From cytogenetics to proteogenomics: new horizons in the study of aneuploidies.

Abstract

Aneuploidy is defined as the loss or gain of a whole chromosome or its region. Even at early stages of development, it usually leads to fatal consequences, including developmental defects/abnormalities and death. For a long time, it was believed that the disruption of gene balance results in pronounced effects at both the cellular and organismal levels, adversely affecting organism formation. It has been shown that the gene imbalance resulting from aneuploidy leads to proteotoxic and metabolic stress within the cell, reduced cell proliferation, genomic instability, oxidative stress, etc. However, some organisms have exhibited tolerance to aneuploidies, which may even confer adaptive advantages, such as antibiotic resistance in pathogenic fungal strains. A significant factor likely lies in the complexity of the tissue and organ organization of specific species. Polyploid organisms are generally more tolerant of aneuploidy, particularly those that have recently undergone whole-genome duplication. This review places special emphasis on the examination of sex chromosome aneuploidies in humans. In addition to primary effects, or cis effects (changes in the quantity of the transcripts of genes located on the aneuploid chromosome), aneuploidy can induce secondary or trans effects (changes in the expression levels of genes located on other chromosomes). The results of recent studies have prompted a reevaluation of the impact of aneuploidy on the structural-functional organization of the genome, transcriptome, and proteome of both the cell and the entire organism. Despite the fact that, in the cases of aneuploidy, the expression levels for most genes correlate with their altered copy numbers in the cell, there have been instances of dosage compensation, where the transcript levels of genes located on the aneuploid chromosome remained unchanged. The review presents findings from recent studies focused on compensatory mechanisms of dosage compensation that modify gene product quantities at post-transcriptional and post-translational levels, alleviating the negative effects of aneuploidy on cellular homeostasis. It also discusses the influence of extrachromosomal elements on the spatial organization of the genome and the changes in gene expression patterns resulting from their presence. Additionally, the review specifically examines cases of segmental aneuploidy and changes in copy number variants (CNVs) in the genome. Not only the implications of their composition are considered, but also their localization within the chromosome and in various compartments of the interphase nucleus. Addressing these questions could significantly contribute to enhancing cytogenomic diagnostics and establishing a necessary database for accurate interpretation of identified cases of segmental aneuploidy and CNVs in the genome.