Hutch News

The battleground called centromeres

Jan. 16, 2003
Drs. Steve Henikoff and Dr. Harmit Malik

Drs. Steve Henikoff (above) discusses his Basic Sciences Division lab's research on centromeres with Dr. Harmit Malik, postdoctoral fellow, who holds a bottle of fruit flies, the model organism for their studies.

Photo by Todd McNaught

Self-help books and human resources staff often herald conflict management as a way to achieve personal satisfaction and workplace productivity.

But research suggests that nature takes a more positive view of discord. In fact, according to Basic Sciences Division investigators, conflict may be the driving force behind what Darwin described as the "mystery of mysteries": how new species evolve.

The sources of this turmoil are parts of chromosomes, known as centromeres, whose importance in ensuring accurate partitioning of genetic material during cell division was recognized more than a century ago.

Now, work from postdoc Dr. Harmit Malik and Dr. Steven Henikoff suggests that these genetic elements also represent "battlegrounds" of struggles among chromosomes vying for evolutionary dominance.

They propose that this newly discovered "survival of the fittest" function may explain the mysterious yet remarkably general evolutionary phenomenon of hybrid sterility, which occurs in the progeny of different species. Organisms such as the mule, the infertile offspring of a horse and donkey, exemplify the condition.

Chromosomal midsections

As early as 1880, centromeres (from the Greek for centro, or middle, and mere, or part) caught the attention of cell biologists, who observed images of newly duplicated chromosomes separating as one cell becomes two. These classic pictures revealed spaghetti-like chromosomes being tugged apart at their midsections - or centromeres - during cell division.

Scientists now know that these focal points (not always located at the middle of chromosomes) serve as attachment sites for the fibers that pull chromosomes apart. Unlike a gene, which is a stretch of DNA that contains the code to make a protein, centromeres serve only as structural platforms to anchor proteins involved in chromosome segregation.

Despite centromeres' importance in cell division, their analysis has lagged behind other parts of the genome since they are composed of segments of DNA repeated multiple times. Because repetitive DNA is difficult to sequence, centromeres are one of the few unsequenced portions of the human genome, which has led Henikoff to liken them to the chromosomal equivalent of "black holes."

Henikoff said that scientists have long been puzzled by the fact that centromeres differ so significantly among all organisms yet still manage to perform the identical function in chromosome segregation that is critical to life.

"The mystery has been, why is there so much complexity for a common essential function?" said the Howard Hughes Medical Institute investigator.

The first clue emerged from a study led by Malik, published in 2001, of a protein that binds to centromeres.

Chromosomal DNA in all organisms, both the parts that contain genes and those that do not, is wrapped around proteins known as histones. While most DNA coils around a common pool of histones, one type of histone at centromeres - known in fruit flies as Cid proteins - is unique.

Because of their ubiquitous role in nature, the common histones from all organisms are virtually identical. Yet when Malik compared the centromere-specific Cid proteins from distinct species of fruit flies, he found more differences in Cid from two closely related species of fruit flies than are found among the common histones from all plants and animals.

"All the differences in Cid were in the part of the protein that specifies the DNA to which the histone will bind," he said. "This suggested a simple solution to an old paradox: how does the rapidly evolving centromeric DNA continue to correctly assemble the well-conserved machinery that pulls the chromosomes apart? It appeared that the Cid proteins were acting as adaptors between the two."

Though these results explained how the variable centromeres perform a common role, still a mystery was the force that drives the changes in centromere DNA to be adopted in the first place.

For that explanation, researchers looked toward the process that occurs during egg formation. In many organisms, including humans, eggs are produced as the result of a cell that undergoes two divisions to generate four cells, three of which are destroyed. The remaining cell develops into an egg capable of being fertilized.

Malik and Henikoff speculate that an intense competition occurs between each of the four potential eggs' chromosomes. The centromeres most adept at correctly positioning their chromosomes win the battle and end up in the egg cell, instead of being destroyed. These victorious centromeres thus ensure their own evolutionary survival, much like selfish parasites do to persist in their hosts.

For this reason, Henikoff describes centromeres as "old battlegrounds," whose complexity is derived from this conflict.

Big effects on reproduction

Centromere evolution has big effects on reproduction. Bringing together egg and sperm with incompatible centromere/Cid pairs could impact the ability of the hybrid to produce reproductive cells of its own, as Cid proteins contributed by sperm would be unable to bind to the centromere from the egg, or vice-versa.

Their hypothesis provides the simplest explanation to date for how newly evolved species become genetically incompatible, meaning that offspring produced by their mating are sterile. Such "reproductive isolation" is the very definition of new species.

"Our idea is that, as a consequence of centromere evolution, you'll get reproductive isolation," Henikoff said.

Malik plans to test their hypothesis by observing the offspring produced by mating two species of fruit flies.

"Typically, one sex of the offspring produced by such mating would be sterile and often one sex is inviable (incapable of survival)," he said. "But with the right combination of centromere DNA and Cid, the defects could be repaired.

"Most interesting is that we see the same phenomenon in plants, which have evolved completely independently from animals. It would be remarkable if competition between chromosomes were the most important driving force for the amazing diversity of flora and fauna that we see on the planet."

Whoever said conflict is never constructive?

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