Truncated RanGAP Encoded by the
            <i>Segregation Distorter</i>
            Locus of
            <i>Drosophila</i>

Merrill, C.; Bayraktaroglu, Leyla; Kusano, Ayumi; Ganetzky, Barry

doi:10.1126/science.283.5408.1742

Cited by 134 publications

(103 citation statements)

References 22 publications

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“…The Podospora [Het-s] prion, the mouse t locus, and the Drosophila Dox and SD loci are among the few examples of molecularly characterized distortion systems (23)(24)(25)(26)(27)(28). Our molecular characterization of the rsk resistance gene has set the foundation for delineating the Neurospora Spore killer system.…”

Section: Discussionmentioning

confidence: 99%

Molecular dissection of Neurospora Spore killer meiotic drive elements

Hammond

Rehard

Xiao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Meiotic drive is a non-Mendelian inheritance phenomenon in which certain selfish genetic elements skew sexual transmission in their own favor. In some cases, progeny or gametes carrying a meiotic drive element can survive preferentially because it causes the death or malfunctioning of those that do not carry it. In Neurospora, meiotic drive can be observed in fungal spore killing. In a cross of Spore killer (Sk) × WT (Sk-sensitive), the ascospores containing the Spore killer allele survive, whereas the ones with the sensitive allele degenerate. Sk-2 and Sk-3 are the most studied meiotic drive elements in Neurospora, and they each theoretically contain two essential components: a killer element and a resistance gene. Here we report the identification and characterization of the Sk resistance gene, rsk (resistant to Spore killer). rsk seems to be a fungal-specific gene, and its deletion in a killer strain leads to self-killing. Sk-2, Sk-3, and naturally resistant isolates all use rsk for resistance. In each killer system, rsk sequences from an Sk strain and a resistant isolate are highly similar, suggesting that they share the same origin. Sk-2, Sk-3, and sensitive rsk alleles differ from each other by their unique indel patterns. Contrary to long-held belief, the killer targets not only late but also early ascospore development. The WT RSK protein is dispensable for ascospore production and is not a target of the spore-killing mechanism. Rather, a resistant version of RSK likely neutralizes the killer element and prevents it from interfering with ascospore development.intragenomic conflict | segregation distortion | selfish elements I n fungi, plants, and animals, not all genes follow the Mendelian pattern of inheritance. Meiotic drive, sometimes referred to as segregation distortion, describes the phenomenon in which certain "cheating" alleles are recovered in more than half of the progeny (1). Two well-known examples are the segregation distorter (SD) in Drosophila and the t haplotype in Mus. In these cases, sperm not carrying the aggressive allele (the drive element) either degenerate (in flies) or become functionally impaired (in mice) (2, 3). In fungi, meiotic drive can be observed as spore killing, in which ascospores (sexual spores) that carry the "Spore killer" element survive preferentially (4). Examples of spore killing can be found in Neurospora sitophila, Neurospora intermedia, Podospora anserina, Gibberella fujikuroi, and Cochliobolus heterostrophus.Spore killer-2 (Sk-2) and Spore killer-3 (Sk-3), which behave similarly, are the most studied distortion elements in Neurospora (5). Originally discovered in N. intermedia, the two spore-killing factors have been introgressed into Neurospora crassa for extensive genetic studies. In a Spore killer (Sk) × WT (Sk-sensitive or Sk S ) cross, regardless of which acts as the female, the four Skcontaining spores are black (B) and viable, whereas the four Sksensitive spores are white (W) and inviable. Manifestation of killing does not occur until late ascospore de...

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Section: Discussionmentioning

confidence: 99%

Molecular dissection of Neurospora Spore killer meiotic drive elements

Hammond

Rehard

Xiao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Sd-RanGAP differs from its wild-type counterpart by a C-terminal deletion of 234 aa (13), which confers this protein with dominant neomorphic properties. Although Sd-RanGAP appears to retain essentially normal enzymatic activity, its subcellular distribution is markedly altered, and substantial amounts of the mutant protein inappropriately localize to nuclei (ref.…”

Section: Overexpression Of Wild-type Rangap In Male Germ Line Causesmentioning

confidence: 99%

Segregation distortion induced by wild-type RanGAP in Drosophila

Kusano

Staber²,

Ganetzky³

2002

Proc. Natl. Acad. Sci. U.S.A.

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Segregation Distorter (SD) is a meiotic drive system in Drosophila that causes preferential transmission of the SD chromosome from SD͞SD ؉ males owing to the induced dysfunction of SD ؉ spermatids. The key distorter locus, Sd, is a dominant neomorphic allele encoding a truncated, but enzymatically active, RanGAP (RanGTPase-activating protein) whose nuclear mislocalization underlies distortion by disrupting the Ran signaling pathway. Here, we show that even wild-type RanGAP can cause segregation distortion when it is overexpressed in the male germ line or when the gene dosage of a particular modifier locus is increased. Both manipulations result in substantial nuclear accumulation of RanGAP. Distortion can be suppressed by overexpression of Ran or Ran guanine nucleotide exchange factor (RanGEF) in the male germ line, indicating that the primary consequence of nuclear mislocalization of RanGAP is reduction of intranuclear RanGTP levels. These results prove that segregation distortion does not depend on any unique properties of the mutant RanGAP encoded by Sd and provide a unifying explanation for the occurrence of distortion in a variety of experimental situations.A fundamental principle of Mendelian genetics is the equal transmission of both homologues or alleles from a heterozygous pair. Nonetheless, meiotic drive systems, in which this principle is regularly violated by the preferential transmission of a particular chromosome or allele at the expense of its partner, exist in nature (1). Segregation distorter (SD) is a naturally occurring meiotic drive system located on the second chromosome of Drosophila melanogaster (2-4). SD͞SD ϩ males transmit the SD chromosome to almost 100% of the progeny. Distortion at full strength requires not only the primary locus, Sd, but also several upward modifiers including Enhancer of SD [E(SD)], Modifier of SD [M(SD)], and Stabilizer of SD [St(SD)] (2, 3, 5-7).The target of Sd and the upward modifiers is the Responder (Rsp) locus: chromosomes that carry a sensitive (Rsp s ) or supersensitive (Rsp ss ) allele of Responder are sensitive to the action of SD, whereas those carrying an insensitive allele (Rsp i ) are resistant (6,(8)(9)(10). The basic mechanism of distortion is sperm dysfunction, which involves a failure of chromatin condensation in SD ϩ -bearing spermatids, leading to subsequent defects in spermatid elongation and maturation (11,12).Sd, a dominant neomorphic mutation, encodes a truncated RanGTPase-activating protein (RanGAP) lacking 234 aa at the C terminus (Sd-RanGAP; ref. 13). Ran is a small GTPase located predominantly in the nucleus. Along with its cofactors, RanGAP and RanGEF (Ran guanine nucleotide exchange factor), Ran is essential for nuclear transport (14) as well as for other nuclear functions, including cell cycle regulation, mitotic spindle formation, and postmitotic nuclear envelope assembly (15-17). The cytoplasmic localization of RanGAP and the nuclear localization of RanGEF establish a concentration gradient of RanGTP across the nuclear envelope tha...

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“…16 In contrast, the mutant form of RanGAP encodes a truncated RanGAP that is missing one of the NES sequences. 17,18 In Sd mutants RanGAP is enzymatically active and present inside of the nucleus, and it is this mis-localization that causes the observed segregation distortion. 18,19 The Rsp locus "responds" to the presence of the SD chromosome.…”

Section: Introductionmentioning

confidence: 99%