Proteins Responsible for Suppressing Cheating Chromosomes Identified

In a paper published in Cell yesterday, University of Pennsylvania researchers describe a force at work to balance the scales during meiosis, bringing the odds closer to 50-50 that a particular chromosome will get into a viable egg.

The team found that, while a mechanism exists to give certain chromosomes the upper hand during meiosis, a separate, parallel pathway acts to suppress that advantage. Proteins that act in the two pathways appear to be in an evolutionary arms race, the researchers say, potentially to avoid the possibility of biased chromosome inheritance leading to mistakes and abnormalities in eggs or having an abnormal number of chromosomes.

“If we think of these chromosomes that are getting in the egg as being selfish, selfish implies that they’re maximizing their own transmission at some cost to the organism overall,” says study leader Michael Lampson. “If there is a cost, then there might be other genes under pressure to suppress the selfish ones or suppress that cost.”

In previous work, Lampson and his colleagues laid out the mechanism by which an asymmetry arises in the meiotic spindle. This asymmetry led to biases in chromosome transmission. They found that “selfish” centromeres were more likely than “unselfish” centromeres to be able to detach and reattach to the side of the cell that was destined to become a viable egg rather than the polar body, which is typically degraded.  “We had gained this understanding of how selfishness works,” Lampson says, so in the new paper, “we wanted to understand how suppression works.”

Earlier research had shown that some of the proteins acting on the centromere were evolving rapidly in various animal species. Lampson and colleagues hypothesized that this rapid evolution could be evidence of an “arms race” between selfish and suppressive factors. 

“It was surprising to find a whole bunch of rapidly evolving proteins functioning at the centromere because you would probably expect those to be highly conserved because they’re so important in cell division,” Lampson says. “But it’s a signature of the arms race, just like we see in the immune system: If selfish centromeres are going to cheat, there are likely proteins evolving to tamp down that suppression.”

The researchers already knew that effector proteins that bias chromosome transmission were recruited to the centromere by a route known as the kinetochore pathway. To find a suppressive pathway, they looked to heterochromatin, which is also known to recruit proteins to the centromere. To test whether the heterochromatin pathway might be balancing out the biasing effect of the kinetochore pathway, the researchers selectively modified an enzyme that acted in each pathway.

When they modified the protein CENP-C, disrupting the kinetochore pathway, they observed the bias between selfish and unselfish centromere decline, with chromosomes lining up more symmetrically in the cell prior to the completion of meiosis. In contrast, when they deleted the protein CENP-B, which is involved in recruiting proteins in the heterochromatin pathway, the asymmetry in the chromosomes became more pronounced, with selfish centromeres permitted to bias chromosome transmission to the egg.

“There seem to be these subtle changes at work,” Lampson says, “because both of these pathways are essential. You can’t kill the kinetochore pathway because it’s fundamental for cell division, but at the same time you want to reduce the opportunity for centromeres to be selfish. So evolution seems to be acting to respond to these simultaneous pressures.”

The findings illuminate the evolutionary battlefield present in our own bodies, Lampson says. “I think it’s really interesting that there are these selfish components of our own genomes that have essential roles. These very, very fundamental aspects of our cell biology actually reflect competing pressures.”