FEATURE ARTICLE
Tracking Down a Cheating Gene
Some genes will play dirty to gain a selective advantage
Barry Ganetzky
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As this was the first time that the molecular defect in any meiotic-drive system had been identified, it represented a major step forward. Now that we know that Sd encodes an altered RanGAP protein and that RanGAP is important for molecular trafficking across the nuclear membrane, we can start to speculate on possible scenarios for segregation distortion.
We know that chromosome condensation is necessary for spermatids to mature into viable sperm and that this step fails in distorting males when a sensitive Responder is present in spermatid nuclei. Various sperm-specific chromosomal proteins are required to bring about chromosome condensation. The messenger RNAs encoding these proteins must be exported from the nucleus to the cytoplasm where the proteins are manufactured. After their synthesis, the proteins must then be imported into the nucleus. Thus, we can readily imagine how a perturbation in nuclear transport could result in failed chromosome condensation by affecting the production or nuclear abundance of these proteins. Because this extreme compaction of chromosomes happens exclusively during sperm development, this probably explains why sperm but not eggs are affected by Sd.
Our current studies are aimed at trying to unravel how the truncated RanGAP interferes with nuclear transport. Kusano, in my laboratory, has demonstrated that the mutant RanGAP still retains its normal biochemical activity. However, for various reasons we suspect that the truncated RanGAP could be mislocalized within the cell. This is important because the mechanism of nuclear transport is critically dependent on the normal cytoplasmic localization of RanGAP activity. Nuclear transport would be disrupted if RanGAP were within the nucleus. Merrill has obtained some tantalizing preliminary evidence indicating that the truncated RanGAP is indeed mislocalized to the nucleus during some stages of sperm development. These results need to be confirmed, and additional experiments are required to determine whether this is what is ultimately responsible for the failed chromosome condensation that occurs in dysfunctional sperm. Experiments to address these issues are under way.
What is more difficult to understand is why in a distorting male, only those spermatids that receive a Rsps- or Rspss-bearing chromosome are affected by Sd. Why do the Rspi-bearing spermatids still develop normally? One possibility is that, for some reason, the truncated RanGAP is mislocalized to the nucleus only in spermatids containing Rsps or Rspss.
Another possibility is that the spermatids containing Rsps- or Rspss-bearing chromosomes might be more susceptible to a defect in nuclear transport because they contain many more copies of a particular DNA sequence than do Rspi-containing spermatids. These sequences could preferentially bind to the proteins that facilitate chromosome condensation. If the amount of these proteins is limited owing to a defect in nuclear transport, there may not be enough to condense the rest of the chromosomes inside the nucleus.
Of course, much more work is needed to test these ideas. Segregation distortion has been a puzzle for more than 40 years, and it is probably too much to expect that it will fully give up its remaining secrets any time soon. Nevertheless, for the first time we have been able to identify the underlying molecular defect in a meiotic-drive system.
This advance has offered us an entirely new perspective on segregation distortion, enabling us to frame specific questions and pointing us in the direction of further investigations. It is exciting and satisfying that we have been able to establish a link between SD and nuclear transport, a process of fundamental biological importance and currently one of the most vigorously studied areas of cell biology. Undoubtedly, efforts to elucidate the mechanisms of distortion at the cellular level will benefit from the studies of nuclear transport in other experimental systems. Conversely, future studies of SD should not only resolve the remaining questions about its mechanism, but may also offer novel insights into the important process of nuclear transport as well.
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