What is meant by chromosomal instability ?How does having deleted or duplicated chromosomes cause this,and how would this apply to Klinefelters syndrome ?

Question

Daniel Arnold · Accepted Answer

Chromosomal instability is a change in karyotype of cells. This often co-exists with aneuploidy such as in Klinefelter's syndrome.

#color(red)"Defining Chromosomal Instability"#
Chromosomal instability (CIN) is an important hallmark of cancer. CIN is the rate at which whole chromosomes or parts of chromosomes are lost or gained in cells. This can be studied within cell populations (cell-to-cell variation) or between cell populations.

Several types of CIN can be distinguished:

clonal chromosome aberrations (CCA): these are recurring karyotypic alterations. There are short-lived transitional CCA's and late-stage stable CCA's.
non-clonal chromosome aberrations (NCCA): these are randomly occuring alterations, previously considered insignificant or noise. NCCA's can be structural or numerical.
CIN should not be confused with genomic instability. Genomic instability includes CIN, but also other types of instability.

#color(red)"Mechanisms of CIN"#
CIN is an important driver of cancer progression. The focus in research has long been on genes rather than chromosomes. Therfore, the exact mechanisms behind CIN are not yet clarified.

Underlying mechanisms can be put into two categories:
1. Category I: (molecular) mechanisms that are directly related to the chromosomal cycle(condensation, segregation), chromosome structure (integrity of telomeres, centrosomes) and repair mechanisms. These processes are influenced by many genes and pathways.
2. Category II mechanisms on a systemic rather than a molecular level. Factors that cause stress influence system dynamics. Such factors are infection, epigenetic alterations, physiological stress, toxins etc.
#color(red)"Relation between CIN and aneuploidy"#
Aneuploidy is the presence of an abnormal number of chromosomes. Aneuploidy and CIN often co-exist. Aneuploidy can be a cause of CIN and the other way around.

Males with Klinefelter's syndrome have an extra X-chromosome. There is not much known yet about CIN in men with this syndrome.
The current idea is that CIN and aneuploidy are linked in a vicious cycle. So when a person already has a chromosomal aberration, as in Klinefelter's syndrome, it has a higher chance on accumulating other chromosomal aberrations leading to CIN.

The image above gives an overview of the processes that possibly cause this vicious cycle. The main mechanism is dose changes in protein and mRNA, leading to failure in cell cycle processes, finally causing chromosomal aberrations.

Benjamin Alvin · Answer

undefined Chromosomal instability refers to the tendency of chromosomes to undergo abnormal changes, such as deletions or duplications, during cell division. These changes can result in an incorrect number or structure of chromosomes in daughter cells. Deletions or duplications of chromosomes can disrupt the normal functioning of cells by altering the expression of genes or disrupting important genetic pathways. In Klinefelter syndrome, individuals have an extra X chromosome (XXY) instead of the typical male pattern (XY). This chromosomal abnormality can lead to chromosomal instability, increasing the risk of further genetic abnormalities and developmental issues.

Ruby Armstrong · Answer

undefined Chromosomal instability refers to a condition where cells exhibit an increased frequency of chromosomal abnormalities, such as deletions, duplications, translocations, or aneuploidy (an abnormal number of chromosomes). This instability can lead to genetic mutations, genomic instability, and may contribute to the development of various diseases, including cancer.

Having deleted or duplicated chromosomes can disrupt the normal functioning of cells, as certain genes may be missing or present in excess. This can lead to imbalances in gene expression, affecting crucial cellular processes such as cell cycle regulation, DNA repair, and apoptosis (programmed cell death). Consequently, cells may become more susceptible to errors in DNA replication, repair, or segregation, further exacerbating chromosomal instability.

Klinefelter syndrome, a genetic disorder characterized by the presence of an extra X chromosome in males (XXY), exemplifies how chromosomal abnormalities can lead to chromosomal instability. Individuals with Klinefelter syndrome typically experience hormonal imbalances, reduced fertility, and may exhibit physical and developmental abnormalities. The presence of an additional X chromosome disrupts the normal balance of gene expression, affecting various physiological processes and contributing to the observed symptoms.

Furthermore, the presence of an extra X chromosome increases the likelihood of chromosomal missegregation during cell division, leading to aneuploidy and chromosomal instability. This instability can manifest as an increased risk of developing certain cancers, such as breast cancer and testicular germ cell tumors, which are more prevalent in individuals with Klinefelter syndrome. Therefore, chromosomal instability plays a significant role in the pathogenesis and clinical manifestations of Klinefelter syndrome, highlighting the intricate relationship between chromosomal abnormalities and disease development.