Abnormal Number of Chromosomes Induces Variability in Aneuploidy-Caused Disorders

Disorders caused by aneuploidy can differ in severity among patients. Findings from a new study points to aneuploidy alone as the culprit of the significant variability in trait severity.

Aneuploidy is a condition in which cells contain an abnormal number of chromosomes. The condition originates during cell division—–when the chromosomes do not separate correctly or are not equally partitioned between the 2 daughter cells. Aneuploidy is known to cause many types of cancer and genetic disorders, including Down syndrome.

Scientists previously believed that the variation was a result of differences in the genetic makeup of patients with the condition. However, in a study published in Cell, investigators found that aneuploidy alone can cause the significant variability in traits, in otherwise genetically identical cells.

The findings could have significant implications for cancer treatment, according to the authors.

For the study, investigators sought to examine the effects of aneuploidy by inducing either chromosome loss or gain in genetically identical baker’s yeast cells. Baker’s yeast was used for the study because the cells behave similarly to human cells.

The results of the study showed that the induced changes had an immediate impact on the cells.

“We induced aneuploidy, and we found that the response was very variable from cell to cell,” said investigator Angelika Amon. “Some cells slowed down their cycle completely, so that they could no longer divide, whereas other kept diving quite normally and only experienced a small effect.”

The investigators used a systematic analysis to examine the effect on the cells of gaining or losing a variety of different chromosomes. The result of the analysis showed that in both cases, they behaved very differently from each other, even though individual cells had gained or lost the same chromosome.

“So that really suggested that every single chromosome gained or lost had this effect, in that the response (in each case) were quite variable,” Amon said.

Additionally, the investigators examined the impact that aneuploidy had on other biological pathways, such as transcription. They found that the effects of aneuploidy were varied across otherwise identical cells.

The response to environmental changes also varied significantly, which suggests that aneuploidy has an impact on the robustness of many, if not all, biological processes, according to the authors.

To confirm the findings and to ensure that the effect was not unique to baker’s yeast cells, the investigators examined the impact of aneuploidy on mice, and found the same levels of variability.

“This suggests that aneuploidy state itself could create variability, and that could provide an additional explanation of why diseases that are caused by aneuploidy are so variable,” Amon said.

Tumors are known to contain different populations of cells. The genetic differences have often been blamed on unsuccessful chemotherapy or other cancer treatments.

“Unfortunately, our paper suggests that tumors don’t even need to be heterogeneous genetically, the very fact that they have aneuploidy could lead to very variable outcomes, and that represents a significant challenge for cancer therapy,” Amon said.

The investigators hope to conduct further studies to examine the origins of the variability. The current findings suggest that subtle changes in gene dosage across many genes can promote alternate behaviors, according to the authors.

“We’re now trying to track down which the key genes are, and which the key pathways are,” Amon said. “Once we understand what the key pathways are that cause this variability, we can start to think about targeting those pathways, to combat alternate outcomes in cancer treatment, for example.”