Mitotic recombination is a type of

genetic recombination Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryo ...

that may occur in

somatic cells A somatic cell (from Ancient Greek σῶμα ''sôma'', meaning "body"), or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Such cells compo ...

during their preparation for

mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...

in both sexual and asexual organisms. In asexual organisms, the study of mitotic recombination is one way to understand

genetic linkage Genetic linkage is the tendency of DNA sequences that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Two genetic markers that are physically near to each other are unlikely to be separ ...

because it is the only source of recombination within an individual. Additionally, mitotic recombination can result in the expression of recessive genes in an otherwise

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

individual. This expression has important implications for the study of

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

and lethal recessive genes. Mitotic

homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...

occurs mainly between

sister chromatids A sister chromatid refers to the identical copies (chromatids) formed by the DNA replication of a chromosome, with both copies joined together by a common centromere. In other words, a sister chromatid may also be said to be 'one-half' of the dup ...

subsequent to replication (but prior to cell division). Inter-sister homologous recombination is ordinarily genetically silent. During mitosis the incidence of recombination between non-sister homologous

chromatid A chromatid (Greek ''khrōmat-'' 'color' + ''-id'') is one half of a duplicated chromosome. Before replication, one chromosome is composed of one DNA molecule. In replication, the DNA molecule is copied, and the two molecules are known as chro ...

s is only about 1% of that between sister chromatids.

Discovery

The discovery of mitotic recombination came from the observation of twin spotting in ''

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...

''. This twin spotting, or mosaic spotting, was observed in ''D. melanogaster'' as early as 1925, but it was only in 1936 that Curt Stern explained it as a result of mitotic recombination. Prior to Stern's work, it was hypothesized that twin spotting happened because certain genes had the ability to eliminate the chromosome on which they were located. Later experiments uncovered when mitotic recombination occurs in the cell cycle and the mechanisms behind recombination. Mitotic Recombination Illustration

Occurrence

Mitotic recombination can happen at any locus but is observable in individuals that are heterozygous at a given locus. If a crossover event between non-sister chromatids affects that locus, then both homologous chromosomes will have one

containing each genotype. The resulting

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

of the daughter cells depends on how the chromosomes line up on the

metaphase plate In cell biology, the spindle apparatus refers to the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter Cell (biology), cells. It is referred to as the mitotic spindle durin ...

. If the chromatids containing different alleles line up on the same side of the plate, then the resulting daughter cells will appear heterozygous and be undetectable, despite the crossover event. However, if chromatids containing the same alleles line up on the same side, the daughter cells will be homozygous at that locus. This results in ''twin spotting'', where one cell presents the homozygous recessive phenotype and the other cell has the homozygous wild type phenotype. If those daughter cells go on to replicate and divide, the twin spots will continue to grow and reflect the differential phenotype. Mitotic recombination takes place during

interphase Interphase is the portion of the cell cycle that is not accompanied by visible changes under the microscope, and includes the G1, S and G2 phases. During interphase, the cell grows (G1), replicates its DNA (S) and prepares for mitosis (G2). A c ...

. It has been suggested that recombination takes place during G1, when the DNA is in its 2-strand phase, and replicated during DNA synthesis. It is also possible to have the DNA break leading to mitotic recombination happen during G1, but for the repair to happen after replication.

Response to DNA damage

In the budding yeast ''

Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...

'', mutations in several genes needed for mitotic (and meiotic) recombination cause increased sensitivity to inactivation by radiation and/or genotoxic chemicals. For example, gene ''

rad52 RAD52 homolog (S. cerevisiae), also known as RAD52, is a protein which in humans is encoded by the ''RAD52'' gene. Function The protein encoded by this gene shares similarity with ''Saccharomyces cerevisiae'' Rad52, a protein important for DNA ...

'' is required for mitotic recombination as well as meiotic recombination. ''Rad52'' mutant yeast cells have increased sensitivity to killing by

X-ray An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...

methyl methanesulfonate Methyl methanesulfonate (MMS), also known as methyl mesylate, is an alkylating agent and a carcinogen. It is also a suspected reproductive toxicant, and may also be a skin/sense organ toxicant. It is used in cancer treatment.DNA crosslinking agent 8-methoxypsoralen-plus-UV light, suggesting that mitotic recombinational repair is required for removal of the different

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

s caused by these agents.

Mechanisms

The mechanisms behind mitotic recombination are similar to those behind meiotic recombination. These include sister chromatid exchange and mechanisms related to DNA double strand break repair by

such as single-strand annealing, synthesis-dependent strand annealing (

SDSA Synthesis-dependent strand annealing (SDSA) is a major mechanism of homology-directed repair of DNA double-strand breaks (DSBs). Although many of the features of SDSA were first suggested in 1976, the double-Holliday junction model proposed in 1 ...

), and

gene conversion Gene conversion is the process by which one DNA sequence replaces a homologous sequence such that the sequences become identical after the conversion event. Gene conversion can be either allelic, meaning that one allele of the same gene replaces a ...

through a double-Holliday Junction intermediate or SDSA. In addition, non-homologous mitotic recombination is a possibility and can often be attributed to

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direc ...

Method

There are several theories on how mitotic crossover occurs. In the simple crossover model, the two homologous chromosomes overlap on or near a common

Chromosomal fragile site A chromosomal fragile site is a specific heritable point on a chromosome that tends to form a gap or constriction and may tend to break when the cell is exposed to partial replication stress. Based on their frequency, fragile sites are classified ...

(CFS). This leads to a

double-strand break DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...

, which is then repaired using one of the two strands. This can lead to the two chromatids switching places. In another model, two overlapping

form a double Holliday junction at a common repeat site and are later sheared in such a way that they switch places. In either model, the chromosomes are not guaranteed to trade evenly, or even to rejoin on opposite sides thus most patterns of cleavage do not result in any crossover event. Uneven trading introduces many of the deleterious effects of mitotic crossover. Alternatively, a crossover can occur during DNA repair if, due to extensive damage, the homologous chromosome is chosen to be the template over the sister chromatid. This leads to

gene synthesis Artificial gene synthesis, or simply gene synthesis, refers to a group of methods that are used in synthetic biology to construct and assemble genes from nucleotides '' de novo''. Unlike DNA synthesis in living cells, artificial gene synthesis do ...

since one copy of the allele is copied across from the homologous chromosome and then synthesized into the breach on the damaged chromosome. The net effect of this would be one

chromosome and one

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

chromosome.

Advantages and disadvantages

Mitotic crossover is known to occur in ''D. melanogaster'', 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 cell in which it occurs to the development of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. Alternately, a cell may become a homozygous mutant for a tumor-suppressing gene, leading to the same result. For example,

Bloom's syndrome Bloom syndrome (often abbreviated as BS in literature) is a rare autosome, autosomal recessive genetic disorder characterized by short stature, predisposition to the development of cancer, and genomic instability. BS is caused by mutations in the ' ...

is caused by a mutation in

RecQ helicase RecQ helicase is a family of helicase enzymes initially found in ''Escherichia coli'' that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwind ...

, which plays a role in DNA replication and repair. This mutation leads to high rates of mitotic recombination in mice, and this recombination rate is in turn responsible for causing tumor susceptibility in those mice. At the same time, mitotic recombination may be beneficial: it may play an important role in repairing double stranded breaks, and it may be beneficial to the organism if having homozygous dominant alleles is more functional than the heterozygous state. For use in experimentation with genomes in model organisms such as ''

'', mitotic recombination can be induced via X-ray and the

FLP-FRT recombination In genetics, Flp-''FRT'' recombination is a site-directed recombination technology, increasingly used to manipulate an organism's DNA under controlled conditions ''in vivo''. It is analogous to Cre-''lox'' recombination but involves the recombi ...

system.

References

{{reflist * Griffiths et al. 1999.
Modern Genetic Analysis
'. W. H. Freeman and Company. Cellular processes Modification of genetic information Molecular genetics