Increased Transposable Element Expression Associated with Variation in Sex Chromosome Number Suggests a Potential Toxic Effect of the Y Chromosome on Human Longevity

Core Concepts

The presence and number of Y chromosomes in human karyotypes are associated with increased transposable element expression, which may contribute to a toxic effect on male longevity.

Abstract

The study investigates the relationship between transposable element (TE) expression and sex chromosome karyotype composition in humans. The key findings are:

Individuals with more Y chromosomes (47,XXY and 47,XYY) show significantly higher overall TE expression compared to individuals with a normal female karyotype (46,XX). This suggests an association between the presence of the Y chromosome and increased TE expression.

The addition of a Y chromosome appears to amplify TE expression more than the addition of an X chromosome, supporting the "toxic Y" hypothesis that the Y chromosome may have a detrimental impact on longevity.

However, the study did not find a clear association between increased TE expression and aging in individuals with normal karyotypes (46,XY males vs 46,XX females). This may be due to the heterogeneity of the dataset used.

The study identified several differentially expressed TE subfamilies between males and females, as well as between different age groups, particularly in males. This indicates that TE expression is influenced by both sex and age.

The findings suggest a potential link between the Y chromosome, TE deregulation, and reduced longevity in males, opening a new avenue to study the toxic effects of the Y chromosome on human lifespan.

Stats

"The presence and number of Y chromosomes in a karyotype are associated with increased overall TE expression."
"Individuals with 47,XXY and 47,XYY karyotypes show significantly higher TE expression compared to 46,XX females."
"The addition of a Y chromosome appears to amplify TE expression more than the addition of an X chromosome."

Quotes

"The toxic Y hypothesis has been recently proposed to explain the existence of sex gap in longevity. This hypothesis relies on the high transposable element (TE) content in Y (or W) chromosomes."
"Since the Y chromosome is rich in TEs, more TEs might become active in old males compared to old females, generating more somatic mutations, accelerating aging and likely reducing longevity in males."

Key Insights Distilled From

Transposable element expression with variation in sex chromosome number supports a toxic Y effect on human longevity

by Teoli,J., Fa... at www.biorxiv.org 08-03-2023

https://www.biorxiv.org/content/10.1101/2023.08.03.550779v5

Deeper Inquiries

How do the specific TE insertions and their genomic locations contribute to the potential toxic effects of the Y chromosome on male longevity

The specific TE insertions and their genomic locations play a crucial role in the potential toxic effects of the Y chromosome on male longevity. The Y chromosome is known to be enriched in transposable elements (TEs), which are DNA sequences capable of moving within the genome. These TEs can disrupt gene function, cause chromosomal rearrangements, and lead to genomic instability. The location of these TE insertions on the Y chromosome can impact nearby genes, potentially affecting critical cellular processes and contributing to the aging process. As individuals age, the epigenetic regulation of TEs can become disrupted, leading to increased TE activation and potential harmful effects on genomic stability. In the context of the Y chromosome, the accumulation of TE insertions in specific genomic regions can lead to the dysregulation of important genes involved in longevity pathways, ultimately impacting male lifespan.

What are the underlying molecular mechanisms by which the Y chromosome leads to increased TE deregulation, and how do these mechanisms differ from the effects of the X chromosome

The underlying molecular mechanisms by which the Y chromosome leads to increased TE deregulation involve several factors. The Y chromosome is characterized by a high content of TEs, which are normally kept in check by epigenetic silencing mechanisms such as DNA methylation and histone modifications. However, with aging, these regulatory mechanisms can become less effective, leading to the activation of TEs. The Y chromosome's unique structure, with lower rates of recombination and an accumulation of repeated sequences, creates an environment conducive to TE activation. This increased TE expression on the Y chromosome can disrupt gene regulation, interfere with normal cellular processes, and potentially contribute to the acceleration of the aging process in males.
In contrast, the X chromosome, while also containing TEs, does not exhibit the same level of TE enrichment as the Y chromosome. The X chromosome undergoes X chromosome inactivation in females to balance gene expression between the sexes, which may help regulate TE activity. Additionally, the presence of two X chromosomes in females provides redundancy and may buffer against the potential harmful effects of TE deregulation. Overall, the molecular mechanisms underlying TE deregulation on the Y chromosome are distinct from those on the X chromosome, highlighting the unique impact of the Y chromosome on male longevity.

Could interventions targeting TE silencing or regulation provide a potential avenue for mitigating the toxic effects of the Y chromosome and improving male longevity

Interventions targeting TE silencing or regulation could offer a potential avenue for mitigating the toxic effects of the Y chromosome and improving male longevity. By modulating the expression and activity of TEs, it may be possible to reduce the genomic instability and detrimental effects associated with TE deregulation on the Y chromosome. Strategies aimed at enhancing the epigenetic silencing of TEs, such as promoting DNA methylation or histone modifications, could help prevent the activation of TEs and the subsequent disruption of gene function. Additionally, therapies that target specific TE subfamilies or utilize small interfering RNAs to inhibit TE expression could be explored as potential interventions to counteract the toxic effects of TEs on male longevity. Further research into the molecular pathways involved in TE regulation and the specific interactions between TEs and longevity-related genes on the Y chromosome is essential for developing targeted interventions to improve male lifespan.