Uncovering Natural Gene Variants That Disrupt Cell Division

Greg Howard
15th March, 2024

Uncovering Natural Gene Variants That Disrupt Cell Division

Image Source: Natural Science News, 2024

Key Findings

  • Study from Queen Mary, University of London identified 141 gene variants linked to chromosome stability
  • Two key genes, Astrin and SKA3, were found to be crucial for correct chromosome distribution during cell division
  • Some gene variants were harmful, causing chromosome misalignment, while others were harmless due to cellular resilience mechanisms
Understanding the stability of our chromosomes—structures that carry our genetic information—is crucial because when this stability is compromised, it can lead to serious health issues, including cancer. Chromosomal instability (CIN) is a condition where chromosomes are gained or lost, and cells have the wrong number of chromosomes, a state known as aneuploidy. This instability is a common feature of cancer cells and is linked to the progression of the disease and resistance to therapy. Researchers from Queen Mary, University of London have made a significant step forward in understanding the genetic factors that contribute to CIN[1]. By examining the genetic information from over 150,000 humans, they identified 141 candidate variants in 135 genes that are involved in the correct segregation of chromosomes during cell division. These variants are termed chromosomal instability aiding variants (CIVa). Two of the genes that stood out in the study were Astrin and SKA3. These genes encode proteins that are part of the machinery responsible for ensuring chromosomes are accurately distributed to daughter cells during cell division. Previous research has highlighted the importance of such proteins in maintaining chromosome stability and preventing missegregation, which can lead to CIN[2]. The Astrin-SKAP complex, for example, has been shown to play a key role in stabilizing the connections between chromosomes and the microtubules that pull them apart during cell division. The study took an innovative approach by combining live-cell microscopy with controlled protein expression to differentiate between harmful and benign variants. They discovered that not all variants led to problems. For instance, the Astrin p.Q1012* variant was found to be harmful because it did not localize correctly within the cell and caused chromosomes to misalign and segregate incorrectly, acting in a dominant negative manner. This means the variant not only fails to perform its function but also interferes with the normal function of the protein. On the other hand, some variants, like the Astrin p.L7Qfs*21 and the SKA3 p.Q70Kfs*7, were deemed harmless. These variants either produced a shorter version of the protein that still functioned and localized correctly or allowed the normal SKA complex to function properly. These findings suggest that cells have resilience mechanisms that can compensate for certain genetic changes, preventing them from causing CIN. These insights build on previous studies that have explored the role of histone variants in chromosome stability and how their mutations or abnormal expression can contribute to cancer[3]. Histones are proteins that help package DNA into chromosomes, and their variants can influence the structure and function of chromosomes. Understanding the resilience mechanisms against CIVa could also inform future research on how histone variants maintain chromosome stability. Additionally, the use of artificial intelligence (AI) and deep learning techniques in analyzing microscopy images has greatly enhanced the ability to study dynamic cellular processes, such as chromosome segregation[4]. These technological advances have likely facilitated the detailed analysis of how different protein variants affect chromosome behavior in live cells. Integrating genomics and proteomics has also been instrumental in identifying how genetic variants can influence protein levels in the blood, which can be used as biomarkers for disease or targets for drug development[5]. The Queen Mary study adds to this body of work by showing how genetic variants specifically affect proteins involved in chromosome segregation. In summary, the research conducted by Queen Mary, University of London provides a new framework to predict and categorize naturally occurring genetic variants that may contribute to chromosomal instability. By distinguishing between harmful and benign variants, researchers can better understand the underlying causes of CIN and potentially develop targeted therapies to prevent or treat related diseases, such as cancer. This study not only sheds light on the genetic underpinnings of a critical cellular process but also highlights the resilience of the cellular machinery in the face of genetic alterations.

BiotechGenetics

References

Main Study

1) Search for chromosomal instability aiding variants reveal naturally occurring kinetochore gene variants that perturb chromosome segregation.

Published 15th March, 2024

https://doi.org/10.1016/j.isci.2024.109007

Related Studies

2) Counteraction between Astrin-PP1 and Cyclin-B-CDK1 pathways protects chromosome-microtubule attachments independent of biorientation.

https://doi.org/10.1038/s41467-021-27131-9

3) Contribution of histone variants to aneuploidy: a cancer perspective.

https://doi.org/10.3389/fgene.2023.1290903

4) Opportunities and challenges for deep learning in cell dynamics research.

https://doi.org/10.1016/j.tcb.2023.10.010

5) Rare variant associations with plasma protein levels in the UK Biobank.

https://doi.org/10.1038/s41586-023-06547-x


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