Loss of the Y Chromosome: A Review of Molecular Mechanisms, Age Inference, and Implications for Men's Health

Abstract

Until a few years ago, it was believed that the gradual mosaic loss of the Y chromosome (mLOY) was a normal age-related process. However, it is now known that mLOY is associated with a wide variety of pathologies in men, such as cardiovascular diseases, neurodegenerative disorders, and many types of cancer. Nevertheless, the mechanisms that generate mLOY in men have not been studied so far. This task is of great importance because it will allow focusing on possible methods of prophylaxis or therapy for diseases associated with mLOY. On the other hand, it would allow better understanding of mLOY as a possible marker for inferring the age of male samples in cases of human identification. Due to the above, in this work, a comprehensive review of the literature was conducted, presenting the most relevant information on the possible molecular mechanisms by which mLOY is generated, as well as its implications for men's health and its possible use as a marker to infer age.

Keywords: Alzheimer’s disease; men’s health; mosaic loss of Y chromosome.

Figure 1

Implications of mLOY in men. Normally, men’s karyotype configuration is 46, XY (left); however, throughout life, subsets of men’s cells gradually lose the Y chromosome (karyotype: 45, X/46, XY), which is associated with different pathological conditions, both in younger and elderly males (right).

Figure 2

Mechanisms of absence or failure of CENP-A associated with mLOY. During cell division, in the Y chromosome, the kinetochores assemble to centromeric chromatin by CENP-C, which binds to CENP-A (a). When this binding fails, the Y chromosome is more prone to segregation defects, causing mLOY (b). Thus, the absence or failure of CENP-A may trigger mLOY through different mechanisms (c). Interestingly, the protein CENP-B, which is not present in the Y chromosome, enhances the recruitment of CENP-A to reinforce the binding of CENP-C to the centromere and thus make the mitotic process more efficient. Therefore, dysfunction of CENP-A alone could affect the kinetochore binding to the centromere of the Y chromosome, making this chromosome more prone to chromosomal segregation defects. On the other hand, the absence of CENP-A in p53-deficient cells can lead to tumorigenesis (right).

Figure 3

Effects of mLOY on cells. In CENP-A deficient cell models, it has been observed that a micronucleus is formed that houses the unsegregated Y chromosome, and by the second cycle of mitosis, this micronucleus is fragmented into 53 parts.

Figure 4

The effect of AβO on the cell cycle of hippocampal neurons. It can be observed that AβOs, by inducing chromatin restructuring, positive regulation of miR-26b, and expression of IL-1, IFN-γ, TNFα, and VEGF, modify the activity of the Cdk2-cyclin E complex (A), allowing progression from the G1 to the S phase through Rb phosphorylation and, consequently, activation of E2F. Although partial or total replication occurs, generating tetraploid or aneuploid cells, mitosis does not take place (B). This is because the Cdk1/cyclin B1 complex cannot enter the nucleus to trigger envelope-breaking events, as it remains in the cytoplasm associated with hyperphosphorylated tau oligomers.

Figure 5

Implications of mLOY in heart function. As a result of a cardiac injury or the aging process, macrophages carrying LOY can infiltrate the heart and replace resident macrophages. These LOY-deficient macrophages exhibit overexpression of TGFβ1 and galectin-3, which contributes to the excessive proliferation and activation of cardiac fibroblasts, as well as the increased production of extracellular matrix. This process negatively affects cardiac function.