosome, as it is more likely that a cross-over will occur between them.
The physical distance between two genes can be calculated using the offspring of an organism showing two linked genetic traits, and finding the percentage of the offspring where the two traits don't run together. The higher the percentage of descendence that doesn't show both traits, the further apart on the chromosome they are.
A study of the linkages between many genes enables the creation of a linkage map or genetic map.
Among individuals of an experimental population or species, some phenotypes or traits occur randomly with respect to one another in a manner known as independent assortment. Today scientists understand that independent assortment occurs when the genes affecting the phenotypes are found on different chromosomes.
An exception to independent assortment develops when genes appear near one another on the same chromosome. When genes occur on the same chromosome, they are usually inherited as a single unit. Genes inherited in this way are said to be linked. For example, in fruit flies the genes affecting eye color and wing length are inherited together because they appear on the same chromosome.
But in many cases, even genes on the same chromosome that are inherited together produce offspring with unexpected allele combinations. This results from a process called crossing over. Sometimes at the beginning of meiosis, a chromosome pair (made up of a chromosome from the mother and a chromosome from the father) may intertwine and exchange sections or fragments of chromosome. The pair then breaks apart to form two chromosomes with a new combination of genes that differs from the combination supplied by the parents. Through this process of recombining genes, organisms can produce offspring with new combinations of maternal and paternal traits that may contribute to or enhance survival.
Genetic linkage was first discovered by the British geneticists William Bateson and Reginald Punnett shortly after Mendel's laws were rediscovered.
The observations by Thomas Hunt Morgan that the amount of crossing over between linked genes differs led to the idea that crossover frequency might indicate the distance separating genes on the chromosome. Morgan's student Alfred Sturtevant developed the first genetic map, also called a linkage map.
Sturtevant proposed that the greater the distance between linked genes, the greater the chance that non-sister chromatids would cross over in the region between the genes. By working out the number of recombinants it is possible to obtain a measure for the distance between the genes. This distance is called a genetic map unit (m.u.), or a centimorgan and is defined as the distance between genes for which one product of meiosis in 100 is recombinant. A recombinant frequency (RF) of 1 % is equivalent to 1 m.u. A linkage map is created by finding the map distances between a number of traits that are present on the same chromosome, ideally avoiding having significant gaps between traits to avoid the inaccuracies that will occur due to the possibility of multiple recombination events.
Linkage mapping is critical for identifying the location of genes that cause genetic diseases. In a normal population, genetic traits and markers will occur in all possible combinations with the frequencies of combinations determined by the frequencies of the individual genes. For example, if alleles A and a occur with frequency 90% and 10%, and alleles B and b at a different genetic locus occur with frequencies 70% and 30%, the frequency of individuals having the combination AB would be 63%, the product of the frequencies of A and B, regardless of how close together the genes are. However, if a mutation in gene B that causes some disease happened recently in a particular subpopulation, it almost always occurs with a particur allele of gene A if the individual in which the mutation occurred had that variant of gene A and there have not been sufficient generations for recombination to happen between them (presumably due to tight linkage on the genetic map). In this case, called linkage disequilibrium, it is possible to search potential markers in the subpopulation and identify which marker the mutation is close to, thus determining the mutation's location on the map and identifying the gene at which the mutation occurred. Once the gene has been identified, it can be targeted to identify ways to mitigate the disease.
The causes of change in gene frequencies are usually listed as mutation, genetic drift, and natural selection. But there is another process, to which attention has only recently been drawn, which can cause changes in the frequencies, not of single genes, but of haplotypes in closely linked systems.
Linkage equilibration in blood group analysis
Linkage equilibrium is a significant factor in systems such as Rh, MNSs, Kell, and histocompatibility. Each of these involves three or more closely linked loci. If there is no natural selection favouring particular haplotypes in a given system, then in the course of time crossing over will distribute the alleles at one locus so that the ratios between the frequencies of combinations of the genes at a second closely-linked locus will be the same as the ratios between the total frequencies of these genes in the population under consideration. Thus if the total frequencies of the genes at one locus are 50, 30, and 20 per cent, then the combinations with a closely linked gene at another locus, with a total frequency of io per cent, should be 5, 3, and 2 per cent respectively.
It is inevitable that this process of equilibration should go on, but it may in part be counteracted by natural selection under a given set of circumstances favouring a particular haplotype combination. There are two main possible causes for a lack of linkage equilibrium. Either selection is favouring those haplotypes found in excess of equilibrium levels, or the population is the result of recent mixing of two (or more) separate populations. Thus frequencies near equilibrium suggest that the population has existed in a condition of relative isolation for a period probably of several thousand years, while lack of equilibrium suggests one of the two alternatives just mentioned. Where such a lack of equilibrium is found, some authorities favour natural selection as a cause while others favour recent hybridization.
Thus, apart from history and archaeology, there are two independent genetic indications that the population of Europe is the result of relatively recent hybridization. One is the presence at relatively high frequencies of both of the Rh alleles D and d, one of which should, in an equilibrated population, have been eliminated by haemolytic disease of the newborn. The other is the high general degree of linkage disequilibrium for the histocompatibility? system, to which Dr L. Degos has drawn attention and which he, unlike others, attributes to hybridization.
The high frequency of the CDE haplotype in Amerindian and Australian Aborigine populations appears to be due to crossing over between the haplotypes CDe and cDE, and is consistent with each of these great groups of populations having existed in isolation from the outside world for many thousands of years. ()
Linkage and blood group polymorphism
Linkage in man, except between characteristics carried on the sex chromosomes, has only recently been demonstrated, for the M, N blood types and sickle cell anemia. Since the exact genetic mechanism of only a few human characteristics is known, this is perhaps not surprising. The best known characteristics of men, genetically speaking, are the various blood groups and blood types, and if linkage other than sex linkage is to be found in the near future, it is to be expected that it will be between blood groups and some other characteristic.
That genetic linkage between blood types and other features such as morphological characteristics is possible is shown by the detection of such a case of linkage in the rabbit by Sawin and others. ()
Genome-wide linkage analysis of von Willebrand factor plasma levels implicates the ABO locus as a principal determinant. ()
Possible genetic linkage has been reported for Tricho-dento-osseous syndrome with the ABO blood group locus, but the gene defect remains unknown. ()
A few earlier linkage studies have found low to moderately positive lod scores in manic depressive families for ABO which is closely linked to dopamine beta hydroxylase (DBH). ()
There may be a genetic linkage between the ABO blood groups and the molecular structure of the tissue of Achilles tendons. ()
Absence of linkage of ABO blood group locus to familial tuberous sclerosis. ()
Possible linkage of a breast cancer-susceptibility locus to the ABO locus: sensitivity of LOD scores to a single new recombinant observation. ()
Lod score method for linkage
The Lod (log of odds) score is used to calculate the probability of a pedigree arrising randomly or by genetic linkage. The test was developed by Newton E. Morton.
LOD = log (probability of birth sequence with a given linkage value/probability of birth sequence with no linkage)