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Mitotic crossover is a rare type of genetic recombination that may occur in some types of somatic cells during mitosis . Mitotic crossover may occur in organisms that do not have a cycle of sexual reproduction where chromosomal crossover would normally occur during meiosis to generate genetic variation. It can only occur in diploid cells and a pair of chromosomes is required for the crossover to occur.
The mitotic crossover results in the production of homozygous allele combinations in all heterozygous genes that are located on that chromosome arm distal to the crossover. Thus when a mitotic crossover occurs, genes that were previously recessive are expressed creating a new phenotype.
Mitotic crossover is known to occur in some asexually reproducing fungi and in normal human cells, where the event may allow normally recessive cancer-causing genes to be expressed and thus predispose the individual to the development of cancer .
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Genetic distance is a measure of the dissimilarity of genetic material between different species or individuals of the same species.
All of life today is based upon the molecule of inheritance , DNA
(deoxyribonucleic acid). DNA molecules are a double helix , similar to a spiral staircase, in which the backbone sides are comprised of alternating
5-carbon deoxyribose sugar and a phosphate molecule, whilst the "rungs" of the staircase are nitrogenous purine and pyrimidine bases. These bases are adenine (A), which always pairs with thymine (T), and guanine (G), which always pairs with cytosine (C). It is the sequence of these bases on the helix, (e.g. ATTTCGCCAAG) which is copied and passed to descendants in cellular reproduction .

By comparing the percentage difference between the same genes or junk DNA of different species, a figure can be obtained, which is a measure of
"genetic distance". Depending upon the difference, and correcting this for known rates of evolution, genetic distance can be used as a tool to construct cladograms showing the family tree of all living beings.
For instance, the fact that the genetic distance of chimpanzees and human beings is only 1.6% (they are about 98.4% identical), suggests that human beings and chimpanzees last had a common ancestor about 5 million years ago, and that chimpanzees and humans are more closely related than either of the two species are related to gorillas and orangutan (which diverged about 9 million years ago, and 12 million years ago, respectively).
There are several different methods for defining genetic distance. One genetic distance measure is given by the formula D= − log(In). The quantity
In is called the "genetic identity" or "genetic similarity", and defined as In=ΣI÷#loci, where I=(Σ Pix•Piy)÷[(ΣPix²)·( ΣPiy²)]½.
Pix is the proportion of allele i in population X, Piy is the proportion of allele i in population Y.
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Genetic linkage occurs when particular alleles are inherited jointly.
Typically, an organism can pass on an allele without regard to which allele was passed on for a different gene . This is due to the independent assortment of chromosomes 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 daughter cells. There is a greater probability 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 relative 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 descendents that doesn't show both traits, the further apart on the chromosome they are.
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, and are referred to as "linkage groups." 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 . At the beginning of normal meiosis , a chromosome pair (made up of a chromosome from the mother and a chromosome from the father) 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 .
[ hide ]


1 Linkage mapping
2 Linkage map
 3 Lod score method for estimating recombination frequency
 4 Recombination frequency o 4.1 Centimorgan, a unit of recombination frequency
 5 See also
 6 External Links

 7 References
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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 an ideal 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 particular 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.

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A linkage map is a chromosome map of a species or experimental population that shows the position of its known genes and/or markers relative to each other, rather than as specific physical points on each chromosome.
A genetic map is a map based on the frequencies of recombination between markers during crossover of homologous chromosomes . The greater the frequency of recombination (segregation) between two genetic markers, the farther apart they are assumed to be. Conversely, the higher the frequency of association between the markers, the smaller the physical distance between them. Historically, the markers originally used were detectable phenotypes (enzyme production, eye color) derived from coding DNA sequences; eventually, confirmed or assumed noncoding DNA sequences such as microsatellites or those generating RFLPs have been used.
Genetic maps help researchers to locate other markers, such as other genes by testing for genetic linkage of the already known markers.
A genetic map is not a gene map .
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The lod score (logarithm of odds, also called logit by mathematicians) is a statistical test often used for linkage analysis in human populations, and also in animal and plant populations. The test was developed by Newton
E. Morton . Computerized lod score analysis is the best way to analyze complex family pedigrees in order to determine the linkage between mendelian traits (or between a trait and a marker, or two markers).
The method is described in greater detail by Strachan and Read [1] . Briefly, it works as follows:
1.
Establish a pedigree
2.
Make a number of estimates of recombination frequency
3.
Calculate a lod score for each estimate
4.
The estimate with the highest Lod score will be considered the best estimate
The Lod score is calculated as follows:

The reason 0.5 is used in the denominator is that any alleles that are completely unlinked (e.g. alleles on separate chromosomes) have a 50% chance of recombination, due to independent assortment.
In practice, lod scores are looked up in a table which lists lod scores for various standard pedigrees and various values of recombination frequency.
By convention, a lod score greater than 3.0 is considered evidence for linkage. (A score of 3.0 means the likelihood of observing the given pedigree if the two loci are not linked is less than 1 in 1000). On the other hand, a lod score less than -2.0 is considered evidence to exclude linkage.
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Recombination frequency is when crossing-over will take place between two loci (or genes ) during meiosis . Recombination frequency is a measure of genetic linkage and is used in the creation of a genetic linkage map.
A centimorgan (cM) is a unit that describes a recombination frequency of
1%.
During meiosis, chromosomes assort randomly into gametes , such that the segregation of alleles of one gene is independent of alleles of another gene. This is stated in Mendel's Second Law and is known as the law of independent assortment. The law of independent assortment always holds true for genes that are located on different chromosomes, but for genes that are on the same chromosome, it does not always hold true.
As an example of independent assortment, consider the crossing of the pure-bred homozygote parental strain with genotype AABB with a different pure-bred strain with genotype aabb. A and a and B and b represent the alleles of genes A and B. Crossing these homozygous parental strains will result in F1 generation offspring with genotype AaBb. The F1 offspring
AaBb produces gametes that are AB, Ab, aB, and ab with equal frequencies
(25%) due to the law of independent assortment. Note that 2 of the 4 gametes
(50 %)— Ab and aB—were not present in the parental generation. These gametes represent recombinant gametes. Recombinant gametes are those gametes that differ from both of the haploid gametes that made up the

diploid cell. In this example, the recombination frequency is 50% since
2 of the 4 gametes were recombinant gametes.
The recombination frequency will be 50% when two genes are located on different chromosomes or when they are widely separated on the same chromosome. This is a consequence of independent assortment.
When two genes are close together on the same chromosome, they do not assort independently and are said to be linked. Whereas genes located on different chromosomes assort independently and have a recombination frequency of 50%, linked genes have a recombination frequency that is less than 50%.
As an example of linkage, consider the classic experiment by William
Bateson and Reginald Punnett . They were interested in trait inheritance in the sweet pea and were studying two genes—the gene for flower color
( P, purple, and p, red) and the gene affecting the shape of pollen grains
( L, long, and l, round). They crossed the pure lines PPLL and ppll and then self-crossed the resulting PpLl lines. According to Mendelian genetics , the expected phenotypes would occur in a 9:3:3:1 ratio of
PL:Pl:pL:pl. To their surprise, they observed an increased frequency of
PL and pl and a decreased frequency of Pl and pL (see chart below).
Bateson and Punnett experiment
Phenotype and genotype Observed Expected from 9:3:3:1 ratio
Purple, long ( P_L_) 284
Purple, round ( P_ll) 21
Red, long ( ppL_) 21
216
72
72
Red, round ( ppll) 55 24
Their experiment revealed linkage (or coupling) between the P and L alleles and the p and l alleles. The frequency of P occurring together with L and with p occurring together with l is greater than that of the recombinant Pl and pL. The recombinantion frequency cannot be computed directly from this experiment, but intuitively it is less than 50%.
The progeny in this case received two dominant alleles linked on one chromosome (referred to as coupling or cis arrangement). However, after crossover, some progeny could have received one parental chromosome with a dominant allele for one trait (eg Purple) linked to a recessive allele for a second trait (eg round) with the opposite being true for the other parental chromosome (eg red and Long). This is referred to as repulsion or a trans arrangement. The phenotype here would still be purple and long

but a test cross of this individual with the recessive parent would produce progeny with much greater proportion of the two crossover phenotypes.
While such a problem may not seem likely from this example, unfavorable repulsion linkages do appear when breeding for disease resistance in some crops.
When two genes are located on the same chromosome, the chance of a crossover producing recombination between the genes is directly related to the distance between the two genes. Thus, the use of recombinantion frequencies has been used to develop linkage maps or genetic maps .
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In genetics , a centimorgan (abbreviated cM) is a unit of recombinant frequency for measuring genetic linkage. It is often used to imply distance along a chromosome . The centimorgan is equal to a 1% chance that a marker at one genetic locus on a chromosome will be separated from a marker at a second locus due to crossing over in a single generation. A
50 cM distance means that the genes will reassort when an odd number of crossings happen, which happens 31.8% of the time. Note that nonsyntenic genes are inherently unlinked, and cM distances have no meaning.
Another unit of recombination frequency is the map unit (m.u.) with one m.u. equaling a recombination frequency of 1%. A map unit is synonymous with centimorgan.
The centimorgan was named in honor of geneticist Thomas Hunt Morgan by his student Alfred Henry Sturtevant . Note that the parent unit of the centimorgan, the morgan , is rarely used today.
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Biochemistry 3107 - Fall 2002

This model of recombination was first proposed by Robin Holliday in 1964 and re-established by David Dressler and Huntington Potter in 1976 who demonstrated that the proposed physical intermediates existed.
The basic (simple) model
Align two homologous DNA molecules.
Nick the DNA at the same place on the two molecules.
This must happen in strands with the same polarity.
Exchange strands and ligate.
The intermediate that is formed is called a Holliday intermediate or
Holliday structure . The shape of this intermediate in vivo is similar to that of the greek letter chi, hence this is also called a chi form.
Visualization of the next step is made easier if one molecule is now rotated through 180š with respect to the other. This also helps to emphasize the chi-shape of the intermediate:

Resolve the structure.
There are two ways in which this can happen:

If the same strands are cleaved a second time then the original two DNA molecules are generated:

If the other strands are cleaved, then recombinant molecules are generated:
A more realistic model

The above model is too simple and does not explain a number of genetic results, including the occurence of two different recombinant bacteriophage in a single plaque in the Meselson-Weigle experiment.
[ 24-32 ] [ S32-2 ]
These can be explained by modifying the model slightly. As before, two homologous DNA molecules must be aligned and nicked at the same place.
Following strand exchange the intermediate Holliday structure is formed.
At this stage a new step is introduced:
Branch migration.
Migration of the branch can occur over many nucleotides in either direction. The result is a physical transfer of part of one of the strands of one molecule with that of the other:
Once again, visualization of the next step is made easier if one molecule is now rotated through 180š with respect to the other.
Resolve the structure.
There are still two ways in which this can happen, however, the consequences are different:

If the same strands are cleaved a second time then nonrecombinant DNA molecules are generated but they each contain a region of heteroduplex DNA that spans the region of branch migration:


If the other strands are cleaved, then recombinant molecules are generated as before, however, each will also contain a region of heteroduplex DNA that spans the region of branch migration:
View
Animated an
Model of a
Holliday
Junction
View a 3D
Model of a
Holliday
Junction
These models were prepared by Dr. Bill Engels at the University of
Wisconsin
In 1976, David Dressler and Hunt Potter published the results of a series of experiments that demonstrated the validity of the Holliday model of recombination.

They used E. coli cells containing the colicin E1 derived plasmid, pMB9.
This plasmid was one of the very earliest plasmids developed for cloning in Herbert Boyer 's laboratory. Normally, E. coli contain about 20 copies of this plasmid per cell. However, if the cells are exposed to chloramphenicol then, although chromosomal replication stops, plasmid replication does not and the number of plasmid molecules increases to 1000 copies per cell. With so many more copies of the plasmid in the cell, the chances of recombination increase as does the probability of observing a recombination intermediate.
When plasmid was isolated from the cells, purified by CsCl gradient centrifugation, and observed in the electron microscope, a number of candidates for intermediates were observed. These all had the appearance of "figure 8" structures. However, there are 3 possible ways such structures might arise:
 as a double-sized circular plasmid twisted over on itself.

 as two interlocking circular plasmid molecules. as a genuine recombination intermediate.
In order to distinguish between the three possibilities, Potter and
Dressler digested their plasmid preparations with EcoRI. This enzyme will generate monomer sized linear molecules from either of the first two possible structures. However, it will generate unique chi-shaped structures from the third.
[ 24-33 ][ S32-3 S32-6 ]
When they did this, Potter and Dressler found that between 0.5% and 3% of the molecules they observed were chi-shaped structures. The molecules were symmetrical in that the opposite arms were identical lengths and had identical denaturation patterns. Finally, they saw no such structures if they prepared their plasmids from recA strains of E. coli.
From this evidence they concluded:
. . . the intermediates we have observed in the electron microscope provide physical evidence in support of the recombination intermediate postulated by Holliday on genetic grounds.
[ S32-4 ]

Although, the basic features of the Holliday model are well-established, the model does have flaws. For example, the mechanism by which two homologous regions of DNA are paired and then nicked is not well explained.
In addition, the model does not explain all of the observed results in different recombination systems.
[ Recombination movie ]
A central feature of the Holliday model as outlined above is that the heteroduplex regions in recombinant molecules will be identical in length and position. Experimental results suggest, however, that this is not necessarily so.
In order to explain such discrepancies, Matt Meselson and Charles Radding proposed a modified model. In their model, only one strand in one of the two paired homologous
DNA molecules is nicked. This strand is then displaced by
DNA polymerase I and invades the homologous chromosome. A
Holliday intermediate is eventually formed and resolved as above. In this model, the extent of heteroduplex DNA in the resolved products, whether recombinant or nonrecombinant, will be different.
[MVH25-22]

Finally, gene conversion (which is a type of recombination event) in yeast follows a mechanism, proposed by
Szostak , that requires double-strand breaks in one of the recombining molecules.
See also the Meselson-Radding Model - also at the University of Arizona,
ALL you could want to know about General Homologous Recombination at the University of Saskatchewan, and Recombination: A molecular perspective at the University of Illinois.
VOET, VOET &
PRATT
1.
Chapter 24, DNA Replication, Repair and
Recombination, pages 802 - 803
STRYER 1.
Chapter 32, Gene Rearrangments, pages
820-822
LEHNINGER
TAMARIN
WEB SITES
1.
Chapter 24, DNA Metabolism, pages 842 - 843
1.
Chapter 16, pages 480 - 483.

There is a nice Animated Model of a Holliday
Junction and you can also view a 3D Model of a
Holliday Junction prepared by Dr. Bill Engels at the University of Wisconsin.

Charles M. Radding , Professor of Genetics, and
Molecular Biophysics and Biochemistry at Yale
University, is still working on the mechanism of

recombination and in particular on the mechanisms by which E. coli RecA protein promotes homologous pairing and strand exchange. You can read about his current research on his web page.

Matt Meselson has worked on many aspects of recombination over the years. His current research interests are focused on the bdelloid rotifers. These organisms apear to have evolved without any form of sexual reproduction and genetic recombination for millions of years. The
Meselson Laboratory Homepage has more information about this research.

There are some terrific animated models showing branch migration at the Holliday junction in complex with the RuvA protein as proposed in
Rafferty et al. available on the Web at http://www.shef.ac.uk/mfmbb/ruva.html
in the
United Kingdom and at http://www.sdsc.edu/journals/mbb/ruva.html
in the United States. Notice particularly in the first animation how the bases are able to unpair and re-pair with one another at the Holliday junction.
Notice also that only one base is ever unpaired on each strand.

General Homologous Recombination at the
University of Saskatchewan
Format and Original Material © Martin E. Mulligan, 1996-2002
From Wikipedia, the free encyclopedia
Jump to: navigation , search
“Crossing over” redirects here. For other uses, see Crossing Over .

Thomas Hunt Morgan's illustration of crossing over (1916)
Chromosomal crossover (or crossing over) is the process by which two chromosomes , paired up during prophase 1 of meiosis , exchange some portion of their DNA . Crossing over is specifically initiated in zygotene , before the synaptonemal complex develops, and is not completed until near the end of prophase 1. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome.
The result of this process is an exchange of genes , called genetic recombination .
A double crossing over
Recombination involves the breakage and rejoining of parental chromosomes
Crossing over was first described, in theory, by Thomas Hunt Morgan . The physical basis of crossing over was first demonstrated by Harriet
Creighton and Barbara McClintock in 1931 .
[1]

[ hide ]


1 Chemistry of crossover


2 Consequences of crossover
3 Problems of crossover
4 References
 5 See also
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Holliday Junction
Molecular structure of a Holliday junction.
Meiotic recombination initiates with double-stranded breaks that are introduced into the DNA by the Spo11 protein.
[2] One or more exonucleases then digest the 5’ ends generated by the double-stranded breaks to produce 3’ single-stranded DNA tails. The meiosis-specific recombinase
Dmc1 and the general recombinase Rad51 coat the single-stranded DNA to form nucleoprotein filaments.
[3] The recombinases catalyze invasion of the opposite chromatid by the single-stranded DNA from one end of the break.
Next, the 3’ end of the invading DNA primes DNA synthesis, causing displacement of the complementary strand, which subsequently anneals to

the single-stranded DNA generated from the other end of the initial double-stranded break. The structure that results is a cross-strand exchange that is known as a Holliday junction . The Holliday junction is a tetrahedral structure which can be 'pulled' by other recombinases, moving it along the four-stranded structure.
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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. An individual gamete inherits a complete haploid complement of alleles on chromosomes that are independently selected from each pair of chromatids lined up on the metaphase plate. Without recombination, all alleles for those genes linked together on the same chromosome would be inherited together. Meiotic recombination allows a more independent selection between the two alleles that occupy the positions of single genes, as recombination shuffles the allele content between sister chromatids.
Recombination 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 difference between gene conversion and chromosomal crossover. Blue is the two chromatids of one chromosome and red is the two chromatids of another one.
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 really closer.
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Although crossovers typically occur between homologous regions of matching chromosomes, similarities in sequence can result in mismatched alignments. 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 . The result can be a local duplication of genes on one chromosome and a deletion of these on the other, a translocation of part of one chromosome onto a different one, or an inversion .
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1.
^ Creighton H, McClintock B (1931). "A
Correlation of Cytological and Genetical
Crossing-Over in Zea Mays". Proc Natl
Acad Sci U S A 17 (8): 492-7. PMID
16587654 . (Original paper)
2.
^ Keeney S, Giroux CN, and Kleckner N
(1997). "Meiosis-specific DNA double-stranded breaks are catalyzed by
Spo11, a member of a widely conserved protein family." Cell 88(3):375-384.
PMID 9039264 doi : 10.1016/S0092-8674(00)81876-0
3.
^ Sauvageau S, Stasiak AZ, Banville I,
Ploquin M, Stasiak A, and Masson JY (2005).
" Fission yeast rad51 and dmc1, two efficient DNA recombinases forming helical nucleoprotein filaments ." Mol
Cell Biol 25(11):4377-4387. PMID

15899844 doi : 10.1128/MCB.25.11.4377-4387.2005