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How chromosomes 'cheat' to become an egg
Chromosomes can 'cheat,' biasing the chance that they will make it into a sex cell. Biologists show how this bias arises in female cells, detecting molecular signals that create an asymmetry in the machinery that drives meiosis, the cell-division process that gives rise to gametes.
Each of your cells contains two copies of 23 chromosomes, one inherited from your father and one from your mother. Theoretically, when you create a gamete - a sperm or an egg - each copy has a 50-50 shot at being passed on. But the reality isn't so clearcut.
Scientists have observed that chromosomes can "cheat," biasing the chance that they will make it into a sex cell. Now, a team from the University of Pennsylvania has shown how this bias arises in female cells. With careful observation and experiments with mouse oocytes, the precursors of eggs, they've detected molecular signals that create an asymmetry in the machinery that drives meiosis, the cell-division process that gives rise to gametes. Certain chromosomes, the researchers found, exploit this asymmetry to move themselves over to the "right" side of a cell during division and wind up in the egg.
By casting light on this poorly understood facet of meiotic cell division, the scientists hope to understand how mistakes happen. Errors in chromosomes segregation during meiosis, are the root cause of some miscarriages as well as conditions such as Down's syndrome.
"If we understand how these selfish elements are exploiting the mechanics of meiosis, then we'll understand more deeply how that process works in the first place."
The study appears in the journal Science.
For decades, scientists have watched as genetic elements appear to compete during meiosis, with some genes getting transferred at a consistently higher rate than chance would predict. The term for this biased transmission is "meiotic drive."
Lampson: "Usually we think selfish genes happen at the level of natural selection and selection of the fittest. That might mean a gene which makes you live longer or reproduce more or kill your enemies will be more likely to be passed on. But we need also think about selfishness at the level of the gene. In that context, genes are competing with each other to get into the gamete. And while we had evidence that this could happen, we didn't really understand how it did happen."
For biased transmission to occur, the team reasoned it must be enabled by the machinery of cell division. In the case of females, the final stage of meiosis leads to the creation of one cell that becomes the viable egg and another cell called a polar body, with only a small amount of cytoplasm along with the haploid chromosome left from the split.
The researchers chose to focus on the cell-division machinery, studying the meiotic spindle, the structure composed of microtubules that attaches to chromosomes, pulling them to opposite sides of a cell before it divides.
Looking at microtubules in mouse oocytes, they found a lopsided distribution of a modification called tyrosination: The egg side of the cell had less of this modification than the other side, closer to what is called the cortex. This asymmetry was only present at the stage of meiosis when the spindle moves toward the cortex from the middle of the cell.
"That told us that whatever signal is setting up the tyrosine modification is coming from the cortex," Lampson said. "The next question is, What is that signal?"
The researchers already had some information about molecules that increase in expression on the cortical side of the cell, including one called CDC42. To test whether this molecule contributed to the asymmetrical tyrosination, the researchers used an experimental system that Lampson and Chenoweth had devised previously that uses a light-sensitive assay to selectively enrich CDC42 on one side of the pole. Their results suggested that CDC42 was responsible, at least in part, for inducing the tyrosination asymmetry and thus the asymmetry of the spindle in the dividing cell.
Having established that asymmetry exists and how it arises, the Penn researchers set out to show that this asymmetry enables chromosomes to cheat. They did so by focusing on centromeres, the region of a chromosome that attaches to the spindle. Crossing two strains of mice, they wound up with animals that possessed two types of centromeres in each of their cells, one bigger and one smaller.
From earlier work by the group, they knew that the larger centromeres were known to transmit preferentially to the gametes. In the current work, they confirmed that the bigger, "stronger" centromeres were indeed more likely to go toward the pole of the cell that would become the egg.
When the researchers abolished the spindle asymmetry by mutating CDC42 and other targets, the bias in centromere orientation disappeared.
"That connects the spindle asymmetry to the idea of chromosomes or centromeres actually cheating," Lampson said.
But this result also raised the question of when the centromeres became biased in their orientation, as the spindle starts out in the middle of the cell, at which point centromeres are already attached in an unbiased fashion. The asymmetry and biased centromere attachment occur later.
Enter the flipping centromere. Using live imaging of mouse oocytes, the researchers found that the "stronger" centromeres were more likely to detach from the spindle than weaker centromeres and were especially likely to detach if they were oriented to the cortical side of the cell, presumably in order to flip and reorient themselves to the egg pole of the cell. The weaker centromeres only rarely detached and showed no preference for one side of the cell or the other.
"If you're a selfish centromere and you're facing the wrong way, you need to let go so you can face the other way," Lampson said. "That's how you 'win.'"
In future work, Lampson and his team hope to further explore what characteristics of the centromeres make them strong or weak.
"This work gave us some good information about biased transmission of centromeres, but it also brings up a ton of other questions," Lampson said. "Why do our centromeres look the way they do, and how do they evolve to win these competitions? These are fundamental biological questions that we still don't know a lot about."
How selfish genes get their way
At the core of Mendelian genetics is the concept that gametes are equally likely to carry either of the two parental copies of a gene. Selfish genetic elements can cheat, however, by subverting Mendelian segregation to increase their representation in the gametes. Akera et al. show how the inherent asymmetry of female meiosis is translated to an asymmetry within the spindle machinery that segregates the chromosomes (see the Perspective by McNally). Experiments in mouse eggs revealed how asymmetry is exploited by selfish genetic elements to increase their transmission to the egg.
Genetic elements compete for transmission through meiosis, when haploid gametes are created from a diploid parent. Selfish elements can enhance their transmission through a process known as meiotic drive. In female meiosis, selfish elements drive by preferentially attaching to the egg side of the spindle. This implies some asymmetry between the two sides of the spindle, but the molecular mechanisms underlying spindle asymmetry are unknown. Here we found that CDC42 signaling from the cell cortex regulated microtubule tyrosination to induce spindle asymmetry and that non-Mendelian segregation depended on this asymmetry. Cortical CDC42 depends on polarization directed by chromosomes, which are positioned near the cortex to allow the asymmetric cell division. Thus, selfish meiotic drivers exploit the asymmetry inherent in female meiosis to bias their transmission.
Authors: Takashi Akera, Lukáš Chmátal, Emily Trimm, Karren Yang, Chanat Aonbangkhen, David M. Chenoweth, Carsten Janke, Richard M. Schultz, Michael A. Lampson
The study was supported by the National Institutes of Health (grants GM107086 and GM122475), Institut Curie and Uehara Memorial Foundation.
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Signals from the polarized cell cortex (in green) in mouse oocytes regulate microtubule tyrosination (white) to generate spindle asymmetry in meiosis I. This asymmetry can be exploited by selfish genetic elements to bias their transmission to the egg as a form of meiotic drive.
Image Credit: University of Pennsylvania.