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Abnormal Chromosome Number Sparks Large Variation In Yeast And Mice

As this mammalian cell was dividing and divvying up chromosomes (red), two were left behind. These stragglers won’t segregate correctly, and will leave cells with an abnormal number of chromosomes, a condition called aneuploidy. Credit: Angelika Amon

New HHMI research reveals that adding or deleting chromosomes in cells and animals prompts a wide variety of outcomes. The work could help scientists better understand chromosomal abnormalities in humans.

For cells, the loss or gain of a chromosome is a gamble with fate.

Tweaking chromosome number can trigger a vast range of different outcomes in yeast and mice, Howard Hughes Medical Institute (HHMI) Investigator Angelika Amon and colleagues reported April 6, 2017 in the journal Cell.

It’s the first time scientists have shown that abnormal chromosome number can account for differences between individuals — even if they’re genetically identical. The results could help researchers better understand chromosomal abnormalities in humans — why cancers don’t always respond the same way to treatment, for instance, or why Down syndrome can vary so broadly from person to person.

“Gaining or losing chromosomes makes cells unbelievably variable,” says Amon, a yeast geneticist at the Massachusetts Institute of Technology.

Tucked inside nearly every human cell, 23 pairs of chromosomes hold the genetic blueprints for life. Two copies of each chromosome (one each from mom and dad) total up to 46. But sometimes, when cells divvy up DNA, chromosomes can go missing or get duplicated, a condition called aneuploidy.

Such chromosomal mishaps tend to be bad news for cells, Amon says. Her team has studied aneuploidy for almost 15 years. “We’ve shown in many different systems that having the wrong chromosome number makes cells sick.” In humans, an extra copy of chromosome 21 leads to Down syndrome.

In cancer too, cells often add or delete chromosomes. But “there’s a real paradox here,” she says, because cancer cells don’t act like sick cells; instead, they grow furiously, invading organs and rampaging through the body.

Scientists have learned quite a bit about what an extra (or missing) chromosome can do to a cell’s machinery, Amon says, but there’s still a lot to discover. Aneuploidy is a wrench in the gears, somehow, and scientists are still piecing together exactly what it dings up and knocks out of place.

Her team forced budding yeast to split up their chromosomes incorrectly, and closely tracked the cells’ behavior under a microscope. Even cells with the same abnormal number of chromosomes behaved differently, the researchers found. “It was remarkable,” Amon says. Some cells divided almost as well as normal, and others couldn’t divide at all. Aneuploidy also varied cells’ responses to environmental stimuli, like food and heat and chemicals.

The link between errors in chromosome number and variable outcomes also showed up in mice. Genetically identical embryos, all with an extra copy of chromosome 19, showcased a broad spectrum of differences among animals. Neck thickness varied, as well as the amount of blood leaking underneath the skin. Facial structures looked different too. “That was the most striking,” Amon says. “The mice should be identical twins, but some have problems with their eyes and snouts.”

Her team’s results suggest that a mistake in chromosome number can tinker with all sorts of biological systems, and in unpredictable ways. In cancer, this could potentially help tumor cells evolve and survive. “Maybe aneuploidy allows cells to roll the dice more often,” she says. Though most rolls wouldn’t be winners, occasionally cells could gain the ability to grow faster, perhaps, or resist chemotherapy.

For Amon’s lab, the next step is to dig deeper into how aneuploidy makes cells so variable. But for now, the work reveals a new facet of a much-studied phenomenon.

Source: Howard Hughes Medical Institute

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