Segregation distortion induced by wild-type RanGAP in Drosophila

Abstract

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...

Organization of the sex-ratio Meiotic Drive Region in Drosophila simulans

“…Indeed, as far as we are aware, the only other driver for which we have sufficient genetic resolution, the autosomal Segregation distorter of D. melanogaster, also displays a duplication. In that case, it has been demonstrated that gene dosage alone, either of the key distorter locus or of a modifier locus, can confer drive (Kusano et al 2002).…”

Mutations to the piRNA Pathway ComponentAubergineEnhance Meiotic Drive of Segregation Distorter inDrosophila melanogaster

“…While wild-type RanGAP localizes to the cytoplasm, SdRanGAP is retained in the nucleus due to its truncated NES, potentially altering the GTP gradient required for Ranmediated nuclear transport (Gorlich and Mattaj 1996;Gorlich and Kutay 1999b;Merrill et al 1999;Kalab et al 2002). In the proper genetic background, nuclear localization of even wildtype RanGAP is sufficient to cause distortion, suggesting that nuclear enzymatic activity of RanGAP causes abnormal nuclear retention of Ran cargo and sperm dysfunction in SD (Kusano et al 2001(Kusano et al , 2002.The relative strength of Segregation Distorter chromosomes is dependent upon several modifiers distributed along the second chromosome ( Figure 1A). The best studied of these, Enhancer of SD [E(SD)], is located in the h35 heterochromatic region of chromosome 2L (Ganetzky 1977;Brittnacher and Ganetzky 1984).…”

Defects in nuclear transport enhanceSegregation Distortion

“…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. Rsp exists in several different allelic forms, usually described as: Rsp i , which is insensitive to the action of Sd; Rsp s , which is sensitive to Sd; and Rsp ss , which is "supersensitive" to the action of Sd.…”