Genetic recombination (also known asgenetic reshuffling) is the exchange ofgenetic material between differentorganisms which leads to production of offspring with combinations of traits that differ from those found in either parent. Ineukaryotes, genetic recombination duringmeiosis can lead to a novel set ofgenetic information that can be further passed on fromparents to offspring. Most recombination occurs naturally and can be classified into two types: (1)interchromosomal recombination, occurring through independent assortment ofalleles whose loci are on different but homologous chromosomes (random orientation of pairs of homologous chromosomes in meiosis I); & (2)intrachromosomal recombination, occurring through crossing over.[1]
Duringmeiosis ineukaryotes, genetic recombination involves the pairing ofhomologous chromosomes. This may be followed by information transfer between the chromosomes. The information transfer may occur without physical exchange (a section of genetic material is copied from one chromosome to another, without the donating chromosome being changed) (see SDSA – Synthesis Dependent Strand Annealing pathway in Figure); or by the breaking and rejoining ofDNA strands, which forms new molecules of DNA (see DHJ pathway in Figure).
Recombination may also occur duringmitosis in eukaryotes where it ordinarily involves the two sister chromatids formed after chromosomal replication. In this case, new combinations ofalleles are not produced since the sister chromatids are usually identical. In meiosis and mitosis, recombination occurs between similar molecules ofDNA (homologous sequences). In meiosis, non-sister homologous chromosomes pair with each other so that recombination characteristically occurs between non-sister homologues. In both meiotic and mitotic cells, recombination between homologous chromosomes is a common mechanism used inDNA repair.
Gene conversion – the process during which homologous sequences are made identical also falls under genetic recombination.
Genetic recombination and recombinationalDNA repair also occurs inbacteria andarchaea, which useasexual reproduction.
Recombination can be artificially induced in laboratory (in vitro) settings, producingrecombinant DNA for purposes includingvaccine development.
V(D)J recombination in organisms with anadaptive immune system is a type of site-specific genetic recombination that helps immune cells rapidly diversify to recognize and adapt to newpathogens.
During meiosis, synapsis (the pairing of homologous chromosomes) ordinarily precedes genetic recombination.
Genetic recombination iscatalyzed by many differentenzymes.Recombinases are key enzymes that catalyse the strand transfer step during recombination.RecA, the chief recombinase found inEscherichia coli, is responsible for the repair of DNA double strand breaks (DSBs). In yeast and other eukaryotic organisms there are two recombinases required for repairing DSBs. TheRAD51 protein is required formitotic andmeiotic recombination, whereas the DNA repair protein,DMC1, is specific to meiotic recombination. In the archaea, theortholog of the bacterial RecA protein is RadA.
Bacteria regularly undergo genetic recombination in three main ways:
Sometimes a strand of DNA is transferred into the target cell but fails to be copied as the target divides. This is called anabortive transfer.
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Ineukaryotes, recombination duringmeiosis is facilitated bychromosomal crossover. The crossover process leads to offspring having different combinations of genes from those of their parents, and can occasionally produce new chimericalleles.[citation needed] The shuffling of genes brought about by genetic recombination produces increasedgenetic variation. It also allows sexually reproducing organisms to avoidMuller's ratchet, in which thegenomes of anasexualpopulation tend to accumulate more deleterious mutations over time than beneficial or reversing mutations.[citation needed]
Chromosomal crossover involves recombination between the pairedchromosomes inherited from each of one's parents, generally occurring duringmeiosis.[citation needed] Duringprophase I (pachytene stage) the four availablechromatids are in tight formation with one another.[citation needed] While in this formation,homologous sites on two chromatids can closely pair with one another, and may exchange genetic information.[6]
Because there is a small probability of recombination at any location along a chromosome, thefrequency of recombination between two locations depends on the distance separating them.[citation needed] Therefore, for genes sufficiently distant on the same chromosome, the amount of crossover is high enough to destroy the correlation between alleles.[citation needed]
Tracking the movement of genes resulting from crossovers has proven quite useful to geneticists. Because two genes that are close together are less likely to become separated than genes that are farther apart, geneticists can deduce roughly how far apart two genes are on a chromosome if they know the frequency of the crossovers.[citation needed] Geneticists can also use this method to infer the presence of certain genes. Genes that typically stay together during recombination are said to belinked. One gene in a linked pair can sometimes be used as a marker to deduce the presence of the other gene. This is typically used to detect the presence of a disease-causing gene.[7]
The recombination frequency between two loci observed is thecrossing-over value. It is the frequency ofcrossing over between two linkedgene loci (markers), and depends on the distance between the geneticloci observed. For any fixed set of genetic and environmental conditions, recombination in a particular region of a linkage structure (chromosome) tends to be constant, and the same is then true for the crossing-over value which is used in the production ofgenetic maps.[5][8]
In gene conversion, a section of genetic material is copied from one chromosome to another, without the donating chromosome being changed. Gene conversion occurs at high frequency at the actual site of the recombination event duringmeiosis. It is a process by which a DNA sequence is copied from oneDNA helix (which remains unchanged) to another DNA helix, whose sequence is altered. Gene conversion has often been studied in fungal crosses[9] where the 4 products of individual meioses can be conveniently observed. Gene conversion events can be distinguished as deviations in an individual meiosis from the normal 2:2 segregation pattern (e.g. a 3:1 pattern).
Recombination can occur between DNA sequences that contain no sequencehomology. This can causechromosomal translocations, sometimes leading to cancer.
B cells of theimmune system perform genetic recombination, calledimmunoglobulin class switching. It is a biological mechanism that changes anantibody from one class to another, for example, from anisotype calledIgM to an isotype calledIgG.
Ingenetic engineering, recombination can also refer to artificial and deliberate recombination of disparate pieces of DNA, often from different organisms, creating what is calledrecombinant DNA. A prime example of such a use of genetic recombination isgene targeting, which can be used to add, delete or otherwise change an organism's genes. This technique is important tobiomedical researchers as it allows them to study the effects of specific genes. Techniques based on genetic recombination are also applied inprotein engineering to develop new proteins of biological interest.
Examples includeRestriction enzyme mediated integration,Gibson assembly andGolden Gate Cloning.
DNA damages caused by a variety of exogenous agents (e.g.UV light,X-rays, chemicalcross-linking agents) can be repaired by homologous recombinational repair (HRR).[10][11] These findings suggest thatDNA damages arising from natural processes, such as exposure to reactive oxygen species that are byproducts of normal metabolism, are also repaired by HRR. In humans, deficiencies in the gene products necessary for HRR during meiosis likely cause infertility[12] In humans, deficiencies in gene products necessary for HRR, such asBRCA1 andBRCA2, increase the risk of cancer (seeDNA repair-deficiency disorder).
In bacteria, transformation is a process of gene transfer that ordinarily occurs between individual cells of the same bacterial species. Transformation involves integration of donor DNA into the recipient chromosome by recombination. This process appears to be an adaptation for repairing DNA damages in the recipient chromosome by HRR.[13] Transformation may provide a benefit to pathogenic bacteria by allowing repair of DNA damage, particularly damages that occur in the inflammatory, oxidizing environment associated with infection of a host.
When two or more viruses, each containing lethal genomic damages, infect the same host cell, the virus genomes can often pair with each other and undergo HRR to produce viable progeny. This process, referred to as multiplicity reactivation, has been studied in lambda andT4 bacteriophages,[14] as well as in several pathogenic viruses. In the case of pathogenic viruses, multiplicity reactivation may be an adaptive benefit to the virus since it allows the repair of DNA damages caused by exposure to the oxidizing environment produced during host infection.[13] See alsoreassortment.
A molecular model for the mechanism of meiotic recombination presented by Anderson and Sekelsky[15] is outlined in the first figure in this article. Two of the four chromatids present early in meiosis (prophase I) are paired with each other and able to interact. Recombination, in this model, is initiated by a double-strand break (or gap) shown in the DNA molecule (chromatid) at the top of the figure. Other types of DNA damage may also initiate recombination. For instance, an inter-strand cross-link (caused by exposure to a cross-linking agent such as mitomycin C) can be repaired by HRR.
Two types of recombinant product are produced. Indicated on the right side is a "crossover" (CO) type, where the flanking regions of the chromosomes are exchanged, and on the left side, a "non-crossover" (NCO) type where the flanking regions are not exchanged. The CO type of recombination involves the intermediate formation of two "Holliday junctions" indicated in the lower right of the figure by two X-shaped structures in each of which there is an exchange of single strands between the two participating chromatids. This pathway is labeled in the figure as the DHJ (double-Holliday junction) pathway.
The NCO recombinants (illustrated on the left in the figure) are produced by a process referred to as "synthesis dependent strand annealing" (SDSA). Recombination events of the NCO/SDSA type appear to be more common than the CO/DHJ type.[16] The NCO/SDSA pathway contributes little to genetic variation, since the arms of the chromosomes flanking the recombination event remain in the parental configuration. Thus, explanations for the adaptive function of meiosis that focus exclusively on crossing-over are inadequate to explain the majority of recombination events.
Achiasmy is the phenomenon where autosomal recombination is completely absent in one sex of a species. Achiasmatic chromosomal segregation is well documented in maleDrosophila melanogaster. The"Haldane-Huxley rule" states that achiasmy usually occurs in theheterogametic sex.[17]
Heterochiasmy occurs when recombination rates differ between the sexes of a species.[17] In humans, each oocyte has on average 41.6 ± 11.3 recombinations, 1.63-fold higher than sperms. This sexual dimorphic pattern in recombination rate has been observed in many species. In mammals, females most often have higher rates of recombination.[18]
Numerous RNA viruses are capable of genetic recombination when at least two viralgenomes are present in the same host cell.[19][20] Recombination is largely responsible for RNA virus diversity and immune evasion.[21] RNA recombination appears to be a major driving force in determining genome architecture and the course of viral evolution amongpicornaviridae ((+)ssRNA) (e.g.poliovirus).[22] In theretroviridae ((+)ssRNA)(e.g.HIV), damage in the RNA genome appears to be avoided duringreverse transcription by strand switching, a form of recombination.[23][24]
Recombination also occurs in thereoviridae (dsRNA)(e.g. reovirus),orthomyxoviridae ((-)ssRNA)(e.g.influenza virus)[24] andcoronaviridae ((+)ssRNA) (e.g.SARS).[25][26]
Recombination in RNA viruses appears to be an adaptation for coping with genome damage.[19] Switching between template strands during genome replication, referred to as copy-choice recombination, was originally proposed to explain the positive correlation of recombination events over short distances in organisms with a DNA genome (see first Figure,SDSA pathway).[27]
Recombination can occur infrequently between animal viruses of the same species but of divergent lineages. The resulting recombinant viruses may sometimes cause an outbreak of infection in humans.[25]
Especially in coronaviruses, recombination may also occur even among distantly related evolutionary groups (subgenera), due to their characteristic transcription mechanism, that involves subgenomic mRNAs that are formed by template switching.[28][26]
When replicating its(+)ssRNA genome, thepoliovirusRNA-dependent RNA polymerase (RdRp) is able to carry out recombination. Recombination appears to occur by a copy choice mechanism in which the RdRp switches (+)ssRNA templates during negative strand synthesis.[29] Recombination by RdRp strand switching also occurs in the (+)ssRNA plantcarmoviruses andtombusviruses.[30]
Recombination appears to be a major driving force in determining genetic variability within coronaviruses, as well as the ability of coronavirus species to jump from one host to another and, infrequently, for the emergence of novel species, although the mechanism of recombination in is unclear.[25]
In early 2020, many genomic sequences of Australian SARS‐CoV‐2 isolates have deletions or mutations (29742G>A or 29742G>U; "G19A" or "G19U") in the s2m, suggesting that RNA recombination may have occurred in this RNA element. 29742G("G19"), 29744G("G21"), and 29751G("G28") were predicted as recombination hotspots.[31] During the first months of the COVID-19 pandemic, such a recombination event was suggested to have been a critical step in the evolution of SARS-CoV-2's ability to infect humans.[32]Linkage disequilibrium analysis confirmed thatRNA recombination with the 11083G > T mutation also contributed to the increase of mutations among the viral progeny. The findings indicate that the 11083G > T mutation of SARS-CoV-2 spread duringDiamond Princess shipboard quarantine and arose through de novoRNA recombination under positive selection pressure. In three patients on theDiamond Princess cruise, two mutations, 29736G > T and 29751G > T (G13 and G28) were located inCoronavirus 3′ stem-loop II-like motif (s2m) of SARS-CoV-2. Although s2m is considered an RNA motif highly conserved in 3' untranslated region among many coronavirus species, this result also suggests that s2m of SARS-CoV-2 isRNA recombination/mutation hotspot.[33]
SARS-CoV-2's entire receptor binding motif appeared, based on preliminary observations, to have been introduced through recombination from coronaviruses ofpangolins.[34] However, more comprehensive analyses later refuted this suggestion and showed that SARS-CoV-2 likely evolved solely within bats and with little or no recombination.[35][36]
Nowak and Ohtsuki[37] noted that the origin of life (abiogenesis) is also the origin of biologicalevolution. They pointed out that all known life on earth is based onbiopolymers and proposed that any theory for the origin of life must involve biological polymers that act as information carriers and catalysts. Lehman[38] argued that recombination was an evolutionary development as ancient as the origins of life. Smail et al.[39] proposed that in the primordial Earth, recombination played a key role in the expansion of the initially short informational polymers (presumed to beRNA) that were the precursors to life.
This article incorporatespublic domain material fromScience Primer.NCBI. Archived fromthe original on 2009-12-08.
