Most chromosomes have been around for millions of years. Now, researchers at the Stowers Institute for Medical Research have revealed the dynamics of a very young new chromosome in fruit flies that is similar to chromosomes that arise in humans and is associated with refractory cancer and infertility. The findings may one day lead to the development of more targeted therapies for the treatment of these conditions.
A new study published in current biology on May 4, 2023, reveals how this tiny chromosome that arose less than 20 years ago has persisted in a single strain of lab-bred fruit fly, Drosophila melanogasterand correlates with supernumerary (extra) chromosomes in humans.
“I feel like an astronomer watching the birth of a star,” said Stowers researcher Scott Hawley, Ph.D. “We are seeing the birth of a chromosome and are beginning to understand both its capabilities and its limitations.”
Previous research from the Hawley Laboratory had first identified these tiny extra chromosomes, but little was known about their shape, function, or dynamics during cell division. Former Hawley Lab postdoctoral researcher Stacey Hanlon, Ph.D., realized that this discovery could be an ideal system for investigating how new chromosomes arise, which may lead to cancer treatments and more effective methods of overcoming infertility.
Supernumerary chromosomes in humans are found in cancer cells and often interfere with drugs designed to fight tumors, making these types of cancer, such as osteosarcoma, difficult to treat. In addition, the presence of supernumerary chromosomes in males can disrupt normal chromosome segregation during sperm production, which can cause infertility.
“Being able to understand how supernumerary chromosomes arise and what their structures are can potentially illuminate their vulnerabilities,” Hawley said. “This may allow the development of potential therapeutic targets.”
Called B chromosomes, as opposed to the standard “A” set of essential chromosomes, these genetic elements occurred naturally in a single stock of fruit flies in Hawley’s lab. Now, researchers are witnessing the birth and evolution of chromosomes in less than two decades.
How does something like this new chromosome appear seemingly out of nowhere? More importantly, since these newborn B chromosomes do not possess any known essential genes for fruit fly function, how do they persist in a genome? In short, cheating.
“I like to call these genetic rogue B chromosomes,” Hanlon said. “They don’t follow the rules.”
Hanlon discovered that fruit fly B chromosomes are maintained by a mechanism called “meiotic drive” that allows them to rebel against the usual rules of inheritance. The B chromosomes make their way to the next generation during the formation of the ovum to ensure their own persistence through more than half of the next generation.
“Their genetic background, that is, the unique features in the genetic makeup of the B-chromosome flies, support their preferential transmission to the next generation,” Hanlon said. “That gives these guys evolutionary time to develop into a new chromosome, either to pick up an essential gene or to acquire something that allows them to cheat better.”
Importantly, the meiotic drive is a powerful force that can shape how genomes evolve. These findings, which originated in the Hawley Laboratory and are actively investigated by Hanlon, now in his own laboratory at the University of Connecticut, can be used to understand the mechanisms behind what keeps meiosis fair and ensures that cheaters such as B chromosomes , do not prosper. In addition, Hanlon is examining how specific mutations can lead to chromosome breakage and the formation of new chromosomes, revealing the mechanism by which supernumeraries arise and become necessary components of a genome.
“We’re always looking for Achilles heels to get rid of these types of things,” Hawley said of problematic supernumeraries in humans. “If we can identify what encouraged their formation, we can identify the people most likely to form them and take better steps to find and deal with them.”
This work was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K99/R00HD099276 award) from the National Institutes of Health (NIH) and by institutional support from the Stowers Institute for Medical Research. The content is the sole responsibility of the authors and does not necessarily represent the official views of the NIH.
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