Chapter 6 : Genetic Addiction: a Principle of Gene Symbiosis in a Genome

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Observations suggest that the genome is a community of genes that essentially act selfishly and potentially do not have the overall order of the genome as their primary interest. Postsegregational host killing maintains the existence of a genetic element by death. This chapter extracts general rules whereby death is used to govern genomes. It reviews the development of the concept of genetic addiction, and introduces several types of addiction systems. The chapter examines where the addiction modules are located in genomes and how they get there, and discusses their mechanisms of action and their gene expression regulation, which include contributions from structural studies. It sketches various kinds of interactions that take place between addiction systems within a genome and then addresses the central paradox: why a genetic element that is potentially toxic to the genome is ever maintained. The chapter then reviews the evidence that suggests that some forms of genetic addiction have affected genome evolution. Further, the chapter extrapolates these arguments, which are based on bacterial systems, to genome biology in general. Finally, it summarizes the various ways addiction systems can be used in experimental biology, biotechnology, and medicine. The concept of genetic addiction may prove to be one of the most fruitful contributions from plasmid biology to the understanding of life.

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6

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Mobile Genetic Elements
Gene Expression and Regulation
DNA Restriction Enzymes
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Image of Figure 1
Figure 1

The principle of genetic addiction. (A) Once established in a cell, the addiction module is difficult to eliminate because its loss, or some sort of threat to its persistence, leads to cell death. Intact copies of the module survive in the other cells of the clone, (B) Advantage of postsegregational killing in competitive exclusion between genetic elements in a genome. A specific case of postsegregational cell killing shows the fight of the module against an incoming competing genetic element.

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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Image of Figure 2
Figure 2

Stabilization of maintenance of a plasmid by carriage of restriction-modification gene complex and its suppression by M.SsoII. The bacterial cells with a plasmid (RII R*M* [filled circle]; RII R'M* [open circle]) or with two plasmids (RII R*M* and Sso11 R*M* [filled triangle]) were grown in liquid medium after removal of the selection for the RII plasmid (but with selection for the Sso11 plasmid). The culture was continued with appropriate dilutions. Then cells were spread on agar to determine the fraction of viable cells carrying the R11 plasmid. The number of viable cells was used to calculate generation numbers on the horizontal axis. Modified from ( ) with permission of Oxford University Press.

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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Image of Figure 3
Figure 3

A generalized mechanism of genetic addiction. Classification of genetic addiction systems by action of the antitoxin is also included. See text ("Types of Genetic Addiction") for explanation.

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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Image of Figure 4
Figure 4

Three types of genetic addiction. The classification of addiction systems on the basis of the way the antitoxin blocks the activity of the toxin is shown. See text ("Types of Addiction") for explanation.

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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Image of Figure 5
Figure 5

Organization and regulation of addiction modules. A pointed box indicates a gene together with its direction. A thick arrow indicates transcription. The black and gray circle, triangle, and squares indicate gene products. The plus sign indicates a positive effect of the protein on gene expression, while the minus sign indicates a negative effect. See Table 2 and text for references.

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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Image of Figure 6
Figure 6

Contribution of addiction genes to large genome polymorphism, psk: a postsegregational killing gene complex or an addiction module. In A, the boxes indicate open reading frames constituting an operon-like gene cluster. An arrow indicates transcription. In B. a thick arrow indicates a duplicated sequence that is in the order of 100 bp in length. In D, the bent arrows indicate a segment in the order of 10 kbp in length that appears inverted when two genomes are compared. In E, the double lines marked as psk indicate two regions highly homologous with each other and carrying a postsegregational killing module homologue.

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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Figure 7

Postsegregational killing by a restriction-modification module. (A) Restriction enzyme (toxin) and modification methyltransferase (antitoxin). The antitoxin protects the targets of the toxin by methylation. (B) Postsegregational killing by simple dilution. After loss of the restriction-modification gene complex, the toxin (restriction enzyme) and antitoxin (modification enzyme) will become increasingly diluted after cell division. Finally, too few modification enzyme molecules remain to defend all (or sufficiently many) of the recognition sites present on the newly replicated chromosomes. Any one of the remaining molecules of the restriction enzyme can attack these exposed sites. The chromosome breakage then leads to extensive chromosome degradation, and the cell dies unless the breakage is somehow repaired. The chromosome breakage may stimulate recombination and generate a variety of rearranged genomes, some of which might survive.

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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Image of Figure 8
Figure 8

A model for the action of the RelE/RelB system. Genetic organization and regulatory components of the toxinantitoxin operon (left), the site of mRNA cleavage hy RelE (middle), and ribosome rescue by tmRNA (right). Modified from reference with permission of Blackwell Publishing.

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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Image of Figure 9
Figure 9

Interaction between two addiction systems that forces host killing. (A) Invasion and establishment of an addiction module in a new host cell. The regulatory system of the module allows the antitoxin to be expressed first to prevent host cell killing by the toxin. This addiction module thus successfully establishes itself in this new host cell. (B) Superinfection exclusion upon invasion of an addiction module into a cell that harbors another addiction module with similar specificity in its regulatory system. The regulatory system of the resident complex forces the incoming system to express its toxin first. The cell is killed and the establishment of the incoming addiction module is aborted. The resident addiction gene complex survives in the neighboring clonal cells. This represents another example of defense by cell death (see Fig. 1B ).

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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Image of Figure 10
Figure 10

Interaction between two addiction systems that prevents host killing. (A) Postsegregational killing programmed by one addiction system. This addiction molecule can force its maintenance on the host. (B) Inhibition of this postsegregational killing by another addiction system. Antitoxin 2 may inhibit action of toxin 1 after loss of addiction module 1 by interacting with it at the protein level (type A, classical proteic system), by protecting its target (type B. restriction-modification system), or by blocking its gene expression (type C, antisense-RNA-regulated system). Addiction module 1 cannot force its maintenance on the host.

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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Image of Figure 11
Figure 11

The chromosome as a vehicle for mutual addiction among genes. (A) Chromosome breakage by a methylatcd-DNA-specific endonuclease in defense against an invading addiction module. An addiction module (more specifically, a restriction-modification module) enters a cell and starts modifying its target (methylating chromosomal recognition sites). A solitary toxin (a merhylated-DNA-specific endonuclease) senses these changes and triggers cell suicide (by chromosomal cleavage and degradation). The uninfected genome survives in the neighboring clonal cells. (B) Chromosome breakage by an endonuclease in defense against alteration of a gene. Some alteration, such as DNA damage, takes place on gene a in a chromosome. An endonuclease recognizes this alteration and makes a DNA break there. This suicide of gene can lead to loss of all the remaining genes in the chromosome and cell death. The unaltered genome survives in the neighboring clonal cells. Each gene on the chromosome can thus force its maintenance on the genome by postdisturbance cell killing through chromosome breakage. (C) The hypothetical case when each gene is on an independent replication unit. Suicide of one altered gene by DNA breakage cannot lead to loss of all the remaining genes and cell death. A gene thus cannot force its maintenance on the genome. Me, methyl group on the chromosome; a, b, c, gene , gene , gene

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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Figure 12

A genetic addiction hypothesis for the origin of the eukaryotes. Protomitochondriai bacteria entered anaerobic cells to form the ancestral eukaryote cells. The protomitochondria killed the host when there was disturbance to their perpetuation. This host killing resulted in their apparently stable symbiosis with the eukaryote cell. The system of mitochondria-mediated cell death has been inherited in multicellular eukaryotes that include mammals.

Citation: Kobayashi I. 2004. Genetic Addiction: a Principle of Gene Symbiosis in a Genome, p 105-144. In Funnell B, Phillips G (ed), Plasmid Biology. ASM Press, Washington, DC. doi: 10.1128/9781555817732.ch6
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