CAUSES AND CONSEQUENCES OF ANUPLOIDY

CAUSES AND CONSEQUENCES OF ANUPLOIDY

ABSTRACT

Aneuploidy, Genetic instability, which includes both numerical and structural chromosomal abnormalities, chromosomes, is a prevalent genetic anomaly with significant impacts on human reproduction and cancer development. This study investigates the molecular and cellular mechanisms underlying aneuploidy formation during meiotic and mitotic divisions, with a focus on the influence of maternal age and its consequences for embryo viability and genetic disorders. Additionally, the role of aneuploidy in tumorigenesis, genomic instability, and therapy resistance is evaluated. Whereas the structural chromosome rearrangements have received substantial attention, the role of whole-chromosome aneuploidy in cancer is much less well-understood. Here we review recent progress in understanding the roles of whole-chromosome aneuploidy in cancer, including the mechanistic causes of aneuploidy, the cellular responses to chromosome gains or losses and how cells might adapt to tolerate these usually detrimental alterations. Despite advances in detection and analysis, challenges remain in early diagnosis and effective therapeutic targeting of aneuploid cells. This research highlights critical gaps and proposes future directions aimed at improving diagnostic methods and developing targeted interventions. Understanding aneuploidy’s complex biological effects is essential for enhancing reproductive health and cancer management. Recommadation were made; Further studies should focus on elucidating the molecular mechanisms that allow aneuploid cells to survive and proliferate, particularly in cancer, to identify novel therapeutic targets and Investment in non-invasive, highly sensitive early detection methods—such as liquid biopsies analyzing circulating cell-free DNA—will improve screening for aneuploidy in both prenatal and oncological contexts.  

Keyword: Aneuploidy, genetic,  DNA, tumorigenesis, and cancer

TABLE OF CONTENTS

CHAPTER ONE

INTRODUCTION

Background of the Study

Statement of the Problem

Objective of the Study

Research Questions

Significance of the Study

Scope of the Study

Rationale of the Study

Method of the Study

Research Design

Data Collection

Data Analysis

Ethical Considerations

References

CHAPTER TWO

REVIEW OF RELATED LITERATURE

Overview of Aneuploidy

Mechanisms Causing Aneuploidy

Maternal Age and Aneuploidy

Consequences of Aneuploidy in Reproduction

Aneuploidy in Cancer

Advances in Detection and Analysis of Aneuploidy

Aneuploidy

Examining the Association Between Maternal Age and Aneuploidy Risk in

Oocytes

Evaluating the Role of Aneuploidy in Tumorigenesis, Genomic Instability, and Therapy Resistance

Theoretical Frameworks

Chromosomal Instability (CIN) Theory
Spindle Assembly Checkpoint (SAC) Model
Cohesin Degradation Hypothesis
Evolutionary Theory of Aneuploidy in Cancer
Free Radical Theory of Aging and Aneuploidy
Summary of Literature Review

References

CHAPTER THREE

SUMMARY OF FINDING, CONCLUSION, RECOMMENDATION AND

SUGGESTION FOR FURTHER STUDY

Summary of Findings

Conclusion

Recommendations

Suggestions for Further Study

BIBIOGRAPHY

CHAPTER ONE

INTRODUCTION

Background of the Study

Aneuploidy is a chromosomal abnormality characterized by an abnormal number of chromosomes in a cell, resulting from the gain or loss of one or more chromosomes (Nagaoka, Hassold & Hunt, 2012). It is one of the most common causes of genetic disorders and developmental abnormalities in humans. Normally, human cells contain 46 chromosomes, arranged in 23 pairs; deviations from this number, such as in trisomy (an extra chromosome) or monosomy (a missing chromosome), can lead to severe phenotypic consequences (Hassold & Hunt, 2001).

The most well-known example of aneuploidy is Down syndrome (Trisomy 21), where an individual has three copies of chromosome 21. Other forms include Turner syndrome (Monosomy X) and Klinefelter syndrome (XXY) (Munné, 2005). Aneuploidy can arise during meiotic or mitotic cell division, often due to nondisjunction events where chromosomes fail to segregate properly (Chiang et al., 2010). The likelihood of such errors increases with maternal age and can also be influenced by environmental and genetic factors (Yuan et al., 2017).

While many aneuploidies are lethal and result in early pregnancy loss, some are compatible with life and manifest as congenital conditions. Additionally, aneuploidy is a hallmark of many cancer cells, contributing to genomic instability and tumor progression (Ben-David & Amon, 2020). Understanding the mechanisms and outcomes of aneuploidy is therefore crucial for improving reproductive health, diagnosing genetic disorders, and developing targeted therapies in oncology.

During cell division, cells can gain or lose a chromosome, resulting in abnormal chromosome numbers that do not match their parental karyotypes. This is known as aneuploidy. Aneuploidy is a common by‐product of chromosomal missegregation during meiosis and mitosis. It has differential effects on cell fitness, arguably most of them detrimental. In humans, aneuploidy has been linked to genetic disorders including Down's syndrome (Dunlap, Aziz, & Rosenbaum, 1986; Hassold & Hunt, 2001), cancer (Gao et al., 2007; Gao et al., 2016; Kops,Weaver, & Cleveland, 2005), and various forms of karyotype mosaicism (Biesecker & Spinner, 2013). In Saccharomyces cerevisiae, aneuploidy of the largest chromosome (Chr IV) can increase cell doubling time by 167%, slowing down growth dramatically (due to a delay at the G1 stage of mitosis caused by the larger DNA content; Torres et al., 2007). At the same time, aneuploidies of other chromosomes can lead to enhanced proliferative capacity in Saccharomyces, conferring faster growth compared with the corresponding euploid strains under specific conditions (Zhu, Pavelka, Bradford, Rancati, & Li, 2012). Similarly, aneuploid cancer cells often have competitive advantages over euploid cells (Sheltzer & Amon, 2011) and increased metastatic success, spreading from one type of tissue to another (Gao et al., 2016).

Aneuploidy is a significant chromosomal abnormality that plays a critical role in human reproductive biology and disease. Defined as the presence of an abnormal number of chromosomes in a cell, aneuploidy can arise from errors in chromosome segregation during meiosis or mitosis, commonly due to nondisjunction events (Nagaoka, Hassold & Hunt, 2012). This chromosomal imbalance is one of the leading causes of spontaneous miscarriages, congenital birth defects, and infertility, particularly in women of advanced maternal age (Hassold & Hunt, 2001; Chiang et al., 2010).

In human reproduction, meiotic aneuploidy occurs with high frequency, affecting approximately 10–25% of human oocytes, with incidence rising sharply with maternal age (Chiang et al., 2010). This is attributed to age-related weakening of meiotic spindle structures and cohesion proteins that help maintain proper chromosome alignment (Lister et al., 2010). As a result, older women have a significantly increased risk of giving birth to children with aneuploid conditions such as Down syndrome (Trisomy 21), Edwards syndrome (Trisomy 18), and Turner syndrome (Monosomy X) (Munné, 2005).

Beyond its reproductive consequences, aneuploidy is also implicated in the development and progression of many cancers. Chromosomal instability, including both structural and numerical aneuploidy, has been recognized as a hallmark of tumorigenesis and a driver of genetic diversity within tumor cell populations (Ben-David & Amon, 2020). Although many aneuploid cells are non-viable or exhibit reduced cellular fitness, cancer cells often develop mechanisms to tolerate or even exploit aneuploidy for survival and adaptation (Tang & Amon, 2013).

This study is important and timely that we start exploring the connection between hybridisation, aneuploidy, and adaptation in microbes. Chromosomal nondisjunction is known to be a particularly prevalent outcome of interspecific hybrid meiosis in yeast, leaving a large fraction of the F1 hybrids offspring (spores) aneuploid (Boynton, Janzen, & Greig, 2018; Greig, Travisano, Louis, & Borts, 2003; Rogers, McConnell, Ono, & Greig, 2018). Aneuploidy is thus thought to be one of the main reasons for F1 hybrid sterility in yeast, causing almost complete reproductive isolation between species of the Saccharomyces sensu stricto complex (F1 hybrids produce less than 1% viable gametes (Hou, Friedrich, de Montigny, & Schacherer, 2014; Liti, Barton, & Louis, 2006). Although these F1 hybrids can persist mitotically for hundreds to thousands of generations, F1 hybrid meioses can produce high fitness aneuploid offspring with enhanced adaptive potential (e.g., in interspecific Crypococcus hybrids (Hu et al., 2011; Lengeler, Cox, & Heitman, 2001). Although little data exist to date, we explore the idea that some aneuploid hybrids may be evolutionary successful and could outcompete euploid, nonhybrid strains, especially in highly stressful environments. This has particular relevance for hybrid pathogenic microbes and traits related to their epidemiology.

How do cells become aneuploid? In an adult human, millions of cell divisions occur every minute, and the maintenance of a diploid karyotype requires the proper segregation of chromosomes with every cell division. However, the chromosome segregation machinery is imperfect, and in vitro estimates suggest that normal, diploid cells missegregate a chromosome once every hundred cell divisions17,18. The basal rate of spontaneous chromosome missegregation in vivo is an unknown but important quantity that could vary between cell types. Even if this in vivo rate is extremely low, strong selective pressure could enable the proliferation of rare aneuploid cells under certain conditions, as discussed below. The disruption of multiple genes and pathways has been implicated in increasing the rate of chromosome gains and losses above the basal rate and generating CIN7 . These mechanisms include defects in the kinetochore–microtubule attachments and dynamics, centrosome number, spindle-assembly checkpoint (SAC) and chromosome cohesion (FIG. 2). These causes of CIN have been reviewed and discussed in detail elsewhere, so we will only focus on recent progress.

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