Crossing over

The process whereby one or more gene alleles present in one chromosome may be exchanged
with their alternative alleles on a homologous chromosome to produce a recombinant (crossover)
chromosome which contains a combination of the alleles originally present on the two parental
chromosomes. Genes which occur on the same chromosome are said to be linked, and together
they are said to compose a linkage group. In eukaryotes, crossing-over may occur during both
meiosis and mitosis, but the frequency of meiotic crossing-over is much higher. See also Allele;
Chromosome; Gene; Linkage (genetics).

Crossing-over is a reciprocal recombination event which involves breakage and exchange

between two nonsister chromatids of the four homologous chromatids present at prophase I of
meiosis; that is, crossing-over occurs after the replication of chromosomes which has occurred in
premeiotic interphase. The result is that half of the meiotic products will be recombinants, and
half will have the parental gene combinations. Using maize chromosomes which carried both
cytological and genetical markers, H. Creighton and B. McClintock showed in 1931 that genetic
crossing-over between linked genes was accompanied by exchange of microscopically visible
chromosome markers. See also Recombination (genetics).

In general, the closer two genes are on a chromosome, that is, the more closely linked they are,
the less likely it is that crossing-over will occur between them. Thus, the frequency of crossing-
over between different genes on a chromosome can be used to produce an estimate of their order
and distances apart; this is known as a linkage map.

Since each chromatid is composed of a single deoxyribonucleic acid (DNA) duplex, the process
of crossing-over involves the breakage and rejoining of DNA molecules. Although the precise
molecular mechanisms have not been determined, it is generally agreed that the following events
are necessary: (1) breaking (nicking) of one of the two strands of one or both nonsister DNA
molecules; (2) heteroduplex (hybrid DNA) formation between single strands from the nonsister
DNA molecules; (3) formation of a half chiasma, which is resolved by more single-strand
breakages to result in either a reciprocal crossover, a noncrossover, or a nonreciprocal crossover
(conversion event).

Crossing Over

Crossing over, or recombination, is the exchange of chromosome segments between nonsister

chromatids in meiosis. Crossing over creates new combinations of genes in the gametes that are
not found in either parent, contributing to genetic diversity.

Homologues and Chromatids

All body cells are diploid, meaning they contain pairs of each chromosome. One member of each
pair comes from the individual's mother, and one from the father. The two members of each pair
are called homologues. Members of a homologous pair carry the same set of genes, which occur
Crossing over
in identical positions along the chromosome. The specific forms of each gene, called alleles, may
be different: One chromosome may carry an allele for blue eyes, and the other an allele for
brown eyes, for example.

Meiosis is the process by which homologous chromosomes are separated to form gametes.
Gametes contain only one member of each pair of chromosomes. Prior to meiosis, each
chromosome is replicated. The replicas, called sister chromatids, remain joined together at the
centromere. Thus, as a cell starts meiosis, each chromosome is composed of two chromatids and
is paired with its homologue. The chromatids of two homologous chromosomes are called
nonsister chromatids.

Meiosis occurs in two stages, called meiosis I and II. Meiosis I separates homologues from each
other. Meiosis II separates sister chromatids from each other. Crossing over occurs in meiosis I.
During crossing over, segments are exchanged between nonsister chromatids.

Mechanics of Crossing Over

The pairing of homologues at the beginning of meiosis I ensures that each gamete receives one
member of each pair. Homologues contact each other along much of their length and are held
together by a special protein structure called the synaptonemal complex. This association of the
homologues may persist from hours to days. The association of the two chromosomes is called a
bivalent, and because there are four chromatids involved it is also called a tetrad. The points of
attachment are called chiasmata (singular, chiasma).

The pairing of homologues brings together the near-identical sequences found on each
chromosome, and this sets the stage for crossing over. The exact mechanism by which crossing
over occurs is not known. Crossing over is controlled by a very large protein complex called a
recombination nodule. Some of the proteins involved also play roles in DNA replication and
repair, which is not surprising, considering that all three processes require breaking and
reforming the DNA double helix.

One plausible model supported by available evidence suggests that crossing over begins when
one chromatid is cut through, making a break in the double-stranded DNA (recall that each DNA
strand is a double helix of nucleotides). A nuclease enzyme then removes nucleotides from each
side of the DNA strand, but in opposite directions, leaving each side with a single-stranded tail,
perhaps 600 to 800 nucleotides long.

One tail is then thought to insert itself along the length of one of the nonsister chromatids,
aligning with its complementary sequence (i.e., if the tail sequence is ATCCGG, it aligns with
TAGGCC on the nonsister strand). If a match is made, the tail pairs with this strand of the
nonsister chromatid. This displaces the original paired strand on the nonsister chromatid, which
is then freed to pair with the other single-stranded tail. The gaps are filled by a DNA polymerase
enzyme. Finally, the two chromatids must be separated from each other, which requires cutting
all the strands and rejoining the cut ends.
Crossing over
The Consequences of Crossing Over
A chiasma occurs at least once per chromosome pair. Thus, following crossing over, at least two
of the four chromatids become unique, unlike those of the parent. (Crossing over can also occur
between sister chromatids; however, such events do not lead to genetic variation because the
DNA sequences are identical between the chromatids.) Crossing over helps to preserve genetic
variability within a species by allowing for virtually limitless combinations of genes in the
transmission from parent to off-spring.

The frequency of recombination is not uniform throughout the genome. Some areas of some
chromosomes have increased rates of recombination (hot spots), while others have reduced rates
of recombination (cold spots). The frequency of recombination in humans is generally decreased
near the centromeric region of chromosomes, and tends to be greater near the telomeric regions.
Recombination frequencies may vary between sexes. Crossing over is estimated to occur
approximately fifty-five times in meiosis in males, and about seventy-five times in meiosis in
females.

X-Y Crossovers and Unequal Crossovers

The forty-six chromosomes of the human diploid genome are composed of twenty-two pairs of
autosomes, plus the X and Y chromosomes that determine sex. The X and Y chromosomes are
very different from each other in their genetic composition but nonetheless pair up and even
cross over during meiosis. These two chromosomes do have similar sequences over a small
portion of their length, termed the pseudoautosomal region, at the far end of the short arm on
each one.

The pseudoautosomal region behaves similarly to the autosomes during meiosis, allowing for
segregation of the sex chromosomes. Just proximal to the pseudoautosomal region on the Y
chromosome is the SRY gene (sex-determining region of the Y chromosome), which is critical
for the normal development of male reproductive organs. When crossing over extends past the
boundary of the pseudoautosomal region and includes this gene, sexual development will most
likely be adversely affected. The rare occurrences of chromosomally XX males and XY females
are due to such aberrant crossing over, in which the Y chromosome has lost—and the X
chromosome has gained—this sex-determining gene.

Most crossing over is equal. However, unequal crossing over can and does occur. This form of
recombination involves crossing over between nonallelic sequences on nonsister chromatids in a
pair of homologues. In many cases, the DNA sequences located near the crossover event show
substantial sequence similarity. When unequal crossing over occurs, the event leads to a deletion
on one of the participating chromatids and an insertion on the other, which can lead to genetic
disease, or even failure of development if a crucial gene is missing.

Crossing Over As a Genetic Tool

Crossing over
Recombination events have important uses in experimental and medical genetics. They can be
used to order and determine distances between loci (chromosome positions) by genetic mapping
techniques. Loci that are on the same chromosome are all physically linked to one another, but
they can be separated by crossing over. Examining the frequency with which two loci are
separated allows a calculation of their distance: The closer they are, the more likely they are to
remain together. Multiple comparisons of crossing over among multiple loci allows these loci to
be mapped, or placed in relative position to one another.

Recombination frequency in one region of the genome will be influenced by other, nearby
recombination events, and these differences can complicate genetic mapping. The term
"interference" describes this phenomenon. In positive interference, the presence of one crossover
in a region decreases the probability that another crossover will occur nearby. Negative
interference, the opposite of positive interference, implies that the formation of a second
crossover in a region is made more likely by the presence of a first crossover.

Most documented interference has been positive, but some reports of negative interference exist
in experimental organisms. The investigation of interference is important because accurate
modeling of interference will provide better estimates of true genetic map length and intermarker
distances, and more accurate mapping of trait loci. Interference is very difficult to measure in
humans, because exceedingly large sample sizes, usually on the order of three hundred to one
thousand fully informative meiotic events, are required to detect it.

crossing over crossing over, process in genetics by which the two chromosomes of a
homologous pair exchange equal segments with each other. Crossing over occurs in the first
division of meiosis. At that stage each chromosome has replicated into two strands called sister
chromatids. The two homologous chromosomes of a pair synapse, or come together. While the
chromosomes are synapsed, breaks occur at corresponding points in two of the non-sister
chromatids, i.e., in one chromatid of each chromosome. Since the chromosomes are homologous,
breaks at corresponding points mean that the segments that are broken off contain corresponding
genes, i.e., alleles. The broken sections are then exchanged between the chromosomes to form
complete new units, and each new recombined chromosome of the pair can go to a different
daughter sex cell. Crossing over results in recombination of genes found on the same
chromosome, called linked genes, that would otherwise always be transmitted together. Because
the frequency of crossing over between any two linked genes is proportional to the chromosomal
distance between them, crossing over frequencies are used to construct genetic, or linkage, maps
of genes on chromosomes. Mutations, temperature changes, and radiation all affect crossing over
frequency. Under the microscope, a crossover has the appearance of an X and is called a
chiasma.

crossing over
Crossing over
What is crossing over?

When sister (homologous) chromosomes line up during the early stages of meiosis I, segments of
DNA may be moved from one chromosome to another when the two strands overlap. This
process is known as crossing over, since gene sequences cross from one chromosome to its sister
chromosome.

:Chromosomal crossover
 "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 an exchange of genetic material between

homologous chromosomes. It is one of the final phases of genetic recombination, which occurs
during prophase 1 of meiosis (diplotene) in a process called synapsis. Synapsis begins 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.

A double crossing over

Crossing over

Recombination involves the breakage and rejoining of parental chromosomes

Crossing over was described, in theory, by Thomas Hunt Morgan. He relied on the discovery of
the Belgian Professor Frans Alfons Janssens of the University of Leuven who described the
phenomenon in 1909 and had called it 'chiasmatypie'. The term chiasma is linked if not identical
to chromosomal crossover. Morgan immediately saw the great importance of Janssens'
cytological interpretation of chiasmata to the experimental results of his research on the heredity
of Drosophila. The physical basis of crossing over was first demonstrated by Harriet Creighton
and Barbara McClintock in 1931.[1]

Chemistry

Holliday Junction

Molecular structure of a Holliday junction.

Crossing over
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, also known as a Holliday junction. The contact between
two chromatids that will soon undergo crossing-over is known as a chiasma. The Holliday
junction is a tetrahedral structure which can be 'pulled' by other recombinases, moving it along
the four-stranded structure.

Consequences
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 homologous chromosomes.

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
Crossing over
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.

Problems
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.

References
1. ^ Creighton H, McClintock B (1931). "A Correlation of Cytological and Genetical
Crossing-Over in Zea Mays". Proc Natl Acad Sci USA 17 (8): 492–7.
doi:10.1073/pnas.17.8.492. PMID 16587654. (Original paper)
2. ^ Keeney, S (1997). "Meiosis-Specific DNA Double-Strand Breaks Are Catalyzed by
Spo11, a Member of a Widely Conserved Protein Family". Cell 88: 375.
doi:10.1016/S0092-8674(00)81876-0.
3. ^ Sauvageau, S; Stasiak, Az; Banville, I; Ploquin, M; Stasiak, A; Masson, Jy (Jun 2005).
"Fission yeast rad51 and dmc1, two efficient DNA recombinases forming helical
nucleoprotein filaments." (Free full text). Molecular and cellular biology 25 (11): 4377–
87. doi:10.1128/MCB.25.11.4377-4387.2005. ISSN 0270-7306. PMID 15899844. PMC
1140613. http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=15899844.