Genetic recombination

Genetic recombination is the transmission-genetic process by which the combinations of alleles observed at different loci (plural of locus) in two parental individuals become shuffled in offspring individuals. This definition is commonly used in classical transmission genetics, evolutionary biology, and population genetics. Such shuffling can be the result of recombination via intra-chromososomal recombination (crossing over) and via inter-chromososomal recombination (also called independent assortment). Recombination therefore only shuffles already existing genetic variation and does not create new variation at the involved loci. In evolutionary biology, genetic recombination, be it inter- or intra-chromososomal, is thought to have many advantages including that of allowing sexually reproducing organisms to avoid Muller's ratchet.

In molecular biology, recombination generally refers to the molecular process by which genetic variation found associated at two different places in a continuous piece of DNA becomes disassociated (shuffled). In this process one or both of the genetic variants are replaced by different variants found at same two places in a second DNA molecule. One mechanism leading to such molecular recombination is chromosomal crossing over. Such shuffling of variation is also possible between duplicated loci within the same DNA molecule. If the number of loci in each of the recombinant molecules is changed by the shuffling process, one speaks of "unbalanced" recombination or unequal crossing over. Enzymes called recombinases catalyze this reaction. A recombination pathway in DNA is any way by which a broken DNA molecule is reconnected to form a whole DNA strand.

Crossing over
Main article: Chromosomal crossover

Crossing over of one of the chromosomes inherited from each of one's parents occurs during meiosis in that parent. After chromosomal replication during gametogenesis, the four available chromatids are in tight formation with one another. During this time, homologous sites on two chromatids can mesh with one another, and may exchange genetic information. Immediately after replication, the tetrad formed by replication contains two pairs of two identical chromatids; after crossing over, each of the four chromatids carries a unique set of genetic information.

Chemistry of crossover


Enzymes known as recombinases catalyze the reactions that allow for crossover to occur. A recombinase creates a nick in one strand of a DNA double helix, allowing the nicked strand to pull apart from its complementary strand and anneal to one strand of the double helix on the opposite chromatid. A second nick allows the unannealed strand in the second double helix to pull apart and anneal to the remaining strand in the first, forming a structure known as a cross-strand exchange or a Holliday junction. The Holliday junction is a tetrahedral structure which can be 'pulled' by other recombinases, moving it along the four-stranded structure.

Consequences of crossover
In most eukaryotes, a cell carries two copies of each gene, each referred to as an allele. Each parent passes on one allele to each offspring. Even without recombination, each gamete contains a random assortment of chromatids, choosing randomly from each pair of chromatids available. With recombination, however, the gamete can receive a (mostly) random assortment of individual genes, as each chromosome may contain genetic information from two different chromatids.

Recombination results in a new combination of maternal and paternal alleles on the same chromosome. Although the same genes appear in the same order, the alleles are different. This process explains why offspring from the same parents can look so different. In this way, it is theoretically possible to have any combination of parental alleles in an offspring, and the fact that two alleles appear together in one offspring does not have any influence on the statistical probability that another offspring will have the same combination. This theory of "independent assortment" of alleles is fundamental to genetic inheritance. However, there is an exception that requires further discussion. The frequency of recombination is actually not the same for all gene combinations. This leads to the notion of "genetic distance", which is a measure of recombination frequency averaged over a (suitably large) sample of pedigrees. Loosely speaking, one may say that this is because recombination is greatly influenced by the proximity of one gene to another. If two genes are located close together on a chromosome, the likelihood that a recombination event will separate these two genes is less than if they were farther apart. Genetic linkage describes the tendency of genes to be inherited together as a result of their location on the same chromosome. Linkage disequilibrium describes a situation in which some combinations of genes or genetic markers occur more or less frequently in a population than would be expected from their distances apart. This concept is applied when searching for a gene that may cause a particular disease. This is done by comparing the occurrence of a specific DNA sequence with the appearance of a disease. When a high correlation between the two is found, it is likely that the appropriate gene sequence is closer.

Problems of crossover
Crossover recombination can occur between any two double helices of DNA which are very close in sequence and come into contact with one another. Thus, crossover may occur between Alu repeats on the same chromatid, or between similar sequences on two completely different chromosomes. These processes are called unbalanced recombination. Unbalanced recombination is fairly rare compared to normal recombination, but severe problems can arise if a gamete containing unbalanced recombinants becomes part of a zygote. Offspring with severe unbalances rarely live through birth.

Conservative site-specific recombination
In conservative site-specific recombination, a mobile DNA element is inserted into a strand of DNA by means similar to that seen in crossover. A segment of DNA on the mobile element matches exactly with a segment of DNA on the target, allowing enzymes called integrases to insert the rest of the mobile element into the target. Integrases are a special type of Recombinases. Recombinases are enzymes which cleave the double stranded DNA at specific sites resulting in a loss of the Phosphodiester bonds. This reaction is stabilised by the formation of a covalent bond between the Recombinase and the DNA through a Phospho Tyrosine Bond.

Transpositional recombination
Another form of site-specific recombination, transpositional recombination does not require an identical strand of DNA in the mobile element to match with the target DNA. Instead, the integrases involved introduce nicks in both the mobile element and the target DNA, allowing the mobile DNA to enter the sequence. The nicks are then removed by ligases.

nonhomologous recombination
Recombination between DNA sequences that contain no sequence homology, also referred to as nonhomologous end joining.