C. elegans CYK-4: A Rho family gtpase activating protein (GAP) required for central spindle formation and cytokinesis.

During cytokinesis of animal cells, the mitotic spindle plays at least two roles. Initially, the spindle positions the contractile ring. Subsequently, the central spindle, which is composed of microtubule bundles that form during anaphase, promotes a late step in cytokinesis. How the central spindle assembles and functions in cytokinesis is poorly understood. The cyk-4 gene has been identified by genetic analysis in Caenorhabditis elegans. Embryos from cyk-4t1689ts mutant hermaphrodites initiate, but fail to complete, cytokinesis. These embryos also fail to assemble the central spindle. The cyk-4 gene encodes a GTPase activating protein (GAP) for Rho family GTPases. CYK-4 activates GTP hydrolysis by RhoA, Rac1, and Cdc42 in vitro. RNA-mediated interference of RhoA, Rac1, and Cdc42 indicates that only RhoA is essential for cytokinesis and, thus, RhoA is the likely target of CYK-4 GAP activity for cytokinesis. CYK-4 and a CYK-4:GFP fusion protein localize to the central spindle and persist at cell division remnants. CYK-4 localization is dependent on the kinesin-like protein ZEN-4/CeMKLP1 and vice versa. These data suggest that CYK-4 and ZEN-4/CeMKLP1 cooperate in central spindle assembly. Central spindle localization of CYK-4 could accelerate GTP hydrolysis by RhoA, thereby allowing contractile ring disassembly and completion of cytokinesis (Jantsch-Plunger, 2000).

Central spindle assembly and cytokinesis in C. elegans require a kinesin-like protein/RhoGAP complex with microtubule bundling activity

A late step in cytokinesis requires the central spindle, which forms during anaphase by the bundling of antiparallel nonkinetochore microtubules. Microtubule bundling and completion of cytokinesis in C. elegans requires ZEN-4/CeMKLP-1, a kinesin-like protein, and CYK-4, which contains a RhoGAP domain. CYK-4 and ZEN-4 exist in a complex in vivo that can be reconstituted in vitro. The N terminus of CYK-4 binds the central region of ZEN-4, including the neck linker. Genetic suppression data prove the functional significance of this interaction. An analogous complex, containing equimolar amounts of a CYK-4 ortholog and MKLP-1, has been purified from mammalian cells. Biochemical studies indicate that this complex, named centralspindlin, is a heterotetramer. Centralspindlin, but not its individual components, strongly promotes microtubule bundling in vitro (Mishima, 2002).

Genetic and biochemical suppression of CYK-4(S15L) by mutations in ZEN-4 strongly argues that the interaction between CYK-4 and ZEN-4 is critical for CYK-4 function. Indeed, in vivo, the majority of ZEN-4 is in a complex with CYK-4. Surprisingly, the primary structure of the N-terminal region of CYK-4 is not well conserved. However, the function is likely conserved, since the N-terminal 120 residues of HsCYK-4 are sufficient to localize in cultured mammalian cells. In addition, the ortholog of CYK-4 is required for cytokinesis in mammalian cells and in mouse embryos. Moreover, five pieces of evidence together indicate that HsCYK-4 and MKLP-1 are in a tetrameric complex. (1) Immunopurification of HsCYK-4 and MKLP-1 recovered equimolar amounts of the two proteins. (2) These two proteins comigrate on sucrose density gradients with a similar S value as observed for the C. elegans proteins. (3) The two proteins comigrate on a gel filtration column and their fractionation behavior suggests a native molecular mass for the complex of ~300 kDa. (4) Upon reconstitution of the complex in insect cells, equimolar amounts of CYK-4 copurified with ZEN-4. (5) Both CYK-4 and ZEN-4 are able to individually multimerize. Previous determinations of the native molecular mass of MKLP-1 have been reported, and the values are similar to those presented here. These studies had not taken the presence of CYK-4 into consideration, and therefore the data was interpreted to indicate that MKLP-1 exists as a homotetramer. In contrast, the results of this study indicate that the centralspindlin complex is a tetramer containing two molecules of the ZEN-4/MKLP-1 kinesin and two molecules of the CYK-4 RhoGAP (Mishima, 2002).

CYK-4 binds to ZEN-4 in a particularly interesting domain of this kinesin family member. A critical element of the kinesin molecule lies just C-terminal to the catalytic core -- the neck linker region. ATP binding to one catalytic core induces a large conformational change in the neck linker region that causes the other catalytic core present in the kinesin dimer to extend toward the adjacent tubulin subunit situated on the plus side of the initial microtubule contact. CYK-4 binds to a region of ZEN-4 that includes the neck linker region. In conventional kinesin, the neck linker corresponds to a region 15 amino acids long that connects the catalytic core of kinesin to the coiled-coil stalk domain. Among the family of KIN-N motors, the MKLP-1 subfamily has a distinctly divergent neck linker region; it lacks several nearly invariant residues, and the linker between the catalytic core and the coiled-coil region is about five times longer than in other members of the KIN-N family. The divergence of this critical region of the kinesin suggests that MKLP-1-mediated microtubule motility may differ from that of other kinesins. Moreover, since CYK-4 binds to the neck linker region of ZEN-4, it is possible that CYK-4 binding may in fact regulate ZEN-4 motor activity (Mishima, 2002).

The centralspindlin complex appears to contain two kinesin motors and two RhoGAP molecules. Since most kinesin motors are dimers in which both catalytic cores interact with a single microtubule protofilament, the subunit composition for the complex does not easily explain how microtubule bundling is achieved. If the two kinesin subunits of centralspindlin bind to the same microtubule protofilament, how might microtubule crosslinking occur? At this point, at least three possible, though not mutually exclusive, mechanisms can be invisioned (Mishima, 2002).

The first possibility is that there is an additional microtubule binding site elsewhere in the CYK-4/ZEN-4 complex. No additional binding site has been identified yet in CYK-4, nor have MKLP-1, ZEN-4, or Pav been found to have an additional microtubule binding site. However, it has been shown that MKLP-1 interacts differently with microtubules than it does with most kinesin-like proteins. Specifically, ATP is usually sufficient to elute most kinesins from microtubules, but in the case of MKLP-1, both ATP and high salt are required (Kuriyama, 1994; Nislow, 1992). Thus it is possible that MKLP-1 interacts with two microtubules, one by the motor domain and another via a different interaction surface. Consistent with this possibility is the finding that Rab6KIFL kinesin, which is quite similar to MKLP-1 in primary structure as well as in its localization and proposed function, contains a second microtubule binding activity in the C-terminal half of the molecule. However, this possibility does not explain why CYK-4 is required for central spindle assembly (Mishima, 2002 and references therein).

The second alternative is that MKLP-1 forms higher order structures than that of the tetramer. This possibility gains some support from the biochemical characterization of centralspindlin. In vitro, centralspindlin forms higher order complexes at physiological ionic strength. Further support of this possibility comes from localization studies; in both C. elegans and mammalian cells, ring-like structures are found that have been termed division remnants. These persist in the cell cortex after division. These remnants appear to be large aggregates of centralspindlin, which are not in obvious association with microtubule bundles. Higher order oligomers could potentially form in early anaphase and promote microtubule bundling. This model is conceptually similar to the mechanism by which myosin II filaments promote the formation of antiparallel bundles of actin filaments (Mishima, 2002).

The third possibility is that, unlike most N-terminal kinesins, the two catalytic cores of the kinesin subunits in the centralspindlin complex could bind to different microtubules. This would not be without precedent, in that the KIN-N KIF1A moves processively along a microtubule using a single head. The association of the two catalytic cores of MKLP-1 with different microtubules is made feasible by the fact that the linker region between the catalytic core and the coiled-coil domain is much longer than that present in most N-terminal kinesins. Perhaps CYK-4 ensures that the two motor domains are oriented in such a way to bind to antiparallel microtubules. Structural analysis of centralspindlin will help to define the mechanism of antiparallel microtubule bundling (Mishima, 2002).

Several lines of evidence suggest that centralspindlin may be regulated by at least two different kinases. Genetic analysis indicates that Pav localization requires Polo kinase. In addition, the Aurora-B/Incenp complex is also required for the stable localization of centralspindlin in C. elegans embryos, and an in vitro biochemical interaction has been detected between Aurora-B (AIR-2) and ZEN-4. Reconstitution of central spindle assembly in vitro will allow the role of these and other regulators of centralspindlin to be dissected (Mishima, 2002 and references therein).

Important roles of Vilse in dendritic architecture and synaptic plasticity

Vilse/Arhgap39 is a Rho GTPase activating protein (RhoGAP) and utilizes its WW domain to regulate Rac/Cdc42-dependent morphogenesis in Drosophila and murine hippocampal neurons. However, the function of Vilse in mammalian dendrite architecture and synaptic plasticity remained unclear. This study aimed to explore the possible role of Vilse in dendritic structure and synaptic function in the brain. Homozygous knockout of Vilse resulted in premature embryonic lethality in mice. Changes in dendritic complexity and spine density were noticed in hippocampal neurons of Camk2a-Cre mediated forebrain-specific Vilse knockout (VilseDelta/Delta) mice. VilseDelta/Delta mice displayed impaired spatial memory in water maze and Y-maze tests. Electrical stimulation in hippocampal CA1 region revealed that the synaptic transmission and plasticity were defected in VilseDelta/Delta mice. Collectively, these results demonstrate that Vilse is essential for embryonic development and required for spatial memory (Lee, 2017).

Mice with a homozygous gene trap vector insertion in mgcRacGAP die during pre-implantation development

In a phenotypic screen in mice using a gene trap approach in embryonic stem cells, a recessive loss-of-function mutation has been identified in the mgcRacGAP gene. Maternal protein is present in the oocyte, and mgcRacGAP gene transcription starts at the four-cell stage and persists throughout mouse pre-implantation development. Total mgcRacGAP deficiency results in pre-implantation lethality. Such E3.5 embryos display a dramatic reduction in cell number, but undergo compaction and form a blastocoel. At E3.0-3.5, binucleated blastomeres in which the nuclei are partially interconnected are frequently observed, suggesting that mgcRacGAP is required for normal mitosis and cytokinesis in the pre-implantation embryo. All homozygous mutant blastocysts fail to grow out on fibronectin-coated substrates, but a fraction of them can still induce decidual swelling in vivo. The mgcRacGAP mRNA expression pattern in post-implantation embryos and adult mouse brain suggests a role in neuronal cells. These results indicate that mgcRacGAP is essential for the earliest stages of mouse embryogenesis, and add evidence that CYK-4-like proteins also play a role in microtubule-dependent steps in the cytokinesis of vertebrate cells. In addition, the severe phenotype of null embryos indicates that mgcRacGAP is functionally non-redundant and cannot be substituted by other GAPs during early cleavage of the mammalian embryo (Van de Putte, 2001).

Phosphorylation by Aurora B converts MgcRacGAP to a RhoGAP during cytokinesis

Cell division is finely controlled by various molecules including small G proteins and kinases/phosphatases. Among these, Aurora B, RhoA, and the GAP MgcRacGAP have been implicated in cytokinesis, but their underlying mechanisms of action have remained unclear. MgcRacGAP is shown to colocalize with Aurora B and RhoA, but not Rac1/Cdc42, at the midbody. Aurora B phosphorylates MgcRacGAP on serine residues and this modification induces latent GAP activity toward RhoA in vitro. Expression of a kinase-defective mutant of Aurora B disrupts cytokinesis and inhibits phosphorylation of MgcRacGAP at Ser387, but not its localization to the midbody. Overexpression of a phosphorylation-deficient MgcRacGAP-S387A mutant, but not phosphorylation-mimic MgcRacGAP-S387D mutant, arrests cytokinesis at a late stage and induces polyploidy. Together, these findings indicate that during cytokinesis, MgcRacGAP, a GAP for Rac/Cdc42, is functionally converted to a RhoGAP through phosphorylation by Aurora B (Minoshima, 2003).

MgcRacGAP controls the assembly of the contractile ring and the initiation of cytokinesis

In anaphase, microtubules provide a specification signal for positioning of the contractile ring. However, the nature of the signal remains unknown. The small GTPase Rho is a potent regulator of cytokinesis but the involvement of Rho in contractile ring formation is disputed. Rho is shown to serve as a microtubule-dependent signal that specifies the position of the contractile ring. Rho translocates to the equatorial region before furrow ingression. The Rho specific inhibitor C3 exoenzyme and siRNA to the Rho GDP/GTP exchange factor (GEF), ECT2, prevent this translocation and disrupt contractile ring formation, indicating that active Rho is required for contractile ring formation. ECT2 forms a complex with the GTPase activating protein (GAP), MgcRacGAP, and the kinesin-like protein, MKLP1, at the central spindle and the localization of ECT2 at the central spindle depends on MgcRacGAP and MKLP1. In addition, it is shown that the bundled microtubules direct Rho-mediated signaling molecules to the furrowing site and regulate furrow formation. This study provides strong evidence for the requirement of Rho-mediated signaling in contractile ring formation (Kamijo, 2005).

Initiation of cytokinesis requires the establishment of the cleavage plane, the assembly of the contractile ring, and the ingression of the cleavage furrow. MgcRacGAP, a GTPase-activating protein for RhoA, is required for cytokinesis, but the mechanism of its action remains unknown. MgcRacGAP is required for the assembly of anillin and myosin into the contractile ring. In addition, MgcRacGAP is required for the localized activation of myosin through the RhoA-mediated phosphorylation of the myosin regulatory light chain. Cells with MgcRacGAP RNA interference (RNAi) fail cytokinesis without any ingression of the cleavage furrow. Paradoxically, MgcRacGAP, a GTPase-activating protein, associates during cytokinesis with ECT2, a guanine nucleotide exchange factor for RhoA, and the localization of ECT2 to both the central spindle and the contractile ring depends on MgcRacGAP. Knockdown of ECT2 phenocopies that of MgcRacGAP. It is concluded that MgcRacGAP controls the initiation of cytokinesis by regulating ECT2, which in turn induces the assembly of the contractile ring and triggers the ingression of the cleavage furrow (Zhao, 2005).

Cleavage furrow formation marks the onset of cell division during early anaphase. The small GTPase RhoA and its regulators ECT2 and MgcRacGAP have been implicated in furrow ingression in mammalian cells, but the signaling upstream of these molecules remains unclear. The inhibition of cyclin-dependent kinase (Cdk)1 is sufficient to initiate cytokinesis. When mitotically synchronized cells are treated with the Cdk-specific inhibitor BMI-1026, the initiation of cytokinesis is induced precociously before chromosomal separation. Cytokinesis is also induced by the Cdk1-specific inhibitor purvalanol A but not by Cdk2/Cdk5- or Cdk4-specific inhibitors. Consistent with initiation of precocious cytokinesis by Cdk1 inhibition, introduction of anti-Cdk1 monoclonal antibody results in cells with aberrant nuclei. Depolymerization of mitotic spindles by nocodazole inhibits BMI-1026-induced precocious cytokinesis. However, in the presence of a low concentration of nocodazole, BMI-1026 induces excessive membrane blebbing, which appears to be caused by formation of ectopic cleavage furrows. Depletion of ECT2 or MgcRacGAP by RNA interference abolishes both of the phenotypes (precocious furrowing after nocodazole release and excessive blebbing in the presence of nocodazole). RNA interference of RhoA or expression of dominant-negative RhoA efficiently reduces both phenotypes. RhoA was localized at the cleavage furrow or at the necks of blebs. It is proposed that Cdk1 inactivation is sufficient to activate a signaling pathway leading to cytokinesis, which emanates from mitotic spindles and is regulated by ECT2, MgcRacGAP, and RhoA. Chemical induction of cytokinesis will be a valuable tool to study the initiation mechanism of cytokinesis (Niiya, 2005).

In anaphase, the spindle dictates the site of contractile ring assembly. Assembly and ingression of the contractile ring involves activation of myosin-II and actin polymerization. This is triggered by the GTPase RhoA. In many cells, the central spindle affects division plane positioning via unknown molecular mechanisms. This study dissects furrow formation in human cells and shows that the RhoGEF ECT2 is required for cortical localization of RhoA and contractile ring assembly. ECT2 concentrates on the central spindle by binding to centralspindlin. Depletion of the centralspindlin component MKLP1 prevents central spindle localization of ECT2; however, RhoA, F-actin, and myosin still accumulate on the equatorial cell cortex. Depletion of the other centralspindlin component, CYK-4/MgcRacGAP, prevents cortical accumulation of RhoA, F-actin, and myosin. CYK-4 and ECT2 interact, and this interaction is cell cycle regulated via ECT2 phosphorylation. Thus, central spindle localization of ECT2 assists division plane positioning and the CYK-4 subunit of centralspindlin acts upstream of RhoA to promote furrow assembly (Yuce, 2005).

Although Rho regulates cytokinesis, little was known about the functions in mitosis of Cdc42 and Rac. It has been suggested that Cdc42 works in metaphase by regulating bi-orient attachment of spindle microtubules to kinetochores. The role of Cdc42 has been confirmed by RNA interference and the mechanisms for activation and down-regulation of Cdc42 has been identified. Using a pull-down assay, it was found that the level of GTP-Cdc42 elevates in metaphase, whereas the level of GTP-Rac does not change significantly in mitosis. Overexpression of dominant-negative mutants of Ect2 and MgcRacGAP, a Rho GTPase guanine nucleotide exchange factor and GTPase activating protein, respectively, or depletion of Ect2 by RNA interference suppresses this change of GTP-Cdc42 in mitosis. Depletion of Ect2 also impairs microtubule attachment to kinetochores and causes prometaphase delay and abnormal chromosomal segregation, as does depletion of Cdc42 or expression of the Ect2 and MgcRacGAP mutants. These results suggest that Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis (Oceguera-Yanez, 2005).

MgcRacGAP is expressed in male germ cells

In a search for new partners of the activated form of Rac GTPase, a human cDNA has been isolated through a two-hybrid cloning procedure encoding a new GTPase-activating protein (GAP) for Rho family GTPases. A specific mRNA of 3.2 kilobases was detected in low abundance in many cell types and found highly expressed in testis. A protein of the predicted size 58 kDa, which was called MgcRacGAP, was detected in human testis as well as in germ cell tumor extracts by immunoblotting with antibodies specific to recombinant protein. In vitro, the GAP domain of MgcRacGAP strongly stimulates Rac1 and Cdc42 GTPase activity but is almost inactive on RhoA. N-terminal to its GAP domain, MgcRacGAP contains a cysteine-rich zinc finger-like motif characteristic of the Chimaerin family of RhoGAPs. The closest homolog of MgcRacGAP is RotundRacGAP, a product of the Drosophila rotund locus. In situ hybridization experiments in human testis demonstrate a specific expression of mgcRacGAP mRNA in spermatocytes similar to that of rotundRacGAP in Drosophila testis. Therefore, protein sequence similarity and analogous developmental and tissue specificities of gene expression support the hypothesis that RotundRacGAP and MgcRacGAP have equivalent functions in insect and mammalian germ cells. Since rotundRacGAP deletion leads to male sterility in the fruit fly, the mgcRacGAP gene may prove likewise to play a key role in mammalian male fertility (Toure, 1998).

MgcRacGAP is involved in the control of growth and differentiation of hematopoietic cells

In a search for key molecules that prevent murine M1 leukemia cells from undergoing interleukin (IL)-6-induced differentiation into macrophages, an antisense complementary DNA (cDNA) that encodes full-length mouse MgcRac-GTPase-activating protein (GAP) was isolated through functional cloning. Forced expression of this antisense cDNA profoundly inhibits IL-6-induced differentiation of M1 cells into macrophage lineages. A full-length human MgcRacGAP cDNA was isolated, that encodes an additional N-terminal polypeptide of 105 amino acid residues compared with the previously published human MgcRacGAP. In human HL-60 leukemic cells, overexpression of the full-length form of human MgcRacGAP alone induces growth suppression and macrophage differentiation associated with hypervacuolization and de novo expression of the myelomonocytic marker CD14. Analyses using a GAP-inactive mutant and 2 deletion mutants of MgcRacGAP indicate that the GAP activity is dispensable, but the myosin-like domain and the cysteine-rich domain are indispensable for growth suppression and macrophage differentiation. The present results indicate that MgcRacGAP plays key roles in controlling growth and differentiation of hematopoietic cells through mechanisms other than regulating Rac GTPase activity (Kawashima, 2000).

A GTPase-activating protein binds STAT3 and is required for IL-6-induced STAT3 activation and for differentiation of a leukemic cell line

A guanosine triphosphatase (GTPase)-activating protein (GAP) male germ cell Rac GAP (MgcRacGAP) enhances interleukin-6 (IL-6)-induced macrophage differentiation of murine M1 leukemia cells. Later, MgcRacGAP plays crucial roles in cell division. However, how MgcRacGAP enhanced IL-6-induced differentiation has remained elusive. This study shows that MgcRacGAP enhances IL-6-induced differentiation through enhancement of STAT3 activation. MgcRacGAP, Rac, and STAT3 form a complex in IL-6-stimulated M1 cells, where MgcRacGAP interacts with Rac1 and STAT3 through its cysteine-rich domain and GAP domain. In reporter assays, the wild-type MgcRacGAP enhances transcriptional activation of STAT3 while a GAP-domain deletion mutant (DeltaGAP) does not significantly enhance it, suggesting that the GAP domain is required for enhancement of STAT3-dependent transcription. Intriguingly, M1 cells expressing DeltaGAP have no effect on the differentiation signal of IL-6, while forced expression of MgcRacGAP renders M1 cells hyperresponsive to the IL-6-induced differentiation. Moreover, knockdown of MgcRacGAP by RNA interference profoundly suppresses STAT3 activation, implicating MgcRacGAP in the STAT3-dependent transcription. All together, these data not only reveal an important role for MgcRacGAP in STAT3 activation, but also demonstrate that MgcRacGAP regulates IL-6-induced cellular differentiation in which STAT3 plays a pivotal role (Tonozuka, 2004).

Cell type-specific regulation of RhoA activity during cytokinesis

Rho family GTPases play pivotal roles in cytokinesis. By using probes based on the principle of fluorescence resonance energy transfer (FRET), it has been shown that in HeLa cells RhoA activity increases with the progression of cytokinesis. In Rat1A cells RhoA activity remains suppressed during most of the cytokinesis. Consistent with this observation, the expression of C3 toxin inhibits cytokinesis in HeLa cells but not in Rat1A cells. Furthermore, the expression of a dominant negative mutant of Ect2, a Rho GEF, or Y-27632, an inhibitor of the Rho-dependent kinase ROCK, inhibits cytokinesis in HeLa cells but not in Rat1A cells. In contrast to the activity of RhoA, the activity of Rac1 is suppressed during cytokinesis and starts increasing at the plasma membrane of polar sides before the abscission of the daughter cells in both HeLa and Rat1A cells. This type of Rac1 suppression is shown to be essential for cytokinesis because a constitutively active mutant of Rac1 induces a multinucleated phenotype in both HeLa and Rat1A cells. Moreover, the involvement of MgcRacGAP/CYK-4 in this suppression of Rac1 during cytokinesis has been shown by the use of a dominant negative mutant. Because ML-7, an inhibitor of myosin light chain kinase, delays the cytokinesis of Rat1A cells and because Pak, a Rac1 effector, is known to suppress myosin light chain kinase, the suppression of the Rac1-Pak pathway by MgcRacGAP may play a pivotal role in the cytokinesis of Rat1A cells (Yoshizaki, 2004). Med ID: 25486361

SHCBP1 is required for midbody organization and cytokinesis completion

The centralspindlin complex, which is composed of MKLP1 and MgcRacGAP, is one of the crucial factors involved in cytokinesis initiation. Centralspindlin is localized at the middle of the central spindle during anaphase and then concentrates at the midbody to control abscission. A number of proteins that associate with centralspindlin have been identified. These associating factors regulate furrowing and abscission in coordination with centralspindlin. A recent study identified a novel centralspindlin partner, called Nessun Dorma, which is essential for germ cell cytokinesis in Drosophila melanogaster. SHCBP1 is a human ortholog of Nessun Dorma that associates with human centralspindlin. This report analyzes the interaction of SHCBP1 with centralspindlin in detail and determined the regions that are required for the interaction. In addition, it was demonstrated that the central region is necessary for the SHCBP1 dimerization. Both MgcRacGAP and MKLP1 are degraded once cells exit mitosis. Similarly, endogenous and exogenous SHCBP1 were degraded with mitosis progression. Interestingly, SHCBP1 expression was significantly reduced in the absence of centralspindlin, whereas centralspindlin expression was not affected by SHCBP1 knockdown. Finally, it was demonstrated that SHCBP1 depletion promotes midbody structure disruption and inhibits abscission, a final stage of cytokinesis. This study gives novel insight into the role of SHCBP in cytokinesis completion (Asano, 2014).

RacGAP50C: Biological Overview | Regulation | Developmental Biology | Effects of Mutation | References

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