Gregory Bateson

From Wikipedia, the free encyclopedia

Gregory Bateson
Rudolph Arnheim (L) and Bateson (R) speaking at the American Federation of Arts 48th Annual Convention, 1957 Apr 6 / Eliot Elisofon, photographer. American Federation of Arts records, Archives of American Art, Smithsonian Institution
Born	9 May 1904 Grantchester, UK
Died	4 July 1980 (aged 76) San Francisco, US
Known for	double bind, ecology of mind, deuterolearning, schismogenesis
Scientific career:
Fields	anthropology, social sciences, linguistics, cybernetics, systems theory
Influences	Margaret Mead, Conrad Hal Waddington, Warren McCulloch, Norbert Wiener, John von Neumann, Evelyn Hutchinson, Julian Bigelow
Influenced	John C. Lilly, Heinz von Foerster, Francis Jeffrey, Jerry Brown, Richard Bandler, Stewart Brand, Gilles Deleuze, John Grinder, Félix Guattari, Jay Haley, Don D. Jackson, Bradford Keeney, Stephen Nachmanovitch, William Irwin Thompson, R. D. Laing, Paul Watzlawick, Carl Whitaker, Niklas Luhmann, Sharon Traweek; biosemiotics, application of type theory in social sciences, communication theory, ethnicity theory,[1] evolutionary biology, family therapy, brief therapy, neuro-linguistic programming, systemic coaching, anti-psychiatry, visual anthropology

Gregory Bateson (9 May 1904 – 4 July 1980) was an English anthropologist, social scientist, linguist, visual anthropologist, semiotician, and cyberneticist whose work intersected that of many other fields. In the 1940s, he helped extend systems theory and cybernetics to the social and behavioral sciences. He spent the last decade of his life developing a "meta-science" of epistemology to bring together the various early forms of systems theory developing in different fields of science. His writings include Steps to an Ecology of Mind (1972) and Mind and Nature (1979). Angels Fear (published posthumously in 1987) was co-authored by his daughter Mary Catherine Bateson.

Bateson was born in Grantchester in Cambridgeshire, England, on 9 May 1904. He was the third and youngest son of (Caroline) Beatrice Durham and the distinguished geneticist William Bateson. He was named Gregory after Gregor Mendel, the Austrian monk who founded the modern science of genetics.

The younger Bateson attended Charterhouse School from 1917 to 1921, obtained a Bachelor of Arts in biology at St. John's College, Cambridge, in 1925, and continued at Cambridge from 1927 to 1929. Bateson lectured in linguistics at the University of Sydney in 1928. From 1931 to 1937, he was a Fellow of St. John's College, Cambridge, spent the years before World War II in the South Pacific in New Guinea and Bali doing anthropology. During 1936–1950, he was married to Margaret Mead. At that time he applied his knowledge to the war effort before moving to the United States.
In Palo Alto, California, Bateson and his colleagues Donald Jackson, Jay Haley and John H. Weakland developed the double-bind theory (see also Bateson Project).

Bateson's interest in systems theory and cybernetics forms a thread running through his work. He was one of the original members of the core group of the Macy conferences in Cybernetics, and the later set on Group Processes, where he represented the social and behavioral sciences. Bateson was interested in the relationship of these fields to epistemology. His association with the editor and author Stewart Brand helped to widen his influence. From the 1970s until his last years, a broader audience of university students and educated people working in many fields came to know his thought.

In 1956, he became a naturalised citizen of the United States. Bateson was a member of William Irwin Thompson's Lindisfarne Association. In the 1970s, he taught at the Humanistic Psychology Institute (renamed the Saybrook University) in San Francisco; and in 1972 joined the faculty of Kresge College at the University of California, Santa Cruz. He was elected a Fellow of the American Academy of Arts and Sciences in 1976. In 1976, California Governor Jerry Brown appointed Bateson to the Regents of the University of California, in which position he served until his death (although he resigned from the Special Research Projects committee in 1979, in opposition to the university's work on nuclear weapons). He died on Independence Day, 1980, in the guest house of the San Francisco Zen Center.

Personal life

Bateson's life, according to Lipset (1982), was greatly affected by the death of his two brothers. John Bateson (1898–1918), the eldest of the three, was killed in World War I. Martin Bateson (1900–1922), the second brother, was then expected to follow in his father's footsteps as a scientist, but came into conflict with his father over his ambition to become a poet and playwright. The resulting stress, combined with a disappointment in love, resulted in Martin's public suicide by gunshot under the statue of Anteros in Piccadilly Circus on 22 April 1922, which was John's birthday. After this event, which transformed a private family tragedy into public scandal, all William and Beatrice's ambitious expectations fell on Gregory, their only surviving son.

Bateson's first marriage, in 1936, was to American cultural anthropologist Margaret Mead. Bateson and Mead had a daughter, Mary Catherine Bateson (born 1939), who also became an anthropologist. Bateson separated from Mead in 1947, and they were divorced in 1950. In 1951 he married his second wife Elizabeth "Betty" Sumner (1919–1992), the daughter of the Episcopalian Bishop of Oregon, Walter Taylor Sumner. They had a son, John Sumner Bateson (1951-2015), as well as twins who died shortly after birth in 1953. Bateson and Sumner were divorced in 1957, after which Bateson married his third wife, the therapist and social worker Lois Cammack (born 1928), in 1961. They had one daughter, Nora Bateson (born 1969).

Bateson was a lifelong atheist, as his family had been for several generations.

The 2014 novel Euphoria by Lily King is a fictionalized account of Bateson's relationships with Mead and Reo Fortune in pre-WWII New Guinea.

Philosophy

Where others might see a set of inexplicable details, Bateson perceived simple relationships. In "From Versailles to Cybernetics," Bateson argues that the history of the twentieth century can be perceived as the history of a malfunctioning relationship. In his view, the Treaty of Versailles exemplifies a whole pattern of human relationships based on betrayal and hate. He therefore claims that the treaty of Versailles and the development of cybernetics—which for him represented the possibility of improved relationships—are the only two anthropologically important events of the twentieth century.

Work

WWII and Office of Strategic Services career

Although initially reluctant to join the intelligence services, Bateson served in OSS during World War II along with dozens of other anthropologists. He was stationed in the same offices as Julia Child (then Julia McWilliams), Paul Cushing Child, and others. He spent much of the war designing 'black propaganda' radio broadcasts. He was deployed on covert operations in Burma and Thailand, and worked in China, India, and Ceylon as well. Bateson used his theory of schismogenesis to help foster discord among enemy fighters. He was upset by his wartime experience and disagreed with his wife over whether science should be applied to social planning or used only to foster understanding rather than action.

Early Work: New Guinea and Bali

Bateson's beginning years as an anthropologist were spent floundering, lost without a specific objective in mind. He began first with a trip to New Guinea, spurred by mentor A. C. Haddon. His goal, as suggested by Haddon, was to explore the effects of contact between the Sepik natives and whites. Unfortunately for Bateson, his time spent with the Baining of New Guinea was halted and difficult. The Baining turned out to be secretive and excluded him from many aspects of their society. On more than one occasion he was tricked into missing communal activities, and they held out on their religion. He left them, frustrated. He next studied the Sulka, another native population of New Guinea. Although the Sulka were dramatically different from the Baining and their culture much more "visible" to the observer, he felt their culture was dying, which left him feeling dispirited and discouraged.

He experienced more success with the Iatmul people, another indigenous people of the Sepik River region of New Guinea. He would always return to the idea of communications and relations or interactions between and among people. The observations he made of the Iatmul allowed him to develop his concept of schismogenesis. He studied the 'naven', an honorific ceremony among the Iatmul, still continued today, that celebrates first-time cultural achievements. The ceremony entails many antics that are normally forbidden during everyday social life. For example, men and women reverse and exaggerate gender roles; men dress in women's skirts, and women dress in men's attire and ornaments. Additionally, certain categories of female kin smear mud in the faces of other relatives, beat them with sticks, and hurl bawdy insults. Mothers may drop to the ground so their celebrated 'child' walks over them. And during a male rite, a mother's brother may slide his buttocks down the leg of his honoured sister's son, a complex gesture of masculine birthing, pride, and insult, rarely performed before women, that brings the honoured sister's son to tears. Bateson suggested the influence of a circular system of causation, and proposed that:

Women watched for the spectacular performances of the men, and there can be no reasonable doubt that the presence of an audience is a very important factor in shaping the men's behavior. In fact, it is probable that the men are more exhibitionistic because the women admire their performances. Conversely, there can be no doubt that the spectacular behavior is a stimulus which summons the audience together, promoting in the women the appropriate behavior.

In short, the behaviour of person X affects person Y, and the reaction of person Y to person X's behaviour will then affect person X's behaviour, which in turn will affect person Y, and so on. Bateson called this the "vicious circle." He then discerned two models of schismogenesis: symmetrical and complementary. Symmetrical relationships are those in which the two parties are equals, competitors, such as in sports. Complementary relationships feature an unequal balance, such as dominance-submission (parent-child), or exhibitionism-spectatorship (performer-audience). Bateson's experiences with the Iatmul led him to publish a book in 1936 titled Naven: A Survey of the Problems suggested by a Composite Picture of the Culture of a New Guinea Tribe drawn from Three Points of View (Cambridge University Press). The book proved to be a watershed in anthropology and modern social science.

Until Bateson published Naven, most anthropologists assumed a realist approach to studying culture, in which one simply described social reality. Bateson's book argued that this approach was naive, since an anthropologist's account of a culture was always and fundamentally shaped by whatever theory the anthropologist employed to define and analyse the data. To think otherwise, stated Bateson, was to be guilty of what Alfred North Whitehead called the "fallacy of misplaced concreteness." There was no singular or self-evident way to understand the Iatmul naven rite. Instead, Bateson analysed the rite from three unique points of view: sociological, ethological, and eidological. The book, then, was not a presentation of anthropological analysis but an epistemological account that explored the nature of anthropological analysis itself.

The sociological point of view sought to identify how the ritual helped bring about social integration. In the 1930s, most anthropologists understood marriage rules to regularly ensure that social groups renewed their alliances. But Iatmul, argued Bateson, had contradictory marriage rules. Marriage, in other words, could not guarantee that a marriage between two clans would at some definite point in the future recur. Instead, Bateson continued, the naven rite filled this function by regularly ensuring exchanges of food, valuables, and sentiment between mothers' brothers and their sisters' children, or between separate lineages. Naven, from this angle, held together the different social groups of each village into a unified whole.

The ethological point of view interpreted the ritual in terms of the conventional emotions associated with normative male and female behaviour, which Bateson called ethos. In Iatmul culture, observed Bateson, men and women lived different emotional lives. For example, women were rather submissive and took delight in the achievement of others; men fiercely competitive and flamboyant. During the ritual, however, men celebrated the achievement of their nieces and nephews while women were given ritual license to act raucously. In effect, naven allowed men and women to experience momentarily the emotional lives of each other, and thereby to achieve a level of psychological integration.

The third and final point of view, the eidological, was the least successful. Here Bateson endeavoured to correlate the organisation structure of the naven ceremony with the habitual patterns of Iatmul thought. Much later, Bateson would harness the very same idea to the development of the double-bind theory of schizophrenia.

In the Epilogue to the book, Bateson was clear: "The writing of this book has been an experiment, or rather a series of experiments, in methods of thinking about anthropological material." That is to say, his overall point was not to describe Iatmul culture of the naven ceremony but to explore how different modes of analysis, using different premises and analytic frameworks, could lead to different explanations of the same sociocultural phenomenon. Not only did Bateson's approach re-shape fundamentally the anthropological approach to culture, but the naven rite itself has remained a locus classicus in the discipline. In fact, the meaning of the ritual continues to inspire anthropological analysis.

Bateson next travelled to Bali with his new wife Margaret Mead. They studied the people of the Balinese village Bajoeng Gede. Here, Lipset states, "in the short history of ethnographic fieldwork, film was used both on a large scale and as the primary research tool." Indeed, Bateson took 25,000 photographs of their Balinese subjects.

Bateson discovered that the people of Bajoeng Gede raised their children very unlike children raised in Western societies. Instead of attention being paid to a child who was displaying a climax of emotion (love or anger), Balinese mothers would ignore them. Bateson notes, "The child responds to [a mother's] advances with either affection or temper, but the response falls into a vacuum. In Western cultures, such sequences lead to small climaxes of love or anger, but not so in Bali. At the moment when a child throws its arms around the mother's neck or bursts into tears, the mother's attention wanders". This model of stimulation and refusal was also seen in other areas of the culture. Bateson later described the style of Balinese relations as stasis instead of schismogenesis. Their interactions were "muted" and did not follow the schismogenetic process because they did not often escalate competition, dominance, or submission.

After Bali, Bateson and Mead returned to the Sepik River in 1938, and settled into the village of Tambunum, where Bateson spent three days in the 1920s. They aimed to replicate the Balinese project on the relationship between childraising and temperament, and between conventions of the body – such as pose, grimace, holding infants, facial expressions, etc. – reflected wider cultural themes and values. Bateson snapped some 10,000 black and white photographs, and Mead typed thousands of pages of fieldnotes. But Bateson and Mead never published anything substantial from this research.

Bateson and Margaret Mead contrasted first and Second-order cybernetics with this diagram in an interview in 1973.

 Bateson's encounter with Mead on the Sepik river (Chapter 16) and their life together in Bali (Chapter 17) is described in Mead's autobiography Blackberry Winter: My Earlier Years (Angus and Robertson. London. 1973). Catherine's birth in New York on 8 December 1939 is recounted in Chapter 18.

Double bind

In 1956 in Palo Alto, Bateson and his colleagues Donald Jackson, Jay Haley, and John Weakland articulated a related theory of schizophrenia as stemming from double bind situations. The double bind refers to a communication paradox described first in families with a schizophrenic member. The first place where double binds were described (though not named as such) was according to Bateson, in Samuel Butler's The Way of All Flesh (a semi-autobiographical novel about Victorian hypocrisy and cover-up).

Full double bind requires several conditions to be met:

1. The victim of double bind receives contradictory injunctions or emotional messages on different levels of communication (for example, love is expressed by words, and hate or detachment by nonverbal behaviour; or a child is encouraged to speak freely, but criticised or silenced whenever he or she actually does so);
2. No metacommunication is possible – for example, asking which of the two messages is valid or describing the communication as making no sense;
3. The victim cannot leave the communication field;
4. Failing to fulfill the contradictory injunctions is punished (for example, by withdrawal of love).

The strange behaviour and speech of schizophrenics was explained by Bateson et al. as an expression of this paradoxical situation, and were seen in fact as an adaptive response, which should be valued as a cathartic and transformative experience.

The double bind was originally presented (probably mainly under the influence of Bateson's psychiatric co-workers) as an explanation of part of the etiology of schizophrenia. Currently, it is considered to be more important as an example of Bateson's approach to the complexities of communication which is what he understood it to be.

The role of somatic change in evolution

According to Merriam-Webster's dictionary the term somatic is basically defined as the body or body cells of change distinguished from germplasm or psyche/mind. Bateson writes about how the actual physical changes in the body occur within evolutionary processes. He describes this through the introduction of the concept of "economics of flexibility". In his conclusion he makes seven statements or theoretical positions which may be supported by his ideology.

The first is the idea that although environmental stresses have theoretically been believed to guide or dictate the changes in the soma (physical body), the introduction of new stresses do not automatically result in the physical changes necessary for survival as suggested by original evolutionary theory. In fact the introduction of these stresses can greatly weaken the organism. An example that he gives is the sheltering of a sick person from the weather or the fact that someone who works in an office would have a hard time working as a rock climber and vice versa. The second position states that though "the economics of flexibility has a logical structure-each successive demand upon flexibility fractioning the set of available possibilities". This means that theoretically speaking each demand or variable creates a new set of possibilities. Bateson's third conclusion is "that the genotypic change commonly makes demand upon the adjustive ability of the soma". This, he states, is the commonly held belief among biologists although there is no evidence to support the claim. Added demands are made on the soma by sequential genotypic modifications is the fourth position. Through this he suggests the following three expectations:

1. The idea that organisms that have been through recent modifications will be delicate;
2. The belief that these organisms will become progressively harmful or dangerous;
3. That over time these new "breeds" will become more resistant to the stresses of the environment and change in genetic traits.

The fifth theoretical position which Bateson believes is supported by his data is that characteristics within an organism that have been modified due to environmental stresses may coincide with genetically determined attributes. His sixth position is that it takes less economic flexibility to create somatic change than it does to cause a genotypic modification. The seventh and final theory he believes to be supported is the idea that in rare occasions there will be populations whose changes will not be in accordance with the thesis presented within this paper. According to Bateson, none of these positions (at the time) could be tested but he called for the creation of a test which could possibly prove or disprove the theoretical positions suggested within.

Ecological anthropology and cybernetics

In his book Steps to an Ecology of Mind, Bateson applied cybernetics to the field of ecological anthropology and the concept of homeostasis. He saw the world as a series of systems containing those of individuals, societies and ecosystems. Within each system is found competition and dependency. Each of these systems has adaptive changes which depend upon feedback loops to control balance by changing multiple variables. Bateson believed that these self-correcting systems were conservative by controlling exponential slippage. He saw the natural ecological system as innately good as long as it was allowed to maintain homeostasis and that the key unit of survival in evolution was an organism and its environment.

Bateson also viewed that all three systems of the individual, society and ecosystem were all together a part of one supreme cybernetic system that controls everything instead of just interacting systems. This supreme cybernetic system is beyond the self of the individual and could be equated to what many people refer to as God, though Bateson referred to it as Mind. While Mind is a cybernetic system, it can only be distinguished as a whole and not parts. Bateson felt Mind was immanent in the messages and pathways of the supreme cybernetic system. He saw the root of system collapses as a result of Occidental or Western epistemology. According to Bateson, consciousness is the bridge between the cybernetic networks of individual, society and ecology and the mismatch between the systems due to improper understanding will result in the degradation of the entire supreme cybernetic system or Mind. Bateson thought that consciousness as developed through Occidental epistemology was at direct odds with Mind.

At the heart of the matter is scientific hubris. Bateson argues that Occidental epistemology perpetuates a system of understanding which is purpose or means-to-an-end driven. Purpose controls attention and narrows perception, thus limiting what comes into consciousness and therefore limiting the amount of wisdom that can be generated from the perception. Additionally Occidental epistemology propagates the false notion that man exists outside Mind and this leads man to believe in what Bateson calls the philosophy of control based upon false knowledge.

Bateson presents Occidental epistemology as a method of thinking that leads to a mindset in which man exerts an autocratic rule over all cybernetic systems. In exerting his autocratic rule man changes the environment to suit him and in doing so he unbalances the natural cybernetic system of controlled competition and mutual dependency. The purpose-driven accumulation of knowledge ignores the supreme cybernetic system and leads to the eventual breakdown of the entire system. Bateson claims that man will never be able to control the whole system because it does not operate in a linear fashion and if man creates his own rules for the system, he opens himself up to becoming a slave to the self-made system due to the non-linear nature of cybernetics. Lastly, man's technological prowess combined with his scientific hubris gives him the potential to irrevocably damage and destroy the supreme cybernetic system, instead of just disrupting the system temporally until the system can self-correct.

Bateson argues for a position of humility and acceptance of the natural cybernetic system instead of scientific arrogance as a solution. He believes that humility can come about by abandoning the view of operating through consciousness alone. Consciousness is only one way in which to obtain knowledge and without complete knowledge of the entire cybernetic system disaster is inevitable. The limited conscious must be combined with the unconscious in complete synthesis. Only when thought and emotion are combined in whole is man able to obtain complete knowledge. He believed that religion and art are some of the few areas in which a man is acting as a whole individual in complete consciousness. By acting with this greater wisdom of the supreme cybernetic system as a whole man can change his relationship to Mind from one of schism, in which he is endlessly tied up in constant competition, to one of complementarity. Bateson argues for a culture that promotes the most general wisdom and is able to flexibly change within the supreme cybernetic system.

Other terms used by Bateson

• Abduction. Used by Bateson to refer to a third scientific methodology (along with induction and deduction) which was central to his own holistic and qualitative approach. Refers to a method of comparing patterns of relationship, and their symmetry or asymmetry (as in, for example, comparative anatomy), especially in complex organic (or mental) systems. The term was originally coined by American Philosopher/Logician Charles Sanders Peirce, who used it to refer to the process by which scientific hypotheses are generated.
  
• Criteria of Mind (from Mind and Nature A Necessary Unity):

1. Mind is an aggregate of interacting parts or components;
2. The interaction between parts of mind is triggered by difference;
3. Mental process requires collateral energy;
4. Mental process requires circular (or more complex) chains of determination;
5. In mental process the effects of difference are to be regarded as transforms (that is, coded versions) of the difference which preceded them;
6. The description and classification of these processes of transformation discloses a hierarchy of logical types immanent in the phenomena.

• Creatura and Pleroma. Borrowed from Carl Jung who applied these gnostic terms in his "Seven Sermons To the Dead". Like the Hindu term maya, the basic idea captured in this distinction is that meaning and organisation are projected onto the world. Pleroma refers to the non-living world that is undifferentiated by subjectivity; Creatura for the living world, subject to perceptual difference, distinction, and information.
  
• Deuterolearning. A term he coined in the 1940s referring to the organisation of learning, or learning to learn.
  
• Schismogenesis – the emergence of divisions within social groups.
  
• Information – Bateson defined information as "a difference which makes a difference." For Bateson, information in fact mediated Alfred Korzybski's map–territory relation, and thereby resolved, according to Bateson, the mind-body problem.

Continuing extensions of Bateson's work

His daughter Mary Catherine Bateson published a joint biography of her parents (Bateson and Margaret Mead) in 1984. Bateson's legacy was reintroduced to new audiences by his daughter the filmmaker Nora Bateson, with the release of An Ecology of Mind, a documentary that premiered at the Vancouver International Film Festival. This film was selected as the audience favourite with the Morton Marcus Documentary Feature Award at the 2011 Santa Cruz Film Festival, and honoured with the 2011 John Culkin Award for Outstanding Praxis in the Field of Media Ecology by the Media Ecology Association. The Bateson Idea Group (BIG) initiated a web presence in October 2010. The group collaborated with the American Society for Cybernetics for a joint meeting in July 2012 at the Asilomar Conference Grounds in California.

Homologous recombination

From Wikipedia, the free encyclopedia

Figure 1. During meiosis, homologous recombination can produce new combinations of genes as shown here between similar but not identical copies of human chromosome 1

Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks (DSB). Homologous recombination also produces new combinations of DNA sequences during meiosis, the process by which eukaryotes make gamete cells, like sperm and egg cells in animals. These new combinations of DNA represent genetic variation in offspring, which in turn enables populations to adapt during the course of evolution. Homologous recombination is also used in horizontal gene transfer to exchange genetic material between different strains and species of bacteria and viruses.

Although homologous recombination varies widely among different organisms and cell types, most forms involve the same basic steps. After a double-strand break occurs, sections of DNA around the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" a similar or identical DNA molecule that is not broken. After strand invasion, the further sequence of events may follow either of two main pathways discussed below; the DSBR (double-strand break repair) pathway or the SDSA (synthesis-dependent strand annealing) pathway. Homologous recombination that occurs during DNA repair tends to result in non-crossover products, in effect restoring the damaged DNA molecule as it existed before the double-strand break.

Homologous recombination is conserved across all three domains of life as well as viruses, suggesting that it is a nearly universal biological mechanism. The discovery of genes for homologous recombination in protists—a diverse group of eukaryotic microorganisms—has been interpreted as evidence that meiosis emerged early in the evolution of eukaryotes. Since their dysfunction has been strongly associated with increased susceptibility to several types of cancer, the proteins that facilitate homologous recombination are topics of active research. Homologous recombination is also used in gene targeting, a technique for introducing genetic changes into target organisms. For their development of this technique, Mario Capecchi, Martin Evans and Oliver Smithies were awarded the 2007 Nobel Prize for Physiology or Medicine; Capecchi and Smithies independently discovered applications to mouse embryonic stem cells, however the highly conserved mechanisms underlying the DSB repair model, including uniform homologous integration of transformed DNA (gene therapy), were first shown in plasmid experiments by Orr-Weaver, Szostack and Rothstein. Researching the plasmid-induced DSB, using γ-irradiation in the 1970s-1980s, led to later experiments using endonucleases (e.g. I-SceI) to cut chromosomes for genetic engineering of mammalian cells, where nonhomologous recombination is more frequent than in yeast.

History and discovery

Figure 2. An early illustration of crossing over from Thomas Hunt Morgan

In the early 1900s, William Bateson and Reginald Punnett found an exception to one of the principles of inheritance originally described by Gregor Mendel in the 1860s. In contrast to Mendel's notion that traits are independently assorted when passed from parent to child—for example that a cat's hair color and its tail length are inherited independent of each other—Bateson and Punnett showed that certain genes associated with physical traits can be inherited together, or genetically linked. In 1911, after observing that linked traits could on occasion be inherited separately, Thomas Hunt Morgan suggested that "crossovers" can occur between linked genes, where one of the linked genes physically crosses over to a different chromosome. Two decades later, Barbara McClintock and Harriet Creighton demonstrated that chromosomal crossover occurs during meiosis, the process of cell division by which sperm and egg cells are made. Within the same year as McClintock's discovery, Curt Stern showed that crossing over—later called "recombination"—could also occur in somatic cells like white blood cells and skin cells that divide through mitosis.

In 1947, the microbiologist Joshua Lederberg showed that bacteria—which had been assumed to reproduce only asexually through binary fission—are capable of genetic recombination, which is more similar to sexual reproduction. This work established E. coli as a model organism in genetics, and helped Lederberg win the 1958 Nobel Prize in Physiology or Medicine. Building on studies in fungi, in 1964 Robin Holliday proposed a model for recombination in meiosis which introduced key details of how the process can work, including the exchange of material between chromosomes through Holliday junctions. In 1983, Jack Szostak and colleagues presented a model now known as the DSBR pathway, which accounted for observations not explained by the Holliday model. During the next decade, experiments in Drosophila, budding yeast and mammalian cells led to the emergence of other models of homologous recombination, called SDSA pathways, which do not always rely on Holliday junctions.

Much of the later work identifying proteins involved in the process and determining their mechanisms has been performed by a number of individuals including James Haber, Patrick Sung, Stephen Kowalczykowski, and others.

In eukaryotes

Homologous recombination (HR) is essential to cell division in eukaryotes like plants, animals, fungi and protists. In cells that divide through mitosis, homologous recombination repairs double-strand breaks in DNA caused by ionizing radiation or DNA-damaging chemicals. Left unrepaired, these double-strand breaks can cause large-scale rearrangement of chromosomes in somatic cells, which can in turn lead to cancer.

In addition to repairing DNA, homologous recombination also helps produce genetic diversity when cells divide in meiosis to become specialized gamete cells—sperm or egg cells in animals, pollen or ovules in plants, and spores in fungi. It does so by facilitating chromosomal crossover, in which regions of similar but not identical DNA are exchanged between homologous chromosomes. This creates new, possibly beneficial combinations of genes, which can give offspring an evolutionary advantage. Chromosomal crossover often begins when a protein called Spo11 makes a targeted double-strand break in DNA. These sites are non-randomly located on the chromosomes; usually in intergenic promoter regions and preferentially in GC-rich domains These double-strand break sites often occur at recombination hotspots, regions in chromosomes that are about 1,000–2,000 base pairs in length and have high rates of recombination. The absence of a recombination hotspot between two genes on the same chromosome often means that those genes will be inherited by future generations in equal proportion. This represents linkage between the two genes greater than would be expected from genes that independently assort during meiosis.

Timing within the mitotic cell cycle

Figure 3. Homologous recombination repairs DNA before the cell enters mitosis (M phase). It occurs only during and shortly after DNA replication, during the S and G₂ phases of the cell cycle

Double-strand breaks can be repaired through homologous recombination or through non-homologous end joining (NHEJ). NHEJ is a DNA repair mechanism which, unlike homologous recombination, does not require a long homologous sequence to guide repair. Whether homologous recombination or NHEJ is used to repair double-strand breaks is largely determined by the phase of cell cycle. Homologous recombination repairs DNA before the cell enters mitosis (M phase). It occurs during and shortly after DNA replication, in the S and G₂ phases of the cell cycle, when sister chromatids are more easily available. Compared to homologous chromosomes, which are similar to another chromosome but often have different alleles, sister chromatids are an ideal template for homologous recombination because they are an identical copy of a given chromosome. In contrast to homologous recombination, NHEJ is predominant in the G₁ phase of the cell cycle, when the cell is growing but not yet ready to divide. It occurs less frequently after the G₁ phase, but maintains at least some activity throughout the cell cycle. The mechanisms that regulate homologous recombination and NHEJ throughout the cell cycle vary widely between species.

Cyclin-dependent kinases (CDKs), which modify the activity of other proteins by adding phosphate groups to (that is, phosphorylating) them, are important regulators of homologous recombination in eukaryotes. When DNA replication begins in budding yeast, the cyclin-dependent kinase Cdc28 begins homologous recombination by phosphorylating the Sae2 protein. After being so activated by the addition of a phosphate, Sae2 uses its endonuclease activity to make a clean cut near a double-strand break in DNA. This allows a three-part protein known as the MRX complex to bind to DNA, and begins a series of protein-driven reactions that exchange material between two DNA molecules.

Preliminary steps

The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow HR DNA repair, the chromatin must be remodeled. In eukaryotes, ATP dependent chromatin remodeling complexes and histone-modifying enzymes are two predominant factors employed to accomplish this remodeling process.

Chromatin relaxation occurs rapidly at the site of a DNA damage. In one of the earliest steps, the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), phosphorylates SIRT6 on serine 10 in response to double-strand breaks or other DNA damage. This post-translational modification facilitates the mobilization of SIRT6 to DNA damage sites, and is required for efficient recruitment of poly (ADP-ribose) polymerase 1 (PARP1) to DNA break sites and for efficient repair of DSBs. PARP1 protein starts to appear at DNA damage sites in less than a second, with half maximum accumulation within 1.6 seconds after the damage occurs. Next the chromatin remodeler Alc1 quickly attaches to the product of PARP1 action, a poly-ADP ribose chain, and Alc1 completes arrival at the DNA damage within 10 seconds of the occurrence of the damage. About half of the maximum chromatin relaxation, presumably due to action of Alc1, occurs by 10 seconds. This then allows recruitment of the DNA repair enzyme MRE11, to initiate DNA repair, within 13 seconds.

γH2AX, the phosphorylated form of H2AX is also involved in the early steps leading to chromatin decondensation after DNA double-strand breaks. The histone variant H2AX constitutes about 10% of the H2A histones in human chromatin. γH2AX (H2AX phosphorylated on serine 139) can be detected as soon as 20 seconds after irradiation of cells (with DNA double-strand break formation), and half maximum accumulation of γH2AX occurs in one minute. The extent of chromatin with phosphorylated γH2AX is about two million base pairs at the site of a DNA double-strand break. γH2AX does not, itself, cause chromatin decondensation, but within 30 seconds of irradiation, RNF8 protein can be detected in association with γH2AX. RNF8 mediates extensive chromatin decondensation, through its subsequent interaction with CHD4, a component of the nucleosome remodeling and deacetylase complex NuRD.

After undergoing relaxation subsequent to DNA damage, followed by DNA repair, chromatin recovers to a compaction state close to its pre-damage level after about 20 min.

Models

Two primary models for how homologous recombination repairs double-strand breaks in DNA are the double-strand break repair (DSBR) pathway (sometimes called the double Holliday junction model) and the synthesis-dependent strand annealing (SDSA) pathway. The two pathways are similar in their first several steps. After a double-strand break occurs, the MRX complex (MRN complex in humans) binds to DNA on either side of the break. Next a resection, in which DNA around the 5' ends of the break is cut back, is carried out in two distinct steps. In the first step of resection, the MRX complex recruits the Sae2 protein. The two proteins then trim back the 5' ends on either side of the break to create short 3' overhangs of single-strand DNA. In the second step, 5'→3' resection is continued by the Sgs1 helicase and the Exo1 and Dna2 nucleases. As a helicase, Sgs1 "unzips" the double-strand DNA, while Exo1 and Dna2's nuclease activity allows them to cut the single-stranded DNA produced by Sgs1.

Figure 4. The DSBR and SDSA pathways follow the same initial steps, but diverge thereafter. The DSBR pathway most often results in chromosomal crossover (bottom left), while SDSA always ends with non-crossover products (bottom right)

The RPA protein, which has high affinity for single-stranded DNA, then binds the 3' overhangs. With the help of several other proteins that mediate the process, the Rad51 protein (and Dmc1, in meiosis) then forms a filament of nucleic acid and protein on the single strand of DNA coated with RPA. This nucleoprotein filament then begins searching for DNA sequences similar to that of the 3' overhang. After finding such a sequence, the single-stranded nucleoprotein filament moves into (invades) the similar or identical recipient DNA duplex in a process called strand invasion. In cells that divide through mitosis, the recipient DNA duplex is generally a sister chromatid, which is identical to the damaged DNA molecule and provides a template for repair. In meiosis, however, the recipient DNA tends to be from a similar but not necessarily identical homologous chromosome. A displacement loop (D-loop) is formed during strand invasion between the invading 3' overhang strand and the homologous chromosome. After strand invasion, a DNA polymerase extends the end of the invading 3' strand by synthesizing new DNA. This changes the D-loop to a cross-shaped structure known as a Holliday junction. Following this, more DNA synthesis occurs on the invading strand (i.e., one of the original 3' overhangs), effectively restoring the strand on the homologous chromosome that was displaced during strand invasion.

DSBR pathway

After the stages of resection, strand invasion and DNA synthesis, the DSBR and SDSA pathways become distinct. The DSBR pathway is unique in that the second 3' overhang (which was not involved in strand invasion) also forms a Holliday junction with the homologous chromosome. The double Holliday junctions are then converted into recombination products by nicking endonucleases, a type of restriction endonuclease which cuts only one DNA strand. The DSBR pathway commonly results in crossover, though it can sometimes result in non-crossover products; the ability of a broken DNA molecule to collect sequences from separated donor loci was shown in mitotic budding yeast using plasmids or endonuclease induction of chromosomal events. Because of this tendency for chromosomal crossover, the DSBR pathway is a likely model of how crossover homologous recombination occurs during meiosis.

Whether recombination in the DSBR pathway results in chromosomal crossover is determined by how the double Holliday junction is cut, or "resolved". Chromosomal crossover will occur if one Holliday junction is cut on the crossing strand and the other Holliday junction is cut on the non-crossing strand (in Figure 4, along the horizontal purple arrowheads at one Holliday junction and along the vertical orange arrowheads at the other). Alternatively, if the two Holliday junctions are cut on the crossing strands (along the horizontal purple arrowheads at both Holliday junctions in Figure 4), then chromosomes without crossover will be produced.

SDSA pathway

Homologous recombination via the SDSA pathway occurs in cells that divide through mitosis and meiosis and results in non-crossover products. In this model, the invading 3' strand is extended along the recipient DNA duplex by a DNA polymerase, and is released as the Holliday junction between the donor and recipient DNA molecules slides in a process called branch migration. The newly synthesized 3' end of the invading strand is then able to anneal to the other 3' overhang in the damaged chromosome through complementary base pairing. After the strands anneal, a small flap of DNA can sometimes remain. Any such flaps are removed, and the SDSA pathway finishes with the resealing, also known as ligation, of any remaining single-stranded gaps.

During mitosis, the major homologous recombination pathway for repairing DNA double-strand breaks appears to be the SDSA pathway (rather than the DSBR pathway). The SDSA pathway produces non-crossover recombinants (Figure 4). During meiosis non-crossover recombinants also occur frequently and these appear to arise mainly by the SDSA pathway as well. Non-crossover recombination events occurring during meiosis likely reflect instances of repair of DNA double-strand damages or other types of DNA damages.

SSA pathway

Figure 5. Recombination via the SSA pathway occurs between two repeat elements (purple) on the same DNA duplex, and results in deletions of genetic material (Click to view animated diagram in Firefox, Chrome, Safari, or Opera web browsers)

The single-strand annealing (SSA) pathway of homologous recombination repairs double-strand breaks between two repeat sequences. The SSA pathway is unique in that it does not require a separate similar or identical molecule of DNA, like the DSBR or SDSA pathways of homologous recombination. Instead, the SSA pathway only requires a single DNA duplex, and uses the repeat sequences as the identical sequences that homologous recombination needs for repair. The pathway is relatively simple in concept: after two strands of the same DNA duplex are cut back around the site of the double-strand break, the two resulting 3' overhangs then align and anneal to each other, restoring the DNA as a continuous duplex.

As DNA around the double-strand break is cut back, the single-stranded 3' overhangs being produced are coated with the RPA protein, which prevents the 3' overhangs from sticking to themselves. A protein called Rad52 then binds each of the repeat sequences on either side of the break, and aligns them to enable the two complementary repeat sequences to anneal. After annealing is complete, leftover non-homologous flaps of the 3' overhangs are cut away by a set of nucleases, known as Rad1/Rad10, which are brought to the flaps by the Saw1 and Slx4 proteins. New DNA synthesis fills in any gaps, and ligation restores the DNA duplex as two continuous strands. The DNA sequence between the repeats is always lost, as is one of the two repeats. The SSA pathway is considered mutagenic since it results in such deletions of genetic material.

BIR pathway

During DNA replication, double-strand breaks can sometimes be encountered at replication forks as DNA helicase unzips the template strand. These defects are repaired in the break-induced replication (BIR) pathway of homologous recombination. The precise molecular mechanisms of the BIR pathway remain unclear. Three proposed mechanisms have strand invasion as an initial step, but they differ in how they model the migration of the D-loop and later phases of recombination.

The BIR pathway can also help to maintain the length of telomeres (regions of DNA at the end of eukaryotic chromosomes) in the absence of (or in cooperation with) telomerase. Without working copies of the enzyme telomerase, telomeres typically shorten with each cycle of mitosis, which eventually blocks cell division and leads to senescence. In budding yeast cells where telomerase has been inactivated through mutations, two types of "survivor" cells have been observed to avoid senescence longer than expected by elongating their telomeres through BIR pathways.

Maintaining telomere length is critical for cell immortalization, a key feature of cancer. Most cancers maintain telomeres by upregulating telomerase. However, in several types of human cancer, a BIR-like pathway helps to sustain some tumors by acting as an alternative mechanism of telomere maintenance. This fact has led scientists to investigate whether such recombination-based mechanisms of telomere maintenance could thwart anti-cancer drugs like telomerase inhibitors.

In bacteria

Figure 6. Crystal structure of a RecA protein filament bound to DNA.^[53] A 3' overhang is visible to the right of center.

Homologous recombination is a major DNA repair process in bacteria. It is also important for producing genetic diversity in bacterial populations, although the process differs substantially from meiotic recombination, which repairs DNA damages and brings about diversity in eukaryotic genomes. Homologous recombination has been most studied and is best understood for Escherichia coli. Double-strand DNA breaks in bacteria are repaired by the RecBCD pathway of homologous recombination. Breaks that occur on only one of the two DNA strands, known as single-strand gaps, are thought to be repaired by the RecF pathway. Both the RecBCD and RecF pathways include a series of reactions known as branch migration, in which single DNA strands are exchanged between two intercrossed molecules of duplex DNA, and resolution, in which those two intercrossed molecules of DNA are cut apart and restored to their normal double-stranded state.

RecBCD pathway

Figure 7A. Molecular model for the RecBCD pathway of recombination. This model is based on reactions of DNA and RecBCD with ATP in excess over Mg2+ ions. Step 1: RecBCD binds to a double-stranded DNA end. Step 2: RecBCD unwinds DNA. RecD is a fast helicase on the 5’-ended strand, and RecB is a slower helicase on the 3'-ended strand (that with an arrowhead) [ref 46 in current Wiki version]. This produces two single-stranded (ss) DNA tails and one ss loop. The loop and tails enlarge as RecBCD moves along the DNA. Step 3: The two tails anneal to produce a second ss DNA loop, and both loops move and grow. Step 4: Upon reaching the Chi hotspot sequence (5' GCTGGTGG 3'; red dot) RecBCD nicks the 3’-ended strand. Further unwinding produces a long 3'-ended ss tail with Chi near its end. Step 5: RecBCD loads RecA protein onto the Chi tail. At some undetermined point, the RecBCD subunits disassemble. Step 6: The RecA-ssDNA complex invades an intact homologous duplex DNA to produce a D-loop, which can be resolved into intact, recombinant DNA in two ways. Step 7: The D-loop is cut and anneals with the gap in the first DNA to produce a Holliday junction. Resolution of the Holliday junction (cutting, swapping of strands, and ligation) at the open arrowheads by some combination of RuvABC and RecG produces two recombinants of reciprocal type. Step 8: The 3' end of the Chi tail primes DNA synthesis, from which a replication fork can be generated. Resolution of the fork at the open arrowheads produces one recombinant (non-reciprocal) DNA, one parental-type DNA, and one DNA fragment.

 

Figure 7B. Beginning of the RecBCD pathway. This model is based on reactions of DNA and RecBCD with Mg²⁺ ions in excess over ATP. Step 1: RecBCD binds to a DNA double strand break. Step 2: RecBCD initiates unwinding of the DNA duplex through ATP-dependent helicase activity. Step 3: RecBCD continues its unwinding and moves down the DNA duplex, cleaving the 3' strand much more frequently than the 5' strand. Step 4: RecBCD encounters a Chi sequence and stops digesting the 3' strand; cleavage of the 5' strand is significantly increased. Step 5: RecBCD loads RecA onto the 3' strand. Step 6: RecBCD unbinds from the DNA duplex, leaving a RecA nucleoprotein filament on the 3' tail.

The RecBCD pathway is the main recombination pathway used in many bacteria to repair double-strand breaks in DNA, and the proteins are found in a broad array of bacteria.^[58][59][60] These double-strand breaks can be caused by UV light and other radiation, as well as chemical mutagens. Double-strand breaks may also arise by DNA replication through a single-strand nick or gap. Such a situation causes what is known as a collapsed replication fork and is fixed by several pathways of homologous recombination including the RecBCD pathway.

In this pathway, a three-subunit enzyme complex called RecBCD initiates recombination by binding to a blunt or nearly blunt end of a break in double-strand DNA. After RecBCD binds the DNA end, the RecB and RecD subunits begin unzipping the DNA duplex through helicase activity. The RecB subunit also has a nuclease domain, which cuts the single strand of DNA that emerges from the unzipping process. This unzipping continues until RecBCD encounters a specific nucleotide sequence (5'-GCTGGTGG-3') known as a Chi site.

Upon encountering a Chi site, the activity of the RecBCD enzyme changes drastically. DNA unwinding pauses for a few seconds and then resumes at roughly half the initial speed. This is likely because the slower RecB helicase unwinds the DNA after Chi, rather than the faster RecD helicase, which unwinds the DNA before Chi. Recognition of the Chi site also changes the RecBCD enzyme so that it cuts the DNA strand with Chi and begins loading multiple RecA proteins onto the single-stranded DNA with the newly generated 3' end. The resulting RecA-coated nucleoprotein filament then searches out similar sequences of DNA on a homologous chromosome. The search process induces stretching of the DNA duplex, which enhances homology recognition (a mechanism termed conformational proofreading). Upon finding such a sequence, the single-stranded nucleoprotein filament moves into the homologous recipient DNA duplex in a process called strand invasion. The invading 3' overhang causes one of the strands of the recipient DNA duplex to be displaced, to form a D-loop. If the D-loop is cut, another swapping of strands forms a cross-shaped structure called a Holliday junction. Resolution of the Holliday junction by some combination of RuvABC or RecG can produce two recombinant DNA molecules with reciprocal genetic types, if the two interacting DNA molecules differ genetically. Alternatively, the invading 3’ end near Chi can prime DNA synthesis and form a replication fork. This type of resolution produces only one type of recombinant (non-reciprocal).

RecF pathway

Bacteria appear to use the RecF pathway of homologous recombination to repair single-strand gaps in DNA. When the RecBCD pathway is inactivated by mutations and additional mutations inactivate the SbcCD and ExoI nucleases, the RecF pathway can also repair DNA double-strand breaks. In the RecF pathway the RecQ helicase unwinds the DNA and the RecJ nuclease degrades the strand with a 5' end, leaving the strand with the 3' end intact. RecA protein binds to this strand and is either aided by the RecF, RecO, and RecR proteins or stabilized by them. The RecA nucleoprotein filament then searches for a homologous DNA and exchanges places with the identical or nearly identical strand in the homologous DNA.

Although the proteins and specific mechanisms involved in their initial phases differ, the two pathways are similar in that they both require single-stranded DNA with a 3' end and the RecA protein for strand invasion. The pathways are also similar in their phases of branch migration, in which the Holliday junction slides in one direction, and resolution, in which the Holliday junctions are cleaved apart by enzymes. The alternative, non-reciprocal type of resolution may also occur by either pathway.

Branch migration

Immediately after strand invasion, the Holliday junction moves along the linked DNA during the branch migration process. It is in this movement of the Holliday junction that base pairs between the two homologous DNA duplexes are exchanged. To catalyze branch migration, the RuvA protein first recognizes and binds to the Holliday junction and recruits the RuvB protein to form the RuvAB complex. Two sets of the RuvB protein, which each form a ring-shaped ATPase, are loaded onto opposite sides of the Holliday junction, where they act as twin pumps that provide the force for branch migration. Between those two rings of RuvB, two sets of the RuvA protein assemble in the center of the Holliday junction such that the DNA at the junction is sandwiched between each set of RuvA. The strands of both DNA duplexes—the "donor" and the "recipient" duplexes—are unwound on the surface of RuvA as they are guided by the protein from one duplex to the other.

Resolution

In the resolution phase of recombination, any Holliday junctions formed by the strand invasion process are cut, thereby restoring two separate DNA molecules. This cleavage is done by RuvAB complex interacting with RuvC, which together form the RuvABC complex. RuvC is an endonuclease that cuts the degenerate sequence 5'-(A/T)TT(G/C)-3'. The sequence is found frequently in DNA, about once every 64 nucleotides. Before cutting, RuvC likely gains access to the Holliday junction by displacing one of the two RuvA tetramers covering the DNA there. Recombination results in either "splice" or "patch" products, depending on how RuvC cleaves the Holliday junction. Splice products are crossover products, in which there is a rearrangement of genetic material around the site of recombination. Patch products, on the other hand, are non-crossover products in which there is no such rearrangement and there is only a "patch" of hybrid DNA in the recombination product.

Facilitating genetic transfer

Homologous recombination is an important method of integrating donor DNA into a recipient organism's genome in horizontal gene transfer, the process by which an organism incorporates foreign DNA from another organism without being the offspring of that organism. Homologous recombination requires incoming DNA to be highly similar to the recipient genome, and so horizontal gene transfer is usually limited to similar bacteria. Studies in several species of bacteria have established that there is a log-linear decrease in recombination frequency with increasing difference in sequence between host and recipient DNA.

In bacterial conjugation, where DNA is transferred between bacteria through direct cell-to-cell contact, homologous recombination helps integrate foreign DNA into the host genome via the RecBCD pathway. The RecBCD enzyme promotes recombination after DNA is converted from single-strand DNA–in which form it originally enters the bacterium–to double-strand DNA during replication. The RecBCD pathway is also essential for the final phase of transduction, a type of horizontal gene transfer in which DNA is transferred from one bacterium to another by a virus. Foreign, bacterial DNA is sometimes misincorporated in the capsid head of bacteriophage virus particles as DNA is packaged into new bacteriophages during viral replication. When these new bacteriophages infect other bacteria, DNA from the previous host bacterium is injected into the new bacterial host as double-strand DNA. The RecBCD enzyme then incorporates this double-strand DNA into the genome of the new bacterial host.

Bacterial transformation

Natural bacterial transformation involves the transfer of DNA from a donor bacterium to a recipient bacterium, where both donor and recipient are ordinarily of the same species. Transformation, unlike bacterial conjugation and transduction, depends on numerous bacterial gene products that specifically interact to perform this process. Thus transformation is clearly a bacterial adaptation for DNA transfer. In order for a bacterium to bind, take up and integrate donor DNA into its resident chromosome by homologous recombination, it must first enter a special physiological state termed competence. The RecA/Rad51/DMC1 gene family plays a central role in homologous recombination during bacterial transformation as it does during eukaryotic meiosis and mitosis. For instance, the RecA protein is essential for transformation in Bacillus subtilis and Streptococcus pneumoniae, and expression of the RecA gene is induced during the development of competence for transformation in these organisms.

As part of the transformation process, the RecA protein interacts with entering single-stranded DNA (ssDNA) to form RecA/ssDNA nucleofilaments that scan the resident chromosome for regions of homology and bring the entering ssDNA to the corresponding region, where strand exchange and homologous recombination occur. Thus the process of homologous recombination during bacterial transformation has fundamental similarities to homologous recombination during meiosis.

In viruses

Homologous recombination occurs in several groups of viruses. In DNA viruses such as herpesvirus, recombination occurs through a break-and-rejoin mechanism like in bacteria and eukaryotes. There is also evidence for recombination in some RNA viruses, specifically positive-sense ssRNA viruses like retroviruses, picornaviruses, and coronaviruses. There is controversy over whether homologous recombination occurs in negative-sense ssRNA viruses like influenza.

In RNA viruses, homologous recombination can be either precise or imprecise. In the precise type of RNA-RNA recombination, there is no difference between the two parental RNA sequences and the resulting crossover RNA region. Because of this, it is often difficult to determine the location of crossover events between two recombining RNA sequences. In imprecise RNA homologous recombination, the crossover region has some difference with the parental RNA sequences – caused by either addition, deletion, or other modification of nucleotides. The level of precision in crossover is controlled by the sequence context of the two recombining strands of RNA: sequences rich in adenine and uracil decrease crossover precision.

Homologous recombination is important in facilitating viral evolution. For example, if the genomes of two viruses with different disadvantageous mutations undergo recombination, then they may be able to regenerate a fully functional genome. Alternatively, if two similar viruses have infected the same host cell, homologous recombination can allow those two viruses to swap genes and thereby evolve more potent variations of themselves.

Homologous recombination is the proposed mechanism whereby the DNA virus human herpesvirus-6 integrates into human telomeres.

When two or more viruses, each containing lethal genomic damage, infect the same host cell, the virus genomes can often pair with each other and undergo homologous recombinational repair to produce viable progeny. This process, known as multiplicity reactivation, has been studied in several bacteriophages, including phage T4. Enzymes employed in recombinational repair in phage T4 are functionally homologous to enzymes employed in bacterial and eukaryotic recombinational repair. In particular, with regard to a gene necessary for the strand exchange reaction, a key step in homologous recombinational repair, there is functional homology from viruses to humans (i. e. uvsX in phage T4; recA in E. coli and other bacteria, and rad51 and dmc1 in yeast and other eukaryotes, including humans). Multiplicity reactivation has also been demonstrated in numerous pathogenic viruses.

Effects of dysfunction

Without proper homologous recombination, chromosomes often incorrectly align for the first phase of cell division in meiosis. This causes chromosomes to fail to properly segregate in a process called nondisjunction. In turn, nondisjunction can cause sperm and ova to have too few or too many chromosomes. Down's syndrome, which is caused by an extra copy of chromosome 21, is one of many abnormalities that result from such a failure of homologous recombination in meiosis.

Deficiencies in homologous recombination have been strongly linked to cancer formation in humans. For example, each of the cancer-related diseases Bloom's syndrome, Werner's syndrome and Rothmund-Thomson syndrome are caused by malfunctioning copies of RecQ helicase genes involved in the regulation of homologous recombination: BLM, WRN and RECQL4, respectively. In the cells of Bloom's syndrome patients, who lack a working copy of the BLM protein, there is an elevated rate of homologous recombination. Experiments in mice deficient in BLM have suggested that the mutation gives rise to cancer through a loss of heterozygosity caused by increased homologous recombination. A loss in heterozygosity refers to the loss of one of two versions—or alleles—of a gene. If one of the lost alleles helps to suppress tumors, like the gene for the retinoblastoma protein for example, then the loss of heterozygosity can lead to cancer.

Decreased rates of homologous recombination cause inefficient DNA repair, which can also lead to cancer. This is the case with BRCA1 and BRCA2, two similar tumor suppressor genes whose malfunctioning has been linked with considerably increased risk for breast and ovarian cancer. Cells missing BRCA1 and BRCA2 have a decreased rate of homologous recombination and increased sensitivity to ionizing radiation, suggesting that decreased homologous recombination leads to increased susceptibility to cancer. Because the only known function of BRCA2 is to help initiate homologous recombination, researchers have speculated that more detailed knowledge of BRCA2's role in homologous recombination may be the key to understanding the causes of breast and ovarian cancer.

Tumours with a homologous recombination deficiency (including BRCA defects) are described as HRD-positive.

Evolutionary conservation

Figure 8. Protein domains in homologous recombination-related proteins are conserved across the three main groups of life: archaea, bacteria and eukaryotes.

While the pathways can mechanistically vary, the ability of organisms to perform homologous recombination is universally conserved across all domains of life. Based on the similarity of their amino acid sequences, homologs of a number of proteins can be found in multiple domains of life indicating that they evolved a long time ago, and have since diverged from common ancestral proteins.

RecA recombinase family members are found in almost all organisms with RecA in bacteria, Rad51 and DMC1 in eukaryotes, RadA in archaea, and UvsX in T4 phage.

Related single stranded binding proteins that are important for homologous recombination, and many other processes, are also found in all domains of life.

Rad54, Mre11, Rad50, and a number of other proteins are also found in both archaea and eukaryotes.

The RecA recombinase family

The proteins of the RecA recombinase family of proteins are thought to be descended from a common ancestral recombinase. The RecA recombinase family contains RecA protein from bacteria, the Rad51 and Dmc1 proteins from eukaryotes, and RadA from archaea, and the recombinase paralog proteins. Studies modeling the evolutionary relationships between the Rad51, Dmc1 and RadA proteins indicate that they are monophyletic, or that they share a common molecular ancestor. Within this protein family, Rad51 and Dmc1 are grouped together in a separate clade from RadA. One of the reasons for grouping these three proteins together is that they all possess a modified helix-turn-helix motif, which helps the proteins bind to DNA, toward their N-terminal ends. An ancient gene duplication event of a eukaryotic RecA gene and subsequent mutation has been proposed as a likely origin of the modern RAD51 and DMC1 genes.

The proteins generally share a long conserved region known as the RecA/Rad51 domain. Within this protein domain are two sequence motifs, Walker A motif and Walker B motif. The Walker A and B motifs allow members of the RecA/Rad51 protein family to engage in ATP binding and ATP hydrolysis.

Meiosis-specific proteins

The discovery of Dmc1 in several species of Giardia, one of the earliest protists to diverge as a eukaryote, suggests that meiotic homologous recombination—and thus meiosis itself—emerged very early in eukaryotic evolution. In addition to research on Dmc1, studies on the Spo11 protein have provided information on the origins of meiotic recombination. Spo11, a type II topoisomerase, can initiate homologous recombination in meiosis by making targeted double-strand breaks in DNA. Phylogenetic trees based on the sequence of genes similar to SPO11 in animals, fungi, plants, protists and archaea have led scientists to believe that the version Spo11 currently in eukaryotes emerged in the last common ancestor of eukaryotes and archaea.

Technological applications

Gene targeting

Figure 9. As a developing embryo, this chimeric mouse had the agouti coat color gene introduced into its DNA via gene targeting. Its offspring are homozygous for the agouti gene.

Main article: Gene targeting

Many methods for introducing DNA sequences into organisms to create recombinant DNA and genetically modified organisms use the process of homologous recombination. Also called gene targeting, the method is especially common in yeast and mouse genetics. The gene targeting method in knockout mice uses mouse embryonic stem cells to deliver artificial genetic material (mostly of therapeutic interest), which represses the target gene of the mouse by the principle of homologous recombination. The mouse thereby acts as a working model to understand the effects of a specific mammalian gene. In recognition of their discovery of how homologous recombination can be used to introduce genetic modifications in mice through embryonic stem cells, Mario Capecchi, Martin Evans and Oliver Smithies were awarded the 2007 Nobel Prize for Physiology or Medicine.

Advances in gene targeting technologies which hijack the homologous recombination mechanics of cells are now leading to the development of a new wave of more accurate, isogenic human disease models. These engineered human cell models are thought to more accurately reflect the genetics of human diseases than their mouse model predecessors. This is largely because mutations of interest are introduced into endogenous genes, just as they occur in the real patients, and because they are based on human genomes rather than rat genomes. Furthermore, certain technologies enable the knock-in of a particular mutation rather than just knock-outs associated with older gene targeting technologies.

Protein engineering

Protein engineering with homologous recombination develops chimeric proteins by swapping fragments between two parental proteins. These techniques exploit the fact that recombination can introduce a high degree of sequence diversity while preserving a protein's ability to fold into its tertiary structure, or three-dimensional shape. This stands in contrast to other protein engineering techniques, like random point mutagenesis, in which the probability of maintaining protein function declines exponentially with increasing amino acid substitutions. The chimeras produced by recombination techniques are able to maintain their ability to fold because their swapped parental fragments are structurally and evolutionarily conserved. These recombinable "building blocks" preserve structurally important interactions like points of physical contact between different amino acids in the protein's structure. Computational methods like SCHEMA and statistical coupling analysis can be used to identify structural subunits suitable for recombination.

Techniques that rely on homologous recombination have been used to engineer new proteins. In a study published in 2007, researchers were able to create chimeras of two enzymes involved in the biosynthesis of isoprenoids, a diverse class of compounds including hormones, visual pigments and certain pheromones. The chimeric proteins acquired an ability to catalyze an essential reaction in isoprenoid biosynthesis—one of the most diverse pathways of biosynthesis found in nature—that was absent in the parent proteins. Protein engineering through recombination has also produced chimeric enzymes with new function in members of a group of proteins known as the cytochrome P450 family, which in humans is involved in detoxifying foreign compounds like drugs, food additives and preservatives.

Cancer therapy

Cancer cells with BRCA mutations have deficiencies in homologous recombination, and drugs to exploit those deficiencies have been developed and used successfully in clinical trials. Olaparib, a PARP1 inhibitor, shrunk or stopped the growth of tumors from breast, ovarian and prostate cancers caused by mutations in the BRCA1 or BRCA2 genes, which are necessary for HR. When BRCA1 or BRCA2 is absent, other types of DNA repair mechanisms must compensate for the deficiency of HR, such as base-excision repair (BER) for stalled replication forks or non-homologous end joining (NHEJ) for double strand breaks. By inhibiting BER in an HR-deficient cell, olaparib applies the concept of synthetic lethality to specifically target cancer cells. While PARP1 inhibitors represent a novel approach to cancer therapy, researchers have cautioned that they may prove insufficient for treating late-stage metastatic cancers. Cancer cells can become resistant to a PARP1 inhibitor if they undergo deletions of mutations in BRCA2, undermining the drug's synthetic lethality by restoring cancer cells' ability to repair DNA by HR.